Crystalline forms of macrocyclic peptide antibiotics.

Abstract

Described herein is the monohydrochloride salt and the free zwitterion of the macrocyclic peptide antibiotic 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid. Also described are amorphous and crystalline forms of the hydrochloride salt and the free zwitterion, as well as methods of making them and using them in medical therapy.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a novel monohydrochloride salt (hereinafter referred to as "HCl salt") of the macrocyclic peptide antibiotic 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid, as well as a novel free zwitterion (hereinafter referred to as "free base"). The present invention also relates to amorphous and specific crystalline forms of the HCl salt and free base. Finally, the present invention relates to pharmaceutical compositions comprising the novel forms, methods of making them, and their use in medical treatment. [Background technology]

[0002] 2. Background of the Invention WO2019206853, the entire contents of which are incorporated herein by reference, discloses the macrocyclic peptide 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (Formula Ia), which has potent antibacterial properties. [ka]

[0003] More specifically, WO2019206853 discloses a tetrakistetrafluoroacetic acid (TFA) salt of the compound of formula (Ia). However, due to the toxicity of the TFA salt, the TFA salt cannot be directly used as an active pharmaceutical ingredient for the treatment of bacterial infections.

[0004] On the other hand, the "free base" of the compound of formula (Ia) (i.e., the free zwitterion) was found to be poorly soluble in water, which is unacceptable for a pharmaceutical compound anticipated for intravenous administration.

[0005] Additionally, the API was found to contain high levels of palladium and sodium chloride impurities from the manufacturing process, which necessitated laborious purification steps (e.g., nanofiltration to remove sodium chloride). However, repeated purification is highly undesirable in large-scale manufacturing of pharmaceutical products.

[0006] In view of the above, there is an unmet need for new forms of the compound of formula (Ia) that could ultimately be used as a drug for the treatment of bacterial infections. Summary of the Invention

[0007] Summary of the Invention It has now been surprisingly shown that the HCl salts described herein exhibit dramatically increased solubility compared to the free base, particularly in aqueous media, which is of paramount importance for intravenous administration.

[0008] Moreover, it has been surprisingly found that a particular crystalline form of the free base greatly facilitates purification of the drug substance, allowing its manufacture on an industrial scale under GMP conditions.

[0009] Thus, in a first aspect, the present invention provides the monohydrochloride salt of 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (formula I). [ka]

[0010] In a further aspect, the present invention provides certain crystalline and amorphous forms of the monohydrochloride salt of formula (I) described herein, as well as methods of making them, methods of using them and pharmaceutical compositions containing them.

[0011] In a further aspect, the present invention provides the free zwitterion of the free base, i.e., 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (Formula Ia). [ka]

[0012] In a further aspect, the present invention provides certain crystalline and amorphous forms of the free base of formula (Ia) described herein, as well as methods of making them, methods of using them and pharmaceutical compositions containing them. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 shows a characteristic XRPD diffraction pattern of the crystalline polymorphic Form A1 of the monohydrochloride salt of formula (I) as described in Example 3. [Diagram 2] FIG. 2 shows a characteristic FT Raman spectrum of the crystalline polymorphic form A1 of the monohydrochloride salt of formula (I) described in Example 3. [Diagram 3] FIG. 3 shows a characteristic ATR-FTIR spectrum of the crystalline polymorphic form A1 of the monohydrochloride salt of formula (I) described in Example 3. [Figure 4] FIG. 4 shows a characteristic XRPD diffraction pattern of the crystalline polymorphic form A2 of the monohydrochloride salt of formula (I) as described in Example 4. [Diagram 5]FIG. 5 shows a characteristic FT Raman spectrum of the crystalline polymorphic form A2 of the monohydrochloride salt of formula (I) described in Example 4. [Figure 6] FIG. 6 shows a characteristic ATR-FTIR spectrum of the crystalline polymorphic form A2 of the monohydrochloride salt of formula (I) described in Example 4. [Figure 7] FIG. 7 shows a characteristic XRPD diffraction pattern of the crystalline polymorphic form “Pattern 4” of the monohydrochloride salt of formula (I) described in Example 5. [Figure 8] FIG. 8 shows a characteristic XRPD diffraction pattern of the crystalline polymorph “Pattern 5” of the monohydrochloride salt of formula (I) described in Example 6. [Figure 9] FIG. 9 shows characteristic FT Raman spectra of the amorphous form of the monohydrochloride salt of Formula (I) described in Example 2 and the amorphous form of the free base of Formula (Ia) described in Example 7. [Figure 10] FIG. 10 shows a characteristic ATR-FTIR spectrum of the amorphous form of the monohydrochloride salt of formula (I) described in Example 2. [Figure 11] FIG. 11 shows a characteristic XRPD diffraction pattern of the crystalline polymorphic Form A1 of the free base of Formula (Ia) described in Example 8. [Figure 12] FIG. 12 shows a characteristic FT Raman spectrum of the crystalline polymorphic Form A1 of the free base of Formula (Ia) described in Example 8. [Figure 13] FIG. 13 shows a characteristic ATR-FTIR spectrum of the crystalline polymorphic Form A1 of the free base of Formula (Ia) described in Example 8. [Figure 14] FIG. 14 shows a characteristic XRPD diffraction pattern of the crystalline polymorphic Form B of the free base of Formula (Ia) as described in Examples 9 and 10. [Figure 15] FIG. 15 shows a characteristic FT Raman spectrum of the crystalline polymorphic Form B of the free base of Formula (Ia) as described in Examples 9 and 10. [Figure 16] FIG. 16 shows a characteristic ATR-FTIR spectrum of the crystalline polymorphic Form B of the free base of Formula (Ia) as described in Examples 9 and 10. [Figure 17]FIG. 17 shows a characteristic ATR-FTIR spectrum of the amorphous form of the free base of Formula (Ia) described in Example 7. [Figure 18] FIG. 18 shows a characteristic XRPD diffraction pattern of the crystalline polymorphic form “Pattern 10.1” of the free base of Formula (Ia) described in Example 11. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Detailed Description of the Invention definition The terms "zwitterionic state," "free zwitterion," and "free base" are used interchangeably herein and refer to a compound of Formula (Ia) in which the acidic carboxylic acid functional group is deprotonated (negatively charged) while one of the basic amino functional groups is protonated (positively charged).

[0015] The term "pharmaceutical composition" refers to a mixture of the crystalline and / or amorphous forms described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, excipients, etc. A pharmaceutical composition facilitates administration of a compound to a mammal.

[0016] "Detectable amount" means any amount that can be determined by standard analytical methods (e.g., ion chromatography, mass spectrometry, NMR, HPLC, gas chromatography, elemental analysis, IR spectroscopy, inductively coupled plasma atomic emission spectroscopy, USP <231> Method II) (ICH guidances, Q2A Text on Validation of Analytical Procedures (March 1995) and Q2B Validation of Analytical Procedures: Methodology (November 1996)).

[0017] As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means having no lasting deleterious effects on the general health of the subject being treated.

[0018] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent administered that relieves to some extent one or more symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to produce a clinically significant reduction in disease symptoms. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. The effective amount is selected based on the particular patient and disease level. It is understood that the "effective amount" or "therapeutically effective amount" will vary from subject to subject due to variations in the metabolism of the drug, the age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. In one embodiment, the appropriate "effective" amount in any individual case is determined using techniques such as dose escalation studies. In some embodiments, the term "effective amount" or "therapeutically effective amount" is used in reference to the crystalline and amorphous forms described herein administered that relieve to some extent one or more symptoms of the disease or condition being treated.

[0019] The terms "kit" and "article of manufacture" are used synonymously.

[0020] Crystalline and amorphous forms In a first aspect, the present invention provides the monohydrochloride salt of 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (Formula I, "HCl Salt"). [ka] The HCl salts of the present invention have dramatically increased solubility compared to the free base, especially in aqueous media, which is most important for intravenous administration (Example 14).

[0021] In one embodiment, the HCl salt of the present invention is crystalline and has an X-ray powder diffraction (XRPD) pattern including peaks at 5.16, 7.94, 9.98, 10.46, 10.78, 11.66, 17.28, and 18.90 [°2 theta ± 0.2°2 theta, CuKα radiation (1.5406 Å)].

