Salts and Polymorphs of Seldomericin for the Treatment of Diseases Salts and Polymorphs of Seldomericin

Abstract

Disclosed herein are novel salts and polymorphs of cethromycin for the treatment of diseases resulting from infection by bacteria and certain protozoa (including, for example, malaria, babesiosis, toxoplasmosis, diarrhea, respiratory diseases, and sexually transmitted diseases), as well as some bioterrorism organisms (including, for example, plague, tularemia, and inhalation anthrax). Also disclosed herein are novel salts and polymorphs of cethromycin for the treatment of inflammatory diseases (including, for example, pelvic inflammatory disease and peptic ulcer disease).

Description

Technical Field

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 942,508, filed on December 2, 2019, which is incorporated herein by reference as if its disclosure were set forth in full in this specification.

Summary of the Invention

Means for Solving the Problems

[0002] Disclosed herein are novel substituted sethromycin salts and polymorphs and compositions, as well as their use as pharmaceuticals for the treatment of diseases. Also provided are methods of treating diseases caused by infection by bacteria and certain protozoa (e.g., including malaria, babesiosis, toxoplasmosis, diarrhea, respiratory diseases, sexually transmitted bacterial infections), and several bioterror bacteria (e.g., including plague, tularemia, and inhalational anthrax). Also disclosed herein are novel salts and polymorphs of sethromycin for the treatment of inflammatory diseases (e.g., including pelvic inflammatory disease and peptic ulcer disease).

[0003] Some of them are novel compounds and pharmaceutical compositions that have been found to inhibit protein synthesis in bacteria, mycobacteria, and certain protozoa, in addition to methods of synthesizing and using these compounds (including methods for the treatment of infectious diseases in patients by administering these compounds).

Brief Description of the Drawings

[0004]

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Mode for Carrying Out the Invention

[0005] Provided herein is Embodiment 1: A compound having structural formula I

Chemical formula

[0006] Certain compounds disclosed herein have activity useful for inhibiting bacterial protein synthesis and can be used for the treatment or prevention of diseases in which bacterial protein synthesis plays an active role. Certain embodiments provide methods for inhibiting bacterial protein synthesis. Other embodiments are methods for treating diseases caused by bacterial infection in patients in need of such treatment, the methods comprising administering to the patient a therapeutically effective amount of a compound or composition as disclosed herein. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of diseases alleviated by inhibition of bacterial protein synthesis.

[0007] In some embodiments, the bacteria are from the genus Bacteroides (e.g., including B. tectum); the genus Corynebacterium; the genus Chlamydia (e.g., including C. pneumoniae and C. trachomatis); the genus Eikenella (e.g., including E. corrodens); the family Enterobacteriaceae; the genus Fusobacterium (e.g., including F. nucleatum); the genus Haemophilus (e.g., including H. influenzae); the genus Leigonella (e.g., including L. pneumophila); the genus Moraxella (e.g., including M. catarrhalis); the genus Mycobacterium (e.g., including M. avium, M. intracellulare, M. chimaera, M. kansasii, M. malmoense, M. xenopi, M. abscessus, the M. fortuitum complex, and M. chelonae); the genus Mycoplasma (e.g., including M. hominis, M. genitalium, and M. pneumoniae); the genus Neisseria (e.g., including N. gonorrhoeae); the genus Pasturella (e.g., including P. septica and P. multocida); the genus Peptostreptococcus (e.g., including P. magnus and P. micros(P.including Micros); Prevotella (e.g., including P. melaninogenica and P. heparinolytica); Porphyromonas; Propionibacterium; Staphylococcus (e.g., including S. aureus); Streptococcus (e.g., including S. pneumoniae); Ureaplasma (e.g., including U. urealyticum and U. parvum); and Veillonella, and is selected from them.

[0008] Certain compounds disclosed herein have activity useful for inhibiting protozoal protein synthesis and can be used for the treatment or prevention of diseases in which bacterial protein synthesis plays an active role. Certain embodiments provide a method for inhibiting protozoal protein synthesis. Other embodiments are methods for treating diseases caused by protozoal infections in patients in need of such treatment, which methods include administering to the patient a therapeutically effective amount of a compound or composition as disclosed herein. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of diseases alleviated by inhibition of protozoal protein synthesis.

[0009] In some embodiments, the protozoa are selected from Cryptosporidium; Coccidia; Plasmodium; Toxoplasma; (e.g., including Toxoplasma gondii); Babesia; and Neospora. In some embodiments, the protozoa are Toxoplasma gondii. In some embodiments, the protozoa are a species of Plasmodium. In some embodiments, Plasmodium is selected from Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi. In some embodiments, Plasmodium is Plasmodium falciparum.

[0010] Also provided are pharmaceutical compositions comprising one or more of the compounds disclosed herein, together with a pharmaceutically acceptable carrier, and methods of making and using these compounds and compositions.

[0011] The present disclosure provides further embodiments:

[0012] Embodiment 2: The compound of Embodiment 1, wherein M is acetic acid.

[0013] Embodiment 3: The compound of Embodiment 1, wherein M is phosphoric acid.

[0014] Embodiment 4: The compound of Embodiment 1, wherein M is hydrochloric acid.

[0015] Embodiment 5: The compound of any one of Embodiments 1 - 4, wherein the compound is in solid form.

[0016] Embodiment 6: The compound according to any one of Embodiments 1 to 5, wherein the compound is in a crystalline form.

[0017] Embodiment 7: The compound according to Embodiment 1, wherein a is a fraction or an integer between about 0.5 and 3.0 (including the end values).

[0018] Embodiment 8: The compound according to Embodiment 7, wherein a is a fraction or an integer between about 0.5 and 2.0 (including the end values).

[0019] Embodiment 9: The compound according to Embodiment 8, wherein a is a fraction or an integer between about 0.5 and 1.5 (including the end values).

[0020] Embodiment 10: The compound according to Embodiment 9, wherein a is a fraction or an integer between about 0.5 and 1.0 (including the end values).

[0021] Embodiment 11: The compound according to Embodiment 10, wherein a is about 1.0.

[0022] Embodiment 12: The compound according to Embodiment 11, wherein a is 1.0.

[0023] Embodiment 13: The compound according to Embodiment 12, wherein M is acetic acid.

[0024] Embodiment 14: The compound according to Embodiment 13, characterized by the presence of four or more peaks having an interplanar spacing d of about 14.6, 10.6, 9.4, 8.0, 7.4, 6.6, 5.1, 4.3, 4.0, and 3.9 Å.

[0025] Embodiment 15: The compound according to Embodiment 14, characterized by the presence of five or more peaks having an interplanar spacing d of about 14.6, 10.6, 9.4, 8.0, 7.4, 6.6, 5.1, 4.3, 4.0, and 3.9 Å.

[0026] Embodiment 16: The compound according to Embodiment 15, characterized by the presence of six or more peaks having an interplanar spacing d of about 14.6, 10.6, 9.4, 8.0, 7.4, 6.6, 5.1, 4.3, 4.0, and 3.9 Å.

[0027] Embodiment 17: The compound of Embodiment 16, characterized by the presence of seven or more peaks having an interplanar spacing d of about 14.6, 10.6, 9.4, 8.0, 7.4, 6.6, 5.1, 4.3, 4.0, and 3.9 Å.

[0028] Embodiment 18: The compound of Embodiment 17, characterized by the presence of eight or more peaks having an interplanar spacing d of about 14.6, 10.6, 9.4, 8.0, 7.4, 6.6, 5.1, 4.3, 4.0, and 3.9 Å.

[0029] Embodiment 19: The compound of Embodiment 13, characterized by the presence of four or more peaks having 2-theta values using CuKα radiation of about 6.0, 8.3, 9.4, 11.0, 12.0, 13.4, 17.3, 20.9, 22.2, and 22.6 degrees.

[0030] Embodiment 20: The compound of Embodiment 19, characterized by the presence of five or more peaks having 2-theta values using CuKα radiation of about 6.0, 8.3, 9.4, 11.0, 12.0, 13.4, 17.3, 20.9, 22.2, and 22.6 degrees.

[0031] Embodiment 21: The compound of Embodiment 20, characterized by the presence of six or more peaks having 2-theta values using CuKα radiation of about 6.0, 8.3, 9.4, 11.0, 12.0, 13.4, 17.3, 20.9, 22.2, and 22.6 degrees.

[0032] Embodiment 22: The compound of Embodiment 21, characterized by the presence of seven or more peaks having 2-theta values using CuKα radiation of about 6.0, 8.3, 9.4, 11.0, 12.0, 13.4, 17.3, 20.9, 22.2, and 22.6 degrees.

[0033] Embodiment 23: The compound of Embodiment 22, characterized by the presence of eight or more peaks having 2-theta values using CuKα radiation of about 6.0, 8.3, 9.4, 11.0, 12.0, 13.4, 17.3, 20.9, 22.2, and 22.6 degrees.

[0034] Embodiment 24: The compound of Embodiment 12, wherein M is hydrochloric acid.

[0035] Embodiment 25: The compound of Embodiment 24, characterized by the presence of four or more peaks having an interplanar spacing d of about 14.1, 12.9, 10.1, 8.8, 8.5, 6.5, 5.5, 5.1, 4.8, and 4.4 Å.

[0036] Embodiment 26: The compound of Embodiment 25, characterized by the presence of five or more peaks having an interplanar spacing d of about 14.1, 12.9, 10.1, 8.8, 8.5, 6.5, 5.5, 5.1, 4.8, and 4.4 Å.

[0037] Embodiment 27: The compound of Embodiment 26, characterized by the presence of six or more peaks having an interplanar spacing d of about 14.1, 12.9, 10.1, 8.8, 8.5, 6.5, 5.5, 5.1, 4.8, and 4.4 Å.

[0038] Embodiment 28: The compound of Embodiment 27, characterized by the presence of seven or more peaks having an interplanar spacing d of about 14.1, 12.9, 10.1, 8.8, 8.5, 6.5, 5.5, 5.1, 4.8, and 4.4 Å.

[0039] Embodiment 29: The compound of Embodiment 28, characterized by the presence of eight or more peaks having an interplanar spacing d of about 14.1, 12.9, 10.1, 8.8, 8.5, 6.5, 5.5, 5.1, 4.8, and 4.4 Å.

[0040] Embodiment 30: The compound of Embodiment 24, characterized by the presence of four or more peaks having 2-theta values using CuKα radiation of about 6.3, 6.9, 8.7, 10.0, 10.5, 13.7, 16.0, 17.5, 18.6, and 20.2 degrees.

[0041] Embodiment 31: The compound of Embodiment 30, characterized by the presence of five or more peaks having 2-theta values using CuKα radiation of about 6.3, 6.9, 8.7, 10.0, 10.5, 13.7, 16.0, 17.5, 18.6, and 20.2 degrees.

[0042] Embodiment 32: A compound of Embodiment 31, characterized by the presence of six or more peaks having 2-theta values using CuKα radiation of about 6.3, 6.9, 8.7, 10.0, 10.5, 13.7, 16.0, 17.5, 18.6, and 20.2 degrees.

[0043] Embodiment 33: A compound of Embodiment 32, characterized by the presence of seven or more peaks having 2-theta values using CuKα radiation of about 6.3, 6.9, 8.7, 10.0, 10.5, 13.7, 16.0, 17.5, 18.6, and 20.2 degrees.

[0044] Embodiment 34: A compound of Embodiment 33, characterized by the presence of eight or more peaks having 2-theta values using CuKα radiation of about 6.3, 6.9, 8.7, 10.0, 10.5, 13.7, 16.0, 17.5, 18.6, and 20.2 degrees.

[0045] Embodiment 35: A compound of any one of Embodiments 24 to 34, characterized by a mass loss of about 5.3% or less when heated to 100°C.

[0046] Embodiment 36: A compound of any one of Embodiments 24 to 34, characterized by a water content with a water equivalence of about 3.3 or less when measured by Karl Fischer titration.

[0047] Embodiment 37: A compound of any one of Embodiments 24 to 34, characterized by a kinetic solubility of about 27 mg / mL or more in 2 hours in simulated gastric fluid (SGF).

[0048] Embodiment 38: A compound of any one of Embodiments 24 to 34, characterized by a thermodynamic solubility of about 27 mg / mL or more in 24 hours in phosphate buffered saline (PBS).

[0049] Embodiment 39: The compound of Embodiment 24, characterized by the presence of four or more peaks having an interplanar spacing d of about 16.5, 14.5, 10.5, 9.1, 8.3, 7.8, 7.6, 5.2, 4.7, and 4.1 Å.

[0050] Embodiment 40: The compound of Embodiment 39, characterized by the presence of five or more peaks having an interplanar spacing d of about 16.5, 14.5, 10.5, 9.1, 8.3, 7.8, 7.6, 5.2, 4.7, and 4.1 Å.

[0051] Embodiment 41: The compound of Embodiment 40, characterized by the presence of six or more peaks having an interplanar spacing d of about 16.5, 14.5, 10.5, 9.1, 8.3, 7.8, 7.6, 5.2, 4.7, and 4.1 Å.

[0052] Embodiment 42: The compound of Embodiment 41, characterized by the presence of seven or more peaks having an interplanar spacing d of about 16.5, 14.5, 10.5, 9.1, 8.3, 7.8, 7.6, 5.2, 4.7, and 4.1 Å.

