TW201315467A - Formulations of thiophene compounds - Google Patents

Abstract

A pharmaceutical composition comprises: (a) polymorphic form M or tromethamine salt of Compound (1) represented by the following structural formula: ; and (b) a filler. A method of preparing a pharmaceutical composition comprises: providing a mixture of Compound (1) and a filler to form the composition of Compound (1). A method of treating a HCV infection in a subject comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition.

Description

Thiophene compound formulation Related application

The priority of the following provisional application is as follows: US Provisional Application No. 61/545,751, filed on October 11, 2011, and US Provisional Application No. 61/623,144, 2011, filed on April 12, 2012 US Provisional Application No. 61/511,643, filed on July 26, US Provisional Application No. 61/511,648, filed on July 26, 2011, and US Provisional Application No. 61/511,647, filed on July 26, 2011 U.S. Provisional Application No. 61/512,079, filed on July 27, 2011, and U.S. Provisional Application No. 61/511,644, filed on Jul. 26, 2011. All teachings of these applications are incorporated herein by reference.

Hepatitis C virus (HCV) is a positive-stranded RNA virus belonging to the family Flaviviridae and has a recent genetic relationship with the genus Pestivirus including swine fever virus and bovine viral diarrhea virus (BVDV). The HCV strain is replicated by generating a complementary negative strand RNA template. Due to the lack of an efficient culture replication system for the virus, HCV particle lines were isolated from mixed human plasma and displayed by electron microscopy to a diameter of about 50 nm to 60 nm. The HCV genome is a single-stranded sense RNA having approximately 9,600 base pairs encoding a polymeric protein having 3009 to 3030 amino acids, which is cleaved into mature viral proteins during translation and after translation (core, E1, E2, p7, NS2) , NS3, NS4A, NS4B, NS5A, NS5B). The serotonin glycoproteins E1 and E2 are embedded in the viral lipid envelope and form stable heterodimers. The core protein of the salty structure also interacts with the viral RNA genome to form a nucleocapsid. Life Non-structural proteins designated NS2 to NS5 include proteins with enzyme functions involved in viral replication and protein processing, including polymerases, proteases, and helicases.

The main source of HCV contamination is blood. The scale of HCV infection as a health problem is illustrated by the incidence in high-risk groups. For example, in Western countries, 60% to 90% of hemophiliacs and more than 80% of intravenous drug abusers are chronically infected with HCV. For intravenous drug abusers, the incidence rate is between about 28% and 70% depending on the study population. Due to advances in diagnostic tools for screening blood donors, the proportion of new HCV infections associated with post-transfusion has recently decreased significantly.

The combination of pegylated interferon plus ribavirin is the preferred treatment for chronic HCV infection. This therapy does not provide a sustained viral response (SVR) in most patients infected with the most common genotypes (1a and 1b). In addition, significant side effects impede compliance with current therapies and may require reduction or discontinuation of dosing for some patients.

Until recently, the standard of care (SOC) for the treatment of HCV infection included a 48-week administration of pegylated interferon-alpha (weekly subcutaneous injection) in combination with ribavirin (oral, twice daily). Therapy is poorly tolerated and ultimately succeeds in less than half of the treated patient population. Two new treatment regimens for HCV patients have recently been approved by the FDA to include a protease inhibitor (telaprevir or boceprevir) in combination with Peg-IFN/ribavirin. These treatments show a significantly higher cure rate (sustained viral response (SVR)) in clinical trials compared to SOC (Peg-IFN/RBV) and are expected to increase the treatment success rate (SVR) for HCV patients. Therefore, it is extremely necessary It is desirable to continue to develop antiviral agents and pharmaceutical compositions thereof for the treatment or prevention of Flaviviridae viral infections, such as HCV infection.

The present invention generally relates to pharmaceutical compositions comprising the polymorphic form M or the tromethamine salt of the compound ( 1 ), methods of preparing the pharmaceutical compositions, and methods of using the pharmaceutical compositions to treat HCV infection.

In one embodiment, the present invention is directed to a pharmaceutical composition comprising: a) a polymorphic form M of a compound ( 1 ) represented by the formula: or a tromethamine salt: ; and b) fillers.

In another embodiment, the present invention is directed to a pharmaceutical composition comprising: a) a polymorphic form M of Compound ( 1 ) or a tromethamine salt; b) a filler; and c) a disintegrant.

In another embodiment, the present invention is directed to a pharmaceutical composition comprising: a) a polymorphic form M of Compound ( 1 ) or a tromethamine salt; b) a wetting agent; c) a binder; d) a disintegrant; and e) a filler.

In another embodiment, the present invention is directed to a pharmaceutical composition comprising: a) 25 wt% to 70 wt% of a polymorphic form M of a compound ( 1 ) or a tromethamine salt; and b) 25 wt % to 70 wt% of microcrystalline cellulose, based on the weight of the pharmaceutical composition.

In another embodiment, the present invention is directed to a pharmaceutical composition comprising: a) 25 wt% to 60 wt% of a polymorphic form M of a compound ( 1 ) or a tromethamine salt; b) a pharmaceutical combination 0.5% to 10% by weight of polyvinylpyrrolidone; c) 0.25 wt% to 10 wt% of a copolymer of polyoxypropylene and polyoxyethylene by weight of the pharmaceutical composition; d) 0.25 wt% to 10 wt% sodium lauryl sulfate by weight of the pharmaceutical composition; e) 25 wt% to 70 wt% microcrystalline cellulose by weight of the composition; and f) by weight of the pharmaceutical composition 1 wt% to 15 wt% of croscarmellose sodium.

In another embodiment, the present invention is directed to a pharmaceutical composition comprising: a) a polymorphic form M of Compound ( 1 ) or a tromethamine salt; b) a complexing agent; and c) a buffering agent.

In another embodiment, the present invention is directed to a pharmaceutical composition prepared by providing a compound ( 1 ) particle comprising 35 wt% to 95 wt% of a compound ( 1 ) by weight of the particle a polymorphic form M or a tromethamine salt and a filler of from 3 wt% to 60 wt%; and a granule of the compound ( 1 ) and a filler comprising from 10 wt% to 50 wt%, based on the weight of the pharmaceutical composition The extragranular excipients are mixed to form a pharmaceutical composition of the compound ( 1 ).

In another embodiment, the present invention is directed to a pharmaceutical composition prepared by the step of providing a compound ( 1 ) granule comprising from 25 wt% to 90 wt% of the compound by weight of the pharmaceutical composition ( 1 ) a polymorphic form M or a tromethamine salt and a 10 wt% to 25 wt% filler; and a filler of the compound ( 1 ) and a filler comprising 10 wt% to 50 wt%, based on the weight of the pharmaceutical composition The extragranular excipients of the agents are mixed to form a pharmaceutical composition of the compound ( 1 ).

In another embodiment, the present invention is directed to a pharmaceutical composition prepared by the step of providing a binder solution comprising from 0.5 wt% to 10 wt% of binder, based on the weight of the pharmaceutical composition, and a humidity agent of from 0.25 wt% to 10 wt% is used; a pre-granulation composition comprising from 25 wt% to 90 wt% of the polymorphic form M of the compound ( 1 ) by weight of the pharmaceutical composition is provided. a blood acid amine salt, a 10 wt% to 25 wt% filler, and a 0.5 wt% to 5 wt% disintegrant; a binder solution is mixed with the pre-granulation composition to form a blend; and the compound (1) The granules are mixed with an extragranular excipient comprising from 15 wt% to 50 wt% of the filler and from 0.5 wt% to 10 wt% of the disintegrant by weight of the pharmaceutical composition to form a pharmaceutical combination of the compound ( 1 ) The mixing of the binder solution with the pre-granulation composition comprises feeding the pre-granulation composition into a twin-screw extruder and introducing the binder solution into a twin-screw extruder.

In another embodiment, the present invention is directed to a pharmaceutical composition prepared by the step of providing a binder solution comprising from 0.5 wt% to 10 wt% of binder and 0.25 by weight of the pharmaceutical composition. a wetting agent of wt% to 10% by weight; providing a pre-granulation composition comprising from 25 wt% to 60 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt of the pharmaceutical composition a 10 wt% to 25 wt% filler and 0.5 wt% to 5 wt% of a disintegrant; mixing the binder solution with the pre-granulation composition to form a blend; and including the compound ( 1 ) particles and Mixing 15 wt% to 50 wt% of filler and 0.5 wt% to 10 wt% of disintegrant extragranular excipients by weight of the pharmaceutical composition to form a pharmaceutical composition of compound ( 1 ),

Wherein the mixing of the binder solution with the pre-granulation composition comprises feeding the pre-granulation composition into a twin-screw extruder and introducing the binder solution into the twin-screw extruder.

In another embodiment, the present invention is directed to a method of preparing a pharmaceutical composition comprising: providing a mixture comprising a polymorphic form M of Compound ( 1 ) or a tromethamine salt and a filler.

In another embodiment, the present invention is directed to a method of preparing a pharmaceutical composition comprising: providing a mixture comprising a polymorphic form M of Compound ( 1 ) or a tromethamine salt; a filler; and a disintegrant.

In another embodiment, the present invention relates to a method of preparing a pharmaceutical composition comprising: providing a polymorphic form M comprising a compound ( 1 ) or a tromethamine salt, a wetting agent, a binder, a disintegrant And a mixture of fillers.