[0022] In one embodiment, the HCl salt of the present invention is crystalline and is: (a) has an X-ray powder diffraction (XRPD) pattern including peaks at 5.16, 7.94, 9.98, 10.46, 10.78, 11.66, 15.52, 15.70, 17.28, and 18.90 [°2 theta ± 0.2°2 theta, CuKα radiation (1.5406 Å)]; and / or (b) Approximately 103cm -1 , 1390cm -1 , 2246cm -1 , and 2930 cm -1 ±2cm -1 and / or (c) Approximately 752cm -1 , 1386cm -1 , 1534cm -1 , and 1602 cm -1 ±2cm -1 The ATR-FTIR spectrum includes an absorption band at wavenumbers of

[0023] In a preferred embodiment, the HCl salt of the present invention is crystalline and is: (a)5.16, 6.54, 7.94, 9.98, 10.46, 10.78, 11.54, 11.66, 11.98, 12.10, 13.02, 13.16, 14.38, 14.82, 15.04, 15.52, 15 .70, 15.94, 16.74, 17.28, 17.74, 18.10, 18.32, 18.78, 18.90, 19.72, 20.02, 20.28, 20.80, 20.96, 21.16, 21.56, 21. and / or has an X-ray powder diffraction (XRPD) pattern including peaks at 62, 22.38, 22.66, 23.28, 23.50, 23.98, 24.72, 24.92, 25.20, 25.60, 25.98, 26.22, 26.98, 27.20, 27.42, 27.88, 28.10, 28.48, 28.66, 29.00, 29.70, and 30.00 [°2 theta ± 0.2°2 theta, CuKα radiation (1.5406 Å)]; and / or (b) Approximately 103cm -1 , 137cm -1 , 225cm -1 , 279cm -1 , 330cm -1 , 382cm -1 , 416cm -1 , 449cm -1 , 479cm -1 , 517cm -1 , 547cm -1 , 563cm -1 , 596cm -1 , 624cm -1 , 639cm -1 , 685cm -1 , 758cm -1 , 790cm -1 , 807cm -1 , 848cm -1 , 878cm -1 , 898cm -1 , 955cm -1 , 1011cm -1 , 1059cm -1 , 1074cm -1 , 1140cm -1 , 1183cm -1 , 1203cm -1 , 1247cm -1 , 1288cm -1, 1316cm -1 , 1334cm -1 , 1358cm -1 , 1391cm -1 , 1425cm -1 , 1435cm -1 , 1451cm -1 , 1489cm -1 , 1557cm -1 , 1580cm -1 , 1605cm -1 , 1666cm -1 , 2246cm -1 , 2859cm -1 , 2930cm -1 , 2985cm -1 , 3063cm -1 , and 3116 cm -1 ±2cm -1 and / or (c) Approximately 659cm -1 , 717cm -1 , 731cm -1 , 752cm -1 , 778cm -1 , 786cm -1 , 803cm -1 , 847cm -1 , 874cm -1 , 887cm -1 , 906cm -1 , 931cm -1 , 950cm -1 , 971cm -1 , 1010cm -1 , 1017cm -1 , 1080cm -1 , 1098cm -1 , 1134cm -1 , 1148cm -1 , 1180cm -1 , 1215cm -1 , 1248cm -1 , 1282cm -1 , 1334cm -1 , 1385cm -1 , 1439cm -1 , 1459cm -1 , 1534cm -1 , 1602cm-1 , 1659cm -1 , 1682cm -1 , 2936cm -1 , 3054cm -1 , 3239cm -1 , and 3434 cm -1 ±2cm -1 The ATR-FTIR spectrum includes an absorption band at wavenumbers of

[0024] In a particularly preferred embodiment, the HCl salt of the present invention is crystalline and is: (a) has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 1; and / or (b) has substantially the same FT Raman spectrum as shown in FIG. 2; and / or (c) having substantially the same ATR-FTIR spectrum as shown in FIG.

[0025] In one embodiment, the HCl salt of the present invention is crystalline and is: (a) has an X-ray powder diffraction (XRPD) pattern including peaks at 5.20, 7.94, 9.92, 10.36, 10.68, 11.60, 15.58, 17.16, and 18.78 [°2 theta ± 0.2°2 theta, CuKα radiation (1.5406 Å)]; and / or (b) Approximately 163cm -1 , 1391cm -1 , 2920cm -1 , and 2948 cm -1 ±2cm -1 and / or (c) Approximately 753cm -1 , 1387cm -1 , 1541cm -1 , 1604cm -1 ±2cm -1 The ATR-FTIR spectrum includes an absorption band at wavenumbers of

[0026] In a preferred embodiment, the HCl salt of the present invention is crystalline and is: (a)5.20, 6.52, 7.94, 9.92, 10.36, 10.68, 11.60, 12.04, 13.02, 13.10, 14.34, 14.70, 14.92, 15.58, 15.94, 16.68, 17 .16, 17.52, 17.82, 18.06, 18.22, 18.78, 19.70, 19.80, 19.96, 20.64, 20.88, 21.10, 21.50, 22.30, 22.58, 23.18, 23. and / or has an X-ray powder diffraction (XRPD) pattern including peaks at 44, 23.58, 23.94, 24.22, 24.70, 25.02, 25.42, 25.74, 26.18, 26.82, 27.04, 27.24, 27.72, 27.90, 28.34, 28.86, 29.10, 29.52, 29.74, 30.14, 31.08, and 31.52 [°2 theta ± 0.2°2 theta, Cu Kα radiation (1.5406 Å)]; and / or (b) Approximately 107cm -1 , 135cm -1 , 163cm -1 , 225cm -1 , 336cm -1 , 417cm -1 , 450cm -1 , 480cm -1 , 518cm -1 , 546cm -1 , 562cm -1 , 596cm -1 , 621cm -1 , 639cm -1 , 686cm -1 , 758cm -1 , 774cm -1 , 790cm -1 , 813cm -1 , 848cm -1 , 877cm -1 , 899cm -1 , 955cm -1 , 1011cm -1 , 1046cm -1 , 1059cm -1 , 1075cm -1 , 1140cm -1 , 1188cm -1 , 1200cm -1 , 1234cm -1, 1249cm -1 , 1289cm -1 , 1317cm -1 , 1335cm -1 , 1358cm -1 , 1391cm -1 , 1426cm -1 , 1435cm -1 , 1452cm -1 , 1489cm -1 , 1558cm -1 , 1578cm -1 , 1606cm -1 , 1660cm -1 , 2920cm -1 , 2948cm -1 , 2986cm -1 , and 3059 cm -1 ±2cm -1 and / or (c) Approximately 673cm -1 , 718cm -1 , 739cm -1 , 753cm -1 , 773cm -1 , 779cm -1 , 803cm -1 , 848cm -1 , 875cm -1 , 888cm -1 , 898cm -1 , 906cm -1 , 932cm -1 , 946cm -1 , 971cm -1 , 1010cm -1 , 1017cm -1 , 1037cm -1 , 1067cm -1 , 1082cm -1 , 1095cm -1 , 1134cm -1 , 1149cm -1 , 1169cm -1 , 1181cm -1 , 1223cm -1 , 1248cm -1 , 1286cm -1 , 1333cm -1 , 1387cm-1 , 1406cm -1 , 1424cm -1 , 1440cm -1 , 1459cm -1 , 1467cm -1 , 1541cm -1 , 1585cm -1 , 1604cm -1 , 1658cm -1 , 2937cm -1 , 3054cm -1 , 3230cm -1 , 3349cm -1 , and 3429 cm -1 ±2cm -1 The ATR-FTIR spectrum includes an absorption band at wavenumbers of

[0027] In a particularly preferred embodiment, the HCl salt of the present invention is crystalline and is: (a) has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 4; and / or (b) has substantially the same FT Raman spectrum as shown in FIG. 5; and / or (c) having substantially the same ATR-FTIR spectrum as shown in FIG.

[0028] In one embodiment, the HCl salt of the present invention is crystalline and has an X-ray powder diffraction (XRPD) pattern including peaks at 5.6, 7.14, 8.66, 9.92, 10.52, 10.88, 11.92, 15.6, 16.64, 17.7, and 20.94 [°2 theta ± 0.2°2 theta, CuKα radiation (1.5406 Å)]. In a preferred embodiment, the HCl salt of the present invention is crystalline and has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG.

[0029] In one embodiment, the HCl salt of the present invention is crystalline and has an X-ray powder diffraction (XRPD) pattern including peaks at 5.22, 8.16, 9.88, 10.04, 10.48, 10.8, 11.48, 11.72, 12.2, 12.58, 13.1, 13.62, 14.5, 14.82, 15.12, 15.7, 16.02, 17.02, 17.82, 18.16, 18.42, 18.58, 18.72, 18.9, 19.4, 19.62, and 19.84 [°2-theta ± 0.2°2-theta, CuKα radiation (1.5406 Å)].