[0053] Embodiment 43: The compound of Embodiment 42, characterized by the presence of eight or more peaks having an interplanar spacing d of about 16.5, 14.5, 10.5, 9.1, 8.3, 7.8, 7.6, 5.2, 4.7, and 4.1 Å.

[0054] Embodiment 44: The compound of Embodiment 24, characterized by the presence of four or more peaks having a 2-theta value of about 5.3, 6.1, 8.4, 9.8, 10.7, 11.4, 11.6, 17.0, 18.8, and 21.4 degrees using CuKα radiation.

[0055] Embodiment 45: The compound of Embodiment 44, characterized by the presence of five or more peaks having a 2-theta value of about 5.3, 6.1, 8.4, 9.8, 10.7, 11.4, 11.6, 17.0, 18.8, and 21.4 degrees using CuKα radiation.

[0056] Embodiment 46: The compound of Embodiment 45, characterized by the presence of six or more peaks having 2-theta values using CuKα radiation of about 5.3, 6.1, 8.4, 9.8, 10.7, 11.4, 11.6, 17.0, 18.8, and 21.4 degrees.

[0057] Embodiment 47: The compound of Embodiment 46, characterized by the presence of seven or more peaks having 2-theta values using CuKα radiation of about 5.3, 6.1, 8.4, 9.8, 10.7, 11.4, 11.6, 17.0, 18.8, and 21.4 degrees.

[0058] Embodiment 48: The compound of Embodiment 47, characterized by the presence of eight or more peaks having 2-theta values using CuKα radiation of about 5.3, 6.1, 8.4, 9.8, 10.7, 11.4, 11.6, 17.0, 18.8, and 21.4 degrees.

[0059] Embodiment 49: The compound of any one of Embodiments 24 to 48, characterized by a mass loss of about 5.1% or less when heated to 100 °C.

[0060] Embodiment 50: A compound as described in any of Embodiments 1 to 48 for use as a pharmaceutical.

[0061] Embodiment 51: A compound as described in any of Embodiments 1 to 48 for use in the treatment of a disease.

[0062] Embodiment 52: A compound as described in any of Embodiments 1 to 48 for use in the manufacture of a pharmaceutical for the prevention or treatment of a disease.

[0063] Embodiment 53: A pharmaceutical composition comprising a compound as described in any of Embodiments 1 to 48 together with a pharmaceutically acceptable carrier.

[0064] Embodiment 54: A method for inhibiting microbial protein synthesis, comprising contacting a compound as described in any of Embodiments 1 to 48 with bacteria.

[0065] Embodiment 55: A method as described in Embodiment 54, wherein the microorganism is a bacterium.

[0066] Embodiment 56: A method as described in Embodiment 54, wherein the microorganism is a protozoan.

[0067] Embodiment 57: A method for treating an infectious disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as described in any one of Embodiments 1 to 48.

[0068] Embodiment 58: A therapeutically effective amount of a compound as described in any one of Embodiments 1 to 48; and another therapeutic agent A method for treating an infectious disease, comprising administration thereof.

[0069] Embodiment 59: A method as described in any one of Embodiments 57 and 58, wherein the infectious disease is anthrax.

[0070] Embodiment 60: A method as described in any one of Embodiments 57 and 58, wherein the infectious disease is malaria.

[0071] Embodiment 61: A method as described in any one of Embodiments 57 and 58, wherein the infectious disease is caused by bacteria.

[0072] Embodiment 62: A method as described in any one of Embodiments 57 and 58, wherein the infectious disease is caused by protozoa.

[0073] Embodiment 63: An effect in a patient, where the effect is reducing the microorganism level; increasing the rate of microorganism killing; decreasing the minimum dose required for cure (e.g., a decrease in the microorganism level to an undetectable level); and shortening the period required for cure (e.g., a decrease in the microorganism level to an undetectable level). A method for achieving (selected from), the method comprising administering to a patient a therapeutically effective amount of a compound as described in any of embodiments 1 to 48.

[0074] Embodiment 64: The method as described in Embodiment 63, wherein the microorganism is a bacterium.

[0075] Embodiment 65: The method as described in Embodiment 63, wherein the microorganism is a protozoan.

[0076] Embodiment 66: The bacteria include Bacteroides (e.g., including B. tectum); Corynebacterium; Chlamydia (e.g., including C. pneumoniae and C. trachomatis); Eikenella (e.g., including E. corrodens); Enterobacteriaceae; Fusobacterium (e.g., including F. nucleatum); Haemophilus (e.g., including H. influenzae); Leigonella (e.g., including L. pneumophila); Moraxella (e.g., including M. catarrhalis); Mycobacterium (e.g., including M. avium, M. intracellulare, M. chimaera, M. kansasii, M. malmoense, M. xenopi, M. abscessus, M. fortuitum complex, and M. chelonae); Mycoplasma (e.g., including M. hominis, M. genitalium, and M. pneumoniae); Neisseria (e.g., including N. gonorrhoeae); Pasturella (e.g., including P. septica and P. multocida); Peptostreptococcus (e.g., including P. magnus and P. micros (P.including micros); Prevotella (e.g., including P. melaninogenica and P. heparinolytica); Porphyromonas; Propionibacterium; Staphylococcus (e.g., including S. aureus); Streptococcus (e.g., including S. pneumoniae); Ureaplasma (e.g., including U. urealyticum and U. parvum); and Veillonella, the method as described in any of Embodiments 55, 61, and 64.

[0077] Embodiment 67: The method as described in any one of Embodiments 56, 62, and 65, wherein the protozoan is selected from Cryptosporidium; Coccidia; Plasmodium; Toxoplasma; Babesia; and Neospora.

[0078] Embodiment 68: The method as described in Embodiment 67, wherein the protozoan is Toxoplasma gondii.

[0079] Embodiment 69: The method as described in Embodiment 67, wherein the protozoan is a species of Plasmodium.

[0080] Embodiment 70: A method as described in Embodiment 69, wherein the Plasmodium is selected from Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi.

[0081] Embodiment 71: A method as described in Embodiment 70, wherein the Plasmodium is Plasmodium falciparum.

[0082] Also provided are embodiments, where any of the above embodiments can be combined with one or more of these embodiments, provided that the combinations are not mutually exclusive.

[0083] As used herein, two embodiments are "mutually exclusive" if one is defined as being different from the other. For example, an embodiment where the salt is specified as a chloride salt is mutually exclusive with an embodiment where the salt is specified as an acetate salt.

[0084] In certain embodiments, b is 0 (i.e., non-existent). In certain embodiments, b is about 1.0. In certain embodiments, b is about 2.0.

[0085] The present disclosure also relates to a method of inhibiting protein synthesis in microorganisms such as bacteria and certain protozoa, the method comprising contacting a compound as described herein with the bacteria. Changes in cell phenotype, cell proliferation, protein synthesis activity, biochemical outputs related to protein synthesis, or the binding of the compounds disclosed herein to ribosomes, or the binding of biomolecules to ribosomes, can be monitored. Such methods can be in the form of treating diseases, biological assays, cell assays, biochemical assays, and the like.

[0086] Also provided herein is a method of treating an infectious disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as disclosed herein, or a polymorph thereof.

[0087] Also provided herein is a compound as disclosed herein for use as a medicament.

[0088] Also provided herein is a compound as disclosed herein for use as a medicament for the treatment of an infectious disease.

[0089] Also provided is the use of a compound as disclosed herein as a medicament.

[0090] Also provided is the use of a compound as disclosed herein as a medicament for the treatment of an infectious disease.

[0091] Also provided is a compound as disclosed herein for use in the manufacture of a medicament for the treatment of an infectious disease.

[0092] Also provided is the use of a compound as disclosed herein for the treatment of an infectious disease.

[0093] In certain embodiments, the infectious disease is pneumonia.

[0094] In certain embodiments, the infectious disease is malaria.

[0095] In certain embodiments, the infectious disease is babesiosis.

[0096] In certain embodiments, the infectious disease is toxoplasmosis.

[0097] In certain embodiments, the infectious disease is diarrhea.

[0098] In certain embodiments, the infectious disease is a respiratory disease.

[0099] In certain embodiments, the infectious disease is a sexually transmitted bacterial infection.

[0100] In certain embodiments, the infectious disease is plague.

[0101] In certain embodiments, the infectious disease is tularemia.

[0102] In certain embodiments, the infectious disease is brucellosis.

[0103] In certain embodiments, the infectious disease is anthrax (including, for example, inhalational anthrax).

[0104] Also provided is a method for the treatment of an inflammatory disease. In certain embodiments, the inflammatory disease is a pelvic inflammatory disease.

[0105] Also provided is a method for the treatment of a sexually transmitted infectious disease. In certain embodiments, the sexually transmitted infectious disease is caused by Neisseria gonorrhoeae (N. gonorrhoeae). In certain embodiments, the sexually transmitted infectious disease is caused by Chlamydia trachomatis (C. trachomatis). In certain embodiments, the sexually transmitted infectious disease is caused by Mycoplasma genitalium (M. genitalium). In certain embodiments, the sexually transmitted infectious disease is lymphogranuloma venereum ("LGV").

[0106] Also provided is a method for the treatment of peptic ulcer disease. In certain embodiments, the treatment is provided to patients having no risk factors for macrolide resistance.

[0107] Also provided herein is a method of inhibiting protein synthesis, the method comprising contacting a compound as disclosed herein, or a polymorph thereof, with a bacterium or protozoan.

[0108] Also provided herein is a method for achieving an effect in a patient (where the effect is selected from reducing the microbial level; increasing the rate of microbial killing; reducing the minimum dose required for cure (e.g., reduction of the microbial level to an undetectable level); shortening the period required for cure (e.g., reduction of the microbial level to an undetectable level); and decreasing protein synthesis in bacteria and / or protozoa), the method comprising administering to the patient a therapeutically effective amount of a compound as disclosed herein, or a polymorph thereof).

[0109] Also provided is a pharmaceutical composition comprising a compound as disclosed herein, together with a pharmaceutically acceptable carrier).

[0110] In certain embodiments, the pharmaceutical composition is formulated for oral administration).

[0111] In certain embodiments, the pharmaceutical composition is formulated for parenteral administration).

[0112] In certain embodiments, the oral pharmaceutical composition is selected from tablets and capsules).

[0113] The disclosure of embodiments not showing the claims corresponding to those embodiments is not intended to indicate an abandonment of the embodiments).

[0114] Abbreviations and Definitions As used herein, the following terms have the indicated meanings).

[0115] A range of values is disclosed and, unless otherwise specified, when the notation "from n1 to n2" or "between n1 and n2" (where n1 and n2 are numbers) is used, this notation is intended to include the numbers themselves and the ranges between those numbers. This range can be integral or a continuous portion therebetween and includes the end values. By way of example, since carbon is in integer units, the range "from 2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons. In comparison, by way of example, the range "from 1 to 3 μM (micromolar concentration)" is intended to include 1 μM, 3 μM, and all between (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.) of all significant figures therebetween.

[0116] The term "about", as used herein, is intended to modify a numerical value, and the thing being modified represents a value such as a variable within the range of error. In the absence of a specified range of error, such as a standard deviation relative to an average value shown in a data chart or table, the term "about" is to be understood to mean the range that would encompass the recited value and also the range that would be included by rounding up or down to that number, taking significant figures into account.

[0117] The term "alkyl", alone or in combination, as used herein, refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl will contain from 1 to 10 carbon atoms. In further embodiments, said alkyl will contain from 1 to 8 carbon atoms. The alkyl group can be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl, and the like. The term "alkylene", alone or in combination, as used herein, refers to a saturated aliphatic group derived from a straight-chain or branched-chain saturated hydrocarbon that is attached at two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term "alkyl" can include "alkylene" groups.

[0118] The term "amino", alone or in combination, as used herein, refers to -NRR' (wherein R and R' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may be optionally substituted by itself). Further, R and R' may combine to form a heterocycloalkyl (any of which may be optionally substituted).

[0119] The term "aryl", alone or in combination, as used herein, means a carbocyclic aromatic system containing 1, 2, or 3 rings (wherein such polycyclic rings are fused together). The term "aryl" includes aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.

[0120] The terms "benzo" and "benz", alone or in combination, as used herein, refer to the divalent radical C6H4= derived from benzene. Examples include benzothiophene and benzimidazole.

[0121] As used herein, the term "carbonyl" alone includes formyl [-C(O)H], and in combination is a -C(O)- group.

[0122] As used herein, the term "carboxyl" or "carboxy" refers to -C(O)OH, or the corresponding "carboxylic acid" anion, such as that present in a carboxylate salt. The "O-carboxy" group refers to an RC(O)O- group (wherein R is as defined herein). The "C-carboxy" group refers to a -C(O)OR group (wherein R is as defined herein).

[0123] As used herein, the term "cyano" alone or in combination refers to -CN.

[0124] As used herein, the term "cycloalkyl" or alternatively "carbocycle" alone or in combination refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group (wherein each ring moiety contains from 3 to 12 carbon atoms in the ring members and optionally may be a benzo-fused ring optionally substituted as defined herein). In certain embodiments, the cycloalkyl will contain from 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like. As used herein, "bicyclic" and "tricyclic" are intended to include both fused rings such as decahydronaphthalene, octahydronaphthalene, and polycyclic (polycentric) saturated or partially unsaturated forms. Isomers of the latter type are generally exemplified by bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

[0125] The term "ester", when used alone or in combination herein, refers to a carboxy group that bridges two moieties linked by a carbon atom.

