WO2018158298A1

WO2018158298A1 - Crystalline forms of (2r)-n-hydroxy-4-(6-((1-(2-hydroxyethyl)azetidin-3-yl)buta-1,3 diyn-1 yl)-3 oxo-1h pyrrolo[1,2 c]imidazol-2(3h)-yl)-2-methyl-2 (methylsulfonyl)butanamide

Info

Publication number: WO2018158298A1
Application number: PCT/EP2018/054898
Authority: WO
Inventors: Loïc JACOB; Philippe Panchaud; Markus Von Raumer
Original assignee: Idorsia Pharmaceuticals Ltd
Priority date: 2017-03-01
Filing date: 2018-02-28
Publication date: 2018-09-07
Also published as: TW201840569A

Abstract

The present invention relates to polymorphic forms of (2R)-N-hydroxy-4-(6-((1-(2- hydroxyethyl)azetidin-3-yl)buta-1,3-diyn-1-yl)-3-oxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)-2- methyl-2-(methylsulfonyl)butanamide.

Description

Crystalline forms of (2 ?)-N-hydroxy-4-(6-((1-(2-hydroxyethyl)azetidin-3-yl)buta- 1 ,3-diyn-1 -yl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl- 2-(methylsulfonyl)butanamide

The present invention relates to crystalline forms of (2R)-N-hydroxy-4-(6-((1-(2- hydroxyethyl)azetidin-3-yl)buta-1 ,3-diyn-1-yl)-3-oxo-1 /-/-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2- methyl-2-(methylsulfonyl)butanamide (hereinafter referred to as Compound 1 ) which has the following chemical structure:

Compound 1. The present invention concerns crystalline forms of antibacterial Compound 1 , pharmaceutical compositions thereof and uses thereof in the manufacture of medicaments for the treatment of bacterial infections. The crystalline forms of antibacterial Compound 1 are useful as antimicrobial agents effective against a variety of human and veterinary pathogens, especially Gram-negative aerobic and anaerobic bacteria.

We have described in WO 2015/132228 and PCT/EP2016/070695 1 ,2-dihydro- 3/-/-pyrrolo[1 ,2-c]imidazol-3-one derivatives with antibiotic activity.

The aim of the present invention was the provision of certain solid forms of Compound 1 which have advantageous properties.

DESCRIPTION OF FIGURES

Figure 1 shows the X-ray powder diffraction diagram of Compound 1 in crystalline form 1 , wherein the X-ray powder diffraction diagram is displayed against Cu K radiation. In the diagram the angle of refraction 2Θ is plotted on the horizontal axis and the intensity (counts) on the vertical axis. The X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensities given in parenthesis) at the indicated angles of refraction 2theta (selected peaks from the range 5-35° 2theta with relative intensity larger than 10% are reported): 6.7° (23%), 7.5° (100%), 1 1.9° (35%), 13.4° (16%), 15.1 ° (32%), 15.4° (45%), 18.1 ° (65%), 19.0° (25%), 20.3° (17%), 22.7° (1 1 %), 24.5° (72%), 30.4° (16%).

Figure 2 shows the X-ray powder diffraction diagram of Compound 1 in crystalline form 2, wherein the X-ray powder diffraction diagram is displayed against Cu K radiation. In the diagram the angle of refraction 2Θ is plotted on the horizontal axis and the intensity (counts) on the vertical axis. The X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensities given in parenthesis) at the indicated angles of refraction 2theta (selected peaks from the range 5-35° 2theta with relative intensity larger than 10% are reported): 6.8° (25%), 7.4° (100%), 12.1 ° (22%), 13.1 ° (14%), 13.9° (39%), 15.1 ° (23%), 15.3° (17%), 16.5° (37%), 18.1 ° (96%), 19.2° (29%), 21.5° (43%), 24.4° (38%).

Figure 3 shows the X-ray powder diffraction diagram of Compound 1 in crystalline form 3, wherein the X-ray powder diffraction diagram is displayed against Cu Ka radiation. In the diagram the angle of refraction 2Θ is plotted on the horizontal axis and the intensity (counts) on the vertical axis. The X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensities given in parenthesis) at the indicated angles of refraction 2theta (selected peaks from the range 5-35° 2theta with relative intensity larger than 10% are reported): 6.9° (100%), 1 1.9° (40%), 13.9° (15%), 15.1 ° (18%), 18.2° (30%), 19.3° (14%), 23.9° (64%), 24.2° (45%), 25.0° (37%), 27.9 (21 %).

Figure 4 shows the X-ray powder diffraction diagram of Compound 1 in amorphous form, wherein the X-ray powder diffraction diagram is displayed against Cu Ka radiation. In the diagram the angle of refraction 2Θ is plotted on the horizontal axis and the intensity (counts) on the vertical axis. The diffraction diagram is characterized by the absence of sharp diffraction peaks, which is typical for X-ray of amorphous materials.

For the avoidance of any doubt, the above-listed peaks describe the experimental results of the X-ray powder diffraction shown in Figures 1 to 3. It is understood that, in contrast to the above peak list, only a selection of characteristic peaks is required to fully and unambiguously characterize Compound 1 in the respective crystalline form of the present invention. Description of the Invention

1 ) A first embodiment of the invention relates to Compound 1 in crystalline form 1 , characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 1 1 .9°, 13.4° and 20.3°, wherein the X-ray powder diffraction pattern is measured using a Cu K (1 .5418 A) source.

2) Another embodiment of the invention relates to Compound 1 in crystalline form 1 , characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 6.7°, 1 1 .9°, 13.4°, 19.0° and 20.3°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1 .5418 A) source.

3) Another embodiment of the invention relates to Compound 1 in crystalline form 1 , characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 6.7°, 7.5°, 1 1 .9°, 13.4°, 15.1 °, 15.4°, 18.1 °, 19.0°, 20.3° and 24.5°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1 .5418 A) source.

4) Another embodiment of the invention relates to Compound 1 in crystalline form 1 , which essentially shows the X-ray powder diffraction pattern as depicted in Fig. 1 .

5) Another embodiment of the invention relates to Compound 1 in crystalline form 1 , obtainable by the process as described in Example 1 .

6) Another embodiment of the invention relates to Compound 1 in crystalline form 1 according to embodiment 5), characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 1 1.9°, 13.4° and 20.3°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1 .5418 A) source.