[0030] In a preferred embodiment, the HCl salt of the present invention is crystalline and has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. In one embodiment, the HCl salt of the present invention is amorphous and is: (a) Approximately 1296cm -1 , 1608cm -1 , 2928cm -1 , and 3060 cm -1 ±2cm -1 ±2cm -1 and / or (b) Approximately 742cm -1 , 778cm -1 , 1377cm -1 , and 1531 cm -1 ±2cm -1 The ATR-FTIR spectrum includes an absorption band at wavenumbers of

[0031] In a preferred embodiment, the HCl salt of the present invention is amorphous and has the formula: (a) Approximately 334cm -1 , 415cm -1 , 543cm -1 , 641cm -1 , 683cm -1 , 759cm -1 , 803cm -1 , 842cm -1 , 879cm -1 , 912cm -1 , 1011cm -1 , 1061cm -1 , 1077cm-1 , 1137cm -1 , 1203cm -1 , 1296cm -1 , 1359cm -1 , 1381cm -1 , 1437cm -1 , 1453cm -1 , 1557cm -1 , 1579cm -1 , 1609cm -1 , 2928cm -1 , and 3059 cm -1 ±2cm -1 and / or (b) Approximately 680cm -1 , 716cm -1 , 742cm -1 , 778cm -1 , 841cm -1 , 868cm -1 , 1010cm -1 , 1043cm -1 , 1078cm -1 , 1129cm -1 , 1177cm -1 , 1224cm -1 , 1285cm -1 , 1376cm -1 , 1403cm -1 , 1456cm -1 , 1531cm -1 , 1582cm -1 , 1627cm -1 , 2924cm -1 , and 3243 cm -1 ±2cm -1 The ATR-FTIR spectrum includes an absorption band at wavenumbers of

[0032] In a particularly preferred embodiment, the HCl salt of the present invention is amorphous and is: (a) has substantially the same FT Raman spectrum as shown in FIG. 9; and / or (b) Having substantially the same ATR-FTIR spectrum as shown in FIG.

[0033] In a further aspect, the present invention provides the free zwitterion of the free base, i.e., 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (Formula Ia). [ka]

[0034] In one embodiment, the free base of the present invention is crystalline.

[0035] In one embodiment, the free base of the present invention is amorphous.

[0036] In one embodiment, the free base of the present invention is crystalline and is: (a) has an X-ray powder diffraction (XRPD) pattern including peaks at 5.46, 8.08, 10.36, 11.56, 11.86, 16.56, and 17.44 [°2 theta ± 0.2°2 theta, CuKα radiation (1.5406 Å)]; and / or (b) Approximately 838cm -1 , 1079cm -1 , 1373cm -1 , and 1608 cm -1 ±2cm -1 and / or (c) Approximately 746cm -1 , 784cm -1 , 1371cm -1 , and 3437 cm -1 ±2cm -1 The ATR-FTIR spectrum includes an absorption band at wavenumbers of

[0037] In a preferred embodiment, the free base of the present invention is crystalline: (a)5.46, 8.08, 9.90, 10.36, 11.56, 11.86, 12.46, 12.84, 13.36, 13.70, 13.86, 14.82, 14.98, 15.28, 16.56, 17.0 0, 17.44, 17.72, 18.18, 18.42, 18.64, 18.94, 19.26, 19.80, 20.12, 20.52, 20.78, 21.02, 21.14, 21.34, 21.48, 21. 66, 21.80, 22.74, 22.84, 23.22, 23.42, 23.72, 24.02, 24.42, 24.58, 25.10, 25.52, 25.92, 26.18, 26.96, 27.60, 27.82, 27.94, 28.64, 29.16, and 29.92 [°2theta ± 0.2°2theta, CuKα radiation (1.5406 Å)]; and / or (b) Approximately 233cm -1 , 334cm -1 , 415cm -1 , 490cm -1 , 540cm -1 , 575cm -1 , 596cm -1 , 625cm -1 , 642cm -1 , 680cm -1 , 699cm -1 , 719cm -1 , 757cm -1 , 791cm -1 , 810cm -1 , 838cm -1 , 879cm -1 , 899cm -1 , 1010cm -1 , 1060cm -1 , 1080cm -1 , 1134cm -1 , 1204cm -1 , 1234cm -1 , 1288cm -1 , 1345cm -1 , 1359cm -1 , 1374cm -1 , 1437cm -1 , 1556cm -1 , 1576cm -1, 1608cm -1 , 2867cm -1 , 2928cm -1 , 3062cm -1 , and 3114 cm -1 ±2cm -1 and / or (c) Approximately 676cm -1 , 716cm -1 , 746cm -1 , 774cm -1 , 784cm -1 , 838cm -1 , 868cm -1 , 904cm -1 , 933cm -1 , 1009cm -1 , 1043cm -1 , 1077cm -1 , 1125cm -1 , 1175cm -1 , 1216cm -1 , 1249cm -1 , 1286cm -1 , 1301cm -1 , 1370cm -1 , 1457cm -1 , 1470cm -1 , 1533cm -1 , 1587cm -1 , 1651cm -1 , 2863cm -1 , 2927cm -1 , 3041cm -1 , 3223cm -1 , and 3437 cm -1 ±2cm -1 The ATR-FTIR spectrum includes an absorption band at wavenumbers of

[0038] In a particularly preferred embodiment, the free base of the present invention is crystalline and is: (a) has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 11; and / or (b) has substantially the same FT Raman spectrum as shown in FIG. 12; and / or (c) Having substantially the same ATR-FTIR spectrum as shown in FIG.

[0039] Surprisingly, the crystalline "form B" of the free base was found to greatly facilitate purification of the drug substance, making it possible to manufacture on an industrial scale under GMP conditions. Thus, the crystalline "form B" described in Example 10 has significantly reduced levels of palladium and sodium chloride contamination compared to the amorphous form described in Example 7. Thus, providing the API as a free base and crystallizing it in form B is a useful strategy to avoid laborious nanofiltration to remove sodium chloride, as well as an even less efficient purification step to reduce palladium contamination. Thus, the free base form B is highly useful in the manufacture of the API.

[0040] In an embodiment, the free base of the present invention is crystalline and is: (a) has an X-ray powder diffraction (XRPD) pattern including peaks at 6.6, 9.0, 9.9, 10.1, 11.8, 12.0, 14.5, 15.4 [°2 theta ± 0.2°2 theta, CuKα radiation (1.5406 Å)]; and / or (b) Approximately 757cm -1 , 1290cm -1 , 1433cm -1 , and 1548 cm -1 ±2cm -1 and / or (c) Approximately 745cm -1 , 1367cm -1 , 1533cm -1 , and 1638 cm -1 ±2cm -1 The ATR-FTIR spectrum includes an absorption band at wavenumbers of

[0041] In a preferred embodiment, the free base of the present invention is crystalline: (a) has an X-ray powder diffraction (XRPD) pattern including peaks at 6.6, 9.0, 9.9, 10.1, 11.8, 12.0, 14.5, 14.8, 15.4, 15.7, 16.0, 16.4, 16.7, 17.0, 17.8, 18.0, 18.4, 18.7, 19.1, 19.6, 20.0, 20.4, 20.7, 20.9, 21.2, 21.5, 22.1, 23.3, 23.8, 24.2, 24.6, 24.9 and 25.7 [°2 theta ± 0.2°2 theta, Cu Kα radiation (1.5406 Å)]; and / or (b) Approximately 233cm -1 , 331cm -1 , 352cm -1 , 414cm -1 , 462cm -1 , 543cm -1 , 574cm -1 , 596cm -1 , 614cm -1 , 625cm -1 , 641cm -1 , 682cm -1 , 696cm -1 , 718cm -1 , 757cm -1 , 839cm -1 , 878cm -1 , 947cm -1 , 1010cm -1 , 1044cm -1 , 1059cm -1 , 1075cm -1 , 1097cm -1 , 1136cm -1 , 1149cm -1 , 1179cm -1 , 1203cm -1 , 1234cm -1 , 1290cm -1 , 1303cm -1 , 1361cm -1 , 1372cm -1 , 1433cm -1 , 1453cm -1 , 1491cm -1 , 1547cm -1 , 1557cm -1 , 1576cm -1 , 1610cm-1 , 1660cm -1 , 2868cm -1 , 2930cm -1 , 3059cm -1 , and 3113 cm -1 ±2cm -1 and / or (c) Approximately 677cm -1 , 716cm -1 , 745cm -1 , 771cm -1 , 784cm -1 , 801cm -1 , 839cm -1 , 868cm -1 , 906cm -1 , 927cm -1 , 967cm -1 , 1014cm -1 , 1043cm -1 , 1077cm -1 , 1125cm -1 , 1171cm -1 , 1213cm -1 , 1243cm -1 , 1283cm -1 , 1301cm -1 , 1367cm -1 , 1399cm -1 , 1431cm -1 , 1456cm -1 , 1471cm -1 , 1533cm -1 , 1590cm -1 , 1638cm -1 , 1658cm -1 , 1694cm -1 , 2862cm -1 , 2925cm -1 , 3029cm -1 , and 3212 cm -1 ±2cm -1 The ATR-FTIR spectrum includes an absorption band at wavenumbers of

[0042] In a particularly preferred embodiment, the free base of the present invention is crystalline and is: (a) has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 14; and / or (b) has substantially the same FT Raman spectrum as shown in FIG. 15; and / or (c) Having substantially the same ATR-FTIR spectrum as shown in FIG.