In another embodiment, the present invention is directed to a method of preparing a pharmaceutical composition comprising: providing a mixture comprising a polymorphic form M of Compound ( 1 ) or a tromethamine salt, a complexing agent, and a buffering agent.

In another embodiment, the present invention is directed to a method of preparing a pharmaceutical composition comprising: providing a compound ( 1 ) particle comprising a polymorphic form M of the compound ( 1 ) or a tromethamine salt, a moisturizing agent , a binder, and an intragranular excipient comprising a filler and a disintegrant; and mixing the particles of the compound ( 1 ) with an extragranular excipient comprising a disintegrant and a filler to form a blend of the compound ( 1 ) combination.

The invention also provides a method of inhibiting or reducing HCV polymerase activity in a biological in vitro sample comprising administering to the sample an effective amount of a pharmaceutical composition described herein.

Also provided herein is a method of treating an HCV infection in an individual comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition described herein.

Also provided are methods of inhibiting or reducing HCV polymerase activity in an individual by using a therapeutically effective amount of a pharmaceutical composition described herein.

Also provided is the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of HCV infection or inhibition or reduction of HCV polymerase activity.

In one aspect, the invention is generally directed to a pharmaceutical composition comprising a polymorphic form M of Compound ( 1 ) or a tromethamine salt. The compound ( 1 ) represented by the following structural formula and a pharmaceutically acceptable salt thereof are NS5B polymerase inhibitors, and are also described in WO 2008/058393:

Compound ( 1 ) may be present in free form or, where appropriate, in the form of a salt. Pharmaceutically acceptable salts are of particular interest as they are suitable for administration of the above compounds for medical purposes. Non-pharmaceutically acceptable salts are suitable for use in the manufacturing process for isolation and purification purposes, and in some cases, are used to isolate the stereoisomeric forms of the compounds of the invention or intermediates thereof.

The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound which, within the scope of sound medical judgment, is suitable for use in humans and lower animals without undue side effects such as toxicity. , stimuli, allergic reactions, and the like, and are commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences , 1977, 66, 1-19 (incorporated herein by reference). The pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. These salts can be prepared on the spot during the final isolation and purification of the compound.

Specific examples of pharmaceutically acceptable salts of the compound ( 1 ) are described in WO 2008/058393, such as salts derived from amino acids (for example L-arginine, L-isoamine); from a suitable base Salts, including alkali metal (such as sodium, lithium, potassium) salts, alkaline earth metal (such as calcium, magnesium) salts, ammonium salts, NR ₄ ⁺ (wherein R is C _1-4 alkyl) salts, choline and slow-blood Acid amine salt.

In one embodiment, the present invention uses the acid sulfite salt of Compound ( 1 ).

Compound ( 1 ) may exist in different polymorphic forms. As is known in the art, polymorphism is the ability of a compound to crystallize into more than one different crystalline or "polymorphic" material. A polymorph is a solid crystalline phase of a compound having at least two different or polymorphic forms of the molecules of the compound in a solid state. The polymorphic form of any given compound is defined by the same chemical formula or composition, and the chemical structure is generally different as the crystal structure of two different compounds. Different polymorphs can generally be analyzed by methods such as X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) or their melting points or other known in the art. Technology to characterize.

In one embodiment, the invention employs the polymorphic form M of compound ( 1 ). In a particular embodiment, the polymorphic form M is characterized by an X-ray powder diffraction pattern having a strongest characteristic peak at 2[Theta] ± 0.2 at 19.6. In another particular embodiment, the polymorphic form M is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed as 2θ ± 0.2 at the following positions: 19.6, 16.6, 18.1, 9.0, 22.2, and 11.4. In another particular embodiment, the polymorphic form M is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed as 2θ ± 0.2 at: 19.6 (100.0%), 16.6 (72.4%), 18.1 ( 59.8%), 9.0 (47.6%), 22.2 (39.9%) and 11.4 (36.6%), with relative strength in parentheses. In another particular embodiment, the polymorphic form M is characterized by having an X-ray powder diffraction pattern substantially the same as that shown in FIG. The X-ray powder diffraction pattern was obtained using Cu Kα radiation at room temperature.

In another particular embodiment, the polymorphic form M is characterized by an endothermic peak at 230 ± 2 °C in differential scanning calorimetry (DSC). In another particular embodiment, wherein the polymorphic forms M 177.3,134.3,107.4,56.5,30.7 having peaks at 25.3 and the C ¹³ solid-state nuclear magnetic resonance (NMR) spectrum of the. In another particular embodiment, the polymorphic form M is characterized by having a solid ^C13 NMR spectrum substantially identical to that shown in FIG.

Form M of Compound ( 1 ) can be prepared by a method using a mixture of Compound ( 1 ) and a solvent system at a temperature ranging from 10 ° C to 47 ° C to form Form M of Compound ( 1 ), which The solvent system includes isopropanol, ethyl acetate, n-butyl acetate, methyl acetate, acetone, 2-butanone or heptane or a combination thereof. In a particular embodiment, the solvent system comprises: isopropanol; ethyl acetate; n-butyl acetate; a mixture of n-butyl acetate and acetone (eg, 5 wt% to 95 wt% n-butyl acetate and 5 wt%) To 95 wt% acetone, such as 90 wt% n-butyl acetate and 10 wt% acetone; a mixture of n-butyl acetate and methyl acetate (for example, 5 wt% to 95 wt% n-butyl acetate and 5 Wt% to 95 wt% methyl acetate, such as 50 wt% n-butyl acetate and 50 wt% methyl acetate); acetone; 2-butanone (methyl ethyl ketone (MEK)); a mixture of ester and heptane (eg, 5 wt% to 95 wt% n-butyl acetate and 5 wt% to 95 wt% heptane, such as 50 wt% n-butyl acetate and 50 wt% heptane); a mixture of acetone and heptane (for example, 5 wt% to 95 wt% acetone and 5 wt% to 95 wt% heptane, such as 50 wt% acetone and 50 wt% heptane); or ethyl acetate and g A mixture of alkanes (e.g., 5 wt% to 95 wt% ethyl acetate and 5 wt% to 95 wt% heptane, such as 50 wt% ethyl acetate and 50 wt% heptane). In another particular embodiment, the compound (1) of the form M can be prepared by using the mixture of compound (1) under the following conditions:) in isopropanol at a temperature in the range of 10 deg.] C to 47 ℃ I; Ii) in ethyl acetate at a temperature ranging from 45 ° C to 47 ° C; iii) in n-butyl acetate at a temperature ranging from 35 ° C to 47 ° C; iv) a mixture of n-butyl acetate and acetone (for example, 5 wt% to 95 wt% of butyl acetate and 5 wt% to 95 wt% of acetone, such as 90 wt% of butyl acetate and 10 wt% of acetone) in the range of 30 ° C to 47 ° C Lower; v) a mixture of n-butyl acetate and methyl acetate (eg, 5 wt% to 95 wt% n-butyl acetate and 5 wt% to 95 wt% methyl acetate, such as 50 wt% acetic acid n-butyl In the range of 25 ° C to 47 ° C in the ester and 50 wt% of methyl acetate; vi) in the range of 20 ° C to 47 ° C in acetone; vii) in 2-butanone (MEK) Medium at a temperature ranging from 30 ° C to 47 ° C; viii) a mixture of n-butyl acetate and heptane (eg, 5 wt% to 95 wt% n-butyl acetate and 5 wt% to 95 wt% heptane, Such as 50 wt% n-butyl acetate and 50 wt% heptane) in 25 To a temperature in the range of 47 ° C; ix) in a mixture of acetone and heptane (for example 5 wt% to 95 wt% acetone and 5 wt% to 95 wt% heptane, such as 50 wt% acetone and 50 wt % heptane in the range of 25 ° C to 47 ° C; x) or a mixture of ethyl acetate and heptane (eg 5 wt% to 95 wt% ethyl acetate and 5 wt% to 95 wt % heptane, such as 50 wt% ethyl acetate and 50 wt% heptane, is at a temperature ranging from 25 ° C to 47 ° C.

The above compound (1) M may be in the form of crystals as much separated, in pure form or in the form of other known polymorphic forms (i.e. amorphous form compound (1) of Form A with other substances, or other (e.g., Compound (1) Form) or any other substance) a mixture of solid compositions when mixed. Similarly, the tromethamine salt of Compound ( 1 ) may be in a mixture, in pure form or in a solid composition when mixed with other materials, such as other known polymorphic forms of Compound ( 1 ) or any other material. form.

Thus, in one aspect, a polymorphic form M or a tromethamine salt of Compound ( 1 ) in isolated solid form is provided. In another aspect, a polymorphic form M or a tromethamine salt of Compound ( 1 ) is provided in pure form. The pure form means that the form M of the compound ( 1 ) or the tromethamine salt exceeds 95% (w/w), for example, more than 98% (w/w), more than 99% (w/w%), more than 99.5% ( w/w) or more than 99.9% (w/w).