7) Another embodiment of the invention relates to Compound 1 in crystalline form 1 according to embodiment 5), characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 6.7°, 1 1 .9°, 13.4°, 19.0° and 20.3°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1 .5418 A) source. 8) Another embodiment of the invention relates to Compound 1 in crystalline form 1 according to embodiment 5), characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 6.7°, 7.5°, 1 1.9°, 13.4°, 15.1 °, 15.4°, 18.1 °, 19.0°, 20.3° and 24.5°, wherein the X-ray powder diffraction pattern is measured using a Cu K (1.5418 A) source.

9) Another embodiment of the invention relates to a composition comprising the Compound 1 in crystalline form 1 according to any one of embodiments 1 ) to 8), further comprising at least one pharmaceutically acceptable excipient. 10) Another embodiment of the invention relates to Compound 1 in crystalline form 1 according to any one of embodiments 1 ) to 8), or a composition according to embodiment 9), for use as a medicament.

1 1 ) Another embodiment of the invention relates to Compound 1 in crystalline form 1 according to any one of embodiment 1 ) to 8), or a composition according to embodiment 9), for use in the treatment or prevention, preferably in the treatment, of a bacterial disease.

12) Another embodiment of the invention relates to Compound 1 in crystalline form 1 according to any one of embodiments 1 ) to 8), or a composition according to embodiment 9), for use in the treatment or prevention, preferably in the treatment, of a bacterial disease mediated by Gram-negative bacteria.

13) Another embodiment of the invention relates to Compound 1 in crystalline form 1 according to any one of embodiments 1 ) to 8), or a composition according to embodiment 9), for use in the treatment or prevention, preferably in the treatment, of a bacterial disease mediated by Gram-negative bacteria selected from Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli. 14) Another embodiment of the invention relates to Compound 1 in crystalline form 2, characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 7.4°, 13.9° and 16.5°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1.5418 A) source. 15) Another embodiment of the invention relates to Compound 1 in crystalline form 2, characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 6.8°, 7.4°, 13.9°, 16.5° and 21 .5°, wherein the X-ray powder diffraction pattern is measured using a Cu K (1 .5418 A) source. 16) Another embodiment of the invention relates to Compound 1 in crystalline form 2, characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 6.8°, 7.4°, 12.1 °, 13.1 °, 13.9°, 16.5°, 18.1 °, 19.2°, 21 .5° and 24.4°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1 .5418 A) source. 17) Another embodiment of the invention relates to Compound 1 in crystalline form 2, which essentially shows the X-ray powder diffraction pattern as depicted in Fig. 2.

18) Another embodiment of the invention relates to Compound 1 in crystalline form 2, obtainable by the process as described in Example 2.

19) Another embodiment of the invention relates to Compound 1 in crystalline form 2 according to embodiment 18), characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 7.4°, 13.9° and 16.5°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1 .5418 A) source.

20) Another embodiment of the invention relates to Compound 1 in crystalline form 2 according to embodiment 18), characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 6.8°, 7.4°, 13.9°, 16.5° and

21 .5°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1 .5418 A) source.

21 ) Another embodiment of the invention relates to Compound 1 in crystalline form 2 according to embodiment 18), characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 6.8°, 7.4°, 12.1 °, 13.1 °, 13.9°,

16.5°, 18.1 °, 19.2°, 21 .5° and 24.4°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1 .5418 A) source. 22) Another embodiment of the invention relates to a composition comprising the Compound 1 in crystalline form 2 according to any one of embodiments 14) to 21 ), further comprising at least one pharmaceutically acceptable excipient. 23) Another embodiment of the invention relates to Compound 1 in crystalline form 2 according to any one of embodiments 14) to 21 ), or a composition according to embodiment 22), for use as a medicament.

24) Another embodiment of the invention relates to Compound 1 in crystalline form 2 according to any one of embodiments 14) to 21 ), or a composition according to embodiment 22), for use in the treatment or prevention, preferably in the treatment, of a bacterial disease.

25) Another embodiment of the invention relates to Compound 1 in crystalline form 2 according to any one of embodiments 14) to 21 ), or a composition according to embodiment 22), for use in the treatment or prevention, preferably in the treatment, of a bacterial disease mediated by by Gram-negative bacteria.

26) Another embodiment of the invention relates to Compound 1 in crystalline form 2 according to any one of embodiments 14) to 21 ), or a composition according to embodiment 22), for use in the treatment or prevention, preferably in the treatment, of a bacterial disease mediated by Gram-negative bacteria selected from Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli.

27) Another embodiment of the invention relates to Compound 1 in crystalline form 3, characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 6.9°, 1 1.9° and 23.9°, wherein the X-ray powder diffraction pattern is measured using a Cu K (1.5418 A) source.

28) Another embodiment of the invention relates to Compound 1 in crystalline form 3, characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 6.9°, 1 1.9°, 23.9°, 24.2° and 25.0°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1.5418 A) source. 29) Another embodiment of the invention relates to Compound 1 in crystalline form 3, characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 6.9°, 1 1.9°, 13.9°, 15.1 °, 18.2°, 19.3, 23.9°, 24.2°, 25.0° and 27.9°, wherein the X-ray powder diffraction pattern is measured using a Cu K (1.5418 A) source.

30) Another embodiment of the invention relates to Compound 1 in crystalline form 3, which essentially shows the X-ray powder diffraction pattern as depicted in Fig. 3.

31 ) Another embodiment of the invention relates to Compound 1 in crystalline form 3, obtainable by the process as described in Example 3. 32) Another embodiment of the invention relates to Compound 1 in crystalline form 3 according to embodiment 31 ), characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 6.9°, 1 1.9° and 23.9°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1.5418 A) source.

33) Another embodiment of the invention relates to Compound 1 in crystalline form 3 according to embodiment 31 ), characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 6.9°, 1 1.9°, 23.9°, 24.2° and 25.0°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1.5418 A) source.

34) Another embodiment of the invention relates to Compound 1 in crystalline form 3 according to embodiment 31 ), characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction 2Θ: 6.9°, 1 1.9°, 13.9°, 15.1 °, 18.2°, 19.3, 23.9°, 24.2°, 25.0° and 27.9°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1.5418 A) source

35) Another embodiment of the invention relates to a composition comprising the Compound 1 in crystalline form 3 according to any one of embodiments 27) to 34), further comprising at least one pharmaceutically acceptable excipient. 36) Another embodiment of the invention relates to Compound 1 in crystalline form 3 according to any one of embodiments 27) to 34), or a composition according to embodiment 35), for use as a medicament. 37) Another embodiment of the invention relates to Compound 1 in crystalline form 3 according to any one of embodiments 27) to 34), or a composition according to embodiment 35), for use in the treatment or prevention, preferably in the treatment, of a bacterial disease. 38) Another embodiment of the invention relates to Compound 1 in crystalline form 3 according to any one of embodiments 27) to 34), or a composition according to embodiment 35), for use in the treatment or prevention, preferably in the treatment, of a bacterial disease mediated by Gram-negative bacteria. 39) Another embodiment of the invention relates to Compound 1 in crystalline form 3 according to any one of embodiments 27) to 34), or a composition according to embodiment 35), for use in the treatment or prevention, preferably in the treatment, of a bacterial disease mediated by Gram-negative bacteria selected from Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli. 40) Another embodiment of the invention relates to Compound 1 in amorphous form.