[0043] In one embodiment, the free base of the invention is amorphous and is: (a) Approximately 1296cm -1 , 1608cm -1 , 2928cm -1 , and 3060 cm -1 ±2cm -1 ±2cm -1 and / or (b) Approximately 742cm -1 , 778cm -1 , 1379cm -1 , and 1536 cm -1 ±2cm -1 The ATR-FTIR spectrum includes an absorption band at wavenumbers of

[0044] In a preferred embodiment, the free base of the present invention is amorphous and is: (a) Approximately 335cm -1 , 415cm -1 , 544cm -1 , 641cm -1 , 684cm -1 , 759cm -1 , 801cm -1 , 845cm -1 , 879cm -1 , 910cm -1 , 1011cm -1 , 1061cm -1 , 1077cm -1 , 1137cm -1 , 1203cm -1 , 1296cm -1 , 1359cm -1 , 1386cm -1 , 1438cm -1 , 1556cm -1 , 1579cm -1, 1608cm -1 , 2862cm -1 , 2927cm -1 , and 3060 cm -1 ±2cm -1 and / or (b) Approximately 679cm -1 , 716cm -1 , 742cm -1 , 778cm -1 , 842cm -1 , 869cm -1 , 928cm -1 , 1010cm -1 , 1043cm -1 , 1078cm -1 , 1127cm -1 , 1182cm -1 , 1224cm -1 , 1285cm -1 , 1379cm -1 , 1455cm -1 , 1537cm -1 , 1589cm -1 , 1632cm -1 , 2863cm -1 , 2926cm -1 , 3047cm -1 , and 3255 cm -1 ±2cm -1 The ATR-FTIR spectrum includes an absorption band at wavenumbers of

[0045] In a particularly preferred embodiment, the free base of the present invention is amorphous and is: (a) has substantially the same FT Raman spectrum as shown in FIG. 9; and / or (b) Having substantially the same ATR-FTIR spectrum as shown in FIG.

[0046] In one embodiment, the free base of the invention is crystalline and has an X-ray powder diffraction (XRPD) pattern including peaks at 6.93, 7.28, 12.11, 14.52, 15.04, 15.73, 19.44, and 22.00 [°2 theta ± 0.2°2 theta, CuKα radiation (1.5406 Å)].

[0047] In a preferred embodiment, the free base of the present invention is crystalline and has the following average molecular weights: 6.93, 7.28, 8.07, 10.08, 12.11, 13.53, 13.92, 14.52, 15.04, 15.73, 16.21, 16.96, 17.57, 18.13, 18.46, 19.31, 19.44, 19.87, 20.25, 20.51, 20.97, 22.00, 22.29, It has an X-ray powder diffraction (XRPD) pattern including peaks at 22.49, 22.93, 23.12, 23.33, 23.60, 24.03, 24.40, 24.92, 25.04, 25.26, 25.62, 25.86, 26.15, 26.52, 27.26, 28.66, and 30.58 [°2theta ± 0.2°2theta, CuKα radiation (1.5406 Å)].

[0048] In a particularly preferred embodiment, the free base of the present invention is crystalline and has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG.

[0049] Preparation of crystalline forms In one aspect, the invention provides methods for preparing the crystalline and amorphous forms described herein, as outlined in the Examples, with the caveat that the solvents, temperatures and other reaction conditions given in the Examples may vary.

[0050] In a further aspect, the present invention provides the crystalline and amorphous forms described herein when obtained by the methods described in the Examples.

[0051] Suitable Solvent Therapeutic drugs that can be administered to mammals, such as humans, must be prepared according to regulatory guidelines. Such government regulatory guidelines are called Good Manufacturing Practice (GMP). GMP guidelines outline acceptable levels of contamination of active therapeutics, such as, for example, the amount of residual solvent in the final product. Preferred solvents are those that are suitable for use in GMP facilities and consistent with industrial safety concerns. Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005).

[0052] Solvents are divided into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents that have limited use during the manufacture of therapeutic drugs. Class 3 solvents are solvents that have low toxicity and low risk to human health. Data for Class 3 solvents show low toxicity in acute or short-term studies and negative genotoxicity tests.

[0053] Class 1 solvents to be avoided include benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethene; and 1,1,1-trichloroethane.

[0054] Examples of class 2 solvents are acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0055] Less toxic Class 3 solvents include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

[0056] In some embodiments, compositions comprising the crystalline and amorphous forms described herein contain a residual amount of organic solvent. In some embodiments, compositions comprising the crystalline and amorphous forms described herein contain a detectable amount of organic solvent. In some embodiments, compositions comprising the crystalline and amorphous forms described herein contain a residual amount of a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran. In some embodiments, the Class 3 solvent is selected from the group consisting of 1-butanol, 2-butanol, ethanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, 1-propanol, and 2-propanol. In some embodiments, the Class 3 solvent is ethanol or 1-propanol.

[0057] The methods and compositions described herein include the use of the crystalline and amorphous forms described herein.Furthermore, the crystalline and amorphous forms described herein may exist in unsolvated and solvated forms with pharma- ceutically acceptable solvents such as water, 1-propanol, ethanol, etc.

[0058] Pharmaceutical Compositions / Formulations Pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including additives and auxiliary agents that facilitate the processing of active compound into medicament-used preparations.Suitable techniques, carriers and additives are described, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh ed. (Lippincott Williams and Wilkins 1999), each of which is incorporated by reference in its entirety.

[0059] In one aspect, the invention relates to a pharmaceutical composition comprising any of the crystalline and amorphous forms described herein, or a mixture thereof, and at least one additional component selected from pharma- ceutically acceptable carriers, diluents, and excipients.

[0060] In some embodiments, the crystalline or amorphous forms described herein are formulated for intravenous administration to a mammal.

[0061] In one aspect, the present invention provides a method for producing a method for treating a cancer cell comprising: (i) any of the crystalline and amorphous forms described herein, or mixtures thereof; (ii) Water for injection; and (iii) Sodium chloride The present invention provides a solution for intravenous administration to a mammal comprising:

[0062] In one embodiment, the concentration of the crystalline and amorphous forms or mixtures thereof described herein in an intravenous solution according to the invention is 50 mg / mL.

[0063] Contemplated pharmaceutical compositions provide a therapeutically effective amount of the crystalline and amorphous forms described herein that allows for administration, for example, once daily, twice daily, three times daily, etc. In one embodiment, the pharmaceutical composition provides an effective amount of the crystalline and amorphous forms described herein that allows for administration once daily.

[0064] In one embodiment, the pharmaceutical composition described herein is administered for therapeutic treatment.In therapeutic use, the composition is administered to a patient who is already suffering from a disease or condition in an amount sufficient to cure or at least partially stop at least one of the symptoms of the disease or condition.In certain embodiments, the amount effective for this use depends on the severity and course of the disease or condition, previous treatment, the patient's health condition, weight, and response to drugs, and / or the judgment of the treating physician.

[0065] Uses of the Crystalline and Amorphous Forms of the Invention The compounds described herein have beneficial pharmacological properties for treating or preventing infections and resulting diseases caused by pathogens, particularly bacteria, more particularly Acinetobacter species, most particularly Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0066] In one aspect, the present invention provides a compound described herein for use as a medicament.

[0067] In one embodiment, the pharmaceutical agent is an antibiotic.

[0068] In one aspect, the invention provides a method of treating bacterial infection and resulting disease in a mammal, the method comprising administering to said mammal a therapeutically effective amount of a compound described herein.

[0069] In one aspect, the invention provides a compound as described herein for use in treating a bacterial infection and resulting disease in a mammal.

[0070] In one aspect, the invention provides the use of the compounds described herein for treating bacterial infections and resulting diseases in a mammal.

[0071] In one embodiment, the invention provides the use of a compound described herein in the manufacture of a medicament for the treatment of a bacterial infection and resulting disease in a mammal.

[0072] In one embodiment, the bacterial infection and resultant disease is selected from bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0073] In one embodiment, the bacterial infection is selected from infections caused by gram-negative bacteria.

[0074] In one embodiment, the bacterial infection is selected from infections by "ESKAPE" pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species and E. coli), or combinations thereof.

[0075] In one embodiment, the bacterial infection is a hospital-acquired infection.

[0076] In one embodiment, the bacterial infection is selected from infections caused by multi-drug resistant (MDR) bacteria, in particular MDR A. baumanniii.

[0077] In one embodiment, the bacterial infection is selected from infections caused by carbapenem-resistant bacteria, particularly carbapenem-resistant A. baumannii.

[0078] In one embodiment, the bacterial infection is selected from infections caused by Acinetobacter species, most particularly Acinetobacter baumannii.

[0079] Combination treatment The crystalline and amorphous forms described herein may be used alone or in combination with other treatments. For example, a second drug in a pharmaceutical combination formulation or dosing regimen may have complementary activity to the crystalline and amorphous forms described herein so as not to adversely affect each other. The compounds may be administered together in a single pharmaceutical composition or separately. In one embodiment, the crystalline and amorphous forms described herein may be administered together with antibiotics, particularly antibiotics, to treat or prevent infections and resulting diseases caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or E. coli, or combinations thereof.

