WO2007062335A2 - New pleuromutilin derivative and its use - Google Patents

New pleuromutilin derivative and its use Download PDF

Info

Publication number
WO2007062335A2
WO2007062335A2 PCT/US2006/061068 US2006061068W WO2007062335A2 WO 2007062335 A2 WO2007062335 A2 WO 2007062335A2 US 2006061068 W US2006061068 W US 2006061068W WO 2007062335 A2 WO2007062335 A2 WO 2007062335A2
Authority
WO
WIPO (PCT)
Prior art keywords
salt
salt according
compound
solvate
solid
Prior art date
Application number
PCT/US2006/061068
Other languages
French (fr)
Other versions
WO2007062335A3 (en
WO2007062335A8 (en
Inventor
Ann Marie Diederich
Joseph Sisko
Frederick G. Vogt
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2007062335A2 publication Critical patent/WO2007062335A2/en
Publication of WO2007062335A3 publication Critical patent/WO2007062335A3/en
Publication of WO2007062335A8 publication Critical patent/WO2007062335A8/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
    • C07C271/66—Y being a hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics

Definitions

  • the invention is directed to the succinate salt of /r ⁇ / ⁇ s'-4-aminocyclohexyl (lS',2 ⁇ ,3S',4S,6R,7 ⁇ ,8/?,14R)-4-ethenyl-3-hydroxy-2,4,7,14-tetramethyl-9-oxotricyclo[5.4.3.01,8] tetradec-6-yl imidodicarbonate depicted herein as Compound IA, and its use in the treatment of respiratory tract and skin and skin structure infections.
  • WO 02/30929 discloses certain pleuromutilin derivatives useful as antibacterial agents. Specifically, WO 02/30929 discloses C-14 oxycarbonyl carbamate pleuromutilin derivatives according to Formula IA or Formula IB therein.
  • C-14 oxycarbonyl carbamate pleuromutilin derivative encompassed within Formula IA of WO 02/30929 is *r ⁇ mv-4-aminocyclohexyl (lS,2R,3S,43,6R,7R$R,14R)-4-ethen ⁇ l- 3 -hydroxy-2,4,7, 14-tetramethyl-9-oxotricyclo [5.4.3.01, 8]tetradec-6-yl imidodicarbonate
  • Compound I is encompassed within Formula IA of WO 02/30929, it is not specifically disclosed in the specification or claims.
  • Compound I is represented by the following structure:
  • WO 02/30929 discloses that the compounds disclosed therein that contain a basic group "may be in the form, of a free base or an acid addition salt.”
  • Pharmaceutically acceptable salts such as those described by Berge et al. (J. Pharm Sci., 1977, 66, 1-19) are indicated as preferred salts. Hydrochloride, maleate, and methanesulfonate are specifically mentioned.
  • Compound I has recently been identified as a particularly useful compound because it has demonstrated good in vitro and in vivo activity against representative Gram-positive and Gram-negative pathogens associated with respiratory tract and skin and skin structure infections including isolates resistant to existing classes of antimicrobials. In view of the good in vitro and in vivo activity exhibited by Compound 1 against representative Gram-positive and Gram-negative pathogens associated with respiratory tract and skin and skin structure infections there is a need for a form of Compound I suitable for pharmaceutical development.
  • the invention is directed to the succinate salt of ?ra?w-4-aminocyclohexyl (lS ⁇ S ⁇ y ⁇ S ⁇ l ⁇ -ethenyl-S-hydroxy-l ⁇ tetramethyl-Q-oxotricycloCS ⁇ .S.Ol ⁇ ] tetradec-6-yl imidodicarbonate depicted herein as Compound IA.
  • Compound IA is useful in the treatment of a variety of diseases and conditions, such as respiratory tract and skin and skin structure infections. Accordingly, the invention is further directed to pharmaceutical compositions comprising Compound IA. The invention is still further directed to methods of treating respiratory tract and skin and skin structure infections using Compound IA or a pharmaceutical composition comprising Compound IA.
  • Figure 1 is an x-ray powder diffractogram of Compound IA.
  • Figure 2 is an x-ray powder diffractogram of Compound IA.
  • Figure 3 a is an x-ray powder diffractogram of Sample A of Example 23.
  • Figure 3b is an x-ray powder diffractogram of Sample B of Example 23.
  • Figure 3c is an x-ray powder diffractogram of Sample C of Example 23.
  • Figure 3d is an x-ray powder diffractogram of Sample D of Example 23.
  • Figure 3e is an x-ray powder diffractogram of Sample E of Example 23.
  • Figure 3f is an x-ray powder diffractogram of Sample F of Example 23.
  • Figure 4a is a 13 C solid-state NMR spectrum of Sample A of Example 23.
  • Figure 4b is a 13 C solid-state NMR spectrum of Sample B of Example 23.
  • Figure 4c is a 13 C solid-state NMR spectrum of Sample C of Example 23.
  • Figure 4d is a 13 C solid-state NMR spectrum of Sample D of Example 23.
  • Figure 4e is a 13 C solid-state NMR spectrum of Sample E of Example 23.
  • Figure 4f is a 13 C solid-state NMR spectrum of Sample F of Example 23.
  • Figure 6b is a 13 C solid-state TSTMR spectrum of the product of Example 20. Only the deshielded region (230 to 100 ppm) of the spectrum is shown.
  • Figure 6c is a 13 C solid-state NMR spectrum of the product of Example 21. Only the deshielded region (230 to 100 ppm) of the spectrum is shown.
  • the invention is directed to substantially pure Compound IA.
  • substantially pure when used is reference to Compound IA refers to a product which is greater than about 90% pure.
  • substantially pure refers to a product which is greater than about 95% pure, and more preferably greater than about 97% pure. This means the product does not contain any more than about 10%, 5% or 3% respectively of any other compound.
  • the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by an XRPD pattern having (a) a characteristic peak at 10.8 ⁇ 0.2 (° 2 ⁇ ); (b) at least five additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ⁇ 0.2 (° 2 ⁇ ), 12.9 ⁇ 0.2 (° 2 ⁇ ), 13.1 ⁇ 0.2 (° 2 ⁇ ), 17.5 ⁇ 0.2 (° 2 ⁇ ), 18.5 ⁇ 0.2 (° 2 ⁇ ), or 21.2 ⁇ 0.2 (° 20); and (c) at least one additional characteristic peak selected from characteristic peaks at the following positions: 9.8 ⁇ 0.2 (° 20), 15.1 ⁇ 0.2 (° 2 ⁇ ) or 15.6 ⁇ 0.2 (° 2 ⁇ ).
  • the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 3e. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 3f. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 5a.
  • the dichloromethane layer was divided and for the remaining portion of this procedure: 32.4 weight % of the solution of the dichloromethane layer (containing 5.79 g of free base, 11.5 mmol, l.cq) was used.
  • the clear solution was then seeded with 5 mg of Compound IA seed crystals in 0.25 mL 2-propanol.
  • the suspension was distilled to remove dichloromethane over 90 minutes and then cooled slowly to 0 0 C. After one hour at 0 0 C, the solids were filtered and washed with 15 mL of 2-propanol. The solids were dried at 55°C under vacuum to give 6.99 g, a 98% yield.
  • Ep ⁇ mutilin chloroformate (91.7 g, 0.231 mole) in CH 2 Cl 2 (0.5 L) is then added dropwise via addition funnel over 1 hour, and then the mixture is allowed to slowly warm to room temperature and stir overnight (the reaction mixture turns from a reddish brown to grey color).
  • Monitoring can be done by TLC (9:1 CHCljrEtOAc). The mixture was filtered through celite, washing thoroughly with CH 2 Cl 2 - The filtrate was evaporated and purified by chromatography* 5-30% EtOAc/ CHCl 3 to afford the product as a white foam (132.6 g, 97%).
  • TLC was visualized with eerie ammonium molybdate stain and/or phosphomolybdic acid stain.
  • the mixture was purged with nitrogen for 1 hour (20% Na ⁇ COs trap) to remove excess phosgene, and diluted with toluene (500 mL). After washing with IN HCl (2 x 20OmL), water, and brine, the solution was dried over magnesium sulfate, filtered and evaporated to provide the product as a thick syrup (56 g). The product still contained residual toluene, and was used as is in the next step.
  • the H-OTFA- mutilin chloroformate can be obtained as a white solid by trituration with hexane.
  • N-Boc- trans-4-aminocyclohexanol (20.6g, 0.096 mole) and pyridine (1 mL) were added to CH 2 CI 2 (400 mL) in a 2L 3NRB flask equipped with a mechanical stirrer and addition funnel (the mixture was not completely clear).
  • Silver cyanate (Aldrich, 17.3 g, 0.115 mole) was added, and the suspension was cooled in an ice bath.
  • the reactor vessel was wanned to ⁇ 45°C and stirred for ⁇ 2 hours. The reaction was cooled to ⁇ 40°C and the layers were separated. The organics were washed with water (114 g) and the layers were separated. The organic layer was concentrated to ⁇ 115 mL under reduced pressure. Heptane (1 14 mL) and toluene (30 mL) were added and the mixture was warmed to 60 0 C. The contents were stirred for ⁇ 0.5 hours then cooled slowly to 0 0 C and then the solids were filtered. The vessel and cake were rinsed with heptane (2 x 100 mL). The solids were dried under vacuum at ⁇ 30°C overnight to give 42.7g (78% yield) of the product. 1 sodium tert-pentoxide
  • aqueous layers were combined and were slowly added over 40 minutes into a second vessel containing a mixture of 30% ammonium hydroxide (180 mL), water (0.12 L), IPA (0.1 L), and ethyl acetate (0.5 L) that had been cooled to ⁇ 15 0 C keeping the internal temperature ⁇ 26°C.
  • the bottom aqueous layer was separated and discarded.
  • To the top organic layer was added water (0.3 L) and the mixture was stirred for 20 minutes.
  • the bottom aqueous layer was discarded and the top organic portion was concentrated to ⁇ 3 vol under vacuum.
  • IPA 0.5 L was added and the mixture was concentrated to ⁇ 5 vol.
  • the suspension was stirred at 41 0 C for 1 hour and cooled slowly to 0 0 C.
  • the solids were isolated by filtration after 1 hour at 0 0 C and washed with 4ml of cold n-propanol.
  • the solids were dried at 55°C under vacuum to give 564 mg, 91.4% yield.
  • Crude Compound I (2257g, actual charge determined by w/w assay, 2257g at 79.72% w/w in this case is 1800 g net, 1 equivalent) was charged to a 25 L laboratory jacketed lab reactor with overhead stirring. 4500 mL of 2-propanol and 1150 mL of water was added. 215 g (0.51 eq,) of succinic acid was then added. The mixture was stirred and heated to 70-75 0 C until a clear solution was obtained. The solution was filtered through a 1 micron filter into the crystallization reactor. The reactor and filter were rinsed with 5600 mL of 2-propanol. The contents of the crystallization reactor were heated to 70-75 0 C to ensure complete dissolution.
  • the reactor contents were cooled to 62-67 0 C over —25 minutes and seeded with 18g (1.0% wt) of Compound IA seeds suspended in 64mL 2-propanol.
  • the slurry was held at 62-67 0 C for one hour.
  • the slurry was cooled to 20 u C over at least 1 hour.
  • the slurry was then charged with 11240 mL (6.25 vol) of 2-propanol over at least 30 minutes.
  • the slurry was cooled to 0-5 0 C over at least one hour then isolated by filtration.
  • the reactor and the cake were rinsed with 7200 mL of 2-propanol.
  • the product was dried under vacuum at a temperature of 40-60 0 C until residual IPA was not greater than 2.5% w/w.
  • Product weight 1.97 Kg.
  • the total succinic acid content of the product was measured upon dissolution by HPLC and determined to be 0.5 molar equivalents.
  • solid-state NMR of the product confirmed the presence of the core solid-state structure of Compound IA and no additional succinic acid.
  • Crude Compound I (370Og, actual charge determined by w/w assay, 3700 g at 78.1% w/w in this case is 2890 g net, 1 equivalent) and 3600g of additional crude Compound I (actual charge determined by w/w assay, 3600 g at 78.6% w/w in this case is 2830 g net, 1 equivalent) were charged to an 80-L jacketed lab reactor with overhead stirring.
  • 11200 g (2.5 vol) of 2- propanol and 3600 mL (0.63 vol) of water were added.
  • 1140 g (0.85 eq,) of succinic acid was added. The mixture was stirred and heated to 50-70 0 C until a clear solution was obtained.
  • the solution was filtered through a 1 micron filter into the crystallization reactor.
  • the reactor and filter were rinsed with 14000 g (3.13 vol) of 2-propanol.
  • the contents of the crystallization reactor to 70-75 0 C were heated to ensure complete dissolution.
  • the reactor contents were cooled to 50-67 0 C over about 15 minutes and seeded with 57 g (1.0% wt) Compound IA seeds suspended in 114-228 mL 2-propanol.
  • the slurry was held at 50-67 0 C for 30-60 minutes.
  • the slurry was cooled to 20 0 C over at least 1 hour.
  • the slurry was then charged with 28100 g (6.25 vol) of 2-propanol over at least 30 minutes.
  • the slurry was cooled to 0-5 0 C over at least one hour then isolated by filtration.
  • the reactor and the cake were rinsed with 18000 g (4 vol) of 2- propanol.
  • the product was dried at a temperature of 40-60 0 C until residual IPA was not greater than 3% w/w.
  • the total succinic acid content of the product was measured upon dissolution by HPLC and determined to be 0.8 molar equivalents.
  • solid-state NMR of the product confirmed the presence of the core solid-state structure of Compound IA and additional succinic acid.
  • the additional succinic acid content is 0.3 molar equivalents.
  • Crude Compound I (2205 g, actual charge determined by w/w assay, 2205 g at 79.72% w/w in this case is 1757 g net, 1 equivalent) was charged to a 25-L jacketed lab reactor with overhead stirring. To this, 4400 mL of 2-propanol and 1100 mL of water were added. 658 g (1.60 eq,) of succinic acid was added. The contents of the reactor -were stirred and heated to 70- 75 0 C until a clear solution was obtained. The solution was filtered through a 1 micron filter into the crystallization reactor. The reactor and filter were rinsed with 5500 mL of 2-propanol.
  • prevention is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • safe and effective amount in reference to Compound IA or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a safe and effective amount of a compound will vary with the particular compound chosen (e.g.
  • Compound IA may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
  • Compound IA may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or mdefmitely to maintain the desired therapeutic effect. Suitable dosing regimens for Compound IA depend on the pharmacokinetic properties of the compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for Compound IA depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration range from about 100 mg to about 3000 mg per day. In one embodiment of the invention, the patient is administered from about 250 mg to about 2000 mg per day. In another embodiment, the patient is administered from about 1000 mg to about 2000 mg per day. In another embodiment, the patient is administered about 1000 mg per day. In another embodiment, the patient is administered about 2000 mg per day.
  • the invention also provides Compound IA for use in medical therapy, and particularly in respiratory and skin and skin structure infections.
  • the invention is directed to the use of Compound IA in the preparation of a medicament for the treatment of respiratory and skin and skin structure infections.
  • compositions Compound IA will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising Compound IA and one or more pharmaceutically-acceptable excipient.
  • dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; and (3) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of Compound IA once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of Compound IA and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention is directed to the succinate salt of trans-4-aminocyclohexyl (1S,2R,3S,4S,6R,7R,8R,14R)-4-ethenyl-3-hydroxy-2,4,7,14-tetramenthyl-9-oxotricyclo[5.4.3.01,8]tetradec-6-yl imidodicarbonate (Compound IA). Compound IA is useful for the treatment of a variety of diseases and conditions, such as respiratory tract and skin and skin structure infections. Accordingly, the invention is still further directed to methods of treating respiratory tract and skin and skin structure infections using Compound IA or a pharmaceutical composition comprising Compound IA.