41 ) Another embodiment of the invention relates to Compound 1 in amorphous form obtainable by the process as described in Example 4.

42) Another embodiment of the invention relates to a composition comprising the Compound 1 in amorphous form according to any one of embodiments 40) and 41 ), further comprising at least one pharmaceutically acceptable excipient.

43) Another embodiment of the invention relates to Compound 1 according to any one of embodiments 40) and 41 ), or the composition of embodiment 42), for use as a medicament. 44) Another embodiment of the invention relates to Compound according to any one of embodiments 40) and 41), or the composition of embodiment 42) for use in the treatment or prevention, preferably in the treatment, of a bacterial disease. 45) Another embodiment of the invention relates to Compound according to any one of embodiments 40) and 41), or the composition of embodiment 42) for use in the treatment or prevention, preferably in the treatment, of a bacterial disease mediated by Gram-negative bacteria. 46) Another embodiment of the invention relates to Compound according to any one of embodiments 40) and 41), or the composition of embodiment 42) for use in the treatment or prevention, preferably in the treatment, of a bacterial disease mediated by Gram-negative bacteria, selected from Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli.

Based on the dependencies of the different embodiments 1) to 46) as disclosed hereinabove, the following embodiments are thus possible and intended and herewith specifically disclosed in individualized form:

6+5, 7+5, 8+5, 9+1, 9+2, 9+3, 9+4, 9+5, 9+6+5, 9+7+5, 9+8+5, 10+1, 10+2, 10+3, 10+4, 10+5, 10+6+5, 10+7+5, 10+8+5, 10+9+1, 10+9+2, 10+9+3, 10+9+4, 10+9+5. 10+9+6+5, 10+9+7+5, 10+9+8+5, 11+1, 11+2, 11+3, 11+4, 11+5, 11+6+5, 11+7+5, 11+8+5, 11+9+1, 11+9+2, 11+9+3, 11+9+4, 11+9+5, 11+9+6+5, 11+9+7+5, 11+9+8+5, 12+1, 12+2, 12+3, 12+4, 12+5, 12+6+5, 12+7+5, 12+8+5, 12+9+1, 12+9+2, 12+9+3, 12+9+4, 12+9+5, 12+9+6+5, 12+9+7+5, 12+9+8+5.13+1, 13+2, 13+3, 13+4, 13+5, 13+6+5, 13+7+5, 13+8+5. 13+9+1, 13+9+2, 13+9+3, 13+9+4, 13+9+5. 13+9+6+5, 13+9+7+5, 13+9+8+5, 19+18. 20+18, 21+18, 22+14, 22+15. 22+16, 22+17, 22+18, 22+19+18, 22+20+18, 22+21+18. 23+14, 23+15, 23+16, 23+17, 23+18, 23+19+18, 23+20+18, 23+21+18, 23+22+14, 23+22+15, 23+22+16, 23+22+17, 23+22+18, 23+22+19+18, 23+22+20+18, 23+22+21+18, 24+14. 24+15, 24+16, 24+17, 24+18, 24+19+18, 24+20+18, 24+21+18, 24+22+14, 24+22+15, 24+22+16, 24+22+17, 24+22+18, 24+22+19+18, 24+22+20+18, 24+22+21+18. 25+14, 25+15, 25+16. 25+17, 25+18, 25+19+18, 25+20+18, 25+21+18, 25+22+14. 25+22+15, 25+22+16, 25+22+17, 25+22+18, 25+22+19+18, 25+22+20+18, 25+22+21+18, 26+14, 26+15, 26+16, 26+17, 26+18, 26+19+18, 26+20+18, 26+21+18, 26+22+14, 26+22+15, 26+22+16, 26+22+17, 26+22+18, 26+22+19+18.26+22+20+18, 26+22+21+18. 32+31, 33+31, 34+31, 35+27. 35+28. 35+29, 35+30, 35+31, 35+32+31, 35+33+31. 35+34+31, 36+27, 36+28, 36+29, 36+30, 36+31, 36+32+31, 36+33+31, 36+34+31, 36+35+27, 36+35+28, 36+35+29. 36+35+30. 36+35+31, 36+35+32+31, 36+35+33+31, 36+35+34+31, 37+27, 37+28, 37+29, 37+30, 37+31, 37+32+31, 37+33+31, 37+34+31, 37+35+27, 37+35+28, 37+35+29, 37+35+30, 37+35+31, 37+35+32+31, 37+35+33+31, 37+35+34+31, 38+27, 38+28, 38+29, 38+30, 38+31, 38+32+31, 38+33+31, 38+34+31, 38+35+27, 38+35+28, 38+35+29, 38+35+30, 38+35+31, 38+35+32+31, 38+35+33+31, 38+35+34+31, 39+27, 39+28. 39+29, 39+30. 39+31, 39+32+31, 39+33+31, 39+34+31, 39+35+27, 39+35+28, 39+35+29, 39+35+30, 39+35+31, 39+35+32+31, 39+35+33+31, 39+35+34+31, 42+40, 42+41, 43+40, 43+41, 43+42+40, 43+42+41, 44+40, 44+41, 44+42+40. 44+42+41, 45+40, 45+41, 45+42+40, 45+42+41, 46+40, 46+41, 46+42+40. 46+42+41

In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas "+" indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. In other words, "11+9+1" for example refers to embodiment 11) depending on embodiment 9), depending on embodiment 1), i.e. embodiment "11+9+1" corresponds to embodiment 1) further characterized by the features of the embodiments 9) and 11 ).

Definitions provided herein are intended to apply uniformly to the subject matter as defined in any one of embodiments 1) to 46), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or a preferred definition of a term or expression defines and may replace the respective term or expression independently of (and in combination with) any definition or preferred definition of any or all other terms or expressions as defined herein.