[0080] The term "co-administration" refers to simultaneous administration or any manner of separate sequential administration of the crystalline and amorphous forms described herein and one or more additional active pharmaceutical ingredients, particularly antibiotics.When not simultaneously administered, the compounds are administered close to each other in time.Furthermore, it is not important whether the compounds are administered in the same dosage form, for example, one compound may be administered intravenously and another compound may be administered orally.

[0081] Typically, any agent with antibacterial activity may be co-administered. Specific examples of such agents are carbapenems (meropenem), fluoroquinolones (ciprofloxacin), aminoglycosides (amikacin), tetracyclines (tigecycline), colistin, sulbactam, sulbactam plus durobactam, cefidrocor (fetroja), and macrolides (erythromycin).

[0082] In one aspect, the invention provides a pharmaceutical composition as described herein, further comprising an additional therapeutic agent.

[0083] In one aspect, the invention provides pharmaceutical combinations comprising the crystalline and amorphous forms described herein and an additional therapeutic agent.

[0084] In one embodiment, the additional therapeutic agent is an antibiotic agent.

[0085] In one embodiment, the additional therapeutic agent is an antibiotic agent useful for the treatment or prevention of infection and disease resulting from Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof.

[0086] In one embodiment, the additional therapeutic agent is an antibiotic selected from a carbapenem (meropenem), a fluoroquinolone (ciprofloxacin), an aminoglycoside (amikacin), a tetracycline (tigecycline), colistin, sulbactam, sulbactam plus durobactam, cefidrocor (fetroja), and a macrolide (erythromycin). EXAMPLES

[0087] The following examples are given to illustrate the invention and should not be considered as limiting the scope of the invention, but merely as representative thereof.

[0088] Abbreviation The following abbreviations are used in this patent specification: ATR Attenuated Total Reflection FT Fourier transform IR Infrared XRPD X-ray powder diffraction

[0089] Example 1 - Preparation of 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (free base) 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid tetrakis(trifluoroacetate) salt (described in WO2019206853, 5.19 g, 4.2 mmol) was dissolved in water (60 mL) and acetonitrile (120 mL). 32% aqueous NaOH (1.88 g) was added. To this solution, 1 M aqueous NaOH was added until pH=9.8 was reached (approximately 2 g). After a few hours, a suspension is formed and stirred at room temperature for another 1.5 hours. The precipitate is filtered off, washed with water and dried under reduced pressure at 40° C. to give 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (1.90 g, 59%) as a white powder.

[0090] MS:791.37[M+H +]

[0091] Example 2 - Preparation of amorphous 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid, monohydrochloride salt ("HCl Salt") 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (48.7 g, 61.6 mmol) was suspended in water (500 mL) and the pH was brought to 7.0 by the addition of a mixture of 25% aqueous HCl (9.04 g) and water (51.2 mL). The solution was filtered through a 3M™ ZETA PLUS™ filter and then through a 0.2 μm Sartopore® 2XLG® filter. The resulting clear solution was spray dried and dried under reduced pressure to give 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid, monohydrochloride (38.8 g, 76%) as a white powder (amorphous form).

[0092] MS:791.37[M+H + ]

[0093] Example 3 - Preparation of Crystalline Form A1 of 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid, monohydrochloride 200 mg of the amorphous HCl salt (Example 2) was dissolved in 0.5 mL of water at 23° C. with stirring to form a highly viscous solution. Once no solid particles were visible, acetonitrile was added dropwise to the solution. A white turbidity was observed in the solution, which quickly disappeared (small oil droplets form these turbidities). A very slight supersaturation was adjusted by adding additional acetonitrile until the turbidity did not disappear. A spatula tip seed of the crystalline free base (Form A1) was added to the solution. No dissolution of the seed was observed visually. The mixture was stirred at 200 rpm and 22.5° C. for 12 hours. The solid material was separated from the liquid and identified as crystalline material by optical microscopy. The material was then filtered and dried under reduced pressure (20 mbar) and room temperature (22.5° C.) for 14 hours. The white powder was characterized by XRPD as crystalline Form A1.

[0094] On a larger scale, 50.46 g of the amorphous HCl salt (Example 2) was dissolved in 85 mL of water at 23° C. with stirring. Once no solid particles were visible, 150 mL of acetonitrile was slowly added. At about 50 mL, the HCl salt started to become oily. The emulsion was stirred for about 30 minutes until spontaneous crystallization of the oily phase was observed. An additional 50 mL of acetonitrile was added to maintain a stirrable suspension. The suspension was stirred for 24 hours. After filtration, the white powder was dried under reduced pressure (20 mbar) and at room temperature (23° C.) for 14 hours. The resulting solid was identified as pure Form A1 by XRPD. Example 4 - Preparation of crystalline form A2 of 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid, monohydrochloride 100 mg of amorphous HCl salt (Example 2) was dissolved in 0.25 mL of water at 23° C. with stirring to form a highly viscous solution. When no solid particles were visible, a spatula tip of a seed of crystalline form A1 (Example 3) was added. No dissolution of the seed was observed visually. The mixture was stirred at 200 rpm and 23° C. for 12 hours. Afterwards, a white suspension was observed. The material was filtered and dried under reduced pressure (20 mbar) and at room temperature (23° C.) for 14 hours. The white powder was characterized by XRPD, Raman and IR as crystalline form A2, which is isostructural to form A1.

[0095] On a larger scale, 2.02 g of the amorphous HCl salt (Example 2) was dissolved in 3.00 mL of water at 23° C. and stirred for 14 hours. The extremely viscous solution was heated to 35° C. Seeds of Form A2 were added, which dissolved rapidly. The solution was cooled at 2° C. overnight. The viscosity was too high to stir the clear honey-like solution. A temperature cycle from 10° C. to 35° C. was started and the sample was left stirring at 200 rpm for 7 days. A white suspension was observed. The mixture was cooled to 5° C. and stirred at this temperature overnight. The solid was filtered and dried in ambient air (31% rH, 22° C.) for 6 hours. The white powder was characterized by XRPD as pure Form A2.

[0096] Example 5 - Preparation of crystalline form "Pattern 4" of 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid, monohydrochloride Pattern 4 was observed by drying Form A2 (Example 4) at 50° C. and 5 mbar for 24 hours.

[0097] Example 6 - Preparation of crystalline form "Pattern 5" of 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid, monohydrochloride Pattern 5 was observed by grinding Form A1 (Example 3) in acetonitrile with glass beads in a vial on a vortex mixer.

[0098] Example 7 - Preparation of amorphous 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid In a 1000 ml round bottom flask, 11.0 g of amorphous HCl salt (Example 2), 323.5 ml of acetone and 161.8 ml of water were added at room temperature. The mixture was stirred. 0.1 M NaOH was added dropwise to the orange mixture at room temperature until the pH reached 9.80. 145 ml of 0.1 M sodium hydroxide was consumed. The solvent was evaporated as much as possible on a rotary evaporator. The remainder was flash frozen with dry ice and then lyophilized to obtain the title compound (Pd contamination: 3261 ppm, Cl- contamination (from NaCl): 4.2% wt / wt).

[0099] Example 8 - Preparation of crystalline form A1 of 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid 44.21 g of amorphous HCl salt (Example 2) is suspended in 260.2 mL of water and 71.88 mL of acetonitrile at room temperature. 27.61 mL of HCl (0.214 moles, 4 equiv.) is added to the white suspension. The white suspension turns into a pale yellow cloudy solution. Upon heating to 40° C., the solution becomes clear. At room temperature, a mixture of 20.15 mL of water and 20.15 mL of NaOH (0.218 moles, 4.07 equiv.) is added to adjust the pH to a near neutral pH (pH 7.19). The solution is optionally seeded with free base (Form A family, 10.4 mg). The pH of the solution is then adjusted to pH 9.8 by adding 54.9 g of 1N NaOH. The colorless solution becomes increasingly cloudy from pH 9.1 onwards. The resulting suspension is stirred at room temperature for 1 hour and then filtered. The crystals were dried overnight at 65° C. / 2 mbar and in a vacuum drying oven at 25° C. to obtain 41.82 g of pure Form A1. It has been found that the free base can also exist as isostructural mixed solvate / hydrate crystal systems containing various organic solvents and water in the crystal lattice, which will not be described here. For example, such isostructural crystal forms can be obtained from solvent mixtures consisting of water and water in ethanol or propanol.

[0100] Example 9 - Preparation of crystalline form B of 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid 19.775 g of amorphous HCl salt (Example 2) was added to a mixture of 100 mL of water and 15.56 mL of 1-PrOH and dissolved under stirring at 35° C. The pH of the solution was set to 9.2 by adding 50 mL of 8 wt. % aqueous NaOH solution, and 135 mg of ABX free base species was added as a suspension in 1 g of water and 1 g of 1-PrOH. The resulting suspension was aged for 60 min. The pH was then increased to 9.8 by adding 75 mL of 1 wt. % aqueous NaOH solution over 1 h. The suspension was aged for 15 min and the temperature was reduced to 20° C. within 1 h. After an additional 15 min of aging, the suspension was filtered and the solid was washed with water to obtain a sample characterized by XRPD as pure crystalline form A3. The remaining material was dried at 80° C. and 20 mbar for 16 h. The resulting white powder was characterized by XRPD as pure crystalline form B.