[0126] The term "halo" or "halogen", when used alone or in combination herein, refers to fluorine, chlorine, bromine, or iodine.

[0127] The term "heteroalkyl", when used alone or in combination herein, refers to a stable straight-chain, branched-chain, or combination thereof consisting of a specified number of carbon atoms and from 1 to 3 heteroatoms selected from N, O, and S (wherein the N and S atoms may optionally be oxidized and the N heteroatom may optionally be quaternized), which is completely saturated or contains from 1 to 3 degrees of unsaturation. The heteroatoms can be located at any internal position of the heteroalkyl group. Up to two heteroatoms may be consecutive (e.g., -CH2-NH-OCH3, etc.).

[0128] The term "heteroaryl", as used herein alone or in combination, refers to a 3- to 15-membered unsaturated hetero monocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring, in which at least one of the fused rings is aromatic and contains at least one atom selected from N, O, and S. In certain embodiments, the heteroaryl will contain from 1 to 4 heteroatoms as ring members. In further embodiments, the heteroaryl will contain from 1 to 2 heteroatoms as ring members. In certain embodiments, the heteroaryl will contain from 5 to 7 atoms. The term also encompasses fused polycyclic groups, where the heterocyclic ring is fused to an aryl ring, or a heteroaryl ring is fused to another heteroaryl ring, or a heteroaryl ring is fused to a heterocycloalkyl ring, or a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzindolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0129] The terms "heterocycloalkyl", and interchangeably "heterocycle", as used herein alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic), monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member (wherein each said heteroatom is independently selected from nitrogen, oxygen, and sulfur). In certain embodiments, the heterocycloalkyl will contain from 1 to 4 heteroatoms as ring members. In further embodiments, the heterocycloalkyl will contain from 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl will contain from 3 to 8 ring members in each ring. In further embodiments, the heterocycloalkyl will contain from 3 to 7 ring members in each ring. In still further embodiments, the heterocycloalkyl will contain from 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo-fused rings; further, both terms include systems in which the heterocycle is fused to an aryl group as defined herein or an additional heterocyclic group. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocyclic group can be optionally substituted, unless otherwise specifically prohibited.

[0130] The term "hydroxy", as used herein alone or in combination, refers to -OH.

[0131] The terms "sulfonic acid~", "sulfonic acid", and "of sulfonic acid", when used alone or in combination herein, refer to the -SO3H group and its anion, since the sulfonic acid is used in the form of a salt.

[0132] Any definition herein can be used in combination with any other definition for explaining a composite structural group. By convention, the attached elements of any such definition are those attached to the parent moiety. For example, the composite group alkylamide represents an alkyl group attached to the parent molecule via an amide group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule via an alkyl group.

[0133] When a group is defined as "blank", what it means is that the said group does not exist.

[0134] The term R or the term R' that exists by itself without a numerical designation, unless otherwise defined, refers to a moiety selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether there is a numerical designation for the R group or not, any R group (R, R', and R n (where n = (1, 2, 3,...n)) included), any substituent, and any term should be understood to be independent of all others with respect to the selection from the groups. In case any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) appears more than once in a formula or general structure, its definition in each occurrence is independent of its definition in any other occurrence. One of ordinary skill in the art will further understand that certain groups can be attached to the parent molecule or occupy a position within the chain of elements from either of the written ends. For example, an asymmetric group such as -C(O)N(R)- can be attached to the parent moiety at either carbon or nitrogen.

[0135] The compounds disclosed herein have asymmetric centers. These centers are designated by the symbols "R" or "S" according to the arrangement of substituents around the chiral carbon atoms. It should be understood that the present disclosure encompasses all isomeric forms, including diastereomers, enantiomers, and epimeric forms, as well as d-isomers and l-isomers, and mixtures thereof. The individual stereoisomers of the compounds can be prepared by synthesis from commercially available starting materials containing chiral centers or by separation such as the preparation of a mixture of enantiomeric products followed by conversion to a mixture of diastereomers, followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatography columns, or any other suitable method known in the art. Specific stereochemical starting compounds are either commercially available or can be prepared and separated by techniques known in the art. Further, the compounds disclosed herein can exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and suitable mixtures thereof. Further, the compounds can exist as tautomers; all tautomers are provided by the present disclosure. Further, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. Generally, the solvated forms are considered equivalent to the unsolvated forms.

[0136] The term "bond" refers to a covalent bond between two atoms or, where the atoms linked by the bond are considered part of a larger substructure, between two moieties. The bond can be, unless otherwise specified, a single bond, a double bond, or a triple bond. A dashed line between two atoms in a molecular drawing indicates that additional bonds may or may not be present at that position.

[0137] As used herein, the term "salt" and its plural form "salts" refer to ionic compounds that include ions of a compound (e.g., the drug sesithromycin) and counterions. Salts can be referred to herein, interchangeably, by the acid or base used to form them (e.g., "hydrochloric acid" salt or "hydrochloride" salt), or as "chloride" salts, as is commonly done in the art. Salts (and generally compounds) can exist as one or more different polymorphs.

[0138] As used herein, the term "disease" is intended to generally be synonymous with the terms "disorder", "syndrome", and "condition" (such as medical conditions), all reflecting an abnormal state of the body or a part thereof in a human or animal that impairs normal function, typically manifested by characteristic signs and symptoms, and that reduces the lifespan or quality of life of the human or animal, and is used interchangeably therewith.

[0139] The term "combination therapy" means the administration of two or more therapeutic agents for treating a treatment condition or disorder described in the present disclosure. Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, e.g., in a single capsule having a fixed ratio of active ingredients, or in multiple separate capsules for each active ingredient. Further, such administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide a beneficial effect of the combination of drugs when treating the condition or disorder described herein.

[0140] The expression "therapeutically effective" is intended to modify the amount of an active ingredient used in the treatment of a disease or disorder or in the achievement of a clinical endpoint.

[0141] The term "therapeutically acceptable" refers to compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, and allergic response, and that meet a reasonable benefit / risk ratio and are effective for their intended use.

[0142] As used herein, reference to "treatment" of a patient is intended to include prophylaxis. Treatment can in fact be prophylactic, i.e., treatment can include prevention of a disease. Prevention of a disease can include, for example, complete protection from a disease, as in the case of prevention of an infectious disease by a pathogen, or prevention of progression of a disease. For example, prevention of a disease may not mean complete exclusion of any effect associated with the disease at any level, but rather can mean prevention of symptoms of the disease to a clinically significant or detectable level. Prevention of a disease can also mean prevention of progression of the disease to a later stage of the disease.

[0143] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including, for example, humans. Examples of patients include humans, domestic animals such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0144] The term "prodrug" refers to a compound that is more active in vivo. Certain compounds disclosed herein can also exist as prodrugs as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). The prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical change under physiological conditions to provide this compound. Further, the prodrug can be converted to this compound by chemical or biochemical means in an ex vivo environment. For example, the prodrug can be slowly converted to the compound when placed in the reservoir layer of a transdermal patch together with a suitable enzyme or chemical reagent. Prodrugs are often useful because they can be administered more readily than the parent drug in some situations. The prodrug can be bioavailable, for example, by oral administration, while the parent drug may not be. The prodrug can also have improved solubility in a pharmaceutical composition that masks the parent drug. A wide variety of prodrug derivatives are known in the art, such as those relying on hydrolytic cleavage or oxidative activation of the prodrug. Examples of prodrugs include, but are not limited to, esters (the "prodrug") that are administered but then hydrolyzed by metabolism to a carboxylic acid, i.e., the active entity. Additional examples include peptidyl derivatives of the compound.

[0145] Pharmaceutical composition While it may be possible to administer the disclosed compounds as raw chemical substances, it is also possible to provide them as pharmaceutical formulations. Accordingly, provided herein is a pharmaceutical formulation comprising one or more of the disclosed compounds, or one or more pharmaceutically acceptable salts, polymorphs, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic components. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to its recipient. Suitable formulations depend on the chosen route of administration. Any well-known techniques, carriers, and excipients can be used as appropriate in the art and as understood in the art. The pharmaceutical compositions disclosed herein can be manufactured in any manner known in the art, for example, using conventional mixing, dissolving, granulating, sugar coating, levigating, emulsifying, encapsulating, entrapping, or compression processes.

[0146] Formulations include those suitable for oral, parenteral (e.g., subcutaneous, intradermal, intramuscular, intravenous, intra-articular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (e.g., transdermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient. The formulations can conveniently be provided in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art. Typically, these methods include a step of mixing the disclosed compound, or a pharmaceutically acceptable salt, ester, amide, prodrug, or solvate thereof ("active ingredient") with a carrier that constitutes one or more accessory ingredients. Generally, the formulations are prepared by uniformly and sufficiently mixing the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.

[0147] Administration and Treatment The compound can be administered orally or via injection at a dosage of from 0.1 to 500 mg / kg per day. The dosage range for adult humans is generally from 5 mg to 2 g per day. Tablets or other forms of presentation provided in discrete units may conveniently contain units having such dosages or an amount of one or more compounds effective as the same, for example, containing from 5 mg to 500 mg, usually approximately from 10 mg to 200 mg.

[0148] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration.

[0149] The compound can be administered in a variety of ways, for example, orally, topically, or by injection. The exact amount of the compound to be administered to a patient is the responsibility of the attending physician. The specific dosage level for any particular patient will depend on a variety of factors, including, for example, the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, the specific disorder being treated, and the severity of the symptom or condition being treated. Also, the route of administration will vary depending on the condition and its severity.

[0150] Oral administration The compounds of the present disclosure can be administered orally, for example, including by swallowing, whereby the compound enters the gastrointestinal tract or is absorbed directly from the mouth into the bloodstream, for example, including sublingual or buccal administration.

[0151] Compositions suitable for oral administration include solid formulations, such as tablets, pills, cachets, lozenges, and hard or soft capsules (which can contain a liquid), gels, powders, or granules, solutions or suspensions (in aqueous liquids or non-aqueous liquids, or as water-in-oil liquid emulsions or oil-in-water liquid emulsions). The active ingredient can also be provided as a bolus, a pastille, or a paste.

[0152] In tablet or capsule dosage forms, the amount of drug present can be from about 0.05% to about 95% by weight of the dosage form, more typically from about 2% to about 50% by weight.

[0153] Furthermore, tablets or capsules can contain a disintegrant that occupies from about 0.5% to about 35% by weight of the dosage form, more typically from about 2% to about 25% by weight. Examples of disintegrants include methylcellulose, sodium or calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpyrrolidone, hydroxypropylcellulose, starch, and the like.

[0154] Binders suitable for use in tablets include gelatin, polyethylene glycol, sugars, gums, starch, hydroxypropylcellulose, and the like. Diluents suitable for use in tablets include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, and starch.

[0155] Surfactants and fluidizing agents suitable for use in tablets or capsules can be present in amounts from about 0.1% to about 3% by weight and include polysorbate 80, sodium dodecyl sulfate, talc, and silicon dioxide.

[0156] Lubricants suitable for use in tablets or capsules can be present in amounts from about 0.1% to about 5% by weight and include calcium stearate, zinc, or magnesium stearyl fumarate, and the like.

[0157] Tablets can be manufactured by compression or molding, optionally with one or more auxiliary components. Compressed tablets can be prepared by compressing in a suitable machine an active ingredient in free-flowing form, such as a powder or granules, which is optionally mixed with a binder, an inert diluent, or a lubricant, surfactant, or dispersant. Molded tablets can be produced by molding in a suitable machine a mixture of powdered compounds moistened with a liquid diluent. For purposes of identification, or to characterize different combinations of doses of the active compound, dyes or pigments can be added to the tablets.

[0158] Liquid formulations can include emulsions, solutions, syrups, elixirs, and suspensions, which can be used in soft or hard capsules. Such formulations can contain a pharmaceutically acceptable carrier, such as water, ethanol, polyethylene glycol, cellulose, or oil. The formulations can also contain one or more emulsifying and / or suspending agents.

[0159] Compositions for oral administration can be formulated as immediate release or modified release formulations, optionally with enteric coating, including, for example, delayed or sustained release.

[0160] In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0161] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and soft shield capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Tablets can be manufactured by compression or molding, optionally with one or more auxiliary components. Compressed tablets can be prepared by compressing an active ingredient in a free-flowing form, such as a powder or granule, which is optionally mixed with a binder, an inert diluent, or a lubricant, surfactant, or dispersant, in a suitable machine. Wet tablets can be produced by molding a mixture of powdered compounds moistened with a liquid diluent in a suitable machine. Tablets can optionally be coated or scored and formulated to provide sustained or controlled release of the active ingredient in the tablet. All formulations for oral administration should be in a dosage suitable for such administration. Push-fit capsules can contain an active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, a stabilizer can be added. Sugar-coated tablet cores are provided with a suitable coating. For this purpose, a concentrated sugar solution can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. For identification or to characterize different combinations of doses of the active compound, dyes or pigments can be added to the tablets or sugar-coated tablet coatings.

[0162] Parenteral administration The compounds of the present disclosure can be administered directly into the bloodstream, muscle, or visceral organs by injection, for example, by bolus injection or continuous infusion. Suitable means for parenteral administration include intravenous, intramuscular, subcutaneous, intra-arterial, intraperitoneal, intrathecal, intracranial, etc. Suitable devices for parenteral administration include syringes (including, for example, needles and needleless syringes) and infusion methods. The formulations can be provided in unit dose or multiple dose containers, for example, sealed ampoules and vials.