The crystalline forms 1, 2 and 3 of Compound 1, or the amorphous form thereof, may especially be present in essentially pure form. The expression "in essentially pure form" is understood to mean especially that at least 90, preferably at least 95, and most preferably at least 99 per cent by weight of Compound 1 is present in a single form of the present invention.

The term "prevent" or "prevention" or "preventing" used with reference to a disease means either that said disease does not occur in the patient or animal, or that, although the animal or patient is affected by the disease, part or all the symptoms of the disease are either reduced or absent. The term "treat" or "treatment" or "treating" used with reference to a disease means either that said disease is cured in the patient or animal, or that, although the animal or patient remains affected by the disease, part or all the symptoms of the disease are either reduced or eliminated.

When defining the presence of peak in e.g. an X-ray powder diffraction diagram, a common approach is to do this in terms of the S/N ratio (S = signal, N = noise). According to this definition, when stating that a peak has to be present in an X-ray powder diffraction diagram, it is understood that the peak in the X-ray powder diffraction diagram is defined by having an S/N ratio (S = signal, N = noise) of greater than x (x being a numerical value greater than 1 ), usually greater than 2, especially greater than 3.

In the context with stating that the crystalline form essentially shows an X-ray powder diffraction (XRPD) pattern as depicted in Fig. 1 to Fig. 3, respectively, the term "essentially" means that at least the major peaks of the diagram depicted in said figures, i.e. those having a relative intensity of more than 20%, especially more than 10%, as compared to the most intense peak in the diagram, have to be present. However, the person skilled in the art of X- ray powder diffraction will recognize that relative intensities in X-ray powder diffraction diagrams may be subject to strong intensity variations due to preferred orientation effects.

Unless used regarding temperatures, the term "about" placed before a numerical value "X" refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term "about" placed before a temperature Ύ" refers in the current application to an interval extending from the temperature Y minus 5 °C to Y plus 5 °C, and preferably to an interval extending from Y minus 3 °C to Y plus 3 °C. Room temperature means a temperature of about 23 °C.

When specifying an angle of diffraction 2theta (2Θ) for a peak in the present application, it should be understood that the value given is to be understood as an interval from said value minus 0.2° to said value plus 0.2°, and preferably from said value minus 0.1 ° to said value plus 0.1 °.

Each one of crystalline forms 1 , 2 and 3 of Compound 1 , or the amorphous form thereof, either as a single component (preferred) or together with other crystalline forms and/or the amorphous form of Compound 1 , can be used as a medicament, e.g. in the form of pharmaceutical compositions for parenteral and/or enteral administration in humans, especially parenteral administration, and is suitable for the prevention or treatment of bacterial diseases, especially of bacterial diseases caused by Gram-negative bacteria such as Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli.

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by bringing each one of crystalline forms 1 , 2 and 3 of Compound 1 , either as a single component or together with other crystalline forms and/or the amorphous form of Compound 1 , optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants. A pharmaceutical composition may also further contain additional known antibiotics.

Each one of crystalline forms 1 , 2, 3 of Compound 1 , or the amorphous form thereof, is active against bacteria. They may therefore be particularly suitable for treating bacterial infections in mammals, especially humans, for the prophylaxis and chemotherapy of local and systemic infections caused by fermentative or non-fermentative Gram-negative bacteria, especially those caused by susceptible and multi-drug resistant Gram-negative bacteria. Examples of such Gram-negative bacteria include Acinetobacter spp. such as Acinetobacter baumannii or Acinetobacter haemolyticus, Actinobacillus actinomycetemcomitans, Achromobacter spp. such as Achromobacter xylosoxidans or Achromobacter faecalis, Aeromonas spp. such as Aeromonas hydrophila, Bacteroides spp. such as Bacteroides fragilis, Bacteroides theataioatamicron, Bacteroides distasonis, Bacteroides ovatus or Bacteroides vulgatus, Bartonella hensenae, Bordetella spp. such as Bordetella pertussis, Borrelia spp. such as Borrelia Burgdorferi, Brucella spp. such as Brucella melitensis, Burkholderia spp. such as Burkholderia cepacia, Burkholderia pseudomallei or Burkholderia mallei, Campylobacter spp. such as Campylobacter jejuni, Campylobacter fetus or Campylobacter coli, Cedecea, Chlamydia spp. such as Chlamydia pneumoniae, Chlamydia trachomatis, Citrobacter spp. such as Citrobacter diversus (koseri) or Citrobacter freundii, Coxiella burnetii, Edwardsiella spp. such as Edwarsiella tarda, Ehrlichia chafeensis, Eikenella corrodens, Enterobacter spp. such as Enterobacter cloacae, Enterobacter aerogenes, Enterobacter agglomerans, Escherichia coli, Francisella tularensis, Fusobacterium spp., Haemophilus spp. such as Haemophilus influenzae (beta-lactamase positive and negative) or Haemophilus ducreyi, Helicobacter pylori, Kingella kingae, Klebsiella spp. such as Klebsiella oxytoca, Klebsiella pneumoniae (including those encoding extended-spectrum beta-lactamases (hereinafter "ESBLs"), carbapenemases (KPCs), cefotaximase-Munich (CTX-M), metallo-beta-lactamases, and AmpC-type beta-lactamases that confer resistance to currently available cephalosporins, cephamycins, carbapenems, beta-lactams, and beta-lactam/beta-lactamase inhibitor combinations), Klebsiella rhinoscleromatis or Klebsiella ozaenae, Legionella pneumophila, Mannheimia haemolyticus, Moraxella catarrhalis (beta-lactamase positive and negative), Morganella morgan!!, Neisseria spp. such as Neisseria gonorrhoeae or Neisseria meningitidis, Pasteurella spp. such as Pasteurella multocida, Plesiomonas shigelloides, Porphyromonas spp. such as Porphyromonas asaccharolytica, Prevotella spp. such as Prevotella corporis, Prevotella intermedia or Prevotella endodontalis, Proteus spp. such as Proteus mirabilis, Proteus vulgaris, Proteus penneri or Proteus myxofaciens, Porphyromonas asaccharolytica, Plesiomonas shigelloides, Providencia spp. such as Providencia stuartii, Providencia rettgeri or Providencia alcalifaciens, Pseudomonas spp. such as Pseudomonas aeruginosa (including ceftazidime-, cefpirome- and cefepime-resistant P. aeruginosa, carbapenem-resistant P. aeruginosa or quinolone-resistant P. aeruginosa) or Pseudomonas fluorescens, Ricketsia prowazekii, Salmonella spp. such as Salmonella typhi or Salmonella paratyphi, Serratia marcescens, Shigella spp. such as Shigella flexneri, Shigella boydii, Shigella sonnei or Shigella dysenteriae, Streptobacillus moniliformis, Stenotrophomonas maltophilia, Treponema spp., Vibrio spp. such as Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Vibrio alginolyticus, Yersinia spp. such as Yersinia enterocolitica, Yersinia pestis or Yersinia pseudotuberculosis.