[0101] Example 10 - Another Preparation of Crystalline Form B of 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid 1.7 g of amorphous free base (Example 7) was weighed into a 40 mL scale-up glass and 20 mL of solvent (15% v / v water in propanol) was added with stirring (350 rpm). A sticky red film formed on the bottom. The solution was then heated to 80° C., but the red material did not dissolve. The hot solution was filtered through a 0.2 μm Satorius Nutsche filter. The filtrate became cloudy and was heated again to 80° C. The yellow solution was cooled from 80° C. to 10° C. within 8 hours without stirring. Seeding was performed at 25° C. with stirring (350 rpm) with a spatula tip of Form A, leaving a yellow oil. The white suspension was filtered through a Satorius Nutsche 0.2 um filter. The filter cake was washed with 3×10 mL of fresh solvent and then dried overnight at 50° C. / 5 mbar (off-white crystalline solid, Pd contamination: 2048 ppm, Cl - Contamination (from NaCl): 0.1% by weight.

[0102] Example 11 - Preparation of crystalline form "Pattern 10.1" of 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid 1 g of Form B free base was weighed into a 7.5 mL scale-up glass and 5 mL of solvent (5% water in ethanol v / v) was added with stirring (100 rpm) at 20 °C. After 2 days, the white suspension was centrifuged at 5000 rpm. The resulting white wet powder was characterized by XRPD as pure crystalline pattern 10.1.

[0103] Example 12 -ATR FTIR Experimental Method ATR-FTIR spectra were recorded without sample preparation using a ThermoNicolet iS5 FTIR spectrometer equipped with an ATR accessory. The spectral range was 4000 cm-1 ~650cm -1 with a resolution of 2cm -1 and 50 co-addition scans were collected (32 co-addition scans were collected except for the spectrum of Form A1 from the HCl salt). Happ-Genzel apodization was applied. The use of ATR FTIR results in relative intensities in the infrared range that differ from those seen in transmission FTIR using KBr disks or Nujol sample preparations. Due to the nature of ATR FTIR, bands at low wavenumbers are more intense than bands at higher wavenumbers.

[0104] result Crystalline forms A1, A2 and amorphous form of the monohydrochloride salt of Formula (I), and crystalline forms A1, B and amorphous form of the free base of Formula (Ia) were characterized by ATR FTIR as described above. Unique ATR FTIR peaks are shown in Tables 1-6. Characteristic ATR FTIR spectra are shown in Figures 3, 6, 10, 13, 16 and 17. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0105] Example 13 - Raman spectroscopy Experimental Method FT-Raman spectra were recorded without sample preparation using a Bruker MultiRam FT-Raman spectrometer equipped with a liquid nitrogen-cooled germanium detector and a 1064 nm NdYAG laser. The spectral range was 4000 cm.-1 ~100cm -1 with a resolution of 2cm -1 (Excluding spectrum of form A1 from the HCl salt: 4 cm -1 ) and 2048 simultaneous additional scans (excluding the spectrum of form B from the free base: 1024 scans) were collected. The laser power was set at 300 mW (excluding the spectrum of form A1 from the HCl salt: 100 mW) and Blackman-Harris 4-Term apodization was applied.

[0106] result Crystalline forms A1, A2 and amorphous form of the monohydrochloride salt of formula (I), and crystalline forms A1, B and amorphous form of the free base of formula (Ia) were characterized by FT-Raman spectroscopy as described above. Unique FT-Raman peaks are shown in Tables 7-11. Characteristic FT-Raman spectra are shown in Figures 2, 5, 9, 12 and 15. It should be noted that the free base and the amorphous form of the HCl salt are indistinguishable by Raman spectroscopy. [Table 7] [Table 8] [Table 9] [Table 10] [Table 11]

[0107] Example 14 - XRPD Experimental Method X-ray diffraction patterns were recorded at ambient conditions in transmission geometry using a STOE STADIP diffractometer (CuKα radiation (1.5406 Å), primary Ge monochromator, Mythen 1K silicon strip detector, angular range 3°-42° 2-theta, measurement time 20 s per step). Samples were prepared and analyzed without further processing of the material (e.g., grinding or sieving).

[0108] Measurement and evaluation of X-ray diffraction data was performed using WinXPOW software (STOE&Cie GmbH, Darmstadt, Germany).

[0109] result Crystalline forms A1, A2, patterns 4 and 5 of the monohydrochloride salt of Formula (I), and crystal forms A1 and B of the free base of Formula (Ia) were characterized by XRPD as described above. The unique XRPD peaks of the crystal forms are shown in Tables 12-17. Characteristic XRPD diffractograms of the crystal forms are shown in Figures 1, 4, 7, 8, 11 and 14. [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18]

[0110] Example 15 - Solubility Evaluation Experimental Method Approximately 1 g of material was equilibrated in 8.5 mL of water at 20° C. for 2 days. 1 mL of the suspension was centrifuged. The filtrate was analyzed by uPLC. result [Table 19]

Claims

1. 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indole-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid monohydrochloride (Formula I) 【Chemistry 1】 。

2. The aforementioned 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indole-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid is zwitterionic. In this state, 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indole-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (formula Ia) 【Chemistry 2】 。

3. The crystalline form of 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indole-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid according to claim 2.

4. (a) Having an X-ray powder diffraction (XRPD) pattern with peaks at 6.6, 9.0, 9.9, 10.1, 11.8, 12.0, 14.5, 15.4 [°² theta ± 0.2°² theta, CuKα line (1.5406 Å)]; and / or (b) Approximately 757cm －１ , 1290cm －１ , 1433cm －１ , and 1548cm －１ ±2cm －１ It has an FT Raman spectrum that includes an absorption band at the wavenumber; and / or (c) Approximately 745 cm －１ , 1367 cm －１ , 1533 cm －１ , and 1638 cm －１ ± 2 cm －１ The crystalline form according to claim 3, having an ATR-FTIR spectrum including absorption bands at wavenumbers of.

5. (a) Having an X-ray powder diffraction (XRPD) pattern with peaks at 6.6, 9.0, 9.9, 10.1, 11.8, 12.0, 14.5, 14.8, 15.4, 15.7, 16.0, 16.4, 16.7, 17.0, 17.8, 18.0, 18.4, 18.7, 19.1, 19.6, 20.0, 20.4, 20.7, 20.9, 21.2, 21.5, 22.1, 23.3, 23.8, 24.2, 24.6, 24.9 and 25.7 [°² theta ± 0.2°² theta, CuKα line (1.5406 Å)]; and / or (b) Approximately 233cm －１ , 331cm －１ , 352cm －１ , 414cm －１ , 462cm －１ 543cm －１ 574cm －１ 596cm －１ , 614cm －１ , 625cm －１ , 641cm －１ , 682cm －１ 696cm －１ 718cm －１ 757cm －１ , 839cm －１ , 878cm －１ 947cm －１ , 1010cm －１ 1044cm －１ , 1059cm －１ , 1075cm －１ 1097cm －１ 1136cm －１ 1149cm －１ 1179cm －１ , 1203cm －１ , 1234cm －１ , 1290cm －１ , 1303cm －１ 1361cm －１ , 1372cm －１ , 1433cm －１ 1453cm －１ 1491cm －１ , 1547cm －１ , 1557cm －１ 1576cm －１ , 1610cm －１ , 1660cm －１ , 2868cm －１ , 2930cm －１ , 3059cm －１ , and 3113 cm －１ ±2cm －１ It has an FT Raman spectrum that includes an absorption band at the wavenumber; and / or (c) Approximately 677 cm －１ , 716 cm －１ , 745 cm －１ , 771 cm －１ , 784 cm －１ , 801 cm －１ , 839 cm －１ , 868 cm －１ , 906 cm －１ , 927 cm －１ , 967 cm －１ , 1014 cm －１ , 1043 cm －１ , 1077 cm －１ , 1125 cm －１ , 1171 cm<000007​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​

6. (a) Having substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 14; and / or (b) Having substantially the same FT-Raman spectrum as shown in Figure 15; and / or (c) The crystal morphology according to claim 5, having substantially the same ATR-FTIR spectrum as shown in Figure 16.

7. The monohydrochloride salt according to claim 1, which is crystalline and has an X-ray powder diffraction (XRPD) pattern including peaks at 5.16, 7.94, 9.98, 10.46, 10.78, 11.66, 17.28, and 18.90 [°² theta ± 0.2°² theta, CuKα line (1.5406 Å)].