[0163] Most parenteral formulations are aqueous solutions containing excipients (such as salts, buffers, suspending, stabilizing, and / or dispersing agents, antioxidants, bacteriostatic agents, preservatives, and solutes that provide formulations isotonic with the blood of the intended recipient, and carbohydrates).

[0164] Parenteral formulations can also be prepared in dehydrated form (for example, by lyophilization) or as sterile non-aqueous solutions. These formulations can be used with suitable vehicles such as sterile water. Solubility enhancers can also be used in the preparation of parenteral solutions. Compositions for parenteral administration can be formulated as immediate release or modified release formulations, including, for example, delayed or sustained release. The compounds can also be formulated as depot formulations. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymers or hydrophobic materials (such as emulsions in acceptable oils) or ion exchange resins or as slightly insoluble derivatives, for example, as slightly insoluble salts.

[0165] The compounds can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection can be provided in unit dosage forms, for example, in ampoules or in multi-dose containers, with the addition of preservatives. The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can also contain formulating agents such as suspending, stabilizing, and / or dispersing agents. The formulations can be provided in unit dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a powder form or in a freeze-dried state that requires only the addition of a sterile liquid carrier, for example, physiological saline or sterile pyrogen-free water, immediately before use. Injectable solutions and suspensions prepared immediately before use can be prepared from sterile powders, granules, and tablets of the types described above.

[0166] Formulations for parenteral administration can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, aqueous and non-aqueous (oily) sterile injectable solutions of the active compounds; and aqueous and non-aqueous sterile suspensions that can contain suspending and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, or triglycerides, or liposomes. Aqueous injectable suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers, or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0167] In addition to the formulations described above, the compounds can also be formulated as depot formulations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a slightly soluble derivative, e.g., as a slightly soluble salt.

[0168] Topical administration The compounds of the present disclosure can be administered topically (e.g., to the skin, mucosa, ear, nose, or eye) or transdermally. Formulations for topical administration can include, but are not limited to, lotions, solutions, creams, gels, hydrogels, ointments, foams, implantable tablets, patches, etc. Pharmaceutically acceptable carriers for topical administration formulations can include water, alcohol, mineral oil, glycerin, polyethylene glycol, etc. Topical administration can also be carried out, for example, by electroporation, iontophoresis, sonophoresis, etc.

[0169] Typically, the active ingredient for topical administration can constitute from 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient can constitute up to 10% w / w; less than 5% w / w; from 2% w / w to 5% w / w; or from 0.1% to 1% w / w of the formulation.

[0170] Compositions for topical administration can be formulated as immediate release or controlled release formulations, including, for example, delayed or sustained release.

[0171] Certain compounds disclosed herein can be administered topically, i.e., by non-systemic administration. This includes the application of the compounds disclosed herein to the epidermis or the outer side of the buccal cavity such that the compound does not enter the bloodstream very much, as well as the dropping of such compounds into the ear, eye, and nose. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0172] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the inflamed site, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eyes, ears, and nose. The active ingredient for topical administration can, for example, constitute from 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient can constitute up to 10% w / w. In other embodiments, the active ingredient can constitute less than 5% w / w. In certain embodiments, the active ingredient can constitute from 2% w / w to 5% w / w. In other embodiments, the active ingredient can constitute from 0.1% to 1% w / w of the formulation.

[0173] Rectal, buccal, and sublingual administration Suppositories for rectal administration of the compounds of the present disclosure can be prepared by mixing the active agent with a suitable non-irritating excipient such as cocoa butter, synthetic mono-, di-, or triglycerides, fatty acids, or polyethylene glycol (which are solid at room temperature but liquid at rectal temperature and thus will dissolve in the rectum to release the drug).

[0174] For buccal or sublingual administration, the composition can take the form of tablets, lozenges, troches, or gels formulated in a conventional manner. Such compositions can contain the active ingredient in a flavored base such as sucrose and gum arabic or tragacanth.

[0175] The compound can also be formulated into rectal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0176] Administration by inhalation For administration by inhalation, the compounds can conveniently be delivered from an inhaler, nebulizer pressurized pack, or other convenient means for delivering an aerosol spray. The pressurized pack can contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, a dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the present disclosure can be in the form of a dry powder composition, for example, a powder mixture of the compound with a suitable powder base such as lactose or starch. The powder composition can be provided in unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs from which the powder can be administered with the aid of an inhaler or insufflator.

[0177] Other carrier materials and modes of administration known in the pharmaceutical art can also be used. The pharmaceutical compositions of the present disclosure can be prepared by any of the well-known techniques of pharmacy, such as effective formulations and administration procedures. Preferred unit dosage formulations contain an active ingredient in an effective dosage or an appropriate fraction thereof as set forth hereinafter in this specification.

[0178] In addition to the ingredients detailed above, the formulations described above can contain other agents conventional in the art, taking into account the type of formulation in question. For example, those suitable for oral administration can contain flavoring agents, it should be understood.

[0179] Combinations and combination therapies In certain cases, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt thereof) in combination with another therapeutic agent. By way of illustration only, if one of the side effects a patient experiences when receiving one of the compounds herein is hypertension, it may be appropriate to administer an antihypertensive agent in combination with the first therapeutic agent. Or, by way of illustration only, the therapeutic effectiveness of one of the compounds described herein can be enhanced by the administration of an adjuvant (i.e., the adjuvant alone may only have minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of illustration only, the benefit a patient receives can be increased by administering one of the compounds described herein together with another therapeutic agent (which also includes a treatment regimen) that has a similar therapeutic benefit. By way of illustration only, in the treatment of diabetes involving the administration of one of the compounds described herein, an increase in therapeutic benefit can also be obtained by providing the patient with another therapeutic agent for diabetes. In any case, regardless of the disease, disorder, or condition being treated, the overall benefit the patient receives may simply be additive of the two therapeutic agents or the patient may receive a synergistic benefit.

[0180] Specific non-limiting examples of possible combination therapies include the use of donepezil, rivastigmine, galantamine, and memantine with certain compounds of the present disclosure. Further examples include anti-amyloid antibodies and vaccines, anti-Ab antibodies and vaccines, anti-tau antibodies and vaccines, β-secretase inhibitors, 5-HT4 agonists, 5-HT6 antagonists, 5-HT1a antagonists, α7 nicotinic receptor agonists, 5-HT3 receptor antagonists, PDE4 inhibitors, O-GlcNAcase inhibitors, and other pharmaceuticals approved for the treatment of Alzheimer's disease. Further examples include metformin, minocycline, tissue plasminogen activator, and other therapies that improve neuronal survival.

[0181] Further examples include the use of rifamycin and certain compounds of the present disclosure. In certain embodiments, the combination therapy is effective against macrolide-sensitive non-tuberculous mycobacteria including, for example, M. avium, M. intracellulare, M. chimaera, M. kansasii, M. malmoense, M. xenopi, M. abscessus, M. fortuitum complex, and M. chelonae.

[0182] Further examples include the use of ethambutol and certain compounds of the present disclosure. In certain embodiments, the combination therapy is effective against macrolide-sensitive non-tuberculous mycobacteria including, for example, M. avium, M. intracellulare, M. chimaera, M. kansasii, M. malmoense, M. xenopi, M. abscessus, M. fortuitum complex, and M. chelonae.

[0183] Further examples include the use of fluoroquinolone and certain compounds of the present disclosure. In certain embodiments, the combination therapy is effective against plague, anthrax, tularemia, and brucellosis.

[0184] Further examples include the use of aminoglycoside and certain compounds of the present disclosure. In certain embodiments, the combination therapy is effective against plague, anthrax, tularemia, and brucellosis.

[0185] Further examples include the use of doxycycline and certain compounds of the present disclosure. In certain embodiments, the combination therapy is effective against plague, anthrax, tularemia, and brucellosis.

[0186] Further examples include the use of an influenza antiviral drug, such as oseltamivir, in combination with certain compounds of the present disclosure. In certain embodiments, the combination therapy is effective against inflammation.

[0187] Further examples include the use of certain compounds of the present disclosure in combination for the treatment of diseases caused by M. abscessus, including, for example, macrolide-sensitive M. abscessus. Certain compounds that may be useful in combination with the compounds of the present disclosure include one or more of the following: aminoglycoside, beta-lactam, doxycycline, fluoroquinolone, and trimethoprim-sulfamethoxazole.

[0188] Further examples include the use of certain compounds of the present disclosure in combination for the treatment of diseases caused by Babesia. In certain embodiments, the disease is babesiosis. Certain compounds that may be useful in combination with the compounds of the present disclosure include one or more of the following: atovaquone, atovaquone-proguanil, tafenoquine, quinine, and pyrimethamine.

[0189] Further examples include the use of certain compounds of the present disclosure in combination for the treatment of diseases caused by Toxoplasma. In certain embodiments, the disease is toxoplasmosis. Certain compounds that may be useful in combination with the compounds of the present disclosure include one or more of the following: atovaquone, pyrimethamine, and trimethoprim-sulfamethoxazole.

[0190] Further examples include the use of certain compounds of the present disclosure in combination for the treatment of diseases caused by Plasmodium. Certain compounds that may be useful in combination with the compounds of the present disclosure include the following: quinoline compounds (e.g., 8 - aminoquinoline, 4 - aminoquinoline, 4 - quinoline alcohol, primaquine, tafenoquine, chloroquine, mefloquine, pyronaridine, lumefantrine, amodiaquine, quinine, and quinidine); atovaquone; pyrimethamine; and one or more of artemisinin.

[0191] Further examples include the use of certain compounds of the present disclosure in combination for the treatment of respiratory diseases. Certain compounds that may be useful in combination with the compounds of the present disclosure include the following: one or more of beta - lactam, carbapenem, and fluoroquinoline.

[0192] Further examples include the use of certain compounds of the present disclosure in combination for the treatment of peptic ulcer disease. In certain embodiments, the treatment is provided to patients without risk factors for macrolide resistance. Certain compounds that may be useful in combination with the compounds of the present disclosure include the following: proton pump inhibitors (e.g., omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, and rabeprazole); amoxicillin; and one or more of metronidazole.

[0193] Further examples include the use of certain compounds of the present disclosure in combination for the treatment of sexually transmitted infections. In certain embodiments, the sexually transmitted infection is caused by N. gonorrhoeae. In certain embodiments, the sexually transmitted infection is caused by C. trachomatis. In certain embodiments, the sexually transmitted infection is caused by M. genitalium. In certain embodiments, the sexually transmitted infection is lymphogranuloma venereum (“LGV”). Certain compounds that may be useful in combination with the compounds of the present disclosure include one or more of the following: beta-lactam (e.g., ceftriaxone); doxycycline; and fluoroquinolone.

[0194] Further examples include the use of certain compounds of the present disclosure in combination for the treatment of inflammatory diseases. In certain embodiments, the inflammatory disease is pelvic inflammatory disease. Certain compounds that may be useful in combination with the compounds of the present disclosure include metronidazole and metronidazole benzoate.

[0195] Further examples include the use of certain compounds of the present disclosure in combination for the treatment of typhoid fever. Certain compounds that may be useful in combination with the compounds of the present disclosure include ceftriaxone and beta-lactam.

[0196] In any case, a plurality of therapeutic agents, at least one of which is a compound disclosed herein, can be administered in any order or simultaneously. If simultaneously, the plurality of therapeutic agents can be provided in a single integrated form or in multiple forms (by way of example only, as a single pill or as two separate pills). One of the therapeutic agents can be administered by repeated dosing, or both can be administered as repeated dosing. If not simultaneously, the timing between repeated dosing can be any period from a few minutes to 4 weeks.

[0197] Accordingly, in another aspect, certain embodiments provide a method for treating an infectious disorder in a human or animal subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, in combination with at least one additional agent for treating the disorder known in the art, to reduce or prevent the disorder in the subject. In related aspects, certain embodiments provide a therapeutic composition comprising at least one compound disclosed herein, in combination with one or more additional agents for treating an infectious disorder.

[0198] In certain embodiments, the compounds, compositions, and methods disclosed herein can be co-administered with another therapeutic agent.

[0199] In addition to being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals, and livestock animals (including, for example, mammals, rodents, etc.). More preferred animals include horses, dogs, and cats.