In some embodiments, the polymorphic form M or the tromethamine salt of Compound ( 1 ) is in a polymorphic form with one or more other crystalline forms, solvates, amorphous forms, or other polymorphic forms or combinations thereof. In the form of a composition or mixture. In a particular embodiment, the composition may comprise polymorphic form M and one or more other solid forms of compound ( 1 ), such as amorphous form, hydrate, solvate, polymorphic form A, polymorphic form H, Polymorphic form P, polymorphic form X, polymorphic form ZA and/or other forms or combinations thereof. In another particular embodiment, the composition may comprise a tamoate salt and one or more other solid forms of compound ( 1 ), such as an amorphous form, a hydrate, a solvate, a polymorphic form A, a form H, Form P, Form X, Form ZA, and/or other forms or combinations thereof. In another particular embodiment, the composition may comprise from trace amounts to 100% by weight, or such as from 0.1% to 0.5% by weight, from 0.1% to 1% by weight, based on the total of the compound ( 1 ) in the pharmaceutical composition. 0.1% by weight to 2% by weight, 0.1% by weight to 5% by weight, 0.1% by weight to 10% by weight, 0.1% by weight to 20% by weight, 0.1% by weight to 30% by weight, 0.1% by weight to 40% by weight or 0.1% Any number of polymorphic forms M of compound ( 1 ) in the range of from 50% by weight to 50% by weight. In another specific embodiment, the composition may comprise at least 50%, 60%, 70%, 80%, 90%, 95% by weight, based on the total of Compound ( 1 ) in the pharmaceutical composition, 97% by weight, 98% by weight, 99% by weight, 99.5% by weight or 99.9% by weight of the polymorphic form M of the compound ( 1 ). In another particular embodiment, the composition may comprise from trace amounts to 100% by weight, or such as from 0.1% to 0.5% by weight, from 0.1% to 1% by weight, based on the total of the compound ( 1 ) in the pharmaceutical composition. 0.1% by weight to 2% by weight, 0.1% by weight to 5% by weight, 0.1% by weight to 10% by weight, 0.1% by weight to 20% by weight, 0.1% by weight to 30% by weight, 0.1% by weight to 40% by weight or 0.1% Any amount of the tromethamine salt of the compound ( 1 ) in the range of from 50% by weight to 50% by weight. In another specific embodiment, the composition may comprise at least 50%, 60%, 70%, 80%, 90%, 95% by weight, based on the total of Compound ( 1 ) in the pharmaceutical composition, 97% by weight, 98% by weight, 99% by weight, 99.5% by weight or 99.9% by weight of the tromethamine salt of the compound ( 1 ).

In one aspect, the pharmaceutical composition of the present invention comprises the polymorphic form M of the compound ( 1 ) or a tromethamine salt and a filler. In another aspect, the pharmaceutical composition of the present invention comprises the polymorphic form M of the compound ( 1 ) or a tromethamine salt, a filler, and a disintegrant. In another aspect, the pharmaceutical composition of the present invention comprises the polymorphic form M of the compound ( 1 ) or a tromethamine salt, a binder, a disintegrant, and a filler. In another aspect, the pharmaceutical composition of the present invention comprises the polymorphic form M of the compound ( 1 ) or a tromethamine salt, a wetting agent, a binder, a disintegrant, and a filler. Typically, the pharmaceutical composition comprises: from 25 wt% to 75 wt%, from 25 wt% to 70 wt% or from 25 wt% to 60 wt% of the polymorphic form M of the compound ( 1 ) or slow-blooded by weight of the pharmaceutical composition. Acid amine salt. Typically, the filler comprises from 20 wt% to 75 wt%, from 20 wt% to 73 wt%, from 25 wt% to 75 wt%, from 25 wt% to 70 wt%, from 30 wt% to 70 wt%, based on the weight of the pharmaceutical composition. Or 35 wt% to 55 wt%. Typically, the disintegrant comprises from 1 wt% to 15 wt%, from 1 wt% to 10 wt%, from 3 wt% to 8 wt% or from 1 wt% to 5 wt% of the pharmaceutical composition. Typically, the wetting agent comprises from 0.25 wt% to 10 wt%, from 1 wt% to 10 wt% or from 1 wt% to 5 wt% of the pharmaceutical composition. Typically, the binder comprises from 0.5 wt% to 10 wt%, from 1 wt% to 10 wt%, from 3 wt% to 8 wt% or from 1 wt% to 5 wt%, based on the weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises: from 25 wt% to 75 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt of the compound ( 1 ) by weight of the pharmaceutical composition; and 20 by weight of the pharmaceutical composition A wt% to 75 wt% (or 20 wt% to 73 wt%) filler. In another embodiment, the pharmaceutical composition comprises: from 25 wt% to 70 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt; and the weight of the pharmaceutical composition, by weight of the pharmaceutical composition; 25 wt% to 70 wt% filler. In another embodiment, the pharmaceutical composition comprises: from 25 wt% to 70 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt, by weight of the composition; a filler of from wt% to 70 wt%; and a disintegrant of from 1 wt% to 15 wt%, based on the weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises: from 25 wt% to 70 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt, by weight of the composition; a wt% to 73 wt% filler; and 1 wt% to 15 wt% disintegrant based on the weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises: from 25 wt% to 70 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt, by weight of the pharmaceutical composition; by weight of the pharmaceutical composition 0.5 wt% to 10 wt% binder; 1 wt% to 15 wt% disintegrant by weight of the pharmaceutical composition; and 25 wt% to 70 wt% (or 25 wt% by weight of the pharmaceutical composition) Up to 73 wt%) of filler. In another embodiment, the pharmaceutical composition comprises: from 25 wt% to 60 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt, by weight of the composition; 0.25 by weight of the pharmaceutical composition a wtifier of from wt% to 10 wt%; from 0.5 wt% to 10 wt% of the binder by weight of the composition; from 1 wt% to 15 wt% of the disintegrant by weight of the pharmaceutical composition; A filler of from 25 wt% to 70 wt% (or 25 wt% to 73 wt%) by weight of the composition. In another embodiment, the pharmaceutical composition comprises from 25 wt% to 60 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt, by weight of the pharmaceutical composition; a wtifier of from wt% to 5 wt%; from 1 wt% to 5 wt% of the binder of the pharmaceutical composition; from 1 wt% to 5 wt% of the disintegrant by weight of the pharmaceutical composition; A filler of from 30 wt% to 70 wt% (or 25 wt% to 73 wt%) by weight of the pharmaceutical composition. In another example, the pharmaceutical composition comprises from 25 wt% to 60 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt, by weight of the pharmaceutical composition; 1 wt% by weight of the pharmaceutical composition % to 5 wt% of a wetting agent; 1 wt% to 5 wt% of a binder based on the weight of the pharmaceutical composition; 1 wt% to 5 wt% of a disintegrant based on the weight of the pharmaceutical composition; The filler is 35 wt% to 55 wt% filler by weight of the composition. The wetting agents, binders, disintegrants, and fillers suitable for the present invention are compatible with the ingredients of the pharmaceutical compositions of the present invention, for example, which do not substantially reduce chemical stability.

Wetting agents typically include a surfactant such as a nonionic surfactant and an ionic surfactant. Humidifying agents suitable for the present invention generally increase the solubility of the pharmaceutical composition. Exemplary surfactants include sodium lauryl sulfate (SLS), polyoxyethylene sorbitan fatty acid (e.g., TWEEN ^TM), sorbitan fatty acid esters (e.g. Spans®), sodium dodecylbenzenesulfonate ( SDBS), sodium dioctyl sulfosuccinate (Docusate), sodium dioxycholate (DOSS), sorbitan monostearate, sorbitan tristearate, N-lauric Sodium thioglycolate, sodium oleate, sodium tetradecanoate, sodium stearate, sodium palmitate, Gelucire 44/14, ethylenediaminetetraacetic acid (EDTA), vitamin E d-alpha tocopherol polyethylene glycol 1000 succinate (TPGS), lecithin, MW 677-692, monosodium glutamate monohydrate, Labrasol, PEG 8 caprylic/capric glyceride, Transcutol, diethylene glycol monoethyl ether, Solutol HS-15 Polyethylene glycol/hydroxystearate, taurocholic acid, a copolymer of polyoxypropylene and polyoxyethylene (for example, poloxamer), also known as Pluronics® and commercially available, such as Pluronic ® L61, Pluronic® F68, Pluronic® F108 and Pluronic® F127), saturated PEGylated glycerides (Gelucirs®) and combinations thereof. Specific examples include sodium lauryl sulfate, which is an anionic surfactant; and a copolymer of polyoxypropylene and polyoxyethylene, which is a nonionic surfactant. Specific examples of the copolymer of polyoxypropylene and polyoxyethylene include poloxamers such as poloxamers having a molecular weight of 1,800 g/mol and a polyoxyethylene content of 80% (e.g., poloxamer 188). ). A typical amount of the wetting agent relative to the total weight of the pharmaceutical composition can range from 0.25 wt% to 10 wt% or from 1 wt% to 5 wt%.

The binder typically comprises an agent used in the manufacture of granules of the active ingredient by mixing the active ingredient with a diluent filler. Exemplary binders include polyvinylpyrrolidone, pregelatinized starch, starch, microcrystalline cellulose, and modified cellulose (eg, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and Hydroxyethyl cellulose (HEC)) and any combination thereof. Adhesive Specific examples include polyvinylpyrrolidone (PVP). Examples of HPC include low viscosity polymers (HPC-SL). PVP is typically characterized by the so-called "K value", which is a suitable measure of the viscosity of the polymeric composition. PVP is available under the trade names (eg Tokyo Chemical Industry Co., Ltd.): Povidone® K12, Povidone® K17, Povidone® K25, Povidone® K30, Povidone® K60 and Povidone® K90. Specific examples of PVP include soluble spray dried PVP. More specific examples include PVP having an average molecular weight of 3,000 to 4,000, such as Povidone® K12 having an average molecular weight of 4,000. PVP can be used in a wet state or in a dry state. A typical amount of the binder relative to the total weight of the pharmaceutical composition may range from 0.5 wt% to 10 wt% or from 1 wt% to 5 wt%.