8. (a) Having an X-ray powder diffraction (XRPD) pattern with peaks at 5.16, 7.94, 9.98, 10.46, 10.78, 11.66, 15.52, 15.70, 17.28, and 18.90 [°² theta ± 0.2°² theta, CuKα line (1.5406 Å)]; and / or (b) Approximately 103cm －１ , 1390cm －１ , 2246cm －１ , and 2930cm －１ ±2cm －１ It has an FT Raman spectrum that includes an absorption band at the wavenumber; and / or (c) Approximately 752 cm －１ , 1386 cm －１ , 1534 cm －１ , and 1602 cm －１ ± 2 cm －１ The crystalline monohydrochloride according to claim 7, having an ATR-FTIR spectrum containing absorption bands at the wavenumbers of.

9. (a) 5.16, 6.54, 7.94, 9.98, 10.46, 10.78, 11.54, 11.66, 11.98, 12.10, 13.02, 13.16, 14.38, 14.82, 15.04, 15.52, 15 70, 15.94, 16.74, 17.28, 17.74, 18.10, 18.32, 18.78, 18.90, 19.72, 20.02, 20.28, 20.80, 20.96, 21.16, 21.56, 21. Having an X-ray powder diffraction (XRPD) pattern with peaks at 62, 22.38, 22.66, 23.28, 23.50, 23.98, 24.72, 24.92, 25.20, 25.60, 25.98, 26.22, 26.98, 27.20, 27.42, 27.88, 28.10, 28.48, 28.66, 29.00, 29.70, and 30.00 [°2 theta ± 0.2°2 theta, CuKα line (1.5406 Å)]; and / or (b) Approximately 103cm －１ 137cm －１ , 225cm －１ , 279cm －１ , 330cm －１ , 382cm －１ , 416cm －１ 449cm －１ , 479cm －１ 517cm －１ 547cm －１ 563cm －１ 596cm －１ , 624cm －１ , 639cm －１ , 685cm －１ 758cm －１ 790cm －１ , 807cm －１ , 848cm －１ , 878cm －１ , 898cm －１ , 955cm －１ , 1011cm －１ , 1059cm －１ , 1074cm －１ , 1140cm －１ , 1183cm －１ , 1203cm －１ 1247cm －１ , 1288cm －１ , 1316cm －１ , 1334cm －１ , 1358cm －１ 1391cm －１ , 1425cm －１ , 1435cm －１ 1451cm －１ , 1489cm －１ , 1557cm －１ , 1580cm －１ , 1605cm －１ , 1666cm －１ , 2246cm －１ , 2859cm －１ , 2930cm －１ , 2985cm －１ , 3063cm －１ , and 3116 cm －１ ±2cm －１ It has an FT Raman spectrum that includes an absorption band at the wavenumber; and / or (c) Approximately 659cm －１ 717cm －１ 731cm －１ 752cm －１ 778cm －１ 786cm －１ , 803cm －１ 847cm －１ 874cm －１ , 887cm －１ 906cm －１ 931cm －１ , 950cm －１ 971cm －１ , 1010cm －１ , 1017cm －１ , 1080cm －１ , 1098cm －１ , 1134cm －１ , 1148cm －１ , 1180cm －１ , 1215cm －１ , 1248cm －１ , 1282cm －１ , 1334cm －１ , 1385cm －１ , 1439cm －１ 1459cm －１ , 1534cm －１ , 1602cm －１ , 1659cm －１ , 1682cm －１ , 2936cm －１ , 3054cm －１ , 3239cm －１ , and 3434cm －１ ±2cm －１ The crystalline monohydrochloride salt according to claim 8, having an ATR-FTIR spectrum that includes an absorption band at a wavenumber.

10. (a) Having substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1; and / or (b) Having substantially the same FT-Raman spectrum as shown in Figure 2; and / or (c) The crystalline monohydrochloride salt according to claim 9, having substantially the same ATR-FTIR spectrum as shown in Figure 3.

11. (a) Having an X-ray powder diffraction (XRPD) pattern with peaks at 5.20, 7.94, 9.92, 10.36, 10.68, 11.60, 15.58, 17.16, and 18.78 [°² theta ± 0.2°² theta, CuKα line (1.5406 Å)]; and / or (b) Approximately 163cm －１ 1391cm －１ , 2920cm －１ , and 2948cm －１ ±2cm －１ It has an FT Raman spectrum that includes an absorption band at the wavenumber; and / or (c) Approximately 753cm －１ , 1387cm －１ 1541cm －１ , 1604cm －１ ±2cm －１ The crystalline monohydrochloride salt according to claim 7, having an ATR-FTIR spectrum that includes an absorption band at a wavenumber.

12. (a) 5.20, 6.52, 7.94, 9.92, 10.36, 10.68, 11.60, 12.04, 13.02, 13.10, 14.34, 14.70, 14.92, 15.58, 15.94, 16.68, 17 .16, 17.52, 17.82, 18.06, 18.22, 18.78, 19.70, 19.80, 19.96, 20.64, 20.88, 21.10, 21.50, 22.30, 22.58, 23.18, 23. Having an X-ray powder diffraction (XRPD) pattern with peaks at 44, 23.58, 23.94, 24.22, 24.70, 25.02, 25.42, 25.74, 26.18, 26.82, 27.04, 27.24, 27.72, 27.90, 28.34, 28.86, 29.10, 29.52, 29.74, 30.14, 31.08, and 31.52 [°2 theta ± 0.2°2 theta, CuKα line (1.5406 Å)]; and / or (b) Approximately 107cm －１ 135cm －１ , 163cm －１ , 225cm －１ , 336cm －１ , 417cm －１ , 450cm －１ , 480cm －１ , 518cm －１ 546cm －１ 562cm －１ 596cm －１ , 621cm －１ , 639cm －１ , 686cm －１ 758cm －１ 774cm －１ 790cm －１ , 813cm －１ , 848cm －１ 877cm －１ , 899cm －１ , 955cm －１ , 1011cm －１ 1046cm －１ , 1059cm －１ , 1075cm －１ , 1140cm －１ 1188cm －１ , 1200cm －１ , 1234cm －１ , 1249cm －１ , 1289cm －１ , 1317cm －１ , 1335cm －１ , 1358cm －１ 1391cm －１ 1426cm －１ , 1435cm －１ 1452cm －１ , 1489cm －１ , 1558cm －１ , 1578cm －１ , 1606cm －１ , 1660cm －１ , 2920cm －１ , 2948cm －１ , 2986cm －１ , and 3059cm －１ ±2cm －１ It has an FT Raman spectrum that includes an absorption band at the wavenumber; and / or (c) Approximately 673cm －１ 718cm －１ 739cm －１ 753cm －１ 773cm －１ 779cm －１ , 803cm －１ , 848cm －１ , 875cm －１ 888cm －１ , 898cm －１ 906cm －１ , 932cm －１ 946cm －１ 971cm －１ , 1010cm －１ , 1017cm －１ , 1037cm －１ 1067cm －１ , 1082cm －１ , 1095cm －１ , 1134cm －１ 1149cm －１ 1169cm －１ 1181cm －１ , 1223cm －１ , 1248cm －１ , 1286cm －１ , 1333cm －１ , 1387cm －１ , 1406cm －１ , 1424cm －１ , 1440cm －１ 1459cm －１ 1467cm －１ 1541cm －１ , 1585cm －１ , 1604cm －１ , 1658cm －１ , 2937cm －１ , 3054cm －１ , 3230cm －１ , 3349cm －１ , and 3429cm －１ ±2cm －１ The crystalline monohydrochloride salt according to claim 11, having an ATR-FTIR spectrum that includes an absorption band at a wavenumber.

13. (a) Having substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 4; and / or (b) Having substantially the same FT-Raman spectrum as shown in Figure 5; and / or (c) The crystalline monohydrochloride salt according to claim 12, having substantially the same ATR-FTIR spectrum as shown in Figure 6.

14. The crystalline monohydrochloride salt according to claim 7, having an X-ray powder diffraction (XRPD) pattern including peaks at 5.6, 7.14, 8.66, 9.92, 10.52, 10.88, 11.92, 15.6, 16.64, 17.7, and 20.94 [°² theta ± 0.2°² theta, CuKα line (1.5406 Å)].

15. The crystalline monohydrochloride salt according to claim 14, having substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 7.

16. The crystalline monohydrochloride salt according to claim 7, having an X-ray powder diffraction (XRPD) pattern including peaks at 5.22, 8.16, 9.88, 10.04, 10.48, 10.8, 11.48, 11.72, 12.2, 12.58, 13.1, 13.62, 14.5, 14.82, 15.12, 15.7, 16.02, 17.02, 17.82, 18.16, 18.42, 18.58, 18.72, 18.9, 19.4, 19.62, and 19.84 [°2 theta ± 0.2°2 theta, CuKα line (1.5406 Å)].

17. The crystalline monohydrochloride salt according to claim 14, having substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 8.

18. It is amorphous, (a) Approximately 1296cm －１ , 1608cm －１ , 2928cm －１ , and 3060cm －１ ±2cm －１ ±2cm －１ It has an FT Raman spectrum that includes an absorption band at the wavenumber; and / or (b) Approximately 742cm －１ 778cm －１ , 1377cm －１ , and 1531cm －１ ±2cm －１ The monohydrochloride salt according to claim 1, having an ATR-FTIR spectrum that includes an absorption band at a wavenumber.