[0200] List of Abbreviations 11H NMR = Proton nuclear magnetic resonance; ACN = MeCN = Acetonitrile; Ac2O = Acetic anhydride; AcCl = Acetyl chloride; AcOH = Acetic acid; API = Active pharmaceutical ingredient; ASR = Analytical service report; AUC = Area under the curve; ca. = Approximately; CD3OD = Methanol-d4; CDCl3 = Chloroform-d; cHex = Cyclohexane; DCM = Dichloromethane; DCM = Dichloromethane; DIEA = DIPEA; DMAP = 4-Dimethylamino-pyridine; DMF = N,N-Dimethylformamide; DMSO = Dimethyl sulfoxide; DMSO = Dimethyl sulfoxide; DMSO-d6 = Dimethyl sulfoxide-d6; DSC = Differential scanning calorimetry; DVS = Dynamic vapor sorption; eq = Equivalent; Et2O = Diethyl ether; EtOAc = Ethyl acetate; EtOAc = Ethyl acetate; EtOH = Ethanol; EtOH = Ethanol; GVS = Gravimetric vapor sorption; h = Hour; H2O = Water; Hept = n-Heptane; HPLC = High performance liquid chromatography; HR = High resolution; IC = Ion chromatography; ID = Identity; IP = Intellectual property; IPA = 2-Propanol; iPrOH = Isopropanol; iPrOAc = Isopropyl acetate; ISA = Ion strength adjustment; KF = Karl Fischer; MDSC = Temperature-modulated differential scanning calorimetry; MeCN = Acetonitrile; MEK = Methyl ethyl ketone; MeOH = Methanol; MeOH = Methanol; MIBK = Methyl isobutyl ketone; min = Minute; MTBE = Methyl tert-butyl ether; N / A = Not applicable; NMR = Nuclear magnetic resonance; No. = Number; PLM = Polarizing microscope; PBS = Phosphate buffered saline; PXRD = PXRD = Powder X-ray diffraction; Pyr = Pyridine; RH = Relative humidity; RT = Room temperature; RT = Room temperature; sat. = Saturated; SEM = Scanning electron microscope; SGF = Simulated gastric fluid; ss = Saturated solution; TBME = tert-Butyl methyl ether; t-BuOH = tert-Butanol; TEA = Et3N; TFA = Trifluoroacetic acid; TFAA = Trifluoroacetic anhydride; TGA = Thermogravimetric analysis; THF = Tetrahydrofuran; Tol = Toluene; USP = United States Pharmacopeia; UV = Ultraviolet; vol = Volume; VT-PXRD = Variable temperature powder X-ray diffraction.

Example

[0201] Example 1: Cethromycin. [Chemical formula] Cethromycin has the chemical name (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-10-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-3a,7,9,11,13,15-hexamethyl-11-(((E)-3-(quinolin-3-yl)allyl)oxy)octahydro-2H-[1]-oxa-cyclotetradecino[4,3-d]oxazole-2,6,8,14(1H,7H,9H)-tetraone, formula C 42 H 59 N3O 10 and has a molar mass of 765.95 g / mol and is available as a commercial product. PXRD (not shown) did not show evidence of crystallinity. 1H NMR in DMSO-d6 solution for the as-supplied compound is shown in Figure 1. 1 1H NMR is shown in Figure 1.

[0202] Figure 2 shows the HPLC and thermal analysis of cethromycin: (a) full scale and (b) enlarged HPLC. From the HPLC analysis, the as-supplied cethromycin was >98% pure. (c) Thermal analysis: left axis and (i): weight during heating (% of original weight); right axis and (ii) heat flow (right scale, W / g). The weight loss from 25 °C to about 125 °C corresponds to a loss of about 4.5% of the original weight.

[0203] Figure 3 shows the temperature-modulated DSC of cethromycin: (a) (i) heating from RT to 120 °C; (ii) cooling to -80 °C; (iii) temperature-modulated heating to 260 °C; horizontal axis = temperature (°C); vertical axis = heat flow (W / g).

[0204] Figure 4 shows the GVS behavior of sesloxacillin in (a) the isothermal and (b) the kinetic modes. (a): Horizontal axis = target RH (%); vertical axis = change in mass (%); (i) cycle 1 adsorption; (ii) cycle 1 desorption; (iii) cycle 2 adsorption; (iv) cycle 2 desorption; (v) cycle 3 adsorption. (b) Horizontal axis = time (min); left axis and (i) = change in mass (%); right axis and (ii) = target RH (%). Powder XRD of the sesloxacillin sample before and after the DSC experiment showed no signs of crystallinity (not shown).

[0205] Example 2: Method. Powder X-ray diffraction (「PXRD」) A Bruker AXS C2 GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for automatic sample positioning, and a Vantec-500 two-dimensional area detector was used to collect a constant XRPD diffractogram. The X-ray optics consisted of a single Goebel multilayer mirror integrated with a 0.3 mm pinhole collimator.

[0206] The beam divergence angle, i.e., the effective size of the X-ray beam with respect to the sample, was approximately 4 mm. A θ-θ continuous scan mode was used with a sample-detector distance of 20 cm giving an effective 2θ range of 1.5° to 32.5°. Typically, the sample was exposed to the X-ray beam for 120 seconds. The software used for data collection and analysis was GADDS (for Win7 / XP) and Diffrac Plus EVA, respectively.

[0207] For the variable temperature (VT-XRPD) experiment, the sample was mounted on an Anton Paar DHS 900 heating stage at ambient conditions. The sample was then heated at 20 °C / min to the appropriate temperature and subsequently held at a constant temperature for 1 minute until data collection. The sample was prepared and analyzed on a silicon wafer mounted on the heating stage using a thermal conduction paste.

[0208] The XRPD diffractogram was collected on a Bruker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA) and a θ-2θ goniometer equipped with a Ge monochromator. The incident beam passed through a 2.0 mm divergence slit, followed by a 0.2 mm anti-scatter slit, and a knife edge. The diffracted beam passed through an 8.0 mm receiving slit equipped with a 2.5° Soller slit, followed by a Lynxeye detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA, respectively.

[0209] The sample was run as a flat sample under ambient conditions using the as-received powder. This sample was prepared on a polished zero-background (510) silicon wafer by gently pressing it onto the plane or packing it into a recess cut or ground. This sample was rotated on its plane.

[0210] Constant XRPD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu Kα radiation (45 kV, 40 mA) in transmission geometry. For the incident beam, a 0.5° slit, a 4 mm mask, and a 0.04 rad Soller slit were used together with a focusing mirror. The PIXcel3D detector placed on the diffracted beam was equipped with a receiving slit and a 0.04 rad Soller slit. The software used for data collection was X’Pert Data Collector using the X’Pert Operator Interface. The data was analyzed and presented using Diffrac Plus EVA or HighScore Plus.

[0211] Samples were prepared and analyzed in transmission mode using either a metal or a Millipore 96-well plate. An X-ray transmission film was used between the metal sheets on the metal well plate, and the powder (approximately 1 - 2 mg) was used as received. The Millipore plate was used to isolate and analyze the solids from the suspension by directly adding a small amount of the suspension to the plate and then filtering under a slight vacuum. The scan mode for the metal plate used a goniometer scan axis, while for the Millipore plate, a 2θ scan was utilized.

[0212] 1 H NMR 1 1H NMR spectra were collected on a Bruker 400 MHz instrument controlled by a DRX400 console equipped with an autosampler. Samples were prepared in DMSO-d6 solvent unless otherwise stated. Automated experiments were acquired using ICON-NMR settings within Topspin software using standard Bruker-supplied experiments. Offline analysis was performed using ACD Spectrus Processor.

[0213] Differential scanning calorimetry (「DSC」) Certain DSC data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler. Typically, 0.5 - 3 mg of each sample in a pinholed aluminum pan was heated from 25 °C to 250 °C at 10 °C / min. A purge of dry nitrogen at 50 ml / min was maintained over the sample.

[0214] Temperature-modulated DSC was performed using a base heating rate of 2 °C / min and a temperature modulation parameter of ±0.636 °C (amplitude) every 60 seconds (period). The instrument control software was Advantage for Q Series and Thermal Advantage, and the data were analyzed using Universal Analysis or TRIOS.

[0215] Certain DSC data were collected on a TA Instruments Discovery DSC equipped with a 50-position autosampler. Typically, each sample of 0.5 - 3 mg in a pinholed aluminum pan was heated from 25 °C to 300 °C at 10 °C / min. A purge of dry nitrogen was maintained at 50 ml / min for this sample. The instrument control software was TRIOS, and the data were analyzed using TRIOS or Universal Analysis.

[0216] Thermogravimetric analysis ("TGA") TGA data were collected on a TA Instruments Discovery TGA equipped with a 25-position autosampler. Typically, each sample of 5 - 10 mg was loaded into a pre-weighed aluminum DSC pan and heated from ambient temperature to 350 °C at 10 °C / min. A purge of nitrogen was maintained at 25 ml / min for this sample. The instrument control software was TRIOS, and the data were analyzed using TRIOS or Universal Analysis.

[0217] Gravimetric vapor sorption ("GVS") Adsorption isotherms were obtained using an SMS DVS Intrinsic water vapor sorption measurement device controlled by DVS Intrinsic Control software. The sample temperature was maintained at 25 °C by instrument control. Humidity was controlled by mixing streams of dry and humid nitrogen at a total flow rate of 200 ml / min. Relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0 - 100% RH) located near the sample. The weight change (mass relaxation) of the sample as a function of RH (%) was continuously monitored by a microbalance (accuracy ±0.005 mg).

[0218] Typically, a 5 - 30 mg sample was placed in a tared mesh stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40% RH and 25 °C (typical indoor conditions). The moisture sorption isotherm was performed as outlined below (two scans per full cycle). A standard isotherm was performed in the range of 0 - 90% RH, at 10% RH intervals at 25 °C. Typically, a double cycle (four scans) was performed. Data analysis was performed within Microsoft Excel using the DVS Analysis Suite.

[0219] Karl Fischer (KF) titration The moisture content of each sample was measured using Hydranal Coulomat AG oven reagent and nitrogen purge in a 150 °C Metrohm 874 Oven Sample Processor equipped with an 851 Titrano Coulometer. The weighed solid sample was introduced into a sealed sample vial. A sample of approximately 10 mg per titration was used and duplicate measurements were made. Unless otherwise stated, the average of these results is shown. Data collection and analysis were performed using Tiamo software.

[0220] Ion chromatography (IC) Data were collected using IC MagicNet software on a Metrohm 930 Compact IC Flex equipped with an 858 Professional autosampler and an 800 Dosino dosing unit monitor. The accurately weighed sample was prepared as a stock solution in a suitable solvent. Quantification was achieved by comparison with a standard solution of known concentration of the ion being analyzed. The analysis was performed in duplicate and, unless otherwise stated, the average of the values is given. The analytical methods for cations and anions are provided in Tables 1 and 2, respectively.

[0221]

Table 1

[0222]

Table 2

[0223] High Performance Liquid Chromatography (“HPLC”) Purity analysis was performed using an Agilent HP1100 / Infinity II 1260 series system equipped with a diode array detector and OpenLAB software. Details of the complete method are provided in Table 3.

[0224]

Table 3

[0225] Example 3: Preliminary solubility investigation. For the study of salt formation, the following acid solutions were used. When indicated, the acid was added directly as a solid to the reaction mixture.

[0226] Amorphous cethromycin (25 mg) in an HPLC vial was processed with increasing volumes of solvent until the material was completely dissolved or until a maximum of 60 volumes (1.5 ml) had been added. After each addition of solvent, the vial was stirred, gently heated to 50 °C, and then a new aliquot of solvent was added. After evaluation was complete, approximately 1 equivalent of HCl was added at 50 °C and the sample was slowly cooled to 5 °C at 0.1 °C / min. All solids were then isolated by filtration and dried under suction. Poor solvents (n-heptane, 10 or 20 volumes) were added to any solutions and the resulting gums were aged in a chamber that switched from 25 °C to 50 °C every 4 hours. All isolated solids were analyzed by PXRD.

[0227] Sethromycin readily dissolved in 10 volumes of THF:H2O (9:1), 2-propanol, EtOH, EtOAc, acetone, MeCN, THF, TBME, and DCM, with n-heptane, which is considered a poor solvent. After preliminary salt formation experiments, no crystalline solids were obtained. Based on the solubility results, not only methanol, but also EtOAc and acetone were selected as solvents for the salt formation experiments.

[0228]

Table 4

[0229] Example 4: Preliminary investigation of salt formation. To confirm whether sethromycin salts can be prepared and whether any of these salts exhibit favorable properties over the free base, sethromycin was treated with 18 different acids covering a variety of pKa values.

[0230]

Table 5

[0231] Amorphous cethromycin (25 mg) was dissolved in one of three solvents (MeOH, acetone, and EtOAc) at 50 °C in a volume of 10 (250 μl). This solution was then treated with 18 different selected counterions (Table 5) for a total of 54 samples. The resulting solution / suspension / gum was then cooled at 0.1 °C / min to 5 °C and held at 5 °C for 4 hours. Stirring was maintained from start to finish. Any residual solvent was evaporated under ambient conditions by removing the vial caps. To any resulting gum / oil, a poor solvent (heptane, 10 volumes) was added and then this was aged in a chamber that cycled from 25 °C to 50 °C every 4 hours. Any resulting paste was dried by spreading it on a glass slide. Any resulting solid was filtered / isolated and initially analyzed by PXRD. All solids showing a new PXRD diffractogram were isolated and further characterized. Any solid that was amorphous or matched the starting material was aged at 25 - 50 °C for 14 days. The solid was then isolated and analyzed by PXRD.

[0232] The results of the salt formation experiments for cethromycin are summarized in Tables 6, 7, and 8 (the legends are described later). Three different salt forms for cethromycin were observed using phosphoric acid, acetic acid, and hydrochloric acid and were named Phosphate Pattern 1, Acetate Pattern 1, and Chloride Pattern 1, respectively.

[0233] [Table 6]

[0234] [Table 7]

[0235] [Table 8]

[0236] [Table 9]

[0237] Salt formation experiments on celithromycin were carried out using 18 counterions in three different solvent systems (MeOH, acetone, and EtOAc). From these experiments, four new patterns: phosphate pattern 1, acetate pattern 1, free base pattern 1, and chloride pattern 1 were identified.

[0238] Figure 5 shows the PXRD for the products from the salt formation experiments in acetone: (a) (i) Celithromycin phosphate pattern 1 and (ii) SO4, and (iii) free base celithromycin; (b) (i) MSA, (ii) pTSA, (iii) BSA, (iv) OXA, (v) TAR, (vi) AcOH pattern 1 (after 14 days of maturation in n - heptane).