Description

NEW PLEUROMUT1L1JN DERIVATIVE AND ITS USE
FIELD OF THE INVENTION
The invention is directed to the succinate salt of /rα/τs'-4-aminocyclohexyl (lS',2Λ,3S',4S,6R,7β,8/?,14R)-4-ethenyl-3-hydroxy-2,4,7,14-tetramethyl-9-oxotricyclo[5.4.3.01,8] tetradec-6-yl imidodicarbonate depicted herein as Compound IA, and its use in the treatment of respiratory tract and skin and skin structure infections.
BACKGROUND OF THE INVENTION International Application No. PCT/EP01/11603, published as International Publication
Mo. WO 02/30929, discloses certain pleuromutilin derivatives useful as antibacterial agents. Specifically, WO 02/30929 discloses C-14 oxycarbonyl carbamate pleuromutilin derivatives according to Formula IA or Formula IB therein.
One such C-14 oxycarbonyl carbamate pleuromutilin derivative encompassed within Formula IA of WO 02/30929 is *r<mv-4-aminocyclohexyl (lS,2R,3S,43,6R,7R$R,14R)-4-ethenγl- 3 -hydroxy-2,4,7, 14-tetramethyl-9-oxotricyclo [5.4.3.01, 8]tetradec-6-yl imidodicarbonate
("Compound I"). While Compound I is encompassed within Formula IA of WO 02/30929, it is not specifically disclosed in the specification or claims. Compound I is represented by the following structure:
Figure imgf000002_0001
Compound I
In addition, WO 02/30929 discloses that the compounds disclosed therein that contain a basic group "may be in the form, of a free base or an acid addition salt." Pharmaceutically acceptable salts, such as those described by Berge et al. (J. Pharm Sci., 1977, 66, 1-19) are indicated as preferred salts. Hydrochloride, maleate, and methanesulfonate are specifically mentioned.
Compound I has recently been identified as a particularly useful compound because it has demonstrated good in vitro and in vivo activity against representative Gram-positive and Gram-negative pathogens associated with respiratory tract and skin and skin structure infections including isolates resistant to existing classes of antimicrobials. In view of the good in vitro and in vivo activity exhibited by Compound 1 against representative Gram-positive and Gram-negative pathogens associated with respiratory tract and skin and skin structure infections there is a need for a form of Compound I suitable for pharmaceutical development.
SUMMARY OF THE INVENTION
The invention is directed to the succinate salt of ?ra?w-4-aminocyclohexyl (lS^Λ^S^ό^y^S^l^^-ethenyl-S-hydroxy-l^^^^tetramethyl-Q-oxotricycloCS^.S.Ol^] tetradec-6-yl imidodicarbonate depicted herein as Compound IA. Compound IA is useful in the treatment of a variety of diseases and conditions, such as respiratory tract and skin and skin structure infections. Accordingly, the invention is further directed to pharmaceutical compositions comprising Compound IA. The invention is still further directed to methods of treating respiratory tract and skin and skin structure infections using Compound IA or a pharmaceutical composition comprising Compound IA.
BRIEF DESCRIPTION OF THE FIGURES Figure 1 is an x-ray powder diffractogram of Compound IA. Figure 2 is an x-ray powder diffractogram of Compound IA. Figure 3 a is an x-ray powder diffractogram of Sample A of Example 23. Figure 3b is an x-ray powder diffractogram of Sample B of Example 23.
Figure 3c is an x-ray powder diffractogram of Sample C of Example 23. Figure 3d is an x-ray powder diffractogram of Sample D of Example 23. Figure 3e is an x-ray powder diffractogram of Sample E of Example 23. Figure 3f is an x-ray powder diffractogram of Sample F of Example 23. Figure 4a is a 13C solid-state NMR spectrum of Sample A of Example 23.
Figure 4b is a 13C solid-state NMR spectrum of Sample B of Example 23. Figure 4c is a 13C solid-state NMR spectrum of Sample C of Example 23. Figure 4d is a 13C solid-state NMR spectrum of Sample D of Example 23. Figure 4e is a 13C solid-state NMR spectrum of Sample E of Example 23. Figure 4f is a 13C solid-state NMR spectrum of Sample F of Example 23.
Figure 5a is an x-ray powder diffractogram of the product of Example 19. Figure 5b is an x-ray powder diffractogram of the product of Example 20. Figure 5c is an x-ray powder diffractogram of the product of Example 21. Figure 5d is an x-ray powder diffractogram of the product of Example 22. Figure 6a is a 13C solid-state NMR spectrum of the product of Example 19. Only the deshielded region (230 to 100 ppm) of the spectrum is shown.
Figure 6b is a 13C solid-state TSTMR spectrum of the product of Example 20. Only the deshielded region (230 to 100 ppm) of the spectrum is shown. Figure 6c is a 13C solid-state NMR spectrum of the product of Example 21. Only the deshielded region (230 to 100 ppm) of the spectrum is shown.
Figure 6d is a 13C solid-state NMR spectrum of the product of Example 22. Only the deshielded region (230 to 100 ppm) of the spectrum is shown.
DETAILED DESCRIPTION OF THE INVENTION
In describing the invention, chemical elements are identified in accordance with the Periodic Table of the Elements. Abbreviations and symbols utilized herein are in accordance with the common usage of such abbreviations and symbols by those skilled in the chemical and biological arts. For example, the following abbreviations are used herein: "g" is an abbreviation for grams
"mL" is an abbreviation for milliliters "0C" is an abbreviation for degrees Celsius
"DMF" is an abbreviation for the solvent N,N-dimethylformamide "DSC" is an abbreviation for Differential Scanning Calorimetry "vol" or "vols" refers to is an abbreviation for volume or volumes, respectively, and refers to the amount of solvent used relative the weight of a starting material. One volume of solvent is defined as 1 mL of solvent for every 1 g of starting material, "eq" is an abbreviation for molar equivalents "THF" is an abbreviation for the solvent tetrahydrofuran "L" is an abbreviation for liters
"N" is an abbreviation for Normal and refers to the number of equivalents of reagent per liter of solution.
"mmol" is an abbreviation for millimole or millimolar "mol" is an abbreviation for mole or molar "LOD" is an abbreviation for Loss on Drying
"HPLC" is an abbreviation for High Pressure Liquid Chromatography "NMR" is an abbreviation of Nuclear Magnetic Resonance "TLC" is an abbreviation for Thin Layer Chromatography "LCMS" is an abbreviation for Liquid Chromatography/Mass Spectroscopy "KF" is an abbreviation for Karl Fischer water determination "JLR" is an abbreviation for Jacketed Lab Reactor
"TG" and "TGA" are abbreviations for ThermoGravimetric Analysis
"IPA" is an abbreviation for isopropanol, and is also known as 2-propanol
"NMP" is an abbreviation for N-methyl pyrrolidinone
"ppm" is an abbreviation for parts per million
Compound IA
The invention is directed to the succinate salt of Zrαrø-4-aminocyclohexyl QS,2RβS,4Sf6R,7R,8R,14R)A-eUιmyl-3-hydmxy-2^7,14ΛebmaeUiyl-9- oxotricyclo[5.4.3.01,8]tetradec-6-yl iniidodicarbonate depicted below as Compound IA.
Figure imgf000005_0001
Compound IA
Surprisingly, it has been found that Compound IA has advantageous physical properties that make it particularly well suited for pharmaceutical development.
In the solid state, Compound IA can exist in crystalline, semi-crystalline and amorphous structures, as well as mixrm-es thereof. Tn Compound TA the half mole of succinic acid and one mole of Compound 1 arc fully ionized, and this forms the "core solid-state structure" of Compound IA.15
The skilled artisan will appreciate that pharmaceutical molecules may form complexes with a variety of other organic molecules (including other pharmaceutical compounds) in which the host molecule is associated with the guest compound on a molecular level through interactions such as hydrogen bonding. It has now been found that the core solid-state structure of Compound IA contains large channels that can accommodate a variety of small compounds including variable amounts of additional succinic acid to form a co-crystal. It has now further been found that when greater than 0.5 molar equivalents of succinic acid is available upon formation of the solid-state structure, the additional succinic acid can become associated with the solid-state structure of Compound IA. As used herein, the term "additional succinic acid" in reference to Compound IA refers to the succinic acid content held in the solid-state structure of Compound IA over the fully ionized succinic acid present. It is believed that the additional succinic acid of Compound IA occupies the large channels that have now been found to exist in the solid-state structure. It is further believed that the additional molecules of succinic acid are held within the lattice of Compound IA via hydrogen-bonding interactions. This association between the solid-state structure of Compound IA and the additional succinic acid can vary over a defined range in a non-stoichiometric manner. The variable succinic acid content results in an approximate stoichiometry range of 0.5 to 1.4 (molar ratio between total succinic acid and Compound I. Thus, the additional succinic acid content ranges from 0 to about 0.9 molar equivalents. Accordingly, the invention is further directed to succinic acid co-crystalline solid-state structures of Compound IA of variable stoichiometry.
Example 23 and corresponding Figures 3 and 4 illustrate the variability that is possible in the stoichiometry of Compound IA. As described in Example 23, the process of slurrying Compound LA in water/2-propanol with succinic acid concentrations between 0 M and 0.8 M yields a stoichiometry range in the isolated sample as measured by HPLC. For the sample slurried in 0 M succinic acid solution (Sample A), the input ratio of 0.5 to 1 of succinic acid to Compound I was preserved upon analysis of the product isolated after slurry processing. For the sample slurried in 0.8 M succinic acid solution (Sample F), a ratio of 1.4 to 1 of succinic acid to Compound I was determined for the product. The six samples isolated from the slurry experiment were determined to possess the same basic core solid-state structure as Compound IA containing no additional succinic acid. This is confirmed by the similarity of the x-ray powder diffraction ("XRPD") patterns in Figure 3. Each pattern shown in Figure 3 was obtained from the corresponding sample from the slurry experiment. Despite the large change in succinic acid content, the diffraction patterns retain the same basic appearance. This is further confirmed by the solid-state 13C NMR spectra in Figure 4, which were obtained from the same corresponding samples. Signals from succinic acid from both the core solid-state structure of Compound IA and the additional succinic acid are clearly observable in the region of 180 ppm. These signals are not attributable to a second phase containing only free succinic acid, by comparison with the spectra of reference phases of succinic acid, which is further confirmed by the inability to readily remove succinic acid from the samples by washing.
Preparation of Compound IA with a desired stoichiometry may also be achieved by direct crystallization from a solution with varying amounts of succinic acid. In Figure 5, the XRPD patterns obtained from samples isolated from direct crystallization using a range of input succinic acid to Compound I ratios are shown. The preparation of each sample is described in detail in Examples 19, 20, 21 and 22. The stoichiometry of each of these samples was determined using HPLC and found to range between 0.5 to 1 and 1.2 to 1 (succinic acid to Compound 1). As shown in Figure 6, the additional succinic acid is clearly visible in the region of 180 ppm in the 13C solid- state NMR spectra of these samples.
The channels existing in the solid-state structure of Compound IA can also accommodate solvent molecules. Thus, the skilled artisan will appreciate that pharmaceutically-acceptable solvates of Compound IA may be formed wherein solvent molecules are incorporated into the solid-state structure during preparation. Solvates may involve non-aqueous solvents including, but not limited to, ethanol, isopropanol (also referred to as 2-propanol), rø-propanol (also referred to as 1-propanol), DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the solid-state structure. In addition, the solvent content of Compound IA can vary in response to environment and upon storage, for example, water may displace another solvent over time depending on relative humidity and temperature.
Solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as "hydrates. " Solvates wherein more than one solvent is incorporated into the solid-state structure are typically referred to as "mixed solvates". Solvates include "stoichiometric solvates" as well as compositions containing variable amounts of solvent (referred to as "non-stoichiometric solvates"). Stoichiometric solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as "stoichiometric hydrates", and non-stoichiometric solvates wherein water is the solvent that is incorporated into the solid- state structure are typically referred to as "non-stoichiometric hydrates". The invention includes both stoichiometric and non-stoichiometric solvates.