19. (a) Approximately 334cm －１ , 415cm －１ 543cm －１ , 641cm －１ , 683cm －１ 759cm －１ , 803cm －１ 842cm －１ 879cm －１ 912cm －１ , 1011cm －１ 1061cm －１ , 1077cm －１ , 1137cm －１ , 1203cm －１ , 1296cm －１ 1359cm －１ 1381cm －１ , 1437cm －１ 1453cm －１ , 1557cm －１ 1579cm －１ , 1609cm －１ , 2928cm －１ , and 3059cm －１ ±2cm －１ It has an FT Raman spectrum that includes an absorption band at the wavenumber; and / or (b) Approximately 680cm －１ 716cm －１ 742cm －１ 778cm －１ , 841cm －１ , 868cm －１ , 1010cm －１ , 1043cm －１ , 1078cm －１ , 1129cm －１ 1177cm －１ , 1224cm －１ , 1285cm －１ 1376cm －１ , 1403cm －１ 1456cm －１ , 1531cm －１ 1582cm －１ , 1627cm －１ , 2924cm －１ , and 3243cm －１ ±2cm －１ The amorphous monohydrochloride salt according to claim 18, having an ATR-FTIR spectrum that includes an absorption band at a wavenumber.

20. (a) Having substantially the same FT-Raman spectrum as shown in Figure 9; and / or (b) The amorphous monohydrochloride salt according to claim 19, having substantially the same ATR-FTIR spectrum as shown in Figure 10.

21. (a) Having an X-ray powder diffraction (XRPD) pattern with peaks at 5.46, 8.08, 10.36, 11.56, 11.86, 16.56 and 17.44 [°² theta ± 0.2°² theta, CuKα line (1.5406 Å)]; and / or (b) Approximately 838cm －１ , 1079cm －１ , 1373cm －１ , and 1608cm －１ ±2cm －１ It has an FT Raman spectrum that includes an absorption band at the wavenumber; and / or (c) Approximately 746cm －１ 784cm －１ 1371cm －１ , and 3437cm －１ ±2cm －１ The crystal morphology according to claim 3, having an ATR-FTIR spectrum that includes an absorption band at a wavenumber.

22. (a) 5.46, 8.08, 9.90, 10.36, 11.56, 11.86, 12.46, 12.84, 13.36, 13.70, 13.86, 14.82, 14.98, 15.28, 16.56, 17.0 0, 17.44, 17.72, 18.18, 18.42, 18.64, 18.94, 19.26, 19.80, 20.12, 20.52, 20.78, 21.02, 21.14, 21.34, 21.48, 21. Having an X-ray powder diffraction (XRPD) pattern with peaks at 66, 21.80, 22.74, 22.84, 23.22, 23.42, 23.72, 24.02, 24.42, 24.58, 25.10, 25.52, 25.92, 26.18, 26.96, 27.60, 27.82, 27.94, 28.64, 29.16, and 29.92 [°² theta ± 0.2°² theta, CuKα line (1.5406 Å)]; and / or (b) Approximately 233cm －１ 334cm －１ , 415cm －１ , 490cm －１ , 540cm －１ 575cm －１ 596cm －１ , 625cm －１ 642cm －１ , 680cm －１ , 699cm －１ 719cm －１ 757cm －１ 791cm －１ , 810cm －１ , 838cm －１ 879cm －１ , 899cm －１ , 1010cm －１ , 1060cm －１ , 1080cm －１ , 1134cm －１ , 1204cm －１ , 1234cm －１ , 1288cm －１ , 1345cm －１ 1359cm －１ 1374cm －１ , 1437cm －１ 1556cm －１ 1576cm －１ , 1608cm －１ , 2867cm －１ , 2928cm －１ , 3062cm －１ , and 3114 cm －１ ±2cm －１ It has an FT Raman spectrum that includes an absorption band at the wavenumber; and / or (c) Approximately 676cm －１ 716cm －１ 746cm －１ 774cm －１ 784cm －１ , 838cm －１ , 868cm －１ , 904cm －１ , 933cm －１ , 1009cm －１ , 1043cm －１ , 1077cm －１ , 1125cm －１ , 1175cm －１ , 1216cm －１ , 1249cm －１ , 1286cm －１ , 1301cm －１ , 1370cm －１ , 1457cm －１ , 1470cm －１ 1533cm －１ , 1587cm －１ , 1651cm －１ , 2863cm －１ , 2927cm －１ , 3041cm －１ , 3223cm －１ , and 3437cm －１ ±2cm －１ The crystal morphology according to claim 21, having an ATR-FTIR spectrum that includes an absorption band at a wavenumber.

23. (a) Having substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 11; and / or (b) Having substantially the same FT-Raman spectrum as shown in Figure 12; and / or (c) The crystal morphology according to claim 22, having substantially the same ATR-FTIR spectrum as shown in Figure 13.

24. The amorphous 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indole-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid according to claim 2.

25. (a) Approximately 1296cm －１ , 1608cm －１ , 2928cm －１ , and 3060cm －１ ±2cm －１ ±2cm －１ It has an FT Raman spectrum that includes an absorption band at the wavenumber; and / or (b) Approximately 742cm －１ 778cm －１ 1379cm －１ , and 1536cm －１ ±2cm －１ The amorphous compound according to claim 24, having an ATR-FTIR spectrum that includes an absorption band at a wavenumber.

26. (a) Approximately 335cm －１ , 415cm －１ 544cm －１ , 641cm －１ , 684cm －１ 759cm －１ , 801cm －１ , 845cm －１ 879cm －１ , 910cm －１ , 1011cm －１ 1061cm －１ , 1077cm －１ , 1137cm －１ , 1203cm －１ , 1296cm －１ 1359cm －１ 1386cm －１ , 1438cm －１ 1556cm －１ 1579cm －１ , 1608cm －１ , 2862cm －１ , 2927cm －１ , and 3060cm －１ ±2cm －１ It has an FT Raman spectrum that includes an absorption band at the wavenumber; and / or (b) Approximately 679cm －１ 716cm －１ 742cm －１ 778cm －１ 842cm －１ , 869cm －１ 928cm －１ , 1010cm －１ , 1043cm －１ , 1078cm －１ 1127cm －１ , 1182cm －１ , 1224cm －１ , 1285cm －１ 1379cm －１ 1455cm －１ , 1537cm －１ 1589cm －１ , 1632cm －１ , 2863cm －１ , 2926cm －１ , 3047cm －１ , and 3255cm －１ ±2cm －１ The amorphous compound according to claim 25, having an ATR-FTIR spectrum that includes an absorption band at a wavenumber.

27. (a) Having substantially the same FT-Raman spectrum as shown in Figure 9; and / or (b) The amorphous compound according to claim 26, having substantially the same ATR-FTIR spectrum as shown in Figure 17.

28. The crystal morphology according to claim 3, having an X-ray powder diffraction (XRPD) pattern including peaks at 6.93, 7.28, 12.11, 14.52, 15.04, 15.73, 19.44, and 22.00 [°² theta ± 0.2°² theta, CuKα line (1.5406 Å)].

29. 6.93, 7.28, 8.07, 10.08, 12.11, 13.53, 13.92, 14.52, 15.04, 15.73, 16.21, 16.96, 17.57, 18.13, 18.46, 19.31, 19.44, 19.87, 20.25, 20.51, 20.97, 22.00, 22.29, 22.49, 22.93, 23.12, 23. The crystal morphology according to claim 28, having an X-ray powder diffraction (XRPD) pattern including peaks at 33, 23.60, 24.03, 24.40, 24.92, 25.04, 25.26, 25.62, 25.86, 26.15, 26.52, 27.26, 28.66, and 30.58 [°² theta ± 0.2°² theta, CuKα line (1.5406 Å)].

30. The crystal morphology according to claim 28, having substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 18.

31. A pharmaceutical composition comprising a compound or mixture thereof according to any one of claims 1 to 30, and at least one additional component selected from pharmaceutically acceptable carriers, diluents, and additives.

32. The pharmaceutical composition according to claim 31, wherein the pharmaceutical composition is in a form suitable for intravenous administration to mammals.

33. (i) The compound according to any one of claims 1 to 30; (ii) Water for injection; and (iii) Sodium chloride A solution containing the above for intravenous administration to mammals.

34. The intravenous solution according to claim 33, wherein the concentration of the compound is 50 mg / mL.

35. A compound according to any one of claims 1 to 30, for use as a pharmaceutical.

36. A compound according to any one of claims 1 to 30 for use in the treatment of bacterial infections and resulting diseases in mammals.

37. A method for treating a bacterial infection and resulting disease in a mammal, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 30 to the mammal.

38. Use of the compound in the method according to claim 37.

39. Use of the compound according to any one of claims 1 to 30 in the manufacture of a pharmaceutical product for the treatment of bacterial infections and resulting diseases in mammals.

40. The invention as described above in this specification.

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