Fillers (or diluents) typically include microcrystalline cellulose (eg, Avicel® PH 101), lactose, sorbitol, cellulose, calcium phosphate, starch, sugars (eg, mannitol, sucrose, or the like) or Any combination. Specific examples of the filler include microcrystalline cellulose and lactose. Specific examples of microcrystalline cellulose include the commercially available Avicel® series, such as microcrystalline cellulose (e.g., Avicel® PH 101) having a mesh size of more than 70% and a mesh size of less than 10%. Specific examples of lactose suitable for the present invention include lactose monohydrate. Typical amounts of filler relative to the total weight of the pharmaceutical composition may range from 20 wt% to 75 wt%, 20 wt% to 73 wt%, 25 wt% to 75 wt%, 25 wt% to 70 wt%, 30 wt%. Up to 70 wt% or 35 wt% to 55 wt%.

Disintegrants typically enhance the dispersion of the pharmaceutical composition. Examples of the disintegrant include croscarmellose sodium, starch (for example, corn starch, potato starch) Powder), sodium starch glycolate, crospovidone, and any combination thereof. Specific examples of the disintegrant include croscarmellose sodium (e.g., Ac-Di-Sol®) and sodium starch glycolate. A typical amount of the disintegrant relative to the total weight of the pharmaceutical composition may be from 1 wt% to 15 wt%, from 1 wt% to 10 wt%, from 3 wt% to 8 wt% or from 1 wt% to 5 wt% of the pharmaceutical composition. %.

In one embodiment, the pharmaceutical composition of the present invention comprises from 25 wt% to 60 wt% of the polymorphic form M or the tromethamine salt of the compound ( 1 ) by weight of the pharmaceutical composition; by weight of the composition 0.5 wt% to 10 wt% of polyvinylpyrrolidone; 0.25 wt% to 10 wt% of a copolymer of polyoxypropylene and polyoxyethylene by weight of the pharmaceutical composition; 0.25 wt% based on the weight of the pharmaceutical composition Up to 10% by weight of sodium lauryl sulfate; from 25 wt% to 70 wt% of microcrystalline cellulose by weight of the pharmaceutical composition; and from 1 wt% to 15 wt% of crosslinked carboxymethyl by weight of the pharmaceutical composition Cellulose sodium. In a particular embodiment, the pharmaceutical composition of the present invention comprises from 25 wt% to 60 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt, by weight of the pharmaceutical composition; 1 wt% to 5 wt% of polyvinylpyrrolidone; 1 wt% to 5 wt% of a copolymer of polyoxypropylene and polyoxyethylene by weight of the pharmaceutical composition; 1 by weight of the pharmaceutical composition From wt% to 5 wt% of sodium lauryl sulfate; from 30 wt% to 70 wt% of microcrystalline cellulose by weight of the pharmaceutical composition; and from 1 wt% to 5 wt% of cross-linking by weight of the pharmaceutical composition Sodium carboxymethyl cellulose. In another specific embodiment, the pharmaceutical composition of the present invention comprises from 25 wt% to 60 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt, by weight of the composition; 1 wt% to 5 wt% of polyvinylpyrrolidone; 1 wt% to 5 wt% of a copolymer of polyoxypropylene and polyoxyethylene by weight of the pharmaceutical composition; 1 by weight of the pharmaceutical composition From wt% to 5 wt% of sodium lauryl sulfate; from 35 wt% to 55 wt% of microcrystalline cellulose by weight of the pharmaceutical composition; and from 1 wt% to 5 wt% of cross-linking by weight of the pharmaceutical composition Sodium carboxymethyl cellulose. In another specific embodiment, the pharmaceutical composition of the present invention comprises from 25 wt% to 70 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt, based on the weight of the pharmaceutical composition; 1 wt% to 5 wt% of polyvinylpyrrolidone; 1 wt% to 5 wt% of a copolymer of polyoxypropylene and polyoxyethylene by weight of the pharmaceutical composition; by weight of the pharmaceutical composition 1 wt% to 5 wt% of sodium lauryl sulfate; 35 wt% to 55 wt% of microcrystalline cellulose by weight of the pharmaceutical composition; and 1 wt% to 5 wt% by weight of the pharmaceutical composition Sodium carboxymethylcellulose. In another specific embodiment, the pharmaceutical composition of the present invention comprises: from 25 wt% to 70 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt of the compound ( 1 ) by weight of the pharmaceutical composition; 0.5% to 10% by weight of polyvinylpyrrolidone; 0.25 wt% to 5 wt% of a copolymer of polyoxypropylene and polyoxyethylene by weight of the pharmaceutical composition; by weight of the pharmaceutical composition 0.25 wt% to 5 wt% of sodium lauryl sulfate; 0.25 wt% to 5 wt% of stearin sodium fumarate based on the weight of the pharmaceutical composition; 20 wt% to the weight of the pharmaceutical composition 60 wt% (or 20 wt% to 55 wt%) of microcrystalline cellulose; 0.5 wt% to 15 wt% (or 0.5 wt% to 10 wt%) of lactose by weight of the pharmaceutical composition; The weight of the material is from 1 wt% to 10 wt% of croscarmellose sodium. In another specific embodiment, the pharmaceutical composition of the present invention comprises: from 25 wt% to 70 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt of the compound ( 1 ) by weight of the pharmaceutical composition; From 0.5 wt% to 10 wt% of hydroxypropylcellulose by weight; from 0.25 wt% to 10 wt% of stearin sodium fumarate (or magnesium stearate) by weight of the pharmaceutical composition; 20% to 60% by weight (or 20% to 55% by weight) of microcrystalline cellulose by weight of the pharmaceutical composition; 0.5% to 15% by weight (or 0.5% by weight to the weight of the pharmaceutical composition) 10 wt%) of lactose; and 1 wt% to 15 wt% of croscarmellose sodium, based on the weight of the pharmaceutical composition. In another specific embodiment, the pharmaceutical composition of the present invention comprises: from 25 wt% to 70 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt of the compound ( 1 ) by weight of the pharmaceutical composition; 0.25 wt% to 10 wt% of magnesium stearate (or sodium stearyl fumarate) by weight; 25 wt% to 70 wt% of microcrystalline cellulose by weight of the pharmaceutical composition; 1 wt% to 15 wt% of croscarmellose sodium, based on the weight of the pharmaceutical composition.

In particular, polyvinylpyrrolidone has an average molecular weight of 3,000 to 4,000, such as Povidone® K12 having an average molecular weight of 4,000. In particular, the copolymer of polyoxypropylene and polyoxyethylene is a poloxamer, such as a poloxamer having a molecular weight of 1,800 g/mol and a polyoxyethylene content of 80% (eg, poloxamer). 188). In particular, hydroxypropylcellulose is a water soluble polymer. In particular, hydroxypropylcellulose is a low viscosity polymer such as HPC-SL. In particular, microcrystalline cellulose has a particle size of more than 70% of 200 mesh and a particle size of less than 10% of 65 mesh, such as Avicel® PH 101.

In some embodiments, the pharmaceutical compositions of the present invention further utilize a glidant or a glidant. Glidants typically enhance the flow of the pharmaceutical composition. Exemplary glidants include colloidal ceria, talc, and combinations thereof. Glidant Specific examples include amorphous colloidal ceria having an average particle size of from 0.2 micron to 0.3 m, such as Cab-O-Sil® M5P. A typical amount of the glidant relative to the total weight of the pharmaceutical composition may range from 0.1 wt% to 3 wt% or from 0.1 wt% to 1 wt%.

In some embodiments, the pharmaceutical compositions of the present invention further utilize a lubricant. Lubricants typically improve the compression and release of pharmaceutical compositions from, for example, molding presses. Exemplary lubricants include magnesium stearate, stearic acid (stear), hydrogenated oil, sodium stearyl fumarate, and any combination thereof. Specific examples of the lubricant include stearin sodium fumarate. Another specific example of the lubricant includes magnesium stearate. A typical amount of lubricant relative to the total weight of the pharmaceutical composition can range from 0.25 wt% to 5 wt% or from 1 wt% to 5 wt%.

In another aspect, the pharmaceutical composition of the present invention is an IV formulation comprising a polymorphic form M of Compound ( 1 ) or a tromethamine salt, a complexing agent, and a buffering agent. Typically, the pharmaceutical composition comprises: from 1 mg/mL to 20 mg/mL of the polymorphic form M of the compound ( 1 ) or the tromethamine salt; a combination of from 1 wt% to 25 wt% based on the weight of the pharmaceutical composition a buffer; and a buffer of 0.01 M to 0.1 M. More typically, the pharmaceutical composition comprises: from 1 mg/mL to 15 mg/mL of the polymorphic form M of the compound ( 1 ) or the tromethamine salt; from 1 wt% to 25 wt% by weight of the pharmaceutical composition a compounding agent; and a buffer of 0.01 M to 0.1 M or 0.05 M to 0.1 M. More typically, the pharmaceutical composition comprises: from 1 mg/mL to 10 mg/mL of the polymorphic form M of the compound ( 1 ) or the tromethamine salt; from 1 wt% to 25 wt% by weight of the pharmaceutical composition a compounding agent; and a buffer of 0.01 M to 0.1 M or 0.05 M to 0.1 M. Typical complexing agents include cyclodextrins. More typical complexing agents include sulfo-butyl-beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin. Typical buffers include sodium dihydrogen phosphate and disodium hydrogen phosphate.