Each one of crystalline forms 1 , 2, 3 of Compound 1 , or the amorphous form thereof, may be used for the preparation of a medicament.

Each one of crystalline forms 1 , 2, 3 of Compound 1 , or the amorphous form thereof, are suitable for the prevention or treatment (and especially the treatment) of infections caused by biothreat Gram-negative bacterial pathogens as listed by the US Center for Disease Control (www.selectagents.gov/Select AgentsandToxinsList.html), and in particular by Gram- negative pathogens selected from the group consisting of Yersinia pestis, Francisella tularensis (tularemia), Burkholderia pseudomallei and Burkholderia mallei. The preceding lists of pathogens are to be interpreted merely as examples and in no way as limiting. Each one of crystalline forms 1 , 2, 3 of Compound 1 , or the amorphous form thereof, may be used for veterinary applications, such as treating infections in livestock and companion animals. Animals such as pigs, ruminants, horses, dogs, cats and poultry may be treated.

Said forms may further be used in preserving inorganic and organic materials in particular all types of organic materials for example polymers, lubricants, paints, fibers, leather, paper and wood; for cleaning purposes, e.g. for removing pathogenic microbes and bacteria from surgical instruments, catheters and artificial implants or for surface disinfection. For such purposes, said forms could be contained in solution, suspension, aerosol or solid formulations. Each one of crystalline forms 1 , 2, 3 of Compound 1 , or the amorphous form thereof, may further be used for the preparation of a medicament for the prevention or treatment, especially treatment, of a disease mentioned herein.

Each one of crystalline forms 1 , 2, 3 of Compound 1 , or the amorphous form thereof, may thus especially be used for the preparation of a medicament, and are suitable, for the prevention or treatment of a bacterial infection selected from urinary tract infections, systemic infections (such as bacteraemia and sepsis), skin and soft tissue infections (including burn patients), surgical infections; intraabdominal infections and lung infections (including those in patients with cystic fibrosis) and in particular for the prevention or treatment of a bacterial infection selected from urinary tract infections and intraabdominal infections. The present invention also relates to a method for the prevention or treatment, especially treatment, of a disease mentioned herein comprising administering to a subject (especially a human subject) in need thereof a pharmaceutically active amount of a crystalline forms 1 , 2, 3 of Compound 1 , or the amorphous form thereof.

Each one of crystalline forms 1 , 2, 3 of Compound 1 and the amorphous form thereof, display intrinsic antibacterial properties and have the ability to improve permeability of the outer membrane of Gram-negative bacteria to other antibacterial agents. Their use in combination with another antibacterial agent might offer some further advantages such as lowered side-effects of drugs due to lower doses used or shorter time of treatment, more rapid cure of infection shortening hospital stays, increasing spectrum of pathogens controlled, and decreasing incidence of development of resistance to antibiotics. The antibacterial agent for use in combination with a Compound 1 according to this invention will be selected from the group consisting of a penicillin antibiotic (such as ampicillin, piperacillin, penicillin G, amoxicillin, or ticarcillin), a cephalosporin antibiotic (such as ceftriaxone, cefatazidime, cefepime, cefotaxime) a carbapenem antibiotic (such as imipenem, or meropenem), a monobactam antibiotic (such as aztreonam or carumonam), a fluoroquinolone antibiotic (such as ciprofloxacin, moxifloxacin or levofloxacin), a macrolide antibiotic (such as erythromycin or azithromycin), an aminoglycoside antibiotic (such as amikacin, gentamycin or tobramycin), a glycopeptide antibiotic (such as vancomycin or teicoplanin), a tetracycline antibiotic (such as tetracycline, oxytetracycline, doxycycline, minocycline or tigecycline), and linezolid, clindamycin, telavancin, daptomycin, novobiocin, rifampicin and polymyxin. Preferably, the antibacterial agent for use in combination with Compound 1 according to this invention will be selected from the group consisting of vancomycin, tigecycline and rifampicin.

EXPERIMENTAL PART

Abbreviations as used herein: AcOH acetic acid aq. aqueous

CC column chromatography over silica gel

DAD diode array detection

DCM dichloromethane DMSO dimethylsulfoxid

EA ethyl acetate

ELSD evaporative light scattering detector

ESI electron spray ionization

Et₂0 diethyl ether EtOH ethanol

Fig. figure h hour(s)

¹H-NMR proton nuclear magnetic resonance Hept heptane

HPLC high pressure liquid chromatography

IT internal temperature

LC liquid chromatography

LC-MS liquid chromatography - mass spectrometry

MeCN acetonitrile

MeOH methanol

min minute(s)

MS mass spectrometry

NBS N-bromosuccinimide

org. organic

prep-HPLC preparative HPLC

rpm revolutions per minute

rt room temperature

sat. saturated

sec second(s)

TBAF tetra-n-butylammonium fluoride

TBME ferf-butyl methyl ether

TFA trifluoroacetic acid

TLC thin layer chromatography tR retention time

XRPD X-ray powder diffraction METHODS USED

Analytical TLC characterizations were performed with 0.2 mm plates: Merck, Silica gel 60 F254. Elution is performed with EA, Hept, DCM, MeOH or mixtures thereof. Detection was done with UV-light or with a solution of KMn0₄ (3 g), K2CO3 (20 g), 5% NaOH (3 mL) and H₂O (300 mL) with subsequent heating.

Column chromatography (CC) was performed using Brunschwig 60A silica gel (0.032- 0.63 mm) or using an ISCO CombiFlash system and prepacked S1O2 cartridges, elution being carried out with either Hept-EA or DCM-MeOH mixtures with an appropriate gradient. When the compounds contained an acid function, 1 % of AcOH was added to the eluent(s). When the compounds contained a basic function, 1 % of NH4OH (25% aq. solution) was added to the eluents. At the end of the elution, the fractions containing the desired compound were combined and concentrated to dryness under reduced pressure.

¹H-NMR (400 MHz, Bruker Avance 400 or 500 MHz, Bruker Avance 500 Cryoprobe) was used for characterization. Chemical shifts δ are given in ppm relative to the solvent used; multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, hex = hexet, hep = heptet, m = multiplet, br. = broad; coupling constants J are given in Hz.