[0239] Figure 6 shows the PXRD for the products from the salt formation experiments in EtOAc. (a) Acetate pattern 1 (i) Chloride pattern 1, (ii) MSA, (iii) pTSA; PHOA: (iv) experiment, (v) reference; Acetate pattern 1: (vi) experiment, (vii) reference. (b) (i) SO4, (ii) BSA, (iii) OXA, (iv) MEA, (v) DHBA, (vi) TAR, (vii) FUA, (viii) CA, and (ix) MA.

[0240] Phosphate pattern 1 is an insufficiently crystalline form isolated from acetone and EtOAc, which is potentially characterized as a solvated hemiphosphate. For phosphate pattern 1 1 1H NMR (not shown) is substantially the same as that for free base celithromycin.

[0241] Acetate pattern 1 is a crystalline solid isolated from salt formation experiments in both acetone and EtOAc after aging the gum initially obtained in heptane. This is potentially a monoacetate which is a monohydrate. For acetate pattern 1 11H NMR (not shown) contains a peak at δ 1.9 for acetic acid and is otherwise substantially the same as that for free base sethromycin.

[0242] Chloride Pattern 1 is a crystalline solid isolated from an EtOAc salt formation experiment via cooling to 5°C. For Chloride Pattern 1 1 1H NMR (not shown) is substantially the same as that for free base sethromycin. This sample contains only trace amounts of EtOAc by NMR and has a significant mass loss indicating hydration of this form from ambient temperature to 100°C.

[0243] Phosphate Pattern 1, Acetate Pattern 1, and Chloride Pattern 1 were advanced further for scale-up.

[0244] Figure 7 shows the PXRD and TGA characteristics of Phosphate Pattern 1 from the salt formation experiment. (a) PXRD. (b) TGA, horizontal axis = temperature (°C), left axis and (i) = weight (%); right axis and (ii) = heat flow (W / g).

[0245] Figure 8 shows the PXRD and TGA characteristics of Acetate Pattern 1 from the salt formation experiment. (a) PXRD. Peak information from the relevant diffractogram for the 20 most intense peaks is provided in Table 10. (b) TGA, horizontal axis = temperature (°C), left axis and (i) = heat flow (W / g); right axis and (ii) = weight (%); further details were provided in Table 9.

[0246]

Table 10

[0247] Figure 9 shows the PXRD and TGA characteristics of Chloride Pattern 1 from the salt formation experiment. (a) PXRD. Peak information from the relevant diffractogram for the 20 most intense peaks is provided in Table 11. (b) TGA, horizontal axis = temperature (°C), vertical axis = weight (%); 5.7% decrease in mass upon heating to about 110°C.

[0248]

Table 11

[0249] Example 5: Temperature-Variable PXRD. Thermal analysis of acetate pattern 1 showed a complex thermal profile. To investigate this further, a VT PXRD experiment was performed on this material. Upon heating, the initial white powder is first converted to a translucent solid up to 130 °C and then to a translucent white solid up to 170 °C. This conversion is accompanied by the loss of the original diffraction pattern and the appearance of a new diffraction pattern. Figure 10 follows the conversion process: (i) acetate pattern 1 at rt, followed by (ii) heating to 90 °C, (iii) 130 °C, and (iv) 170 °C, and finally (v) cooling back to rt. 1 1H NMR analysis revealed that this material does not contain acetic acid, and thus the new diffraction pattern is due to the free base form represented as free base pattern 1. This material is stable at RT. Figure 11 shows the PXRD of free base pattern 1.

[0250] Example 6: Investigation of Salt Formation Scale-Up. Cethromycin (250.5 mg) of phosphate pattern 1 scale-up was treated with 10 volumes (2.5 ml) of EtOAc and warmed in a Polar Bear at 50 °C. Phosphoric acid (1 M THF stock solution, 359 μl, 1 equivalent) was added. A thick yellow gum was observed, which appeared to lose particles with stirring. The sample was maintained at 50 °C for 30 minutes and then cooled slowly to 5 °C at 0.1 °C per minute, resulting in a white paste with some yellow gum. This white material (120.3 mg) was isolated by filtration through a Buchner funnel. PXRD analysis (not shown) of this white powder revealed that this solid is very weakly crystalline.

[0251] Phosphate Pattern 1 is weakly crystalline upon scale-up, contains approximately 3 equivalents of water, and is likely a hemisalt. It is 98.5% pure according to HPLC and deliquesces under accelerated storage at 25 °C / 97% RH. This material is highly hygroscopic and has a moisture uptake of 21.0% at 0% to 90% RH. This material appears in the form of glassy flakes.

[0252] Figure 12 shows the GVS behavior of Phosphate Pattern 1 in (a) isothermal and (b) kinetic modes. (a): Horizontal axis = Target RH (%); Vertical axis = Change in mass (%); (i) Cycle 1 adsorption; (ii) Cycle 1 desorption; (iii) Cycle 2 adsorption; (iv) Cycle 2 desorption; (v) Cycle 3 adsorption. (b) Horizontal axis = Time (min); Left axis and (i) = Change in mass (%); Right axis and (ii) = Target RH (%).

[0253] Due to its insufficient crystallinity, this material was not further investigated.

[0254] Cethromycin (250.0 mg) of acetate pattern 1 scale-up was treated with 10 volumes (2.5 ml) of EtOAc and warmed in a Polar Bear at 50 °C. Acetic acid (1 M THF, 359 μl, 1 equivalent) was added. The sample was maintained at 50 °C for 30 minutes and then slowly cooled to 5 °C at 0.1 °C per minute. This resulted in a colorless, clear solution, which was then evaporated under ambient conditions. This yielded a very pale yellow gum. This material was stirred with a spatula, treated with 10 volumes of heptane, and aged for 2 days by repeating from 25 °C to 50 °C every 4 hours. The resulting white suspension was isolated by filtration through a Buchner funnel, yielding a white powder (228.4 mg).

[0255] Acetate Pattern 1 is a monohydrate and was isolated with a purity of 98.5%. This material is hygroscopic and has a moisture uptake of 8.6% at 0% to 90% RH, and due to its hygroscopicity, the stoichiometry of water could not be determined. For acetate pattern 1 scale-up 11H NMR and PXRD (not shown) are substantially the same as those for the acetate form 1 material of Example 4.

[0256] Acetate form 1 has a complex thermal profile and loses acetic acid starting at approximately 130 °C, converting to free base form 1. This sample also loses acetic acid at high humidity (accelerated storage conditions and GVS). Acetate form 1 was found to convert to a new form designated acetate form 2 by subjecting this material to GVS conditions or storage at 40 °C / 75% RH. Acetate form 2 remained unchanged even at 97% RH but was demonstrated to have a lower acetate content. Further investigation of the thermal profile of the compound was not performed due to the apparent dissociation to the free base upon heating.

[0257] Figure 13 shows the GVS behavior for the acetate form 1 scaled-up material in (a) isothermal and (b) kinetic modes. (a): x-axis = target RH (%); y-axis = mass change (%); (i) cycle 1 adsorption; (ii) cycle 1 desorption; (iii) cycle 2 adsorption; (iv) cycle 2 desorption; (v) cycle 3 adsorption. (b) x-axis = time (min); left axis and (i) = mass change (%); right axis and (ii) = target RH (%).

[0258] Figure 14 shows the PXRD of acetate form 1 (i) before and (ii) after GVS.

[0259] Chloride Pattern 1 scaled-up sesloxamycin (249.7 mg) was treated with 10 volumes (2.5 ml) of EtOAc and warmed in a Polar Bear at 50 °C. HCl (1 M THF, 359 μl, 1 equivalent) was added. After acid addition, a yellow gum was observed. The sample was maintained at 50 °C for 30 minutes and then slowly cooled to 5 °C at 0.1 °C per minute. The resulting yellow gum was stirred with a spatula and stirred overnight at 5 °C. This gave a white suspension. The solid was isolated by filtration on a Buchner funnel and washed with cold n-heptane. This gave an off-white powder (168.6 mg). For Chloride Pattern 1 scaled-up 1 1H NMR, PXRD, and TGA (not shown) are substantially the same as those for the Chloride Pattern 1 material of Example 4.

[0260] NMR analysis of Chloride Pattern 1 shows peak shifts consistent with salt formation. Chloride Pattern 1 is obtained as a microcrystalline aggregated powder and is a mono-hydrate. This material is hygroscopic and has a moisture uptake of 8.6% at 0% to 90% RH. This hygroscopicity makes it difficult to quantify the stoichiometry of the hydrate. The isolated material is 98.6% pure by HPLC and this solid form is stable under accelerated storage conditions.

[0261] The solubility of the salt forms was measured and compared to the solubility data collected for the amorphous seslomicin free base. The kinetic solubility data collected in SGF media increased to over 35 mg / ml for the phosphate and acetate pattern 1, showing an increase in solubility of approximately 10 mg / ml, compared to the amorphous free base (25 mg / ml). The solubility of the chloride pattern 1 in SGF (27 mg / ml) was not significantly different from the amorphous free base. There was no significant difference in the thermodynamic solubility in PBS across all identified salt forms and the amorphous free base. The thermodynamic solubility in DI water was improved for all salt forms compared to the free base. Some of this increase may be due to a decrease in pH due to the presence of the acidic counterion; however, for phosphate at pH 7, there was a significant increase from 0.4 mg / ml of the free base to over 35 mg / ml for phosphate pattern 1.

[0262] For future polymorphism studies, chloride pattern 1 was selected because this salt had the most favorable solid state properties and some improvement in solubility, particularly in DI water.

[0263]

Table 12

[0264] Further characterization was performed on three salts and is detailed in Table 13 below.

[0265]

Table 13

[0266]

Table 14

[0267] Example 7: Polymorphs of free base seslomicin. The acetate pattern 1 material was converted to the free base pattern 1 by the following procedure. The acetate pattern 1 (approximately 10 mg, Example 4) was transferred to a TGA pan. The material was then heated using a TGA apparatus from room temperature to 150 °C at 10 °C per minute, held at 150 °C for 20 minutes, and then cooled at 10 °C per minute to return to RT. The sample was removed from the TGA pan and analyzed by PXRD. The PXRD (not shown) for the free base pattern 1 scale-up was substantially the same as that for the free base pattern 1 material of Example 5 by VT PXRD. This batch and other batches of the free base pattern 1 were then used to characterize this form.

[0268] Other polymorphs of cethromycin, designated as free base pattern 2, can be obtained. Cethromycin (100 mg) was suspended in 25 volumes (2.5 ml) of deionized water and in PBS. The resulting suspensions were slurried at 25 °C for 24 hours. The samples were filtered through a Buchner funnel and then analyzed by PXRD. The 1 1H NMR (not shown) for the free base pattern 2 was substantially the same as that for the free base cethromycin.

[0269] Figure 15 shows the PXRD characteristics of the free base pattern 2 obtained from (a) H2O and (b) PBS.

[0270]

Table 15

[0271] Example 8: Scale-up investigation of the chloride pattern 1 Sethromycin (2498.8 mg) was treated with 10 volumes (25 ml) of EtOAc, warmed in a Polar Bear at 40 °C to form a very pale brown solution. HCl (1 M THF stock solution, 3590 μl, 1.1 eq) was added. A yellow gum was observed after acid addition. The sample was maintained at 40 °C for 5 minutes and then cooled slowly to 5 °C at 0.1 °C per minute. The sample was maintained at 5 °C for 3 days. This gave a white suspension which was filtered through a Buchner funnel. This resulted in a white powder (2177 mg). For chloride pattern 1 scale-up 1 1H NMR and PXRD (not shown) are substantially the same as those for the chloride pattern 1 material of Example 4.

[0272] Example 9: Investigation of amorphous sethromycin chloride. Three portions of sethromycin chloride pattern 1 (Example 8, 25 mg) were each dissolved in ACN:H2O (1:1 v / v), THF:H2O (7:3 v / v), and t-butanol:H2O (1:1 v / v), (0.5 ml). An attempt to dissolve the same material in t-butanol (30 volumes, 0.75 ml) was unsuccessful. The resulting solutions were then filtered to remove any remaining solid particles. These solutions were then frozen in a dry ice-acetone bath and the solvent removed by lyophilization. The residual solid was analyzed by PXRD and NMR. HPLC purity was also performed on the sample obtained from ACN:H2O (1:1).

[0273] The preparation of amorphous sethromycin chloride was attempted in four different solvents (Table 24). Preparation was successful in ACN:H2O (1:1 v / v), THF:H2O (7:3 v / v), and t-butanol:H2O (1:1 v / v). The sample prepared from ACN:H2O (1:1 v / v) contained no residual solvent according to NMR; thus, this solvent system was selected for further preparation of the amorphous material. HPLC analysis of the compound from this solvent system showed its purity to be >98.9%.

[0274]

Table 16

[0275] Example 10: Scale-up of amorphous cethromycin chloride. Cethromycin chloride pattern 1 (1 g) was dissolved in 20 ml (20 volumes) of ACN:H2O (1:1 v / v), filtered through a nylon filter to remove any residual seed particles. The resulting solution was pipetted into 40 HPLC vials in 500 μl aliquots (approximately 25 mg of HCl salt per vial). The samples were frozen in an acetone / dry ice bath and then placed in a lyophilizer at -80 °C and 1 mbar pressure for 16 h. The samples formed white low-density solids.