In some embodiments, the IV formulation further comprises dextrose and/or mannitol as a tonicity modifying agent.

In some embodiments, the pharmaceutical compositions of the present invention further comprise a colorant, such as Opadry II white.

In some embodiments, the pharmaceutical compositions of the present invention are in the form of a solid dosage form, particularly in the form of a tablet.

Methods of preparing the above pharmaceutical compositions are also encompassed by the present invention. In one embodiment, the methods employ the step of providing a mixture comprising a polymorphic form M of Compound ( 1 ) or a tromethamine salt and a filler to form a pharmaceutical composition. In another embodiment, the methods employ the steps of providing a mixture comprising a polymorphic form M of compound ( 1 ) or a tromethamine salt, a wetting agent, a binder, a disintegrant, and a filler to form a medicinal product. combination. Typical examples (including specific examples) of the wetting agent, binder, disintegrant, and filler are each and independently as described above.

In another embodiment, the methods employ the step of mixing the polymorphic form M of the compound ( 1 ) or the tromethamine salt, the complexing agent, and a buffer. Specific examples of the complexing agent and the buffering agent are each and independently as described above.

In another embodiment, the methods employ the steps of: providing a compound ( 1 ) particle comprising a polymorphic form M of the compound ( 1 ) or a tromethamine salt and an intragranular excipient comprising a filler; The compound (1) particles are mixed with an extragranular excipient including a filler to form a blend composition of the compound ( 1 ). In some particular embodiments, the intragranular and extragranular excipients independently further comprise a disintegrant.

In another embodiment, the methods employ the steps of: i) providing a compound ( 1 ) particle comprising a polymorphic form M of the compound ( 1 ) or a tromethamine salt; a binder; an intragranular excipient, It comprises a filler and a disintegrant; and optionally a wetting agent, and ii) mixing the compound ( 1 ) particles with an extragranular excipient comprising a disintegrant and a filler to form a compound ( 1 ) The composition is blended. Typically, the intragranular excipient comprises from 10% to 25% by weight of the filler and from 0.5% to 5% by weight of the disintegrant, based on the weight of the pharmaceutical composition, and the extragranular excipient comprises the pharmaceutical composition. The weight ranges from 15 wt% to 50 wt% of the filler and from 0.5 wt% to 10 wt% of the disintegrant. Alternatively, the intragranular excipient comprises from 3 wt% to 50 wt% (or 5 wt% to 50 wt% or 10 wt% to 25 wt%) of filler, and from 0.5 wt% to 10 wt%, based on the weight of the particles ( Or 0.5 wt% to 5 wt%) of a disintegrant, and the extragranular excipient comprises 15 wt% to 50 wt% of a filler and 0.5 wt% to 10 wt% of a disintegrant based on the weight of the pharmaceutical composition. . Typical examples (including specific examples) of the wetting agent, binder, disintegrant, and filler are each and independently as described above.

In a specific embodiment, the preparation of the compound (1) particles comprises: providing a binder solution comprising a binder and a wetting agent; providing a pre-granulation composition comprising the polymorphic form M of the compound ( 1 ) or A blood acid amine salt and an intragranular excipient; a binder solution is added to the pre-granulation composition to form a compound ( 1 ) particle. In particular, the mixing of the binder solution with the pre-granulation composition comprises feeding the pre-granulation composition into a twin-screw extruder and introducing the binder solution into a twin-screw extruder. Typically, the intragranular excipient comprises from 3 wt% to 50 wt% (or 5 wt% to 50 wt% or 10 wt% to 25 wt%) of filler and 0.5 wt% to 10 wt%, based on the weight of the particles. (or 0.5 wt% to 5 wt%) of a disintegrant, and the extragranular excipient comprises 15 wt% to 50 wt% of filler and 0.5 wt% to 10 wt% of disintegration by weight of the pharmaceutical composition Agent. Typically, the binder solution comprises from 0.5 wt% to 10 wt% binder and from 0.25 wt% to 10 wt% of a wetting agent, by weight of the pharmaceutical composition. In some particular embodiments, the binder solution further comprises water in the range of from 5 wt% to 60 wt%, from 5 wt% to 30 wt%, or from 5 wt% to 15 wt%, based on the weight of the pharmaceutical composition.

In another specific embodiment, the methods employ a twin-screw wet granulation of the polymorphic form M of the compound ( 1 ) or the tromethamine salt. In another particular embodiment, the methods employ the step of providing a compound ( 1 ) particle comprising from 35 wt% to 95 wt% of the polymorphic form M of the compound ( 1 ) or hapromouric acid, by weight of the particles An amine salt and a filler of from 3 wt% to 60 wt%; and mixing the particles of the compound ( 1 ) with an extragranular excipient comprising from 10 wt% to 50 wt% of the filler by weight of the pharmaceutical composition to form A pharmaceutical composition of the compound ( 1 ). In another particular embodiment, the methods employ the step of providing a compound ( 1 ) particle comprising: i) from 40 wt% to 90 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt And ii) an intragranular excipient comprising from 5 wt% to 50 wt% of filler by weight of the granule; and the granule of compound ( 1 ) comprising from 15 wt% to 50 wt% by weight of the pharmaceutical composition The extragranular excipients of the filler of % are mixed. In another specific embodiment, the compound ( 1 ) particles comprise from 25 wt% to 90 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt and from 10 wt% to 50 wt%, based on the weight of the granule. Filler.

In another specific embodiment, the methods employ the steps of providing a binder solution comprising from 0.5 wt% to 10 wt% binder, and optionally from 0.25 wt% to 10 wt%, based on the weight of the pharmaceutical composition. a wetting agent; comprising a pre-granulation composition comprising from 25 wt% to 90 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt, 2 wt% to the weight of the pharmaceutical composition 40 wt% of the filler and 0.5 wt% to 8 wt% of the disintegrant; mixing the binder solution with the pre-granulation composition to form the compound ( 1 ) particles; and combining the compound ( 1 ) particles with the pharmaceutical composition a 15 wt% to 50 wt% filler and a 0.5 wt% to 10 wt% disintegrant extragranular excipient are mixed to form a blend composition of compound ( 1 ), wherein the binder solution Mixing with the pre-granulation composition includes feeding the pre-granulation composition into a twin-screw extruder and introducing the binder solution into a twin-screw extruder. In another specific embodiment, the methods employ the steps of providing a binder solution comprising from 0.5 wt% to 10 wt% binder, and optionally from 0.25 wt% to 10 wt%, based on the weight of the pharmaceutical composition. % of a wetting agent; providing a pre-granulation composition comprising from 25 wt% to 75 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt, 10 wt% to the weight of the pharmaceutical composition 25 wt% of the filler and 0.5 wt% to 5 wt% of the disintegrant; mixing the binder solution with the pre-granulation composition to form the compound ( 1 ) particles; and combining the compound ( 1 ) particles with the pharmaceutical composition a 15 wt% to 50 wt% filler and a 0.5 wt% to 10 wt% disintegrant extragranular excipient are mixed to form a blend composition of compound ( 1 ), wherein the binder solution Mixing with the pre-granulation composition includes feeding the pre-granulation composition into a twin-screw extruder and introducing the binder solution into a twin-screw extruder. In some specific embodiments, the pre-granulation composition comprises 25 wt% to 90 wt%, 25 wt% to 75 wt%, 25 wt% to 60 wt%, or 25 wt% to 55 wt% of the compound ( 1 ). Polymorphic form M or tromethamine salt. In some particular embodiments, the pre-granulation composition comprises from 10 wt% to 25 wt% filler and from 0.5 wt% to 5 wt% disintegrant by weight of the pharmaceutical composition.

In another particular embodiment, the methods use high shear wet granulation. In particular, the methods employ the steps of providing a granulation composition comprising from 25 wt% to 90 wt%, 25 wt% to 75 wt% or 25 wt% to 90 wt%, based on the weight of the pharmaceutical composition. a polymorphic form M of compound ( 1 ) or a tromethamine salt, filled with from 20 wt% to 75 wt% (or 25 wt% to 75 wt% or 20 wt% to 60 wt%) by weight of the pharmaceutical composition a binder, 0.5 wt% to 10 wt% of the binder by weight of the pharmaceutical composition, and 1 wt% to 10 wt% of the disintegrant based on the weight of the pharmaceutical composition, and optionally, by weight of the pharmaceutical composition 0.25 wt% to 10 wt% of a wetting agent; high shear wet granulation in the presence of 10 wt% to 30 wt% water relative to the total weight of the granulation composition (eg using a high shear granulator), To form compound ( 1 ) particles. The compound ( 1 ) particles are ground and the ground particles are mixed with a filler and a disintegrant and, if necessary, further with a lubricant. Typically, 60% to 80% by weight of the ground compound ( 1 ) particles and 10% to 30% by weight of the filler and 1% to 15% by weight of the disintegrant and, as the case, further 0.25 wt% Mix up to 5 wt% of lubricant.

For the tablet compositions of the present invention, the methods further comprise coating the tablet composition. Typical coating materials include one or more coloring agents, such as Opadry II white.