In addition, solid-state structures of Compound IA, including solvates thereof, may contain solvent molecules, which are not incorporated into the solid-state structure. For example, solvent molecules may become trapped within larger particles upon isolation. In addition, solvent molecules may be retained on the surface of the crystals. The invention includes such solid-state structures of Compound IA.
The skilled artisan will further appreciate that Compound IA, including solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline packing arrangements). Different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different IR spectra, solid-state NMR spectra, and X-ray powder diffraction patterns, which may be used for identification. Polymorphs may also exhibit different melting points, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in the production of different polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
Representative Embodiments
In one embodiment, the invention is directed to Compound IA in the solid state. In one embodiment, the invention is directed to Compound IA in crystalline form. In another embodiment, the invention is directed to Compound IA in semi-crystalline form. In another embodiment, the invention is directed to Compound IA in amorphous form.
In another embodiment, the invention is directed to substantially pure Compound IA. As used herein, the term "substantially pure" when used is reference to Compound IA refers to a product which is greater than about 90% pure. Preferably, "substantially pure" refers to a product which is greater than about 95% pure, and more preferably greater than about 97% pure. This means the product does not contain any more than about 10%, 5% or 3% respectively of any other compound.
In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA contains up to about 0.9 molar equivalents of additional succinic acid. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA contains up to about 0.7 molar equivalents of additional succinic acid. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA contains up to about 0.5 molar equivalents of additional succinic acid. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA contains up to about 0.3 molar equivalents of additional succinic acid. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA contains from about 0.3 to about 0.7 molar equivalents of additional succinic acid. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA contains no additional succinic acid. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA contains about 0.3 molar equivalents of additional succinic acid. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA contains about 0.5 molar equivalents of additional succinic acid. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA contains about 0.7 molar equivalents of additional succinic acid.
In another embodiment, the invention is directed to a solvate of Compound IA. In another embodiment, the invention is directed to an isopropanol solvate of Compound IA. In another embodiment, the invention is directed to an w-propanol solvate of Compound IA. In another embodiment, the invention is directed to a hydrate of Compound IA.
In another embodiment, the invention is directed to a non-stoichiometric solvate of Compound IA. In another embodiment, the invention is directed to a non-stoichiometric isopropanol solvate of Compound IA. In another embodiment, the invention is directed to a non- stoichiometric 7?-ρropanol solvate of Compound IA. In another embodiment, the invention is directed to a non-stoichiometric hydrate of Compound IA.
In another embodiment, the invention is directed to a non-stoichiometric isopropanol solvate of Compound IA containing up to about 6% isopropanol. In another embodiment, the invention is directed to a non-stoichiometric isopropanol solvate of Compound IA containing up to about 4% isopropanol. In another embodiment, the invention is directed to a non- stoichiometric isopropanol solvate of Compound JLA containing from about 2% to about 4% isopropanol.
In another embodiment, the invention is directed to a non-stoichiometric n-propanol solvate of Compound IA containing up to about 6% w-propanol. In another embodiment, the invention is directed to a non-stoichiometric n-propanol solvate of Compound IA containing up to about 4% n-propanol. In another embodiment, the invention is directed to a non-stoichiometric n- propanol solvate of Compound IA containing from about 2% to about 4% 7z-propanol.
In another embodiment, the invention is directed to a non-stoichiometric hydrate of
Compound IA containing up to about 6% water. In another embodiment, the invention is directed to a non-stoichiometric hydrate of Compound IA containing up to about 4% water. In another embodiment, the invention is directed to a non-stoichiometric hydrate of Compound IA containing from about 2% to about 4% water.
In another embodiment, the invention is directed to a mixed solvate of Compound IA. In another embodiment, the invention is directed to a mixed solvate of Compound IA wherein the solvents are isopropanol and water. In another embodiment, the invention is directed to a mixed solvate of Compound IA wherein the solvents are 77-propanol and water. In another embodiment, the invention is directed to a mixed solvate of Compound IA containing up to about 6% of solvent. In another embodiment, the invention is directed to a mixed solvate of Compound IA containing up to about 4% of solvent. In another embodiment, the invention is directed to a mixed solvate of Compound IA containing from about 2% to about 4% of solvent. The core solid-state structure of Compound IA is characterized by an XRPD pattern having characteristic peaks at the following positions: 10.8 ± 0.2 (° 2Θ), 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Q), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Q), 18.5 ± 0.2 (° 2Q), and 21.2 ± 0.2 (° 2Θ). In addition to these XRPD peaks, several additional peaks present in the patterns may vary with solvent and water content. Accordingly, in another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by an XRPD pattern having a characteristic peak at 10.8 ± 0.2 (° 2Θ) and at least one additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 2Θ). In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by an XRPD pattern having a characteristic peak at
10.8 ± 0.2 (° 2Θ) and at least two additional characteristic peaks selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 2Θ). In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by an XRPD pattern having a characteristic peak at 10.8 ± 0.2 (° 2Θ) and at least three additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ),
12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 2Θ). In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by an XRPD pattern having a characteristic peak at 10.8 ± 0.2 (° 2Θ) and at least four additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 2Θ). In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by an XRPD pattern having a characteristic peak at 10.8 ± 0.2 (° 2Θ) and at least five additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 2Θ). In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by an XRPD pattern having characteristic peaks at the following positions: 10.8 ± 0.2 (° 2Θ), 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), and 21.2 ± 0.2 (° 2Θ).
The core solid-state structure of Compound IA containing additional succinic acid is characterized by XRPD patterns having characteristic peaks at the following positions: 10.8 ± 0.2 (° 2Θ), 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Q), and 21.2 ± 0.2 (° 20), as well as several additional peaks that vary in intensity with succinic acid content, in particular peaks at 9.8 ± 0.2 (° 20), 15.1 ± 0.2 (° 2Θ) and 15.6 ± 0.2 (° 2Θ). Furthermore, several additional peaks present in the patterns may vary with solvent and water content. Accordingly, in another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by an XElPD pattern having (a) a characteristic peak at 10.8 ± 0.2 (° 20); (b) at least one additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 20), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 2Θ); and (c) at least one additional characteristic peak selected from characteristic peaks at the following positions: 9.8 ± 0.2 (° 20), 15.1 ± 0.2 (° 20) or 15.6 ± 0.2 (° 2Q). In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by an XRPD pattern having (a) a characteristic peak at 10.8 ± 0.2 (° 2Θ); (b) at least two additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 20), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 20); and (c) at least one additional characteristic peak selected from characteristic peaks at the following positions: 9.8 ± 0.2 (° 2Θ), 15.1 ± 0.2 (° 2Θ) or 15.6 ± 0.2 (° 20). In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by an XRPD pattern having (a) a characteristic peak at 10.8 ± 0.2 (° 20); (b) at least three additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 20), 18.5 ± 0.2 (° 20), or 21.2 ± 0.2 (° 20); and (c) at least one additional characteristic peak selected from characteristic peaks at the following positions: 9.8 ± 0.2 (° 20), 15.1 ± 0.2 (° 2Θ) or 15.6 ± 0.2 (° 20). In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by an XRPD pattern having (a) a characteristic peak at 10.8 ± 0.2 (° 2Θ); (b) at least four additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 20), 12.9 ± 0.2 (° 20), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 2Θ); and (c) at least one additional characteristic peak selected from characteristic peaks at the following positions: 9.8 ± 0.2 (° 20), 15.1 ± 0.2 (° 2Θ) or 15.6 ± 0.2 (° 2Θ). In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by an XRPD pattern having (a) a characteristic peak at 10.8 ± 0.2 (° 2Θ); (b) at least five additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 20); and (c) at least one additional characteristic peak selected from characteristic peaks at the following positions: 9.8 ± 0.2 (° 20), 15.1 ± 0.2 (° 2Θ) or 15.6 ± 0.2 (° 2Θ). In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by an XRPD pattern having characteristic peaks at the following positions: 9.8 ± 0.2 (° 2Θ), 10.8 ± 0.2 (° 2Θ), 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 15.1 ± 0.2 (° 2θ), 15.6 ± 0.2 (° 2θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), and 2T.2 ± 0.2 (° 2Θ). In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 1. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 2. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 3 a. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 3b. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 3c. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 3d. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 3e. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 3f. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 5a. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 5b. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 5c. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by substantially the same XRPD pattern as depicted in Figure 5d.
The XRPD data described herein was acquired using a Philips X'Pert Pro powder X-ray diffractometer. Samples were gently flattened onto a zero-background silicon holder. A continuous 2Θ scan range of 2° to 40° was used with a CuKLa radiation source and a generator power of 40 kV and 40 mA. A 2Θ step size of 0.0167 degrees/step with a step time of 10.16 seconds was used. Samples were rotated at 25 rpm and all experiments were performed at room temperature. Characteristic XRPD peak positions are reported in units of angular position (2Θ) with a precision of +/- 0.1°, which is caused by instrumental variability and calibration. The location (° 20 values) of these peaks was obtained from an XRPD pattern expressed in terms of 2-theta angles and obtained with a diffractometer using copper Ka -radiation. The XRPD patterns provided herein are expressed in terms of 2-theta angles and obtained with a diffractometer using copper Ka -radiation. It will be understood by those skilled in the art that an XRPD pattern will be considered to be substantially the same as a given XRPD pattern if the difference in peak positions of the XRPD patterns are not more than ± 0.2 (° 2Θ).
The core solid-state structure of Compound JLA is also characterized by a 13C solid-state NMR spectrum having characteristic peaks at 224.0, 222.5, 181.1, 177.8, 140.7, and 139.8 ppm. In addition to these peaks, several additional NMR peaks vary in intensity with succinic acid content, in particular peaks at 223.1, 182.0, 178.8, 175.1, and 141.8 ppm. Accordingly, in another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by a 13C solid-state NMR spectrum having characteristic peaks at 224.0, 222.5, 181.1, 177.8, 140.7, and 139.8 ppm. In another embodiment, the invention is directed to Compound IA in the solid state wherein the solid-state structure of Compound IA is characterized by a 13C solid-state NMR spectrum having characteristic peaks at 224.0, 223.1, 222.5, 182.0, 181.1, 178.8, 177.8, 175.1, 141.8, 140.7, and 139.8 ppm.