LC-MS (Sciex API 2000 with Agilent 1 100 Binary Pump with DAD and ELSD or an Agilent quadrupole MS 6140 with Agilent 1200 Binary Pump, DAD and ELSD) was used for characterization in certain cases. The analytical LC-MS data have been obtained using the following respective conditions:

o Column: Zorbax SB-Aq, 30.5 μιη, 4.6 x 50 mm;

o Injection volume: 1 μί;

o Column oven temperature: 40°C;

o Detection: UV 210 nm, ELSD and MS;

o MS ionization mode: ESI+;

o Eluents: A: H₂0 + 0.04% TFA; and B: MeCN;

o Flow rate: 40.5 imL/min;

o Gradient: 5% B to 95% B (0.0 min - 1.0 min), 95% B (1.0 min - 1.45 min).

The number of decimals given for the corresponding [M+H⁺] peak(s) as well as the retention times (t_R) of each tested compound depends upon the accuracy of the LC-MS device actually used. Preparative HPLC separations were performed on a Gilson HPLC system, equipped with a Gilson 215 autosampler, Gilson 333/334 pumps, Dionex MSQ Plus detector system, and a Dionex UVD340U (or Dionex DAD-3000) UV detector, using the following conditions:

o Column: Waters XBridge C18, 10 μιτι, 30^75 mm;

o Flow rate: 75 imL/min;

o Eluents: A: H₂0 + 0.5% NH₄OH solution (25%); B: MeCN;

o Gradient: 90% A to 5% A (0.0 min - 4.0 min), 5% A (4.0 min - 6.0 min).

At the end of the elution, the fractions containing the desired compound were combined and concentrated to dryness under reduced pressure.

X-ray powder diffraction patterns were collected on a Bruker D8 X-ray diffractometer equipped with a Lynxeye detector operated with CuK -radiation in reflection mode. Typically, the X-ray tube was run at of 40kV/40mA. A step size of 0.02° (20) and a step time of 37 sec over a scanning range of 2.5 - 50° in 20 were applied. Powders were slightly pressed into a silicon single crystal sample holder with depth of 0.1 mm and samples were rotated in their own plane during the measurement. Diffraction data are reported using Cu Κ (λ = 1.5418 A). The accuracy of the 2Θ values as provided herein is in the range of +/- 0.1-0.2° as it is generally the case for conventionally recorded X-ray powder diffraction patterns. For avoidance of any doubt, whenever one of the above embodiments refers to "peaks in the X- ray powder diffraction diagram at the following angles of refraction 2Θ", said X-ray powder diffraction diagram is obtained by using Cu K radiation (λ = 1.5418 A); and it should be understood that the accuracy of the 2Θ values as provided herein is in the range of +/- 0.1- 0.2°. Notably, when specifying an angle of refraction 2theta (2Θ) for a peak in the invention embodiments and the claims, the 2Θ value given is to be understood as an interval from said value minus 0.2° to said value plus 0.2° (2Θ +/- 0.2°); and preferably from said value minus 0.1 ° to said value plus 0.1 ° (2Θ +/- 0.1 °).

Minimal Inhibitory Concentration (MIC; mg/L) was determined in cation-adjusted Mueller- Hinton Broth by a micro-dilution method following the description given in "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically" , Approved standard, 7^th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, PA, USA (2006). PREPARATION OF COMPOUND 1

All temperatures are stated in °C. Unless otherwise indicated, the reactions take place at rt. The combined organic layers resulting from the workup of an aqueous layer are, unless otherwise indicated, washed with a minimal volume of brine, dried over MgSCU, filtered and evaporated to dryness to provide a so-called evaporation residue.

Preparation A: 3-(bromoethynyl)-1-(2-((fert-butyldimethylsilyl)oxy)ethyl)azetidine

A.i. Tert-butyl 3-(bromoethynyl)azetidine-1-carboxylate: To a stirring solution of ferf-butyl 3- ethynylazetidine-1-carboxylate (9.89 g; 54.6 mmol; prepared as described in WO 2015/13228) and NBS (1 1.69 g; 65.7 mmol) in acetone (220 mL) was added AgN0₃ (989 mg; 5.82 mmol). The reaction mixture was stirred at rt for 2 h and filtered over Celite. The filtrate was concentrated to dryness and the residue was purified by CC (Hex-TBME) to afford the title compound as a colorless oil (14.15 g, 100% yield). ¹H NMR (c 6-DMSO) δ: 4.10-4.03 (m, 2H); 3.78-3.71 (m, 2H); 3.50-3.43 (m, 1 H); 1.38 (s, 9H). A/7. 3-(bromoethynyl)azetidine hydrochloride: A solution of intermediate A.i (14.15 g; 54.4 mmol) in a AM HCI solution in dioxane (141 mL) was stirred at rt for 30 min. The reaction mixture was concentrated to dryness and the residue triturated in Et₂0 (60 mL). The solid was collected and dried to give the title compound as an off-white solid (9.76 g; 91 % yield). ¹H NMR (c 6-DMSO) δ: 9.26 (br. s, 2H); 4.13-4.07 (m, 2H); 3.94-3.88 (m, 2H); 3.78-3.70 (m, 1 H).

A.iii 3-(bromoethynyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)azetidine: To a solution of intermediate A.ii (9.76 g; 49.7 mmol) in DCM (300 mL) were added {tert- butyldimethylsilyloxy)acetaldehyde (1 1.6 mL; 54.6 mmol) and NaBH(OAc)₃ (14.81 g, 69.9 mmol). The reaction mixture was stirred at rt for 2 h. MeOH (34 mL), sat. aq. NaHC03 (400 mL) and DCM (300 mL) were added. The two layers were separated, the aq. layer was extracted with DCM (2 x 300 mL) and the combined org. layers were washed with brine. The evaporation residue was purified by CC (Hept-EA) to afford the title compound as an orange oil (12.85 g; 81 % yield). Ή NMR (c 6-DMSO) δ: 3.52 (t, J = 5.7 Hz, 2H); 3.49-3.45 (m, 2H); 3.20 (p, J = 7.4 Hz, 1 H); 3.02-2.96 (m, 2H); 2.45 (t, J = 5.7 Hz, 2H); 0.86 (s, 9H); 0.03 (s, 6H). MS (ESI, m/z): 318.01 and 320.00 [M+H⁺ of the two main isotopes] for Ci3H₂₄NOBrSi; t_R = 0.70 min. Preparation B: (2 ?)-4-(6-((1 -(2-hydroxyethyl)azetidin-3-yl)buta-1 ,3-diyn-1 -yl)-3-oxo-1 H- pyrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)-W-((2 ?S)-(tetrahydro-2H- pyran-2-yl)oxy)butanamide