The dissolution of the pharmaceutical compositions of the present invention can be estimated, for example, using a standard USP Type II instrument using a suitable dissolution medium. Examples of suitable dissolution media include 0.4% sodium lauryl sulfate and FeSSIF (fed state simulated intestinal fluid) dissolved in 900 mL of deionized water and buffered at pH 4.8 using a citrate buffer, exemplified in the Journal of Pharmacy and Pharmacology. , 56, 453-462 (2004), the entire contents of which is incorporated herein by reference. Typically, the dissolution is measured at a temperature of about 37 ° C with stirring at 50 rpm to 75 rpm. In some particular embodiments, 50% or more than 50% of the pharmaceutical composition of the invention dissolves within 30 minutes.

As described below, the dissolution of the pharmaceutical composition of the present invention can also be measured by the dissolution constant z according to formula (1): Where M is the mass of the active drug dissolved, M ₀ is the initial mass of the active drug, t is the dissolution time, C _s is the solubility of the drug in the dissolution medium, V is the volume of the dissolution medium, and z is the dissolution rate constant. z represents the mass transfer property of the drug in the specified medium. See Takano et al., "Oral Absorption of Poorly Water-Soluble Drugs: Computer Simulation of Fraction Absorbed in Humans from a Miniscale Dissolution Test", Pharmaceutical Research , 23(6), 1144 (2006). In one embodiment, the pharmaceutical composition disclosed herein has a dissolution rate factor z of at least 0.025 ml/mg/min in a simulated human intestinal medium (eg, FeSSIF). In another embodiment, the dissolution rate factor z in the simulated human intestinal fluid ranges from 0.025 ml/mg/min to 100 ml/mg/min. In another embodiment, the dissolution rate factor z in the simulated human intestinal fluid ranges from 10 ml/mg/min to 100 ml/mg/min.

Simulated human intestinal media suitable for the present invention can be found in the art, for example, as described by Jantratid et al., "Dissolution Media Simulating Conditions in the Proximal Human Gastrointestinal Tract: An Update", Pharmaceutical Research , 25(7), 2008. . In one embodiment, human feeding state simulated intestinal fluid (FESSIF) is used in the present invention. Typical FESSIF includes sodium hydroxide, citric acid, sodium chloride, sodium taurocholate, and lecithin (L-alpha-phospholipid choline). A specific example is described in Example 9 below.

Compound (1) can be determined by any suitable method known in the art of dissolution medium of solubility (C _s). In one embodiment, the compound (1) in FESSIF in the solubility as follows: in the form of compound (1) of A is 0.9 mg / mL; Compound (1) of the form M of 0.825 mg / mL; Compound (1) of tromethamine The acid amine salt was 2.6 mg/mL.

In some embodiments, the invention relates to methods of producing an in vivo dissolution profile of an active drug, such as Compound ( 1 ). The methods typically comprise: a) an in vitro dissolution profile (eg, dissolution of the active drug versus time) and in vivo dissolution using a first pharmaceutical composition comprising the active drug and a pharmaceutically acceptable carrier or excipient A curve (eg, concentration of active drug in plasma versus time) to provide a z-factor correlation between in vivo z-value and in vitro z-value of formula (1); b) use of active drug and pharmaceutically acceptable An in vitro dissolution profile of a second pharmaceutical composition of a carrier or excipient to provide an in vitro z value of formula (1); and c) using a z factor correlation and an in vitro dissolution profile of the second pharmaceutical composition to produce The in vivo dissolution profile of the second pharmaceutical composition. The z-factor correlation can be generated using the in vitro dissolution profile of the first pharmaceutical composition and the in vivo dissolution profile. In particular, from the in vitro and in vivo dissolution profiles of the first pharmaceutical composition, the in vitro and in vivo z values of equation (1) can be obtained and a z factor between the in vitro z value and the in vivo z value can be produced. Correlation (eg, in vitro z-value versus in vivo z-value). Typically, in vivo and in vitro z values can be estimated from in vivo and in vitro dissolution profiles using any suitable fitting program or model known in the art. For example, in vitro z-values can be obtained by fitting the in vitro dissolution profile using Mathematica® software, and in vivo z-values can be obtained from in vivo dissolution profiles using biopharmaceutical models known in the art (eg, "Predicting the Impact of Physiological and Biochemical Processes on Oral Drug Bioavailability, Adv . Drug Delivery Review , 50 (Supp. 1), 2001, S41-67). Model-based biopharmaceutical typically established using e.g. Gastroplus ^TM software to describe the human active drug plasma concentration versus time curve of. Biopharmaceutical models typically contain a high-grade chamber and metastasis (ACAT) model to describe dissolution and oral absorption in the gastrointestinal tract, and a 2-chamber pharmacokinetic model. In general, the in vitro dissolution profile can be obtained in a suitable dissolution medium such as the above-described simulated human intestinal medium (e.g., human FESSIF). In some specific embodiments, the methods comprise: a) providing an in vitro and in vivo dissolution profile of a first pharmaceutical composition comprising an active drug and a pharmaceutically acceptable carrier or excipient; b) using a living The in vivo dissolution profile provides the in vivo z value of equation (1) and uses the in vitro dissolution profile to provide the in vitro z value of equation (1); c) produces the in vivo z value obtained in step b) and the in vitro z value Between z factor correlation; d) in vitro dissolution profile of a second pharmaceutical composition comprising an active drug and a pharmaceutically acceptable carrier or excipient; e) in vitro dissolution using a second pharmaceutical composition The curve provides the in vitro z value of formula (1); and f) uses the z factor correlation and the in vitro dissolution profile of the second pharmaceutical composition to produce an in vivo dissolution profile of the second pharmaceutical composition. As used herein, the term "providing" includes forming or generating a graph, computer output, and the like. Without being bound by a particular theory, such methods may accelerate the active drug (such as a compound) without obtaining an in vivo (eg, human plasma) dissolution profile of each pharmaceutically acceptable composition under development. ( 1 )) The development of a pharmaceutically acceptable composition.

In another aspect, the invention provides a computer system for use in the above method of producing an in vivo dissolution profile of an active drug. In one embodiment, a computer system includes a data storage medium containing data storage material encoded with machine readable material. In a particular embodiment, the data comprises in vivo and in vitro z values of formula (1). In another specific embodiment, the data comprises in vivo and in vitro z values of formula (1), and in vivo and in vitro dissolution profiles of the first pharmaceutical composition of the active drug. In another specific embodiment, the data comprises the in vivo and in vitro z values of formula (1), the in vivo and in vitro dissolution profiles of the first pharmaceutical composition of the active drug, and the living body of the second pharmaceutical composition of the active drug. External dissolution curve. The storage medium encoded by such data is displayed on a computer screen or the like when viewed and utilized by a computer programmed with appropriate software. In another embodiment, the computer system further comprises: i) a working memory for storing instructions for processing machine readable data; ii) a central processing unit coupled to the working memory and the machine readable data storage medium In order to process machine readable material and produce a living body of formula (1) The z-factor correlation between the internal z value and the in vitro z value. In a particular embodiment, the central processing unit further uses the in vitro dissolution profile to generate the in vitro z value of equation (1) and/or uses the respective dissolution profile to generate the in vivo z value of equation (1). In another specific embodiment, the central processing unit further uses the in vitro and in vivo dissolution profiles of the first pharmaceutical composition to produce in vitro and in vivo z values of formula (1); generating in vitro z values and in vivo z The z-factor correlation between the values; and the in vitro dissolution profile of the second pharmaceutical composition to produce the in vitro z-value of equation (1). In another specific embodiment, the central processing unit further uses the z-factor correlation and the in vitro dissolution profile of the second pharmaceutical composition to produce an in vivo dissolution profile of the second pharmaceutical composition. In another embodiment, the computer system further includes a display for displaying z-factor correlation in the form of a graphical representation. In another embodiment, the computer system further includes a commercially available software program to display a graphical representation of z-factor correlation and the like.

Figure 15 shows a version of these embodiments. The system 10 includes a computer 11 including a central processing unit ("CPU") 20; a working memory 22, which may be, for example, a RAM (random access memory) or "core"memory; a mass storage memory 24 (such as One or more disk drives or CD-ROM drives), one or more cathode ray tube ("CRT") display terminals 26, one or more keyboards 28, one or more input lines 30, and one or more outputs Lines 40, all of which are interconnected by conventional bidirectional system bus bars 50. Input hardware 36 (coupled to computer 11 by input line 30) can be implemented in a variety of ways. The machine readable material of the present invention can be input via the use of a data machine 32 connected by a telephone line or dedicated data line 34. Alternatively or additionally, the input hardware 36 can include a CD-ROM drive or disk drive 24. In conjunction with display terminal 26, keyboard 28 can also be used as an input device. The output hardware 46 (coupled to the computer 11 by the output line 40) can similarly be performed by conventional means. The output hardware can also include a printer 42 to produce a hard copy output, or a disk drive 24 to produce a storage system output for later use. Output hardware may also include a display terminal, CD or DVD recorder, ZIP ^TM or JAZ ^TM drive or other machine-readable data storage device. In operation, CPU 20 coordinates the use of various input devices 36 and output devices 46, coordinates data access from mass storage device 24, and accesses from and into working memory 22 and determines the sequence of data processing steps. A number of programs are available for processing the machine readable material of the present invention. These programs are discussed with reference to the calculation of drug discovery as described herein. The components of the particular reference hardware system 10 are included as appropriate in the following description of the data storage medium.