The solid-state NMR data described herein was acquired using a Bruker Avance 400 triple-resonance spectrometer operating at a 1H frequency of 399.87 MHz. The spectra shown were obtained using a 13C cross-polarization pulse sequence with a Bruker 4-mm triple resonance magic-angle spinning probe at a rotor frequency of 8 kHz. A linear power ramp from 75 to 90 kHz was used on the 1H channel to enhance cross-polarization efficiency. Spinning sidebands were eliminated by a fivc-pulsc total sideband suppression pulse sequence. Characteristic 13C NMR peak positions are reported relative to tetramethylsilane at 0 ppm (parts per million) and are quoted to a precision of +/- 0.3 ppm, because of instrumental variability and calibration. The locations of these peaks are obtained from a 13C solid-state NMR spectrum obtained using cross-polarization and sideband suppression. It will be understood by those skilled in the art that a 13C solid-state NMR spectrum will be considered to be substantially the same as a given 13C solid-state NMR spectrum if the difference in peak positions of the spectra are not more than + 0.3 ppm.
Compound Preparation Generally speaking, Compound IA is prepared from pleuromutilin. Pleuromutilin may be produced by the fermentation of microorganisms such as Cϊitopilus species, Octojuga species and Psathyrella species using methods known to those skilled in the art. Pleuromutilin is then isolated from the fermentation broth with organic solvent. Alternatively, Compound I can be prepared from mutilin. Pleuromutilin may be converted to mutilin by alkaline hydrolysis. Such methods are well known in the art. Other starting materials and reagents are commercially available or are made from commercially available starting materials using known methods.
One approach to making Compound IA is to prepare Compound I (as the free base), dissolve in an appropriate solvent, and mix. with succinic acid. For example, Compound I can be prepared according to the methods described in WO 02/30929. This approach generally produces Compound 1 as a foam. One variation in this approach involves preparing Compound 1 as an isopropanol solvate. The isopropanol solvate of Compound I can be prepared by dissolving the foam in isopropanol and allowing the isopropanol solvate to crystallize. Either way, Compound 1 dissolves readily in common organic solvents and aqueous mixtures of water miscible organic solvents such as alcohols, acetonitrile, and tetrahydrofuran. Succinic acid can then be added and the salt allowed to crystallize thereby forming Compound IA.
Alternatively, the hydrochloride salt of Compound I can be prepared according to the method described in Example 7 below. The hydrochloride salt of Compound I can then be converted to Compound IA with succinic acid under appropriate reaction conditions. The succinic acid content of the final product can be controlled by adjusting the amount of succinic acid added to the free base during the salt- forming reaction, or by slurrying Compound IA in succinic acid solutions of varying concentration to achieve additional succinic acid contents ranging from 0 to about 0.9.
Examples
The following examples arc not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare the compounds of the invention.
Example 1
Preparation of Intermediate 1
Figure imgf000015_0001
Pleu rom utilin 1 a
Figure imgf000015_0002
Inte rm ed iate 1
1 b
To a reaction vessel under nitrogen atmosphere were charged pleuromutilin (59.2 grams), methanol (240 mL) and trimethyl orthoformate (95 mL). The mixture was cooled to O0C. Concentrated sulfuric acid (18 mL) was added slowly to keep the reaction temperature below 100C. After addition, the reaction mixture was heated to 300C. After 3 hours at 300C and 14 hours at 18°C, the reaction was deemed complete by HPLC analysis. The crude product in the reaction mixture was used in next reaction directly. Ia in the reaction mixture was cooled to -100C. Water (70 mL) was added slowly to keep the internal temperature below 15°C. An aqueous solution of sodium hydroxide (135 mL, 50% w/w) was charged slowly to keep the internal temperature below 15°C. The reaction was then heated to 65°C. After 30 minutes at 65°C the reaction was complete based on HPLC analysis. The reaction was cooled to ~40°C. Methanol was distilled out under reduced pressure. Water (300 mL) and toluene (350 mL) were added to the mixture. The mixture was heated to ~65°C and was stirred for 10 minutes. After settling for 30 minutes, the aqueous layer was separated. The aqueous layer was extracted with toluene (200 ml). The organic layers were combined and distilled under reduced pressure to a final volume of ~300 mL. The crude product in toluene was used directly in next reaction. To the product from above in toluene was added more toluene (350 mL) at ambient temperature. Sodium cyanate (27.4 grams) was added with stirring. Trifluoroacetic acid (29 mL) was slowly added over 0.5 hour. The mixture was stirred for 14 hours at ambient temperature. No starting material was detected in the reaction mixture by HPLC analysis. Water (360 mL) was added to the reaction with stirring. The layers were separated and the aqueous layer was discarded. Toluene was distilled under reduced pressure until a final volume of -100 mL. Heptane (300 mL) was added. The mixture was stirred at 65°C for 30 minutes then cooled to O0C and stirred for one hour. The resulting slurry was filtered and washed twice with cold heptane (80 mL). The crude product was dried at 65-700C under vacuum to give 42.1 grams of Intermediate 1. Yield: 71%.
Example 2
Preparation of Intermediate 1
Figure imgf000016_0001
Pleuromutiliπ 2a
Figure imgf000016_0002
Intermediate 1
2b
To a reaction vessel under nitrogen atmosphere were charged pleuromutilin (20.0 grams), methanol (80 mL) and trimethyl orthoformate (32 mL). The mixture was cooled to 00C. Concentrated sulfuric acid (6 mL) was added slowly to keep the reaction temperature below 100C. After addition, the reaction mixture was heated to 300C. After 5 hours at 300C and 14 hours at 18°C, the reaction was deemed completed by HPLC analysis. The reaction mixture was cooled to ~10°C. Triethylamine (32 mL) was added slowly to keep the internal temperature below 300C. Water (110 mL) was added to the reaction with vigorous stirring. The mixture was stirred at ~20°C for 4 hours. The crude product was filtered and washed with water (60 mL) twice. The wet solid was dried at 500C under vacuum to give 16.0 grams of product. Yield: 77%.
To a flask were charged methanol (80 mL) and water (10 mL). Potassium hydroxide (5.7 g) was added. The mixture was stirred for ~5 minutes to a solution. 2a (20.0 g) was added to the mixture. The reaction mixture was heated to 65°C and stirred for 1 hour. The reaction was deemed complete by HPLC analysis and the mixture was cooled to ~25°C and slowly transferred into a larger flask containing water (100 mL) and 2b seed (50 mg) with vigorous stirring. The resulted slurry was cooled to ~5°C and stirred for 1 hour. The crude 2b was filtered and washed with water (50 mL) twice. The wet product was dried at ~65UC for 24 hours to give 15.3 grams of solid. Yield: 90%.
To a flask were charged toluene (180 mL), 2b (20.0 g) and sodium cyanate with stirring. Trifluoroacetic acid (10 mL) was slowly added over 1 hour. The mixture was stirred for 16 hours at ambient temperature after which no 2b was detected by HPLC analysis. Water (100 mL) was added to reaction with stirring and the layers were separated. The aqueous layer was discarded and the toluene layer was concentrated under reduced pressure to a final volume of ~30 mL. Heptane (100 mL) was added and the mixture was stirred at 65°C for 30 minutes. The mixture was cooled to 00C and stirred for 1 hour. The resulted slurry was filtered and washed with cold heptane (20 mL, ~0°C) twice. The crude product was dried at 65°C under vacuum to give 19.1 grams of Intermediate 1. Yield: 85%.
Example 3
Preparation of Intermediate 1
Figure imgf000017_0001
Intermediate 1
Figure imgf000017_0002
To a flask were charged N-methyl pyrrolidone (24 mL), 2a solid (from Example 2) (12.0 grams), and water (10 mL). Sodium hydroxide aqueous solution (20 mL, 50%w/w) was added. The reaction mixture was heated to 700C and stirred for 1 hour. Toluene (120 mL) was added to the mixture, stirred for 30 minutes and the layers were separated. The toluene layer was washed with water (30 mL) and concentrated under vacuum to ~ 100 mL final volume. The crude product in toluene was used directly in the next reaction.
To 3a in toluene was added sodium cyanate. Trifluoroacetic acid (5 mL) was slowly added over 1 hour. The mixture was stirred for —15 hours at ambient temperature until no 3a was detected by HPLC analysis. Water (30 mL) was added to reaction with stirring, the layers were separated, and the aqueous layer was discarded. Toluene was distilled under reduced pressure until ~10 xnL remained. Heptane (50 mL) was added and the mixture was stirred at 65°C for 30 minutes. The mixture was cooled to 00C and stirred for one hour. The resulting slurry was filtered and was washed twice with cold heptane (15 mL each, ~0°C). The crude product was dried at 650C under vacuum to give 9.5 grams of Intermediate 1. Yield: 82%.
Example 4
Preparation of N-Boc-frαns-4-aminocyclohexanol
Figure imgf000018_0001
crystallization rrαns-4-aminocyclohexanol hydrochloride (Aldrich, 96.5g, 0.636 mole) was added with mechanical stirring to 636 mL of 1.0N NaOH in a 3L 3N RBF, equipped with a 50OmL addition funnel. After a clear solution was obtained 30OmL of dioxane was added, and then the misture was cooled in an ice bath to about 5°C. A solution of di-tert-butyldicarbonate (Aldrich, 138.9g, 0.636 mole) in dioxane (30OmL) was added to the addition funnel and added dropwise to the reaction mixture over 1 hour. The reaction -was then allowed to slowly warm to room temperature with stirring in the bath overnight (milky white mixture). The whole was extracted with EtOAc (I x 80OmL, 2 x 50OmL), the organics were combined and washed with water and brine. At this point the product began to precipitate from the organic layer. 400 mL of ethanol was added to aid solubility of the product. The mixture was dried over magnesium sulfate then filtered and evaporated to 50OmL. Then hexanes (600 mL) was added slowly with stirring. The product, N-Boc-ή*α/is-4-aininocyclohexanol, was filtered, and washed thoroughly with hexanes to afford the product as white flakes. (98g, 72%).
Example 5 Preparation of Intermediate 2
Figure imgf000018_0002
Intermediate 2 To a IL flask was charged N-Boc-*rø/ts~4-aminocyclohexanol (made from commercially available frαws-4-aminocycIohexanol using methods known to those skilled in the art, 30.4 g, 0.141 mole) and DMF (338 ml). 1, 1 '-carbonyldiimidazole ("CDI", 162.15& 0.184 mole) was charged in one portion. The mixture was stirred at 180C for 2.5 hours until HPLC analysis indicated there was no N-Boc-/rα«s-4-aminocycIohexanoI present. The reaction was then cooled to 100C. Water (450 mL) was added slowly to keep temperature below 200C. The mixture was cooled to 00C and was stirred for 1 hour. The product was filtered and washed with water (50 mL) twice. The wet product was dried at 60-650C under vacuum for 24 hours. Yield: 40. Ig, 92%.
Example 6 Preparation of Intermediate 2
1) di-tert-butyl dicarbonate
Figure imgf000019_0002
2) 1 ,T-carbonyl
Figure imgf000019_0001
trans-4-aminocyclohexanol diimidazole Intermediate 2
To a 250ml flask under nitrogen atmosphere was charged DMF (98 mL) and di-t-butyl dicarbonate (63.6g, 0.291 mole). The mixture was stirred at ambient temperature to give a solution. To a second IL flask was charged tfrø/zs-4-aminocyclohexanol (commercially available) (32.5 g, 0.285 mole) and DMF (160 mL). The mixture was heated to 55-600C to give a solution. Approximately 33% of the di-t-butyl dicarbonate in DMF solution was slowly added to the tfraHS-4-aminocyclohexanol over approximately 30 minutes, keeping the process temperature below 75"C during the charge. The mixture was stirred for ~30min- 1 hour at 55-6O0C. The slow addition of ~33% of the di-t-buryl dicarbonate DMF solution was repeated twice more and the mixture was stirred for ~30min - 1 hour at 55-600C after each addition. After the last addition the reaction mixture was stirred at 70-750C over 1-2 hours. When GC analysis indicated that the ratio between intermediate N-Boc-*raws-4-aminocyclohexanol and ft-«ns-4-aminoeyclohexanol was greater than 33:1, the reaction mixture was cooled to 15-200C. DMF (250 mL) was charged to the reaction and stirred to give a solution. 1, 1 '-Carbonyldiimidazole (59.2g, 1.3 eq) was charged to the reaction in one portion. The reaction was stirred at ~19°C for 15 hours and reaction progress was monitored by HPLC. When the HPLC analysis indicated that the ratio between Intermediate 2 and N-Boc-ftwϊ.s-4-aiiiinocyclohexanol was greater than 49:1, the reaction mixture was cooled to ~0°C. Water (600 mL) was charged slowly to the reaction mixture while keeping the process temperature below ~20°C. The white solid product precipitated out of solution. The mixture was cooled to ~ 0°C and stirred for 1 hour. The product was filtered and the wet cake was washed with water (100 mL) twice. The product was dried at 60-650C under vacuum to a constant weight. Yield: 82.1 g, 94%.