B.i (2R)-4-(6-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)aze 1, 3-diyn-1-yl)-3-oxo- 1H^yrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methyls ^

pyran-2-yl)oxy)butanamide

To a solution of n-butylamine (6.5 mL) in water (16.5 mL) at rt was added CuCI (257 mg, 2.60 mmol). To the resulting blue solution was added NH₂OH.HCI (1.82 g, 26.1 mmol), the resulting colorless reaction mixture was further stirred at rt for 15 min and then treated with (2R)-4-(6-ethynyl-3-oxo-1 /-/-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)-/V- (((2RS)-tetrahydro-2/-/-pyran-2-yl)oxy)butanamide (5.50 g; 13.0 mmol; prepared as described in WO 2015/13228). The reaction mixture was stirred at rt for 15 min and cooled down to 0 °C. A solution of the compound of Preparation A (5.17 g; 16.2 mmol) in n-butylamine (6.5 mL) was added dropwise over 40 min while keeping IT below 6 °C. At the end of the addition, the reaction mixture was stirred at 0 °C for 10 min and then at rt for 1 h. The reaction mixture was cooled down to 0 °C and a solution of the compound of Preparation A (727 mg; 0.18 mmol) in n-butylamine (1.0 mL) was added dropwise while keeping IT below 6 °C. At the end of the addition, the reaction mixture was stirred at 0 °C for 10 min and then at rt for 2 h. Water (200 mL) and EA (300 mL) were added and the two layers were separated. The aq. layer was extracted with EA (2 x 200 mL) and the combined org. layers were washed with brine. The evaporation residue was then purified by CC (Hept-EA then EA-MeOH 9:1 ) to give the title compound as a yellow foam (6.21 g; 72%). ¹H NMR {d6- DMSO) (mixture of stereoisomers): δ: 1 1.37 (br. s, 0.5H); 1 1.35 (br. s, 0.5H); 7.56 (d, J = 0.7 Hz, 0.5H); 7.55 (d, J = 0.7 Hz, 0.5H); 6.27-6.24 (m, 1 H); 4.88-4.84 (m, 0.5H); 4.50-4.47 (m, 0.5H); 4.46-4.37 (m, 2H); 4.06-3.99 (m, 0.5H); 3.98-3.92 (m, 0.5H); 3.56-3.50 (m, 4H); 3.50- 3.35 (m, 4H); 3.08-3.02 (overlapped m, 2H); 3.06 (s, 1.5H); 3.03 (s, 1.5H); 2.70-2.56 (m, 1 H); 2.47 (t, J = 5.6 Hz, 2H); 2.02-1.93 (m, 1 H); 1.70-1.61 (m, 2H); 1.58-1.45 overlapped (m, 4H); 1.56 (s, 1.5H); 1.54 (s, 1.5H); 0.87 (s, 9H); 0.04 (s, 6H). MS (ESI, m/z): 661.24 [M+H⁺] for C32H48N4O7SS1; t_R = 0.82 min.

B.ii (2R)-4-(6-((1-(2-hydroxyethyl)azetidin-3-yl)buta-1,3-diyn-1-yl)-3-oxo-1H^ c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)-N^

yl)oxy)butanamide

To a solution of solution of intermediate B.i (6.21 g; 9.4 mmol) in THF (16 mL) was added a 1 M solution of TBAF in THF (20 mL). The resulting solution was stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was taken in EA (250 mL). Water (150 mL) was added and the two layers were separated. The aq. layer was extracted with EA (2 x 150 mL) and the combined org. layers were washed with NhUCI and brine. The evaporation residue was purified by CC (DCM-MeOH) to afford the title compound as a beige foam (4.25 g; 83% yield). ¹H NMR (c 6-DMSO) (mixture of stereoisomers) δ: 1 1.37-1 1.34 (m, 1 H); 7.56 (d, J = 0.7 Hz, 0.5H); 7.55 (d, J = 0.7 Hz, 0.5H); 6.27-6.24 (m, 1 H); 4.88-4.84 (m, 0.5H); 4.50-4.47 (m, 0.5H); 4.46-4.37 (m, 3H); 4.05-3.99 (m, 0.5H); 3.98-3.91 (m, 0.5H); 3.56-3.46 (m, 4H); 3.45-3.38 (m, 2H); 3.37-3.30 (m, 2H); 3.07 (s, 1.5H); 3.05-3.00 (overlapped m, 2H); 3.04 (s, 1.5H); 2.70-2.55 (m, 1 H); 2.43 (t, J = 6.0 Hz, 2H); 2.02-1.93 (m, 1 H); 1.70-1.60 (m, 2H); 1.60-1.44 (overlapped m, 4H); 1.55 (s, 1.5H); 1.53 (s, 1.5H). MS (ESI, m/z): 547.10 [M+H⁺] for C26H34N4O7S; t_R = 0.58 min.

Example 1 : Preparation of crystalline form 1 of Compound 1

To a solution of the compound of Preparation B (1.88 g; 3.44 mmol) in MeOH (30 mL) and water (10 mL) at 0 °C was added 2M aq. HCI (14 mL; 28 mmol). The reaction mixture was stirred at 0 °C for 1 h and at rt for 1 h. The reaction mixture, after neutralization with 25% aq. NH4OH and removal of MeOH under reduced pressure, was purified by prep-HPLC followed by CC (DCM-MeOH +1 % NH₄OH). The residue was taken up in MeCN (4 mL), the resulting suspension stirred at rt for 30 min, filtered and the solid collected and dried to give white crystalline form 1 of Compound 1 (1 10 mg, 7% yield). ¹H NMR (c 6-DMSO) δ: 10.94 (br. s, 1 H); 9.20 (br. s, 1 H); 7.57 (d, J = 1.0 Hz, 1 H); 6.27-6.25 (m, 1 H); 4.43 (s, 2H); 4.42 (t, J = 5.5 Hz, 1 H); 3.51 (t, J = 6.9 Hz, 2H); 3.54-3.45 (overlapped m, 1 H); 3.43- 3.30 (overlapped m, 4H); 3.06 (s, 3H); 3.03 (t, J = 6.9 Hz, 2H); 2.63-2.56 (m, 1 H); 2.43 (t, J = 6.0 Hz, 2H); 2.00-1.93 (m, 1 H); 1.53 (s, 3H). MS (ESI, m/z): 463.03 [M+H⁺] for C21 H26N4O6S; t_R = 0.49 min. Example 2: Preparation of crystalline form 2 of Compound 1