[0276] PXRD analysis was performed on 4 of these vials and further characterization was also performed on some samples. The first batch (batch "A") was amorphous, 1 consistent with cethromycin chloride by 1H NMR and had trace amounts of residual solvent. In TGA, a significant mass loss was observed, likely due to water. In DSC, a glass transition was observed at approximately 161 °C. Approximately 0.9 equivalents of HCl were present in the sample and a significant decrease in purity (from 98.7 to 89.0%) was noted. This decrease in purity was due to a low retention peak around the solvent front point, approximately 10% auc, RRT = 0.18. This analysis could not be repeated due to inappropriate materials.

[0277] Two further batches (batches "B" and "C") were analyzed by PXRD and 1 1H NMR and were consistent with cethromycin chloride. The last batch (batch "D") was analyzed by PXRD, 1 1H NMR, IC, HPLC, and after storage at 40 °C / 75% RH for 9 days. PXRD indicated that the material was amorphous. For amorphous cethromycin chloride 1The 1H NMR (not shown) was substantially the same as that for the chloride pattern 1 material of Example 4. IC analysis showed that the material contained 1 equivalent of chloride according to IC. The material did not crystallize during storage at high temperature and humidity. No decrease in purity was observed in this batch.

[0278] Of the 40 samples prepared, 18 were subsequently used for the solubility evaluation of amorphous cethromycin.

[0279]

Table 17

[0280] Example 11: Solubility evaluation of amorphous cethromycin. Amorphous cethromycin (18 individual vials of the material of Example 10, approximately 25 mg per vial) was treated with selected individual solvents at 25 °C. This study was carried out using up to 5 volumes of each solvent. Amorphous cethromycin was found to dissolve in 10 out of the 18 solvents investigated (Table 17). A slurry was obtained with heptane, EtOAc, isopropyl acetate (iPrOAc), methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), methyl t-butyl ether (MTBE), cyclohexane (cHex), and toluene.

[0281]

Table 18

[0282] Example 12. Polymorph experiments on cethromycin. The polymorph experiments on cethromycin were carried out using various techniques to maximize the possibility of discovering new forms.

[0283] Procedure 1: Cooling and aging of chloride pattern 1 The formation of polymorphs from chloride pattern 1 was investigated using the procedure described below. In the first step, the solubility of the material in selected individual solvents at 50 °C was investigated. Up to 60 volumes of solvent were used. The results of this extended study are shown in Table 18.

[0284]

Table 19

[0285] For each sample, the procedure for the investigation of polymorph formation was selected based on the results of the solubility experiment for that sample. The next sample that dissolved completely at 50 °C was cooled. The sample remaining in the solution after one week was evaporated under ambient conditions.

[0286]

Table 20

[0287] The next sample that did not dissolve completely at 50 °C was aged for one week in a shaker incubator repeating from 25 °C to 50 °C every 4 hours. The saturated solution was cooled to 5 °C at 0.1 °C per minute and then maintained at 5 °C in a refrigerator for one week.

[0288]

Table 21

[0289] Figure 16 shows the PXRD characteristics of the polymorph experiment for cethromycin chloride using Procedure 1. Trace (a) is chloride pattern 1 from Example 8; the designations for the remaining traces correspond to the experiment numbers in Table 19. For experiments (vi) and (xiv), PXRD diffractograms were not obtained.

[0290] Procedure 2: Aging of amorphous cethromycin chloride (5 - 25 °C) The procedure for the study of polymorph formation was selected for each sample based on the results of the solubility experiments for that sample described in Example 11. The following samples that formed a suspension at 25 °C in Example 11 were aged for 4 days in a Polar Bear that repeated from 5 °C to 25 °C every 4 hours. One day after the treatment, the samples were observed. After aging, the samples that formed a paste were dried with the tip of a spatula.

[0291]

Table 22

[0292] The following samples that formed a solution at 25 °C in Example 11 were aged for 1 day in a Polar Bear. The samples that formed a solid precipitate after this period were dried. Additional amorphous cethromycin (an additional 25 - 50 mg) was seeded into the samples remaining in the solution and aged for an additional 3 - 4 days under the same conditions.

[0293]

Table 23

[0294] Experiment (xii) conducted in MeOH provided a new polymorph classified as chloride pattern 2. The overall characteristics of this material are presented below in Example 13.

[0295] Figure 17 shows the PXRD characteristics of the polymorph experiment for cethromycin using Procedure 2. Trace (a) is the material of Example 8; the designations for the remaining traces correspond to the experiment numbers in Table 21. For experiments (ii), (iv), and (v), PXRD diffractograms were not obtained.

[0296] Procedure 3: Aging of amorphous cethromycin (25 - 50 °C) Amorphous cethromycin (25 mg) was treated with 10 volumes of solvent (250 μl). The samples were aged in a shaker incubator repeating from 25 °C to 50 °C every 4 hours. The samples that formed a paste were isolated by drying with the spatula tip.

[0297]

Table 24

[0298] Figure 18 shows the PXRD characteristics of the polymorph experiments for cethromycin using Procedure 3. Trace (a) is the material of Example 8; the designations for the remaining traces correspond to the experiment numbers in Table 22. For experiment (vii), no PXRD diffractogram was obtained. The diffractograms for experiments (i) and (viii), which correspond to amorphous materials, are not shown.

[0299] Procedure 4: Poor Solvent Addition Cethromycin Pattern 1 (25 mg, Example 8) was treated with a minimum amount of solvent until a solution was formed at 50 °C or until a maximum of 100 volumes was reached. This sample was first treated with an equal volume of poor solvent (n-heptane), which was increased to a ratio of 1:3 (solvent:poor solvent). The sample with the initial large volume of solvent (100 volumes) was treated with 1 equal volume of heptane (1:1 ratio). All samples were cooled to 5 °C at 0.1 °C / min. Any resulting solid was isolated and analyzed by PXRD. Any remaining solution was evaporated under ambient conditions and analyzed by PXRD.

[0300] Figure 19 shows the PXRD characteristics of the polymorph experiments for cethromycin using Procedure 4. Trace (a) is the material of Example 8; the designations for the remaining traces correspond to the experiment numbers in Table 22. For experiment (vii), no PXRD diffractogram was obtained. The diffractograms for experiments (i) and (viii), which correspond to amorphous materials, are not shown.

[0301]

Table 25

[0302] Example 13. Characteristics of Chloride Pattern 2. Chloride sesloxacine pattern 2 (Example 12, procedure 2, experiment xii: MeOH) was characterized using various techniques. This is likely to be the monohydrate and was found to lose crystallinity upon isolation. TGA shows a 5.1% mass loss due to water. This corresponds to 2.4 equivalents of water, but as this material is hygroscopic, it is difficult to establish exact stoichiometry. In DSC, a broad endotherm corresponding to this loss is observed, followed by a second endotherm at 186.5 °C, presumably melting. By HPLC, it was confirmed that the purity is consistent with the starting material.

[0303]

Table 26

[0304] Figure 20 shows (i) chloride pattern 2 (Example 8) and (ii) (a) PXRD for chloride pattern 2. Peak information from the relevant diffractograms for the 18 most intense peaks is provided in Table 25. Also shown is (b) thermal analysis for chloride pattern 2. Further details are provided in Table 24.

[0305]

Table 27

[0306] Figure 21 shows the GVS behavior for chloride pattern 2.

[0307] Using input materials of both amorphous cethromycin (prepared by lyophilization) and crystalline cethromycin chloride, polymorph formation experiments were carried out using cooling, temperature cycling, anti-solvent addition, and evaporation techniques. Most of the samples were amorphous or chloride pattern 1. In two cases from methanol, another crystalline solid, designated as chloride pattern 2, was isolated. Initial characterization of chloride pattern 2 indicated that the material was crystalline, with a significant mass loss due to water according to TGA and no residual solvent according to 1H NMR. This material was 98.8% pure and had a chloride content of 0.97 equivalents as confirmed by IC. In the bulk sample after isolation, there was a decrease in crystallinity compared to the initial analysis carried out on a small aliquot.

[0308] Example 14. Preparation of Chloride Pattern 2. Cethromycin chloride pattern 1 (350 mg, Example 8) was dissolved in 5 volumes of MeCN:water (1:1) (v / v) (1.75 ml). This solution was passed through a nylon filter and placed into a 25 ml round bottom flask. The sample was then frozen in an acetone / dry ice bath and then lyophilized at -80 °C and 1 mbar pressure to yield amorphous cethromycin chloride. This material was amorphous according to PXRD and 98.7% pure according to HPLC. The 1H NMR (not shown) for the amorphous cethromycin chloride was substantially the same as that for the chloride pattern 1 material of Example 4. 1 The 1H NMR (not shown) for the amorphous cethromycin chloride was substantially the same as that for the chloride pattern 1 material of Example 4.

[0309] The amorphous cethromycin from the previous step was treated with one volume (290 μl) of methanol at 25 °C, resulting in a pale brown solution with small remaining solid particles. The sample was then aged for one day in a Polar Bear that cycled from 25 °C to 5 °C every 4 hours, which resulted in the formation of a white suspension. The sample was cooled from 25 °C to 5 °C (maximum cooling rate) and maintained at this temperature for 30 minutes to maximize precipitation. Attempts to filter the suspension showed that it was too viscous to filter. Therefore, the sample was dried by evaporation for 2 days under ambient conditions.

[0310]

Table 28

[0311] Example 15. Competitive slurry experiment. Preparation of Chloride Pattern 1 Amorphous cethromycin (2500 mg) was treated with ten volumes (25 ml) of EtOAc, resulting in a pale brown turbid solution. This was warmed to 40 °C and treated with 1.1 equivalents of HCl (3590 μl of 1 M THF stock solution). This resulted in the formation of a pale yellow gum. The sample was cooled to 5 °C at 0.1 °C / min and maintained at this temperature with stirring for 2 days. The sample was seeded with Chloride Pattern 1 and stirred at 5 °C for an additional 3 days. After this period, a white suspension was observed and the sample was filtered through a Buchner funnel and then dried under suction for 20 minutes. This resulted in an off-white powder that was confirmed by PXRD to be Chloride Pattern 1, with a yield = 2316.3 mg (88.4%). For the scale-up of Chloride Pattern 1 1 1H NMR (not shown) is substantially the same as that for the Chloride Pattern 1 material of Example 4.

[0312] Preparation of Amorphous Cethromycin Chloride Sethromycin pattern 1 chloride (600 mg) was dissolved in MeCN:H2O (1:1, v / v) (3 ml, 5 volumes). An additional 1 ml of MeCN (aqueous solution) solvent was added (since small particles remained undissolved). The solution was then filtered through a nylon filter into a 50 ml flask to remove any remaining seed particles. The solution was then frozen in an acetone / dry ice bath and then lyophilized at -80 °C and 1 mbar pressure for 24 hours. This resulted in a low density white solid which was confirmed to be amorphous by PXRD. For amorphous sethromycin chloride 1 1H NMR (not shown) is substantially the same as that for the chloride pattern 1 material of Example 4.

[0313] Preparation of chloride pattern 2 Amorphous sethromycin chloride (520 mg) was treated with MeOH (520 μl, 1 volume). The resulting pale brown solution was aged for 1 day in a Polar Bear that switched from 25 °C to 5 °C every 4 hours. The resulting white suspension was cooled to 5 °C (from 25 °C) and maintained at this temperature for 30 minutes. The sample was then dried by evaporation under ambient conditions. This resulted in an off-white solid which was confirmed to be chloride pattern 2 by PXRD and the yield = 499.9 mg. PXRD and 1 1H NMR (not shown) is substantially the same as that for chloride pattern 2 from the experiment of Example 14.

[0314]

Table 29

[0315] Using sethromycin pattern 1 chloride, a saturated solution at 40 °C was prepared as shown in Table 28. All samples except EtOAc were stirred at 40 °C for 12 hours. The EtOAc suspension was stirred at this temperature for 1 hour (to reduce the risk of evaporation). The saturated solution was then filtered.

[0316]

Table 30

[0317] Approximately 350 mg portions of chloride pattern 1 and chloride pattern 2 were gently (separately) ground in a mortar and pestle to yield particles of uniform size. A 1:1 mixture of the ground chloride pattern 1 and the ground chloride pattern 2 was prepared by mixing 300 mg of each material in a roller mixer for 24 hours. Figure 24 shows the PXRD for (i) cethromycin chloride pattern 1 (from Example 15), (b) cethromycin chloride pattern 2 (from Example 15), and (III) the mixture.

[0318] A portion of the above materials was weighed into 12 HPLC vials and numbered as shown in Table 29. Each vial was treated with 0.3 ml of a saturated solution, except for the samples carried out in MeOH (which were treated with 0.35 ml of a MeOH saturated solution). Prior to the addition of the saturated solution, each saturated solution was brought to the corresponding temperature and equilibrated for 30 minutes. The resulting suspension was allowed to settle and the saturated solution was taken from the top. Note: Due to the high solubility of the HCl salt in methanol (and limited materials), it was not possible to saturate the MeOH solution. When treated with a partially saturated MeOH solution, the solid completely dissolved. Thus, it was not possible to carry out competitive slurries in MeOH. All other samples were slurried at 5 °C, 25 °C, and 40 °C for 3 days and then analyzed by PXRD.