Example 7 Preparation of Intermediate 3 (hydrochloride salt of Compound T)
Figure imgf000020_0001
Figure imgf000020_0002
Intermediate 3
A solution of Intermediate 1 (5.0 g, 13.2 mmol,l eq) in dry THF (50 mL, 10 vols) under a nitrogen atmosphere was cooled to -5 to 00C. To the solution was added sodium tert-pentoxide (3.6 g, 32.7 mmol, 2.5 eq) over ~10 minutes, maintaining the process temperature below 5°C. The reaction mixture was stirred at 0 to 5°C for ~0.5 hour. To the reaction mixture was added Intermediate 2 (4.5 g, 14.5 mmol, 1.1 cq) over —10 minutes, maintaining the process temperature below 50C. The reaction mixture was stirred at ~5°C and after 1 hour aqueous NH4CI solution (70 mL, 14 vols, 7.5%w/w) was added slowly at 25°C followed by ethyl acetate (60 mL, 12 vols). After stirring for ~15 minutes the organic layer was separated and washed with aqueous NH4CI solution (35 mL, 7 vols, 15%w/w). The organic portion was concentrated to ~8 volumes keeping the process temperature below ~45°C. The crude product 7a in ethyl acetate was used in the next step directly.
The crude mixture was cooled to ~ 1O0C and concentrated hydrochloric acid (20 mL, 4 vols) added slowly keeping the process temperature below 300C. The reaction mixture was heated to ~43°C and the reaction progress monitored by HPLC. After 2 hours, the reaction was complete. The reaction mixture was cooled to ~0°C and water (20 mL, 4 vols) added, keeping the process temperature at ~ 5°C. The pH of the reaction solution was adjusted to 4.5-5 by slowly adding aqueous ammonium hydroxide (-30% solution, ~15 mL, ~3 vols) over 20 minutes keeping the process temperature below 15°C. The reaction mixture/suspension was cooled to ~0°C, stirred for ~1 hour and filtered. The wet cake was washed with ethyl acetate (25 mL, 5 vols) twice. The solid product was dried under vacuum to constant weight at ~20°C (LOD ~5.2% w/w). Weight of solid product was 7.2 g (72 % w/w). Note: AU charges were based on the amount of Intermediate 1.
Example 8
Preparation of Compound IA from Intermediate 3
Figure imgf000021_0001
Compound IA
Into an extraction funnel was added 16 mL of dichloromethane ("DCM"), 4 g of crude Intermediate 3 (net 2.2 g), and 1.35 g of potassium carbonate dissolved in 12 mL of water. The layers were mixed well, and the dichloromethane layer was removed. The aqueous layer was re- extracted with 8 mL of dichloromethane. The dichloromethane layers were combined and extracted with 8 mL of water.
The dichloromethane was divided into two -equal portions and filtered into fresh flasks. To one portion was added 0.24 g succinic acid (1.0 eq) that was dissolved in 5 mL of n-propanol. The solution was seeded with Compound TA and distilled at atmospheric pressure to remove the dichloromethane. The solution was then cooled to room temperature and the product was isolated by filtration and dried to give 82% yield.
The total succinic acid content of the product was measured upon dissolution by HPLC and determined to be 1.0 molar equivalents. In addition, solid-state NMR of the product confirmed the presence of the core solid-state structure of Compound IA and additional succinic acid. The additional succinic acid content is 0.5 molar equivalents. Example 9
Preparation of Compound IA from Intermediate 3
Figure imgf000022_0001
Compound IA Into an extraction funnel was added 8 mL of diehloromethane (DCM), 2g of crude
Intermediate 3 (net 1.34 g), and 0.675 g of potassium carbonate dissolved in 6 mL of water. The layers were mixed well, and the diehloromethane layer was removed. The aqueous layer was re- extracted with 4 mL of diehloromethane. The diehloromethane layers were combined and extracted with 4 mL of water. 0.35 g of succinic acid (1.2 eq) was dissolved in 12 mL of n-propanol and added to the diehloromethane solution. The solution was stirred and seeded with Compound IA. and left overnight. The slurry was distilled at atmospheric pressure to remove the diehloromethane. The solution was then cooled to room temperature and the product was isolated by filtration and dried to give 89% yield. The total succinic acid content of the product was measured upon dissolution by HPLC and determined to be 1.0 molar equivalents. In addition, solid-state NMR of the product confirmed the presence of the core solid-state structure of Compound IA and additional succinic acid. The additional succinic acid content is 0.5 molar equivalents.
Example 10
Preparation of Compound IA from Intermediate 3
Figure imgf000023_0001
Compound IA
Into an Erlenmeyer flask was added 56 mL of dichloromethane (DCM), 14 g of crude Intermediate 3 (net 9.4 g), and 4.72 g of potassium carbonate dissolved in 42 mL of water. The layers were mixed well and transferred to a separatory funnel. The dichloromethane layer was removed. The aqueous layer was re-extracted with 28 mL of methylene chloride. The dichloromethane layers were combined and extracted with 28 mL of water.
2.46 g of succinic acid (1.2 eq) was dissolved in 84 mL of n-propanol and added to the dichloromethane solution. The solution was seeded with Compound IA. The slurry was distilled at atmospheric pressure over 4 h to remove the dichloromethane. The solution was then cooled to room temperature overnight and cooled to 0°C and the product was isolated by filtration and dried to give 86% yield, 9.29gm.
Example 11
Preparation of Compound IA from Intermediate 3
Figure imgf000023_0002
Compound IA A l L jacketed reactor was charged with 240 mL of dichloromethane (DCM) and 6Og of crude Intermediate 3 (net 38.7 g). Potassium carbonate (20.2 g) was dissolved in 180 mL of water and charged to the reactor over 15 minutes. The reaction was stirred for 15 minutes, settled, and then the layers were separated. The aqueous layer was re-extracted with 120 mL of dichloromethane. The dichloromethane layers were combined and extracted with 120 mL of water. The dichloromethane layers were filtered into a 1 L flask.
10.14 g of succinic acid (1.2 eq) was dissolved in 300 mL of n-propanol and added to the dichloromethane solution. The solution was seeded with Compound IA. The slurry was distilled at atmospheric pressure over ~5 h to remove the dichloromethane and stirred at room temperature overnight. The solution was then slowly cooled to 5 0C in an ice bath and the product was isolated by filtration and washed with 180 mL of cold n-propanol. The wet cake was dried under vacuum at 600C to give 84% yield, 37.2gm.
Example 12
Preparation of Compound IA from Intermediate 3
Figure imgf000024_0001
Compound IA
24.12 g of Intermediate 3 (74.03 %w/w, net 17.86 g, 35.4 mmol) was charged to a flask. To this solid were added 96.5 mL of dichloromethane (DCM) and 72.4 mL of water containing 8.0 g of potassium carbonate. This mixture was stirred for 45 minutes at room temperature until 2 clear layers were observed. The bottom dichloromethane layer was removed, and the aqueous layer was re-extracted with 48 mL of dichloromethane. The combined dichloromethane layers were extracted with 48 mL of water. The dichloromethane layer was divided and for the remaining portion of this procedure: 32.4 weight % of the solution of the dichloromethane layer (containing 5.79 g of free base, 11.5 mmol, l.cq) was used. To this solution was charged a solution of succinic acid (1.63g, 1.2 eq) dissolved in 39.1 mL of 2-propanol. The clear solution was then seeded with 5 mg of Compound IA seed crystals in 0.25 mL 2-propanol. The suspension was distilled to remove dichloromethane over 90 minutes and then cooled slowly to 00C. After one hour at 00C, the solids were filtered and washed with 15 mL of 2-propanol. The solids were dried at 55°C under vacuum to give 6.99 g, a 98% yield.
Example 13
Preparation of Compound I
Figure imgf000025_0001
A 12L 3NRB flask equipped with overhead stirrer and under argon was charged with pleuromutilin (389g, 1.03 mole), methanol (6 L), and trimethylorthoformate (620 mL). The homogeneous clear solution was cooled with stirring in an ice bath, and concentrated sulfuric acid (103 mL) was added dropwise keeping the temperature < 5°C. The reaction was then allowed to warm to room temperature and stir until complete (~4 days) as determined by TLC (2:1 hexanes:EtOAc). The reaction mixture was concentrated to about. IL, and diluted with methylene chloride (3L). The slightly brown mixture was washed with water (1 L) until the washings were at about. pH = 5. The mixture was then wash with saturated NaHCO3, dried (MgSO4), filtered and evaporated. The residue was dissolved in a minimum amount of boiling hexanes (3-5 L), allowing to cool to room temperature, when crystals began to form. The flask was placed in the refrigerator overnight, then the crystals were collected, washed with a small amount of hexanes and dried to give 31Og of the product, epi-plcuromutilin, (77%).
Figure imgf000025_0002
epi-pleuromutiHn (418 g, 1.065 mole) was dissolved in MeOH (5.4 L) with stirring, and a solution of KOH (153 g) in water (800 mL) was added. The reaction was stirred overnight at
45°C when the reaction was complete by TLC (2:1 hexanes :EtO Ac). The mixture was concentrated to about 1.5 L total volume, and EtOAc (1.5 L) was added. The aqueous layer was separated and extracted with EtOAc (0.5 L), and the combined organics was washed with IN HCl (1 L), which was back-extracted with EtOAc (0.5 L). The combined organics was washed with brine (2 x 0.5 L), dried (MgSO4), filtered and evaporated. The residue was dissolved in boiling hexanes (~ 1.6 L), filtered and allowed to cool to room temperature. Seeds were added and the mixture was cooled in a refrigerator for 90 minutes, then in a freezer 90 minutes. The mother liquor was decanted off, and the solid rinsed with hexanes and dried to give 214g of the product, epimutilin (60%). The mother liquor and washes were combined and evaporated to give additional product as a pale yellow solid 152.2g.
146g of epimutilin (0.437 mole) was dissolved in THF (0.5 L) in a 2L 3NRB flask equipped with mechanical stirrer and argon inlet. The solution was cooled in an ice bath with stirring an pyridinc(35.3 mL, 0.437 mole) was added, followed by portionwisc addition of triphosgene (129.6g, 0.437 mole, 3 phosgene eq.) over 10 minutes (immediate white precipitate). The mixture was allowed to warm slowly to room temperature and stir overnight. TLC (3:1 hexanes :EtO Ac). The mixture was diluted with hexanes (2L), washed with water (oaτe! efforvescence), (3 x 0.5 L), then brine (0.5 L), and dried (MgSO4). Filtration and evaporation provided the product, epimutilin chloroformate, as a pale yellow solid 167.9 g (97%).
Figure imgf000026_0002
A 2L, 3NRB flask equipped with a mechanical stirrer was charged with N-Boc-ή*««s-4- aminocyclohexanol (44.7 g, 0.208 mole), pyridine (2.0 mL, catalytic), and CH2Ck (0.5 L) under an argon atmosphere (the mixture remains slightly cloudy, since the alcohol is not completely soluble). Silver cyanate (Aldrich, 38.3 g, 0.254 mole) is added, and the heterogeneous mixture is cooled in an ice bath. Epϊmutilin chloroformate (91.7 g, 0.231 mole) in CH2Cl2 (0.5 L) is then added dropwise via addition funnel over 1 hour, and then the mixture is allowed to slowly warm to room temperature and stir overnight (the reaction mixture turns from a reddish brown to grey color). Monitoring can be done by TLC (9:1 CHCljrEtOAc). The mixture was filtered through celite, washing thoroughly with CH2Cl2- The filtrate was evaporated and purified by chromatography* 5-30% EtOAc/ CHCl3 to afford the product as a white foam (132.6 g, 97%).
Figure imgf000027_0001