To a solution of the compound of Preparation B (4.55 g; 8.32 mmol) in MeOH (25 mL) and water (10 mL) at 0 °C was added 2M aq. HCI (15 mL; 30 mmol). The reaction mixture was stirred at 0 °C for 10 min and at rt for 1 h. The reaction mixture was cooled down to 0 °C, 25% aq. NH₄OH (2.5 mL) was added and the suspension stirred at rt for 15 min. The precipitate was collected, dried and additionally taken up in 0.5% aq. NH4OH (30 mL) and stirred at rt for 30 min. The suspension was filtered and the solid was collected and dried to give white crystalline form 2 of Compound 1 (2.42 g; 63% yield). ¹H NMR (c 6-DMSO) δ: 10.94 (br. s, 1 H); 9.20 (br. s, 1 H); 7.57 (d, J = 1 .0 Hz, 1 H); 6.27-6.25 (m, 1 H); 4.43 (s, 2H); 4.42 (t, J = 5.5 Hz, 1 H); 3.51 (t, J = 6.9 Hz, 2H); 3.54-3.45 (overlapped m, 1 H); 3.43- 3.30 (overlapped m, 4H); 3.06 (s, 3H); 3.03 (t, J = 6.9 Hz, 2H); 2.63-2.56 (m, 1 H); 2.43 (t, J = 6.0 Hz, 2H); 2.00-1 .93 (m, 1 H); 1 .53 (s, 3H). MS (ESI, m/z): 463.03 [M+H⁺] for C21 H26N4O6S; t_R = 0.49 min.

Example 3: Preparation of crystalline form 3 of Compound 1

0.1 g of Compound 1 in form 1 was dissolved in 1 mL DMSO in a new 4 mL glass vial. After complete dissolution the solvent was evaporated for 80 min in a Combidancer device from Hettich AG (Bach, Switzerland) shaken at 300 rpm and operated at 40°C and 0.035 mbar. Immediately thereafter 0.5 mL of MeCN was added to the vial and the vial was allowed to stand closed for 1 day at room temperature. Solid residue was crystalline form 3 of Compound 1 according to XRPD measured in MeCN wet state.

Example 4: Preparation of amorphous form of Compound 1

0.1 g of Compound 1 in form 1 was dissolved in 1 mL DMSO in a new 4 mL glass vial. After complete dissolution the solvent is evaporated for 80 min in a Combidancer device from Hettich AG (Bach, Switzerland) shaken at 300 rpm and operated at 40°C and 0.035 mbar. The residue is Compound 1 in amorphous form.

PHARMACOLOGICAL PROPERTIES OF COMPOUND 1

Compound 1 was tested against several Gram-negative bacteria, namely Klebsiella pneumoniae A-651 (multiply resistant strain; in particular quinolone-resistant) and two quinolone-sensitive strains - Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853 by means of in vitro assay as described hereinabove. Compound 1 exhibited bacterial growth minimal inhibitory concentration (MIC) of 0.5 mg/L against all tested strains.

Claims

1. A crystalline form of (2R)-N-hydroxy-4-(6-((1-(2-hydroxyethyl)azetidin-3-yl)buta- 1 ,3-diyn-1-yl)-3-oxo-1 /-/-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl- 2-(methylsulfonyl)butanamide, characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction: 7.4°, 13.9° and 16.5°, wherein the X-ray powder diffraction pattern is measured using a Cu K (1.5418 A) source.

The crystalline form according to claim 1 , characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction: 6.8°, 7.4°, 13.9°, 16.5° and 21.5°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1.5418 A) source.

The crystalline form according to claim 1 , characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction: 6.8°, 7.4°, 12.1 °, 13.1 °, 13.9°, 16.5°, 18.1 °, 19.

2°, 21.5° and 24.4°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1.5418 A) source.

A crystalline form of (2R)-N-hydroxy-4-(6-((1-(2-hydroxyethyl)azetidin-3-yl)buta- 1 ,

3-diyn-1-yl)-3-oxo-1 /-/-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl- 2-(methylsulfonyl)butanamide, characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction: 1 1.9°, 13.

4° and 20.3°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1.5418 A) source.

5. The crystalline form according to claim 4, characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction: 6.7°, 1 1.9°, 13.4°, 19.0° and 20.3°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1.5418 A) source.

6. The crystalline form according to claim 4, characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction: 6.7°, 7.5°, 1 1.9°, 13.4°, 15.1 °, 15.4°, 18.1 °, 19.0°, 20.3° and 24.5°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1.5418 A) source.

7. A crystalline form of (2R)-N-hydroxy-4-(6-((1-(2-hydroxyethyl)azetidin-3-yl)buta- 1 ,3-diyn-1-yl)-3-oxo-1 /-/-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl- 2-(methylsulfonyl)butanamide, characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction: 6.9°, 1 1.9° and 23.9°, wherein the X-ray powder diffraction pattern is measured using a Cu K (1.5418 A) source.

8. The crystalline form according to claim 7, characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction: 6.9°, 1 1.9°, 23.9°, 24.2° and 25.0°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1.5418 A) source.

9. The crystalline form according to claim 7, characterized by an X-ray powder diffraction pattern having peaks at the following angles of refraction: 6.9°, 1 1.9°, 13.9°, 15.1 °, 18.2°, 19.3, 23.9°, 24.2°, 25.0° and 27.9°, wherein the X-ray powder diffraction pattern is measured using a Cu Ka (1.5418 A) source.

10. A composition comprising the crystalline form according to any one of claims 1 to 9, further comprising at least one pharmaceutically acceptable excipient.

1 1. The crystalline form according to any one of claims 1 to 9, or the composition according to claim 10, for use as a medicament.

12. The crystalline form according to any one of claims 1 to 9, or the composition according to claim 10, for use in the treatment or prevention of a bacterial disease.

13. The crystalline form according to any one of claims 1 to 9, or the composition according to claim 10, for use in the treatment or prevention of a bacterial disease mediated by Gram-negative bacteria.

14. The crystalline form according to any one of claims 1 to 9, or the composition according to claim 10, for use in the treatment or prevention of a bacterial disease mediated by Klebsiella pneumonia and/or Pseudomonas aeruginosa and/or Escherichia coli.