[0319] Figure 22 shows the PXRD analysis of the slurry experiments. Cethromycin chloride (a) pattern 1, (b) pattern 2, (c) mixture of pattern 1 + pattern 2; (d) THF at 5 °C, (e) 25 °C, (f) 40 °C; (g) H2O at 5 °C, (h) 25 °C, (i) 40 °C; slurries using EtOAc at (d) 5 °C, (e) 25 °C, (f) 40 °C.

[0320]

Table 31

[0321] Example 16. Kinetic Solubility Study on Cethromycin Chloride Sufficient samples for the free form of the compound at an estimated maximum concentration of approximately 40 mg / ml were suspended in 0.25 ml of the medium. The resulting suspension was then shaken at 25 °C / 750 rpm for 2 hours. After equilibration, the appearance was recorded and the pH of the saturated solution was measured. The samples were then filtered through a glass "C" fiber filter (particle retention 1.2 μm). All samples were diluted 100-fold with SGF medium. Quantification was by HPLC, conforming to a standard solution of approximately 0.15 mg / ml. Different volumes of the standard and diluted sample solutions were injected. Solubility was calculated using the peak area determined by integration of the peak found at the same retention time as the major peak in the standard injection.

[0322] [Table 32]

[0323] Example 17. Thermodynamic Solubility Study on Cethromycin Chloride Sufficient samples for the free form of the compound at an estimated maximum concentration of approximately 40 mg / ml were suspended in 0.25 ml of the medium. The resulting suspension was then shaken at 25 °C / 750 rpm for 24 hours. The pH of the samples suspended in PBS (pH 7.4) was confirmed and adjusted after 2 hours if necessary (change in pH > 0.05). After equilibration, the appearance was recorded and the pH of the saturated solution was measured. The samples were then filtered through a glass "C" fiber filter (particle retention 1.2 μm). Samples suspended in PBS (pH 7.4) buffer were diluted 10-fold with PBS buffer and samples suspended in DI water were diluted 100-fold.

[0324] [Table 33]

[0325] The solubility results from the analysis performed on Chloride Pattern 1 were generally consistent throughout both batches analyzed. Cethromycin Pattern 2 shows increased solubility compared to Pattern 1, but this is only a difference of approximately 6 mg / ml in DI water and SGF and 0.4 mg / ml in PBS.

[0326] The solubility of cethromycin chloride is comparable to that of the amorphous free base in both PBS and SGF media. However, according to the results, in DI water, cethromycin chloride (both Pattern 1 and Pattern 2) is shown to be significantly more soluble than the amorphous free base. This may be due to a slight change in pH, as the chloride salts equilibrate from pH 4.5 to 5.2, while the free base remains at pH 7.0, following the general trend that cethromycin is more soluble under more acidic conditions.

[0327] PXRD analysis was performed on the residue that remained undissolved after the solubility analysis to confirm changes in the solid form. In PBS, both Chloride Pattern 1 and Pattern 2 were converted to the free base Pattern 2 previously observed by slurrying the free base Pattern 1 in PBS or water for 24 hours. In SGF and deionized water, a clear solution was obtained for Chloride Pattern 2, so solubility values could not be reported for this form. In SGF and deionized water, Chloride Pattern 1 remained unchanged.

[0328] Example 18. Solubility study on cethromycin chloride.

[0329]

Table 34

[0330]

Table 35

[0331]

Table 36

[0332] The following samples from the solubility experiment provided materials characterized as cethromycin pattern 1 chloride. Figure 25 shows the diffractograms for four samples, along with the diffractogram for cethromycin pattern 1 chloride from Example 8 (a) included for comparison.

[0333]

Table 37

[0334] The following samples from the solubility experiment provided materials characterized as cethromycin free base pattern 2. Figure 26 shows the diffractograms for four samples, along with the diffractograms for (a) cethromycin pattern 1 chloride from Example 8, (b) cethromycin pattern 2 chloride from Example 14, and (c) cethromycin free base pattern 2 from Example 7 included for comparison.

[0335]

Table 38

[0336] Example 19. Stability study on cethromycin chloride. Studies were conducted on various cethromycin forms to determine their stability during storage.

[0337] Figure 23 shows the PXRD study on the storage of chloride pattern 2. (a) (i) PXRD of chloride pattern 2 after storage (25 °C, 97% RH, 9 days), (ii) chloride pattern 1 from Example 8, and (iii) chloride pattern 2 from Example 14. (b) (i) PXRD of chloride pattern 2 after storage (40 °C, 75% RH, 9 days), and (ii) chloride pattern 2 from Example 14.

[0338] Example 20. Comparison of the in vivo activities of cethromycin and the base An assay was performed to compare the blood-stage antimalarial activity of cethromycin chloride with the free base of cethromycin. Balbc mice (n = 3 / dose) were given 500,000 rodent malaria parasites (P. berghei) (a species of the genus Plasmodium that infects rodents) infected erythrocytes i.p., and then a daily dose of 60 mg / kg of cethromycin chloride or the free base of cethromycin was administered once daily for 4 days via forced oral administration. Blood was collected daily to follow the course of infection and quantified by luciferase assay. As shown in Figure 27, the cethromycin salt was superior to the base, killing at twice the rate of the free base and resulting in a 1-day delay until the first parasitemia returned. Therefore, the cethromycin salt is expected to be superior to the free base in the treatment of malaria in humans (infected by other species of the genus Plasmodium) and similarly in other mammals.

[0339] Example 21. In vitro human hepatotoxicity study. Against Plasmodium falciparum (or other species of the genus Plasmodium), in vitro, to compare cethromycin chloride, its M1 metabolite N-demethylcethromycin, and / or the free base of cethromycin, chloroquine-sensitive and -resistant isolates can be used according to methods known in the art to evaluate antimalarial activity and hepatotoxicity.

[0340] In one embodiment, in the HIAT assay using additional 48-hour cytotoxicity plates, cryopreserved human hepatocytes were plated in 384-well collagen-coated tissue culture plates (black wall, clear bottom), treated with test compounds or controls using a 10-point dose-response range of concentrations, and then incubated between two time points: 24 and 48 hours. At the end of the incubation period, the cells were loaded with appropriate dyes / antibodies for each cell health marker. These plates were then scanned using an automated high-content imager (ArrayScanTM VTI HCS Reader). Nuclear intensity, GSH depletion, mitochondrial potential (TMRE), and ROS (reactive oxygen species) can be evaluated, for example, at the 24-hour time point, and AC 50 values are reported; cell loss and nuclear size can be evaluated, for example, at the 48-hour time point. Positive controls for each of these readings can also be included. For readings other than cell viability, statistical methods for data analysis are used. Vehicle controls are used to define the "normal" definition for each parameter. Vehicle control wells are then used to determine significance limits for wells with low or high responders that exceed the expected rate.

[0341] In certain embodiments, it is expected that cethromycin chloride is superior to the free base and also to the M1 metabolite in the avoidance of hepatotoxicity.

[0342] Example 22. Comparison of In Vivo Activity of Cethromycin Chloride and the Base In the in vivo killing of Plasmodium falciparum or other species of the genus Plasmodium that cause malaria, an assay comparing cesium chloride, the N-demethylcesium of its M1 metabolite, and / or the cesium free base can be carried out according to the methods disclosed herein and known in the art. Each compound can be administered at one or more dose levels over a period of time; parasite levels, malaria disease, shortening of the period to cure, survival extension, toxicity (especially liver toxicity), and other metrics can be evaluated during and after the study using both in-life and post-mortem methods. In certain embodiments, cesium chloride is expected to be superior to the free base in reducing parasite levels, treating malaria disease, shortening the period to cure, extending survival, and avoiding toxicity (especially liver toxicity).

[0343] Example 23. Additional in vivo mouse activity assay The liver stage activity of cesium chloride and / or its M1 metabolite, N-demethylcesium, can be tested in a mouse malaria model (n = 5 mice / dose) after mosquito bite or injection of infectious sporozoites according to methods known in the art. Quantifiable evaluation items may include the measured activity against malaria. The activity of the cesium chloride salt is expected to be superior to the activity of the M1 metabolite and the free base. In certain embodiments, the activity of the M1 metabolite is expected to be less than 30% of the activity of cesium chloride.

[0344] Alternatively, murine blood-stage malaria activity can be tested in a high parasitemia parasite killing model (n = 5 mice / dose) to evaluate the rate of kill, minimum dose, and period to cure, as disclosed above and / or according to methods known in the art. Quantifiable evaluation items may include the measured activity against malaria. The activity of cethromycin chloride is expected to be superior to that of the M1 metabolite and free base, for example, in increasing the rate of kill and reducing the minimum dose and period to cure. In certain embodiments, the activity of the M1 metabolite is expected to be less than 30% of the activity of cethromycin chloride.

[0345] Example 24. In vitro human hepatotoxicity study. A human 3D primary hepatotoxicity study comparing cethromycin chloride, cethromycin free base, and the N-demethyl cethromycin M1 metabolite of cethromycin with other macrolides, such as clarithromycin, azithromycin, and / or telithromycin, can be performed according to methods known in the art. An in vitro assay can be performed to evaluate drug-induced liver injury, which can be determined by measuring the cellular health markers glutathione, ROS formation, mitochondrial dysfunction, and cellular ATP in human hepatocytes, for example, after 14 days of repeated compound exposure. Quantifiable evaluation items may include the measured toxicity compared to other macrolides as determined by methods known in the art. Cethromycin chloride is expected to have a tolerably low level of liver toxicity and, in certain embodiments, a liver toxicity effect that is not as great as that of other macrolides in general or the cethromycin free base.

[0346] Summary Cethromycin phosphate Form 1 showed a decrease in crystallinity upon scale-up and deliquesced under accelerated storage at 25 °C / 97% RH. Acetate Form 1 exhibited complex thermal behavior and lost acetic acid at 150 °C and high humidity. Based on their solid state properties, cethromycin chloride Form 1 was selected from the salts examined in this study for future polymorphic studies to be pursued.

[0347] Competitive slurry experiments (1:1 physical mixtures) of cethromycin chloride Form 1 and cethromycin chloride Form 2 were conducted in THF, H2O, and EtOAc at three different temperatures (5 °C, RT, and 40 °C). In all experiments, conversion to chloride Form 1 was observed in suspension within 3 days. Chloride Form 1 was determined to be the most stable chloride salt under the conditions investigated. Chloride Form 2 showed only a slight increase in solubility compared to chloride Form 1. The ability of a compound to form a functional solid form, provide appropriate solubility in a physiologically relevant state, and exhibit sufficient stability are each important considerations for the development of a compound as a pharmaceutical. Often, the selection of a preferred compound form corresponds to a balance of these factors. Thus, in certain embodiments, cethromycin chloride Form 1 is a suitable candidate for development as a drug.

[0348] Cethromycin chloride also appears to be superior to the free base in the treatment of malaria, as demonstrated by a mouse model of the disease. Further, the superiority of cethromycin chloride over the free base and M1 metabolite in the treatment of malaria and avoidance of toxicity is predicted to be demonstrated by assays disclosed herein and known in the art.

[0349] All references, patents, or applications (U.S. or foreign) cited in this application are hereby incorporated by reference herein as if fully set forth herein. In case of any conflict, the entity disclosed in this specification in literal terms shall govern.

[0350] From the foregoing description, those skilled in the art can easily identify the basic features of the present disclosure and can make various changes and modifications to the present disclosure without departing from its spirit and scope in order to adapt to various usage methods and conditions.

Claims

1. A compound of Structural Formula I 【Chemical 1】 or a polymorph thereof (where: a is about 1.0; b is a fraction or integer between about 0 and 10 (including the end values); M is hydrochloric acid).

2. The compound according to claim 1, characterized by the presence of four or more, six or more, or eight or more peaks having an interplanar spacing d of about 14.1, 12.9, 10.1, 8.8, 8.5, 6.5, 5.5, 5.1, 4.8, and 4.4 Å.

3. The compound according to claim 1, characterized by the presence of four or more, six or more, or eight or more peaks having an interplanar spacing d of about 16.5, 14.5, 10.5, 9.1, 8.3, 7.8, 7.6, 5.2, 4.7, and 4.1 Å.

4. A medicament comprising the compound according to any one of claims 1 to 3.

5. The medicament according to claim 4, for use in the treatment of infectious diseases.

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 together with a pharmaceutically acceptable carrier.

7. a. A therapeutically effective amount of the compound according to any one of claims 1 to 3; and b. Another therapeutic agent The medicament according to claim 4, for use in a method comprising the administration of.

8. The medicament according to claim 5, wherein the infectious disease is malaria.

9. The medicament according to claim 5 or 8, wherein the infectious disease is caused by protozoa.

10. A medicament comprising the compound according to any one of claims 1 to 3, reducing the microbial level; Increasing the rate of microbial killing; Reducing the minimum dose for cure (e.g., reduction of the level of the microorganism to an undetectable level); and Shortening the period required for cure (e.g., reduction of the level of the microorganism to an undetectable level) A medicament for use in a method of achieving in a patient an effect selected from: Claim 11 The medicament according to claim 10, wherein the microorganism is a protozoan. Claim 12 The medicament according to claim 9 or 11, wherein the protozoan is selected from the genus Cryptosporidium; subclass Coccidia; genus Plasmodium; genus Toxoplasma; genus Babesia; and genus Neospora. Claim 13 The medicament according to claim 12, wherein the protozoan is a species of the genus Plasmodium selected from Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi. Claim 14 The compound according to claim 1, wherein b is about 2.5.

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