The above material (132.6 g, 0.214 mole) was dissolved in 1,4-dioxane (670 mL) and cooled in an ice bath with stirring. Concentrated aqueous HCl (335 mL) was added through a droppong funnel at such a rate to maintain the internal temperature < 5°C (about. 65 minutes). The reaction mixture was allowed to warm to room temperature and stir for 1-1.5 hours, when LCMS showed the absence of starting material and only the desired product. The mixture was concentrated to about 500 mL, then added slowly to rapidly stirring ice cold water (1.5 L). After stirring 30 minutes the aqueous solution was washed with EtOAc (2 x 500 mL), and the combine extracts back washed with, water (250 mL). The combined aqueous phases were cooled in an ice bath and basified to pH=8.5 (maintain the internal temperature < 100C) with concentrated NH4OH. The resulting cloudy basic mixture was extracted with EtOAc (1 x IL, 2 x 0.5 L). The combined extracts were dried over MgSO4, then filtered and evaporated to give a white foam (96 g). This foam was taken up in hot (~80°C) isopropanol (700 mL), giving a clear colorless solution. The heating mantel was removed and the mixture allowed to cool slowly to room temperature. The white solid precipitate was filtered off, and washed with cold isopropanol (200 mL), and hexanes (250 mL) to give Compound I as the isopropanol solvate (98.6 g). After further drying at 800C under high vacuum, the material weighed 87.6 g. There was a slight excess of 1 molar equivalent of isopropanol in the NMR spectrum.
TLC was visualized with eerie ammonium molybdate stain and/or phosphomolybdic acid stain. Example 14
Preparation of Compound I
Figure imgf000028_0001
A solution of mutilin (93g, 0.29 mole) in EtOAc (1 L) was cooled to -45 degrees C (CHsCN/dry ice bath) with mechanical stirring under nitrogen. Trifluoroacetyl imidazole (Aldrich, 5 x 1Og ampules, 5Og, 0.30 mole) was then added dropwise over 30-45 minutes. After stirring for 1 hour, TLC (10% EtOAc/hexanes) showed complete consumption of mutilin. The mixture was allowed to ward to — 200C, and was then washed with IN HCl (2 x 30OmL), water, brine and then was dried over magnesium sulfate and filtered. After concentration to 300-40OmL, IL of hexanes was added with stirring. The precipitated product was filtered and washed with hexanes (IL) to afford pure H-OTF A-mutilin as a white crytalline solid (55g). Additional product was obtained by evaporating the filtrate, and stirring the residue in ethyl ether (10OmL), and diluting with hexanes (40OmL). Filtration and washing with hexanes gave a second crop (47g) which was -90% pure by NMR.
phosgene (2.0 eq) pyridine (1.5 eq) toluene, 0-RT
Figure imgf000028_0002
Figure imgf000028_0003
To a mechanically stirred solution of 11-OTFA-mutilin (40 g, 0.096 mole) in toluene (10OmL) was added pyridine (11.6 mL, 0.144 mole) and the whole was cooled in an ice bath under nitrogen. A solution of phosgene in toluene (Fluka, assumed ~2M, 96 mL, 0.192 mole) was then added steadily over 10 minutes. The resulting suspension was stirred 30 minutes in the ice bath, then allowed to warm to room temperature and stir 1 hour, at which point TLC (10% EtOAc/ hexanes) showed complete consumption of starting material. The mixture was purged with nitrogen for 1 hour (20% NaϊCOs trap) to remove excess phosgene, and diluted with toluene (500 mL). After washing with IN HCl (2 x 20OmL), water, and brine, the solution was dried over magnesium sulfate, filtered and evaporated to provide the product as a thick syrup (56 g). The product still contained residual toluene, and was used as is in the next step. The H-OTFA- mutilin chloroformate can be obtained as a white solid by trituration with hexane.
Figure imgf000029_0001
N-Boc- trans-4-aminocyclohexanol (20.6g, 0.096 mole) and pyridine (1 mL) were added to CH2CI2 (400 mL) in a 2L 3NRB flask equipped with a mechanical stirrer and addition funnel (the mixture was not completely clear). Silver cyanate (Aldrich, 17.3 g, 0.115 mole) was added, and the suspension was cooled in an ice bath. The above crude 11-OTFA-mutilin chloroformate (0.096 mole) in CH2Ck (400 mL) was added dropwise over 1 hour, and the reaction was allowed to slowly warm to room temperature and stir overnight (the mixture gradually turned from a reddish-brown to gray suspension over the course of the reaction). TLC (10% EtOAc/CHCl3) showed mostly product and a small amount of alcohol, starting material, and a byproduct close to the starting material Rf. The mixture was diluted with EtOAc and filtered through a thin pad of Celite, washing thoroughly with EtOAc. The filtrate was evaporated to give a foam which was used for the next step.
Figure imgf000029_0002
To the above crude material in EtOH (600 mL) at room temperature was added concentrated NH4OH (32 mL) dropwise with stirring over 20 minutes. After 3 hours the reaction was complete (TLC 20%EtOAc/hexanes). The solvent was evaporated, dioxane (10OmL) was added, and concentration afforded a foam.
The resulting foam was dissolved in dioxane (300 mL), and concentrated HCl (150 mL) was added dropwise over 30 minutes (reaction warmed to ~40°C). After stirring 1 hour, LCMS indicated complete conversion to product. The mixture was concentrated to 300 mL, and then slowly added with stirring to ice cold water (600 mL). The aqueous layer was washed with
EtOAc (2 x 250 mL), which were combined and back-extracted with water (100 mL). The combined aqueous material was cooled in an ice bath, and basified to pH 8-9 by slow dropwise addition of concentrated NH4OH, keeping the temperature < 100C. The basic mixture was then extracted with EtOAc (1 x 600 mL, 2 x 300 mL), the combined organics was washed with brine and dried over sodium sulfate. Filtration and evaporation, and trituration afforded a total of 37 g of Compound I which was ca. 86% pure by HPLC, major impurity was present at 8%.
TLC was visualized with eerie ammonium molybdate stain. HPLC purity determinations were performed by Karl Erhard.
Example 15 Preparation of Compound I
1. Methanol
Figure imgf000030_0001
Pleuromutilin (10Og) was dissolved in methanol (700 mL). Trimethyl orthoformate (130 mL) was charged in one portion and the mixture was cooled to 15°C. Concentrated sulphuric acid (25 mL) was slowly charged maintaining the temperature below 25°C. The mixture was stirred at 23°C for 22 hours. Triethylamine (100 mL) was charged and the mixture was heated to 50°C. Water (440 mL) was added followed by methyl isobutyl ketone (20 mL). A mixture of methanol (MeOH) (62 mL) and water (39 mL) was added, followed by seed crystals of the expected product (Ig). The mixture was stirred at 500C for 10 minutes then cooled to 35°C. The mixture was reheated to 500C and an additional 20 mL of methyl isobutyl ketone and Ig of seed was added. The mixture was cooled over 3 hours to 27°C, then held for 51 hours at 27°C, then cooled to 2°C for 3 hours. The product was filtered, rinsed with water (600 mL) and dried under vacuum overnight at room temperature to yield 73.1g of epi-pleuromutilin.
Figure imgf000031_0001
Figure imgf000031_0002
Figure imgf000031_0003
Intermediate 1
Stage 2
Methanol (143 mL) was charged to a 1 L jacketed lab reactor followed by epi- pleuromutilin solid (57.0 g, 0.145 moles). The contents were warmed to 40°C to give a solution. In a separate vessel, KOH (16.5g) was dissolved in water (29 mL) and this solution was added to the methanol mixture. The vessel contents were heated to 630C and held for 2 hours. The reaction was cooled to 45°C. Heptane (342 mL) and water (171 mL) were added. The mixture was stirred at 45°C, and then settled for 35 minutes. The aqueous layer was removed. The heptane layer was washed with water (130 mL, 2.3 vol). The pH was checked and was < 9. Heptane was distilled out under reduced pressure until ~ 115 mL remained in the reactor. With the agitator stirring, the contents were sampled and tested for KF. TBME (400 mL) was added to the reactor. The contents were cooled to ~ 5°C. Chlorosulfonyl isocyanate (26.7 g) was added slowly in 3 portions, keeping the temperature at < 200C. The reaction was held at ~18°C for ~1 hour and water (143 mL) was added slowly. Triethylamine (29.3 g) was added to the reaction, keeping the temperature ~27°C during addition. The reactor vessel was wanned to ~45°C and stirred for ~2 hours. The reaction was cooled to ~40°C and the layers were separated. The organics were washed with water (114 g) and the layers were separated. The organic layer was concentrated to ~115 mL under reduced pressure. Heptane (1 14 mL) and toluene (30 mL) were added and the mixture was warmed to 600C. The contents were stirred for ~ 0.5 hours then cooled slowly to 00C and then the solids were filtered. The vessel and cake were rinsed with heptane (2 x 100 mL). The solids were dried under vacuum at ~30°C overnight to give 42.7g (78% yield) of the product. 1 sodium tert-pentoxide
Figure imgf000032_0001
2
Intermediate 2 Intermediate 1
Figure imgf000032_0002
Intermediate 1 (60.0 g) and Intermediate 2 (60.0 g) were slurried together in NMP (120 mL) and cooled to 5°C. A solution of sodium tert-pentoxide (44 g) in NMP (180 mL) was added to this slurry over 10 minutes. The mixture was held at ~5-10°C for 2 hours, then warmed to room temperature overnight. The reaction was quenched with a 0.5M citric acid solution (12 mL) and the entire reaction mass was added to a citric acid solution (1080 mL, 0.5 M) to precipitate out the product. After 3 hours, the slurry was filtered, washed with water (IL) and the cake is kept under suction for 2 hours then stored. The crude product 15a may be used directly in the next step.
Stage 4
Figure imgf000032_0003
Figure imgf000032_0004
Compound I
A 2 L Jacketed Laboratory Reactor was charged with toluene (400 mL) followed by 15a
(10Og based on wt/wt assay). The mixture was heated to 60-650C and held for 30 minutes. Stirring was stopped to allow phase separation and the bottom aqueous portion was discarded. To remaining the top organic layer was added water (0.3 L) and the mixture was stirred at 60-650C for ~ 30 minutes. Stirring was stopped to allow phase separation and the bottom aqueous portion was discarded. The contents in the reactor are cooled to room temperature and left overnight. The mixture was cooled to 15°C and concentrated HCl (0.15 L) was slowly added over 50 minutes while maintaining the reaction temperature between 13-18°C overnight. The layers were separated and the organic portion was washed with concentrated HCl (25 mL) and the layers separated. The aqueous layers were combined and were slowly added over 40 minutes into a second vessel containing a mixture of 30% ammonium hydroxide (180 mL), water (0.12 L), IPA (0.1 L), and ethyl acetate (0.5 L) that had been cooled to ~ 150C keeping the internal temperature < 26°C. After stirring the mixture at room temperature for ~0.5 hours, the bottom aqueous layer was separated and discarded. To the top organic layer was added water (0.3 L) and the mixture was stirred for 20 minutes. The bottom aqueous layer was discarded and the top organic portion was concentrated to ~ 3 vol under vacuum. IPA (0.5 L) was added and the mixture was concentrated to ~ 5 vol. The mixture was heated and seeded with 30 mg of Compound I at 500C and was stirred for ~1 hour. The mixture was cooled to ~ 25°C and held for 2 days. After stirring for ~ 1 hour at ~ 5°C the mixture was filtered and the wet cake rinsed with cold JLPA (0.2 L). The product was dried under vacuum (~ 600C) to give 68g of Compound I as a white solid.
Example 16 Preparation of 15a
sodium tert-pentoxide
Figure imgf000033_0001
Intermediate 2 Intermediate 1
Figure imgf000033_0002
Intermediate 1 (20 g) and Intermediate 2 (20 g) were slurried together in NMP (1OmL) and toluene (82 mL) and cooled to about 0 to 2°C. A solution of sodium tert-pentoxide (58.5 g solution) in toluene (25 wt %) was added to the mixture. Once the reaction was deemed complete, itwas held overnight at 100C. The mixture was warmed back to 20 °C and quenched with a 2M citric acid solution (100 mL). The phases were cut and the organic phase was wash ed with 100 mL water. The phases were cut and the toluene layer containing the product was stored until further use. Example 17
Preparation of Compound I
Figure imgf000034_0001
Compound 1
A solution of 15a (32.8 g crude) in toluene (131 mL) was cooled to 150C. To the solution was added concentrated HCl (49 mL) over —20 minutes while maintaining the reaction temperature at ~ 15°C. Once the HCl addition was complete the temperature was raised to room temperature and kept for 4 hours. The temperature was then raised to 36°C. After stirring for 1.5 hours the reaction was complete. HCl (16.4 mL) was added and the bottom aqueous layer was separated. A mixture of 30% ammonium hydroxide (69 mL), water (32.8 mL), IPA (32.8 mL), and ethyl acetate (164 mL) was cooled to ~ 15°C. To this mixture was added the separated aqueous layer. The temperature in the receiving vessel was maintained at 15-25°C during addition and the final pH was 9.3 after complete addition. After stirring the mixture at ~ 25°C for ~ 0.5 hour the bottom aqueous layer was separated and discarded and the top organic layer was washed with water (96 mL). The top organic layer was concentrated to ~ 3 vol. IPA (164 mL) was added and the mixture was concentrated to ~ 5 vol. The mixture was slurried at 500C for ~1 hour and then cooled to ~ 5°C. The mixture was filtered and the wet cake was washed with cold IPA (65.6 mL). After drying under vacuum at 600C, 27 g of the product was obtained. Example 18
Preparation of Compound IA from Compound I
Figure imgf000035_0001