16 shows a cross section of a magnetic data storage medium 100 that can be encoded with machine readable material that can be executed by a system such as system 10. The medium 100 can be a conventional floppy or hard disk having a suitable substrate 101 (which can be a conventional substrate) and a suitable coating 102 (which can be a conventional coating) on one or both sides, which contains A magnetic region (not visible) whose polarity or orientation can be changed magnetically. Media 100 may also have an opening (not shown) for receiving a spindle of a disk drive or other data storage 24. The magnetic regions of the coating 102 of the media 100 are polarized or oriented to encode machine readable material, such as described herein, for execution by a system such as system 10 in a manner that is well known. 17 shows a cross section of an optically readable data storage medium 110 that can also be read by the machine. Data or instruction set encoding, such machine readable material or set of instructions may be executed by a system such as system 10. Media 110 can be a conventional optical disc-only memory (CD-ROM) or rewritable medium such as an optically readable and magneto-optical writable magneto-optical disc. The media 110 preferably has a suitable substrate 111 (which may be a conventional substrate) and typically has a suitable coating 112 (which may be a conventional coating) on one side of the substrate 111. In the case of a CD-ROM, as is well known to us, the coating 112 is reflective and embossed with a plurality of pits 113 to encode machine readable material. The pit arrangement is read by the laser light reflected from the surface of the coating 112. A protective coating 114 (preferably substantially transparent) is provided on the coating 112. In the case of magneto-optical discs, as is well known to us, coating 112 does not have pits 113, but has a plurality of magnets that can be magnetically altered in polarity when heated by a laser (not shown) above a certain temperature or Oriented magnetic zone. The orientation of the magnetic regions can be read by measuring the polarization of the laser light reflected from the coating 112. The magnetic zone arrangement encodes the data as described above.

In addition to the above ingredients, the pharmaceutical composition of the present invention may further comprise one or more pharmaceutically acceptable carriers. "Pharmaceutically acceptable" as used herein means inert and does not unduly inhibit the biological activity of the compound. A pharmaceutically acceptable carrier should be biocompatible after administration to an individual, such as non-toxic, non-inflammatory, non-immunogenic or otherwise unintended or side effects. Standard pharmaceutical blending techniques are available.

Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins (such as human serum albumin); Phosphate or glycine); a mixture of partial glycerides of saturated vegetable fatty acids; water; Electrolyte (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salt); colloidal ceria; magnesium tricaprate; polyvinylpyrrolidone; polyacrylate; wax; Polyethylene-polyoxypropylene-block polymer; methylcellulose; hydroxypropylmethylcellulose; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and Derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered xanthine; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil , safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and hydrogen Alumina; alginic acid; pyrogen-free water; isotonic physiological saline; Ringer's solution; ethanol and phosphate buffer solution; and other non-toxic compatible lubricants, such as sodium lauryl sulfate and Magnesium stearate And coloring agents; release agents; coating agent; sweetening agents; flavoring and perfuming agents, according to the judgment of the formulator, preservatives and antioxidants can also be present in the composition.

For the purposes of the present invention, chemical elements are determined according to the Periodic Table of the CAS version of the Chemistry and Physics Handbook, 75th Edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausolito: 1999 and "March's Advanced Organic Chemistry", fifth edition, editors: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformation, and rotational) forms of the structure. For example, unless only one isomer is specifically drawn, the invention includes R and S configurations, (Z) and (E) double bond isomers and (Z) and (E) of each asymmetric center. Configuration isomers. As will be appreciated by those skilled in the art, the substituents are free to rotate about any rotatable key. For example, draw as Substituent .

Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, cis/trans, conformational, and rotational mixtures of the present compounds are within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

In addition, unless otherwise indicated, structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention but having hydrogen replaced by hydrazine or hydrazine or substituted by carbon with ¹³ C or ¹⁴ C enriched carbon are within the scope of the invention. Such compounds are for example suitable as analytical tools or probes in biological assays. Such compounds, especially guanidine (D) analogs, may also be therapeutically applicable.

The compounds described herein are defined herein by their chemical structure and/or chemical name. When a compound is referred to by both chemical structure and chemical name and the chemical structure contradicts the chemical name, the chemical structure determines the identity of the compound.

Those skilled in the art will appreciate that the compounds of the invention may be stereoisomers (e.g., optical isomers (+ and -), geometric isomers (cis and trans), and conformations). The form of the isomer (axial and equatorial)) exists. All such stereoisomers are included within the scope of the invention.

Those skilled in the art will appreciate that the compounds of the invention may contain a palm center. Thus, the compound of formula ( I ) can exist in the form of two different optical isomers (i.e., the (+) or (-) enantiomer). All such enantiomers and mixtures thereof, including racemic mixtures, are included within the scope of the invention. A single optical isomer or enantiomer can be obtained by methods well known in the art, such as for palm HPLC, enzymatic analysis, and for palm auxiliaries.

In one embodiment, the compounds of the invention are provided in a form that is at least 95%, at least 97%, and at least 99% free of the single enantiomer of the corresponding enantiomer.

In another embodiment, the compound of the invention is in a form that is at least 95% free of the (+) enantiomer of the corresponding (-) enantiomer.

In another embodiment, the compound of the invention is at least 97% free of the (+) enantiomer of the corresponding (-) enantiomer.

In another embodiment, the compound of the invention is in the form of at least 99% free of the (+) enantiomer of the corresponding (-) enantiomer.

In another embodiment, the compound of the invention is in a form that is at least 95% free of the (-) enantiomer of the corresponding (+) enantiomer.

In another embodiment, the compound of the invention is in the form of at least 97% free of the (-) enantiomer of the corresponding (+) enantiomer.

In another embodiment, the compound of the invention is in the form of at least 99% free of the (-) enantiomer of the corresponding (+) enantiomer.

Depending on the severity of the infection, oral, rectal, non-oral The invention is administered to humans and other animals via the intestine, in the cerebral cistern, intravaginally, intraperitoneally, on the surface (such as by powders, ointments or drops), by buccal (such as by oral or nasal spray) or the like. A pharmaceutically acceptable composition. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. . In particular, the composition is administered orally, intraperitoneally or intravenously.

Any orally acceptable dosage form including, but not limited to, a capsule, lozenge, aqueous suspension or solution can be used for oral administration. In the case of tablets for oral use, carriers which are usually employed include, but are not limited to, lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in a capsule form, suitable diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. Some sweeteners, flavoring or coloring agents may also be added as needed.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents such as water or other solvents conventionally employed in the art; solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzoyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrogen Fatty acid esters of sterols, polyethylene glycols and sorbitans and mixtures thereof. In addition to the inert diluent, the oral compositions may also include adjuvants, Such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

Solid dosage forms for oral administration include capsules, lozenges, pills, powders, and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and/or a) filler or Dosing agents such as starch, lactose, sucrose, glucose, mannitol and citric acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) moisturizing Agents such as glycerin, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain citrates and sodium carbonate, e) solvents, such as paraffin, f) absorption enhancers, such as Tetraammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, 1) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate , solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, lozenges and pills, the dosage form may also contain a buffer.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose and high molecular weight polyethylene glycols and the like. The solid dosage forms of lozenges, dragees, capsules, pills, and granules can be prepared with coatings and shells (such as enteric coatings and other coatings well known in the art. It may optionally contain an opacifying agent and may be of a composition such that it will release the active ingredient in a delayed manner, as appropriate, or preferably in a particular portion of the intestinal tract. Examples of embedding compositions that can be used include polymeric materials and waxes. Solid compositions of a similar type may also be employed as the use of such as lactose as well as high molecular weight polyethylene glycols and the like. Soft filling of the agent and filler in the hard-filled gelatin capsule.

The active compound (e.g., the polymorphic form M of compound ( 1 ) or the amine salt of tromethamine) can also be in microencapsulated form with one or more of the above indicated excipients. The solid dosage forms of lozenges, dragees, capsules, pills, and granules can be prepared with coatings and shells (such as enteric coatings, controlled release coatings, and other coatings well known in the art of pharmaceutical formulation). In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. As a matter of convention, such dosage forms may also contain other materials than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, lozenges and pills, such dosage forms may also contain buffering agents. It may optionally contain opacifying agents and may also be of a composition such that the active compound is released in a delayed manner, as appropriate, or preferably in a particular portion of the intestinal tract. Examples of embedding compositions that can be used include polymeric materials and waxes.

Injectable preparations (for example, sterile injectable aqueous or oily suspensions) may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic, parenterally acceptable diluent or solvent, for example, as a solution in propylene glycol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution (U.S.P.) and isotonic sodium chloride solution. In addition, it is customary to employ sterile, fixed oils as a solvent or suspension medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable formulations.

Injectable formulations can be eliminated, for example, by filtration through a bacterial retention filter The bacteria, or by incorporation of a sterilizing agent, are sterilized in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

The sterile injectable form can be an aqueous or oily suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example, as a solution in propylene glycol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, it is customary to employ sterile, fixed oils as a solvent or suspension medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are suitable for the preparation of injectable preparations, as are pharmaceutically acceptable natural oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersing agent, such as carboxymethylcellulose or similar dispersing agents, which are typically used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants (such as Tween, Span) and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used. The purpose of the deployment.