To a round bottom flask 4 mL of n-propanol was added and heated to 410C. To this was added 0.5 g of Compound I (0.99 mmol, 1 cq). In a separate flask 0.14 g of succinic acid (1.2 cq) was dissolved in 5 mL of n-propanol. Add 0.26 g of the Compound I solution to the succinic acid solution. This solution was seeded with 3 mg of Compound IA seed crystals in 0.25 mL of n- propanol. The resulting suspension was stirred for 30 minutes, and the remaining solution of Compound T was added slowly over 1.5 hours. The suspension was stirred at 410C for 1 hour and cooled slowly to 00C. The solids were isolated by filtration after 1 hour at 00C and washed with 4ml of cold n-propanol. The solids were dried at 55°C under vacuum to give 564 mg, 91.4% yield.
Example 19
Preparation of Compound IA from Compound I
Figure imgf000035_0002
Crude Compound I (2257g, actual charge determined by w/w assay, 2257g at 79.72% w/w in this case is 1800 g net, 1 equivalent) was charged to a 25 L laboratory jacketed lab reactor with overhead stirring. 4500 mL of 2-propanol and 1150 mL of water was added. 215 g (0.51 eq,) of succinic acid was then added. The mixture was stirred and heated to 70-75 0C until a clear solution was obtained. The solution was filtered through a 1 micron filter into the crystallization reactor. The reactor and filter were rinsed with 5600 mL of 2-propanol. The contents of the crystallization reactor were heated to 70-75 0C to ensure complete dissolution. The reactor contents were cooled to 62-67 0C over —25 minutes and seeded with 18g (1.0% wt) of Compound IA seeds suspended in 64mL 2-propanol. The slurry was held at 62-67 0C for one hour. The slurry was cooled to 20uC over at least 1 hour. The slurry was then charged with 11240 mL (6.25 vol) of 2-propanol over at least 30 minutes. The slurry was cooled to 0-5 0C over at least one hour then isolated by filtration. The reactor and the cake were rinsed with 7200 mL of 2-propanol. The product was dried under vacuum at a temperature of 40-60 0C until residual IPA was not greater than 2.5% w/w. Product weight 1.97 Kg. The total succinic acid content of the product was measured upon dissolution by HPLC and determined to be 0.5 molar equivalents. In addition, solid-state NMR of the product confirmed the presence of the core solid-state structure of Compound IA and no additional succinic acid.
Example 20
Preparation of Compound JA from Compound 1
Crude Compound I (370Og, actual charge determined by w/w assay, 3700 g at 78.1% w/w in this case is 2890 g net, 1 equivalent) and 3600g of additional crude Compound I (actual charge determined by w/w assay, 3600 g at 78.6% w/w in this case is 2830 g net, 1 equivalent) were charged to an 80-L jacketed lab reactor with overhead stirring. 11200 g (2.5 vol) of 2- propanol and 3600 mL (0.63 vol) of water were added. 1140 g (0.85 eq,) of succinic acid was added. The mixture was stirred and heated to 50-70 0C until a clear solution was obtained. The solution was filtered through a 1 micron filter into the crystallization reactor. The reactor and filter were rinsed with 14000 g (3.13 vol) of 2-propanol. The contents of the crystallization reactor to 70-75 0C were heated to ensure complete dissolution. The reactor contents were cooled to 50-67 0C over about 15 minutes and seeded with 57 g (1.0% wt) Compound IA seeds suspended in 114-228 mL 2-propanol. The slurry was held at 50-670C for 30-60 minutes. The slurry was cooled to 200C over at least 1 hour. The slurry was then charged with 28100 g (6.25 vol) of 2-propanol over at least 30 minutes. The slurry was cooled to 0-50C over at least one hour then isolated by filtration. The reactor and the cake were rinsed with 18000 g (4 vol) of 2- propanol. The product was dried at a temperature of 40-600C until residual IPA was not greater than 3% w/w.
The total succinic acid content of the product was measured upon dissolution by HPLC and determined to be 0.8 molar equivalents. In addition, solid-state NMR of the product confirmed the presence of the core solid-state structure of Compound IA and additional succinic acid. The additional succinic acid content is 0.3 molar equivalents.
Example 21 Preparation of Compound TA from Compound T
Crude Compound I (2205 g, actual charge determined by w/w assay, 2205 g at 79.72% w/w in this case is 1757 g net, 1 equivalent) was charged to a 25-L jacketed lab reactor with overhead stirring. To this, 4400 mL of 2-propanol and 1100 mL of water were added. 658 g (1.60 eq,) of succinic acid was added. The contents of the reactor -were stirred and heated to 70- 75 0C until a clear solution was obtained. The solution was filtered through a 1 micron filter into the crystallization reactor. The reactor and filter were rinsed with 5500 mL of 2-propanol. The contents of the crystallization reactor were heated to 70-750C to ensure complete dissolution. The reactor contents were cooled to 62-67°C over about 15 minutes and seeded with 18g (1.0% wt) of Compound IA seeds suspended in 64mL 2-propanol. The slurry was held at 62-67°C for ~30-60 minutes, then cooled to 200C over at least 1 hour. The slurry was then charged with 11000 mL of 2-propanol over at least 30 minutes. The slurry was cooled to 0-5 0C over at least one hour then isolated by filtration. The reactor and the cake were rinsed with 7000 mL of 2-propanol. The product was dried under vacuum at a temperature of 40-600C until residual IPA was not greater than 2.5% w/w. Product weight 2.03 Kg.
The total succinic acid content of the product was measured upon dissolution by HPLC and determined to be 1.0 molar equivalents. In addition, solid-state NMR of the product confirmed the presence of the core solid-state structure of Compound IA and additional succinic acid. The additional succinic acid content is 0.5 molar equivalents.
Example 22
Preparation of Compound IA from Compound I
Crude Compound I (actual charge determined by w/w assay, 2300 g at 78.6% w/w in this case is 1800 g net, 1 equivalent) and 4900 g of crude Compound I (actual charge determined by w/w assay, 4900 g at 79.7% w/w in this case is 3900 g net, 1 equivalent) was charged to an 80-
L jacketed lab reactor with overhead stirring. 11200 g (2.5 vol) of 2-propanol and 3600 mL (0.63 vol) of water were added. 2540 g (1.90 eq,) of succinic acid was added. The mixture was stirred and heated to 50-700C until a clear solution was obtained. The solution was filtered through a 1 micron filter into the crystallization reactor. The reactor and filter were rinsed with 14000 g (3.13 vol) of 2-propanol. The contents of the crystallization reactor were heated to 70-75 0C to ensure complete dissolution. The reactor contents were cooled to 50-670C over about 15 minutes and seeded with 57 g (1.0% wt) of Compound IA seeds suspended in 1 14-228 mL 2-propanol. The slurry was held at 50-670C for 30-60 minutes. The slurry was cooled to 200C over at least 1 hour. The slurry was then charged with 28100 g (6.25 vol) of 2-proρanol over at least 30 minutes. The slurry was cooled to 0-50C over at least one hour then isolated by filtration. The reactor and the cake were rinsed with 18000 g (4 vol) of 2-propanol. The product was dried at a temperature of 40-600C until residual IPA was not greater than 3% w/w.
The total succinic acid content of the product was measured upon dissolution by HPLC and determined to be 1.2 molar equivalents. In addition, solid-state NMR of the product confirmed the presence of the core solid-state structure of Compound IA and additional succinic acid. The additional succinic acid content is 0.7 molar equivalents.
Example 23 Preparation of non-stoichiometric solid-state structures of Compound IA with additional succinic acid by slurry processing
Succinic acid solutions of varying molarity were prepared by weighing out the following amounts of succinic acid into six separate vials: 0 g (0 M), 0.0585 g (0.05 M), 0.118 g (0.1 M), 0.2362 g (0.2 M), 0.4724 g (0.4 M), and 0.9448 g (0.8 M). To each vial was charged 1 mL water and 9 mL 2-propanol. The contents were stirred until the succinic acid was dissolved (a few specks of solid remained in the 0.8 M solution). Each vial was then charged with 1.65 g of Compound IA, containing no additional succinic acid. Also, in a seventh vial (Sample G) 8 mL 2-propanol and 2 mL water were charged, followed by 1.65 g of Compound IA. All vials were left to stir for 4 days at 25°C. After four days of stirring, the vials all still showed the presence of a white slurry. The slurry from each vial was isolated via a Buchner funnel. No wash of the wet cake was performed. The isolated product was dried in a vacuum oven for approximately one hour at 23°C.
Analysis of each of the six samples by HPLC was performed, and the stoichiometry ratios were determined. The stoichiometry ratios of the six samples are reported below in Table 1. Table 1
Figure imgf000039_0001
Methods of Use
Compound I demonstrates good in vitro antibacterial activity against the primary respiratory pathogens including S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus, and S. pyogenes, as well as activity against isolates carrying resistance determinants to other antibiotics (penicillin-, macrolide-, methicillin- or levofloxacin-resistant phenotypes). Compound I also demonstrates good in vitro activity against atypical pathogens including C. pneumoniae, L. pneumophila and M. pneumoniae. Additionally, Compound I demonstrates good in vitro activity against biothreat organism F. tύlarensis, anaerobic organisms, and Neisserria Sp. including N. meningitidis and both ciprofloxacin susceptible and resistant N. gonorrhoeae. Accordingly, in another aspect the invention is directed to methods of treating respiratory infections comprising administering a safe and effective amount of Compound IA to a patient in need thereof. Compound I demonstrates good in vitro antibacterial activity against S. aureus and & pyogenes, the primary pathogens associated with skin and skin structure infections. Activity of Compound I is also retained against S. aureus and S. pyogenes isolates carrying resistance determinants to other antibiotics (penicillin-, macrolide-, methicillin- or levofloxacin-resistant phenotypes). Accordingly, in another aspect the invention is directed to methods of treating skin and skin structure infections comprising administering a safe and effective amount of Compound IA to a patient in need thereof.
Assays for testing the antibacterial activity of Compound IA are known to those skilled in the art.
As used herein, "patient" refers to a human or other animal. As used herein, "treat" in reference to a condition means: (1) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition. As indicated above, "treatment" of a condition includes prevention of the condition. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof. As used herein, "safe and effective amount" in reference to Compound IA or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A safe and effective amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan. Compound IA may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
Compound IA may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or mdefmitely to maintain the desired therapeutic effect. Suitable dosing regimens for Compound IA depend on the pharmacokinetic properties of the compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for Compound IA depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration range from about 100 mg to about 3000 mg per day. In one embodiment of the invention, the patient is administered from about 250 mg to about 2000 mg per day. In another embodiment, the patient is administered from about 1000 mg to about 2000 mg per day. In another embodiment, the patient is administered about 1000 mg per day. In another embodiment, the patient is administered about 2000 mg per day.
The invention also provides Compound IA for use in medical therapy, and particularly in respiratory and skin and skin structure infections. Thus, in further aspect, the invention is directed to the use of Compound IA in the preparation of a medicament for the treatment of respiratory and skin and skin structure infections.
Compositions Compound IA will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising Compound IA and one or more pharmaceutically-acceptable excipient.
The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of Compound IA can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of Compound IA. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from about 100 mg to about 1000 mg.
As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of Compound IA when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
Compound IA and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; and (3) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of Compound IA once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically- acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of Compound IA and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre- gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.

Claims

What is claimed is:
1. The succinate salt of frørø-4-aminocyclohexyl (lS,2R,3S,4S,6R,7R,SR,14R)-4-ethenyl-3- hydroxy-2,4,7,14-tetramethyl-9-oxotricyclo[5.4.3.01,8] tetradec-6-yl imidodicarboxiate.
2. The salt according to Claim 1 wherein the salt is represented by the following structure:
Figure imgf000044_0001
3. The salt according to Claim 2 in the solid-state.
4. The salt according to Claim 3 wherein the salt contains up to about 0.9 molar equivalents of additional succinic acid.
5. The salt according to Claim 3 wherein the salt contains up to about 0.7 molar equivalents of additional succinic acid.
6. The salt according to Claim 3 wherein the salt contains up to about 0.5 molar equivalents of additional succinic acid.
7. The salt according to Claim 3 wherein the salt contains up to about 0.3 molar equivalents of additional succinic acid.
8. The salt according to Claim 3 wherein the salt contains from about 0.3 to about 0.7 molar equivalents of additional succinic acid.
9. The salt according to Claim 3 wherein the salt contains no additional succinic acid.
10. The salt according to any of the preceding claims wherein the salt is a solvate.
11. The salt according to Claim 10 wherein the solvate is an isopropanol solvate.
12. The salt according to Claim 11 wherein the solvate is a non-stoichiometric isopropanol solvate containing up to about 6% isopropanol.
13. The salt according to Claim 11 wherein the solvate is a non-stoichiometric isopropanol solvate containing up to about 4% isopropanol.
14. The salt according to Claim 11 wherein the solvate is a non-stoichiometric isopropanol solvate containing from about 2% to about 4% isopropanol.
15. The salt according to Claim 10 wherein the solvate is an 7t-propanol solvate.
16. The salt according to Claim 15 wherein the solvate is a non-stoichiometric /7-propanol solvate containing up to about 6% /ϊ-propanol.
17. The salt according to Claim 15 wherein the solvate is a non-stoichiometric rø-propanol solvate containing up to about 4% /7-propanol.
18. The salt according to Claim 15 wherein the solvate is a non-stoichiometric n-propanol solvate containing from about 2% to about 4% /τ-propanol.
19. The salt according to Claim 15 wherein the solvate is a non-stoichiometric solvate containing from about 2% solvent and wherein the solvent is isopropanol or rø-propanol.
20. The salt according to Claim 10 wherein the solvate is a hyrdrate.
21. The salt according to Claim 20 wherein the hydrate is a non-stoichiometric hydrate containing up to about 6% water.
22. The salt according to Claim 20 wherein the hydrate is a non-stoichiometric hydrate containing up to about 4% water.
23. The salt according to Claim 20 wherein the hydrate is a non-stoichiometric hydrate containing from about 2% to about 4% water.
24. The salt according to Claim 10 wherein the solvate is a mixed isopropanol and water solvate.
25. The salt according to Claim 24 wherein the mixed isopropanol and water solvate contains up to about 6% solvent.
26. The salt according to Claim 24 wherein the mixed isopropanol and water solvate contains up to about 4% solvent.
27. The salt according to Claim 24 wherein the mixed isopropanol and water solvate contains from about 2% to about 4% solvent.
28. The salt according to Claim 10 wherein the solvate is a mixed w-propanol and water solvate.
29. The salt according to Claim 24 wherein the mixed Λ-propanol and water solvate contains up to about 6% solvent.
30. The salt according to Claim 24 wherein the mixed «-propanol and water solvate contains up to about 4% solvent.
31. The salt according to Claim 24 wherein the mixed n-propanol and water solvate contains from about 2% to about 4% solvent.
32. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern having a characteristic peak at 10.8 ± 0.2 (° 2Θ) and at least one additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 20), or 21.2 ± 0.2 (° 2Θ).
33. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern having a characteristic peak at 10.8 ± 0.2 (° 20) and at least two additional characteristic peaks selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 2Θ).
34. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern having a characteristic peak at 10.8 ± 0.2 (° 2Θ) and at least three additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 20), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Q), or 21.2 ± 0.2 (° 2Θ).
35. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern having a characteristic peak at 10.8 ± 0.2 (° 2Θ) and at least four additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ). 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 2Θ).
36. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern having a characteristic peak at 10.8 ± 0.2 (° 2Θ) and at least five additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 2Θ).
37. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern having characteristic peaks at the following positions: 10.8 ± 0.2 (° 2Θ), 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), and 21.2 ± 0.2 (° 2Θ).
38. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern having (a) a characteristic peak at 10.8 ± 0.2 (° 2Θ); (b) at least one additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 20), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 20); and (c) at least one additional characteristic peak selected from characteristic peaks at the following positions: 9.8 ± 0.2 (° 2Θ), 15.1 ± 0.2 (° 2Θ) or 15.6 ± 0.2 (° 2Θ).
39. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern having (a) a characteristic peak at 10.8 ± 0.2 (° 20); (b) at least two additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Q), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 20); and (c) at least one additional characteristic peak selected from characteristic peaks at the following positions: 9.8 ± 0.2 (° 2Θ), 15.1 ± 0.2 (° 2Θ) or 15.6 ± 0.2 (° 2Θ).
40. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern having (a) a characteristic peak at 10.8 ± 0.2 (° 2Θ); (b) at least three additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 20); and (c) at least one additional characteristic peak selected from characteristic peaks at the following positions: 9.8 ± 0.2 (° 20), 15.1 ± 0.2 (° 20) or 15.6 ± 0.2 (° 20).
41. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern having (a) a characteristic peak at 10.8 ± 0.2 (° 2Θ); (b) at least four additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 2Θ); and (c) at least one additional characteristic peak selected from characteristic peaks at the following positions: 9.8 ± 0.2 (° 2Θ), 15.1 ± 0.2 (° 2Θ) or 15.6 ± 0.2 (° 2Θ).
42. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern having (a) a characteristic peak at 10.8 ± 0.2 (° 2Θ); (b) at least five additional characteristic peak selected from characteristic peaks at the following positions: 11.3 ± 0.2 (° 2Θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), or 21.2 ± 0.2 (° 2Θ); and (c) at least one additional characteristic peak selected from characteristic peaks at the following positions: 9.8 ± 0.2 (° 2Θ), 15.1 ± 0.2 (° 2Θ) or 15.6 ± 0.2 (° 2Θ).
43. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern having characteristic peaks at the following positions: 9.8 ± 0.2 (° 2Θ), 10.8 ± 0.2 (° 2Θ), 11.3 ± 0.2 (° 2θ), 12.9 ± 0.2 (° 2Θ), 13.1 ± 0.2 (° 2Θ), 15.1 ± 0.2 (° 2Θ), 15.6 ± 0.2 (° 2Θ), 17.5 ± 0.2 (° 2Θ), 18.5 ± 0.2 (° 2Θ), and 21.2 ± 0.2 (° 2θ).
44. The salt according to Claim 3 wherein the salt is characterized by a 13C solid-state NMR spectrum having characteristic peaks at 224.0, 222.5, 181.1, 177.8, 140.7, and 139.8 ppm.
45. The salt according to Claim 3 wherein the salt is characterized by a 13C solid-state NMR spectrum having characteristic peaks at 224.0, 223.1, 222.5, 182.0, 181.1, 178.8, 177.8, 175.1,
141.8, 140.7, and 139.8 ppm.
46. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern that is substantially the same as the x-ray powder diffraction pattern depicted in Figure 3 a.
47. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern that is substantially the same as the x-ray powder diffraction pattern depicted in Figure 3b.
48. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern that is substantially the same as the x-ray powder diffraction pattern depicted in Figure 3 c.
49. The salt according to Claim 3 wherein the salt is characterized by an x-ray powder diffraction pattern that is substantially the same as the x-ray powder diffraction pattern depicted in Figure 3d.
50. The salt according to Claim 3 wherein the salt is characterized by a 13C solid-state NMR spectrum that is substantially the same as the 13C solid-state NMR spectrum depicted in Figure 4a.
51. The salt according to Claim 3 wherein the salt is characterized by a 13C solid-state NMR spectrum that is substantially the same as the 13C solid-state NMR spectrum depicted in Figure 4b.
52. The salt according to Claim 3 wherein the salt is characterized by a 3C solid-state NMR spectrum that is substantially the same as the 13C solid-state NMR spectrum depicted in Figure 4c.
53. The salt according to Claim 3 wherein the salt is characterized by a 13C solid-state NMR spectrum that is substantially the same as the 13C solid-state NMR spectrum depicted in Figure 4d.
54. A pharmaceutical composition comprising the compound according to any of the proceeding claims and one or more pharmaceutically-acceptable excipient.
55. A method of treating respiratory infections comprising administering a safe and effective amount of the compound according to any of the proceeding claims to a patient in need thereof.
56. A method of skin and skin structure infections comprising administering a safe and effective amount of the compound according to any of the proceeding claims to a patient in need thereof.
PCT/US2006/061068 2005-11-18 2006-11-18 New pleuromutilin derivative and its use WO2007062335A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US73820305P 2005-11-18 2005-11-18
US60/738,203 2005-11-18

Publications (3)

Publication Number Publication Date
WO2007062335A2 true WO2007062335A2 (en) 2007-05-31
WO2007062335A3 WO2007062335A3 (en) 2007-11-29
WO2007062335A8 WO2007062335A8 (en) 2008-07-10

Family

ID=38068018

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2006/061068 WO2007062335A2 (en) 2005-11-18 2006-11-18 New pleuromutilin derivative and its use
PCT/US2006/061067 WO2007062334A2 (en) 2005-11-18 2006-11-18 New pleuromutilin derivative and its use

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US2006/061067 WO2007062334A2 (en) 2005-11-18 2006-11-18 New pleuromutilin derivative and its use

Country Status (3)

Country Link
PE (1) PE20070825A1 (en)
TW (1) TW200738599A (en)
WO (2) WO2007062335A2 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010100582A (en) * 2008-10-24 2010-05-06 Kyorin Pharmaceut Co Ltd Mutilin derivative containing heteroaromatic ring carboxylic acid structure at 14-position substituent
WO2018146264A1 (en) 2017-02-10 2018-08-16 Nabriva Therapeutics GmbH Purification of pleuromutilin
EP4338732A1 (en) 2022-09-16 2024-03-20 Nabriva Therapeutics GMBH Lefamulin and its derivatives for use in the treatment of tularemia

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101671367B (en) * 2008-09-12 2012-09-05 中国科学院上海药物研究所 Pleuromutilin phosphate compounds, medicinal composition thereof, preparation method thereof and application thereof
CN103641702B (en) * 2013-11-18 2015-11-18 宁夏泰瑞制药股份有限公司 A kind of method for hydrolysis of pleuromutilin

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4060542A (en) * 1969-07-25 1977-11-29 Biochemie Gesellschaft M.B.H. 14-Desoxy-14 thiocyanato-acetoxy-mutilin
US4086359A (en) * 1975-09-30 1978-04-25 E. R. Squibb & Sons, Inc. Derivatives of pleuromutilin and compositions
US20030219461A1 (en) * 2000-09-12 2003-11-27 Britten Nancy J. Parenteral combination therapy for infective conditions
US6750064B2 (en) * 2000-12-28 2004-06-15 S.S.C.I. Inc. Methods of screening for possible solid forms
US20050096357A1 (en) * 2000-10-10 2005-05-05 Smithkline Beecham P.L.C. Novel pleuromutilin derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4060542A (en) * 1969-07-25 1977-11-29 Biochemie Gesellschaft M.B.H. 14-Desoxy-14 thiocyanato-acetoxy-mutilin
US4086359A (en) * 1975-09-30 1978-04-25 E. R. Squibb & Sons, Inc. Derivatives of pleuromutilin and compositions
US20030219461A1 (en) * 2000-09-12 2003-11-27 Britten Nancy J. Parenteral combination therapy for infective conditions
US20050096357A1 (en) * 2000-10-10 2005-05-05 Smithkline Beecham P.L.C. Novel pleuromutilin derivatives
US6750064B2 (en) * 2000-12-28 2004-06-15 S.S.C.I. Inc. Methods of screening for possible solid forms

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010100582A (en) * 2008-10-24 2010-05-06 Kyorin Pharmaceut Co Ltd Mutilin derivative containing heteroaromatic ring carboxylic acid structure at 14-position substituent
WO2018146264A1 (en) 2017-02-10 2018-08-16 Nabriva Therapeutics GmbH Purification of pleuromutilin
EP4338732A1 (en) 2022-09-16 2024-03-20 Nabriva Therapeutics GMBH Lefamulin and its derivatives for use in the treatment of tularemia
WO2024056858A1 (en) 2022-09-16 2024-03-21 Nabriva Therapeutics GmbH Lefamulin and its derivatives for use in the treatment of tularemia

Also Published As

Publication number Publication date
TW200738599A (en) 2007-10-16
PE20070825A1 (en) 2007-08-05
WO2007062334A8 (en) 2007-12-21
WO2007062335A3 (en) 2007-11-29
WO2007062334A3 (en) 2007-11-08
WO2007062335A8 (en) 2008-07-10
WO2007062334A2 (en) 2007-05-31

Similar Documents

Publication Publication Date Title
US11149017B2 (en) Solid state forms of apalutamide
US11667646B2 (en) Solid state forms of rucaparib and of rucaparib salts
US8410288B2 (en) Polymorphs of Saxagliptin hydrochloride and processes for preparing them
EP2796458B1 (en) Crystalline raltegravir sodium salts
US11072586B2 (en) Solid state forms of eltrombopag choline
TW202035370A (en) Processes of making and crystalline forms of a mdm2 inhibitor
WO2020102302A1 (en) Solid state forms of daprodustat and process for preparation thereof
US20080269342A1 (en) Pleuromutilin Derivatives and Its Use
EP3303306B1 (en) Crystalline forms of a histone deacetylase inhibitor
WO2007062335A2 (en) New pleuromutilin derivative and its use
JP2019515014A (en) Secoma chloride compound
WO2008102374A1 (en) Amorphous form of docetaxel
US11465974B2 (en) Crystalline polymorphs of Pracinostat and Pracinostat salts
US20230373998A1 (en) Solid state forms of lorecivivint
US20240287090A1 (en) Solid state forms of relugolix
CN115536716A (en) Amphotericin B semisynthetic derivative, preparation method and application thereof
CN115724846A (en) Novel crystal form of isoquinoline sulfonyl derivative, preparation method and application thereof
AU2023220628A1 (en) Processes for the preparation of 1,2,3,5,6,7-hexahydro-s-indacene derivatives
CA3223875A1 (en) Heterocycloalkyl-substituted polyheteroazole derivatives as medicaments for treating and/or preventing rs virus infections
CA2560767A1 (en) Novel crystal of triterpene derivative
CZ430199A3 (en) Crystalline roxifiban

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06839947

Country of ref document: EP

Kind code of ref document: A2