In order to prolong the action of the active compound administered, it is generally desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the compound will depend on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Or by dissolving or suspending the compound in oil A sexual vehicle delays the absorption of a compound administered parenterally. Injectable depot forms are prepared by forming a microcapsule matrix of the active compound in a biodegradable polymer such as polylactide-polyglycolide. The rate of release of the compound can be controlled depending on the ratio of active compound to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Stocked injectable formulations are also prepared by capsulating the compound in liposomes or microemulsions which are compatible with body tissues.

The above formulations suitable for providing sustained release of the active ingredient may be employed as needed.

Compositions for rectal or vaginal administration are, in particular, suppositories which can be prepared by mixing the active compound with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or suppository wax. The excipients or carriers are solid at ambient temperature but liquid at body temperature and thus thaw in the rectal or vaginal cavity and release the active compound.

Dosage forms for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservative or buffer. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the invention. In addition, transdermal patches can be used which have the added advantage of allowing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dissolving the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

Alternatively, the active compound and its pharmaceutically acceptable compositions may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may employ benzyl alcohol or other suitable preservatives, absorption enhancers that enhance bioavailability, fluorocarbons, and/or other conventional solubilization or dispersion. The agent is prepared as a saline solution.

In some embodiments, the pharmaceutical compositions of the invention are in a solid dosage form. In some particular embodiments, the pharmaceutical compositions of the invention are in the form of a troche. In other embodiments, the pharmaceutical compositions of the invention are in a liquid dosage form, in particular an IV dosage form.

The pharmaceutical compositions of the present invention can be formulated in unit dosage form. The term "unit dosage form" refers to a physical unit that is suitable as a single dosage for the subject to be treated, each unit containing a predetermined quantity of active substance calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be used in any of a single daily dose or multiple daily doses (e.g., about 1 to 4 or more than 4 times per day). When multiple daily doses are used, the unit dosage form of each dose may be the same or different. The amount of active compound in unit dosage form will vary depending, for example, on the subject being treated and the particular mode of administration (e.g., 0.01 mg per kilogram of body weight per day to 100 mg per kilogram of body weight per day).

It will be appreciated that the amount of the active compound of the invention described herein for use in therapy will vary not only with the particular compound selected, but also with the route of administration, the nature of the condition to be treated, and the age and condition of the patient. Changes will eventually be determined by the visiting doctor or veterinarian. In general, however, suitable dosages will range from about 0.1 mg to about 750 mg per kilogram of body weight per day, for example, from 0.5 mg/kg to 60 mg/kg per day or, for example, 1 per day. In the range of mg/kg to 20 mg/kg.

The desired dose may conveniently be presented as a single dose or as divided doses administered at appropriate intervals, for example, two, three, four or more than four doses per day.

The pharmaceutical compositions of the present invention can be used to treat or prevent a Flaviviridae viral infection in a subject by administering to the subject a therapeutically effective amount of at least one of the active compounds of the invention described herein.

The terms "individual", "subject" or "patient" include animals and humans (eg male or female, such as children, adolescents or adults). "Individual", "subject" or "patient" is preferably human.

In one embodiment, the viral infection is selected from the group consisting of Flavivirus infections. In one embodiment, the Flavivirus infection is hepatitis C virus (HCV), bovine viral diarrhea virus (BVDV), swine fever virus, dengue fever virus, Japanese encephalitis virus or yellow fever virus.

In one embodiment, the Flaviviridae virus infection is a hepatitis C virus infection (HCV), such as HCV genotype 1, genotype 2, genotype 3 or genotype 4 infection.

In one embodiment, the active compound is useful for treating an HCV genotype 1 infection. The HCV can be genotype 1a or genotype 1b.

In one embodiment, the active compound is useful for treating or preventing a Flaviviridae viral infection in a subject, comprising administering to the subject a therapeutically effective amount of at least one active compound of the invention described herein, and further comprising administering at least Another agent selected from the group consisting of a viral serine protease inhibitor, a viral polymerase inhibitor, a viral helicase inhibitor, and an immunomodulatory Inhibitors, antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotective agents, antisense agents, HCV NS2/3 protease inhibitors and internal ribosome entry site (IRES) inhibitors.

In one embodiment, a method of inhibiting or reducing the activity of a viral polymerase in a subject comprising administering a therapeutically effective amount of an active compound of the invention described herein.

In one embodiment, a method of inhibiting or reducing the activity of a viral polymerase in a subject comprising administering a therapeutically effective amount of an active compound of the invention described herein and further comprising administering one or more viral polymerase inhibitors Agent.

In one embodiment, the viral polymerase is a Flaviviridae viral polymerase.

In one embodiment, the viral polymerase is an RNA dependent RNA polymerase.

In one embodiment, the viral polymerase is HCV polymerase.

In one embodiment, the viral polymerase is HCV NS5B polymerase.

The pharmaceutical composition of the present invention may be formulated in the form of a pharmaceutical composition further comprising one or more other agents selected from the group consisting of a viral serine protease inhibitor, a viral NS5A inhibitor, a viral polymerase inhibitor, and a virus. Helixase inhibitors, immunomodulators, antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotective agents, antisense agents, HCV NS2/3 protease inhibitors, and internal ribosome entry site (IRES) inhibitors. For example, a pharmaceutical composition can include an active compound; one or more additional agents selected from the group consisting of non-nucleoside HCV polymerase inhibitors (eg, HCV-796), nucleoside HCV polymerase inhibitors (eg, R7128, R1626, R1479) ), HCV NS3 protease inhibitors (e.g., VX-950 / telaprevir and ITMN-191), interferons and ribavirin; and at least one pharmaceutically acceptable carrier or excipient.

One or more other active agents may be used in the form of a combination therapy, which may be selected from the group consisting of a viral serine protease inhibitor, a viral polymerase inhibitor, a viral NS5A inhibitor, a viral helicase inhibitor, an immunomodulator, an antioxidant, and an antibacterial agent. Agents, therapeutic vaccines, hepatoprotective agents, antisense agents, HCV NS2/3 protease inhibitors and internal ribosome entry site (IRES) inhibitors.

Compound ( 1 ) and other active agents can be administered sequentially. Alternatively, it can be administered at the same time. Combinations of the above mentioned may suitably be presented for use in the form of a pharmaceutical formulation, and thus a pharmaceutical formulation comprising a combination as defined above and a pharmaceutically acceptable carrier thus constitutes another aspect of the invention.

The term "viral serine protease inhibitor" as used herein means an agent that is effective to inhibit the function of viral serine proteases, including HCV serine proteases, in mammals. HCV serine protease inhibitors include, for example, those compounds described in the following patents: WO 99/07733 (Boehringer Ingelheim), WO 99/07734 (Boehringer Ingelheim), WO 00/09558 (Boehringer Ingelheim), WO 00/09543 (Boehringer Ingelheim), WO 00/59929 (Boehringer Ingelheim), WO 02/060926 (BMS), WO 2006039488 (Vertex), WO 2005077969 (Vertex), WO 2005035525 (Vertex), WO 2005028502 (Vertex), WO 2005007681 (Vertex ), WO 2004092162 (Vertex), WO 2004092161 (Vertex), WO 2003035060 (Vertex) or WO 03/087092 (Vertex), WO 02/18369 (Vertex) or WO 98/17679 (Vertex).

The term "viral polymerase inhibitor" as used herein means an agent that is effective to inhibit the function of a viral polymerase (including HCV polymerase) in a mammal. Inhibitors of HCV polymerase include non-nucleosides, such as those described in the following patents: WO 03/010140 (Boehringer Ingelheim), WO 03/026587 (Bristol Myers Squibb), WO 02/100846 A1, WO 02/100851 A2, WO 01/85172 A1 (GSK), WO 02/098424 A1 (GSK), WO 00/06529 (Merck), WO 02/06246 A1 (Merck), WO 01/47883 (Japan Tobacco), WO 03/000254 (Japan Tobacco) and EP 1 256 628 A2 (Agouron).

In addition, other HCV polymerase inhibitors also include nucleoside analogs, such as those described in the following patents: WO 01/90121 A2 (Idenix), WO 02/069903 A2 (Biocryst Pharmaceuticals Inc.), and WO 02/ 057287 A2 (Merck/Isis) and WO 02/057425 A2 (Merck/Isis).

Specific examples of nucleoside inhibitors of HCV polymerase include R1626, R1479 (Roche), R7128 (Roche), MK-0608 (Merck), R1656 (Roche-Pharmasset), and Valopicitabine (Idenix). Specific examples of HCV polymerase inhibitors include JTK-002/003 and JTK-109 (Japan Tobacco), HCV-796 (Viropharma), GS-9190 (Gilead), and PF-868, 554 (Pfizer).

The term "viral NS5A inhibitor" as used herein means an agent that is effective to inhibit the function of the viral NS5A protease in a mammal. HCV NS5A inhibitors include, for example, the compounds described in the following patents: WO 2010/117635, WO 2010/117977, WO 2010/117704, WO 2010/1200621, WO 2010/096302, WO 2010/017401, WO 2009/102633 WO 2009/102568, WO 2009/102325, WO 2009/102318, WO 2009020828, WO 2009020825, WO 2008144380, WO 2008/021936, WO 2008/021928, WO 2008/021927, WO 2006/133326, WO 2004/014852 WO 2004/014313, WO 2010/096777, WO 2010/065681, WO 2010/065668, WO 2010/065674, WO 2010/062821, WO 2010/099527, WO 2010/096462, WO 2010/091413, WO 2010/094077, WO 2010/111483, WO 2010/120935, WO 2010/126967, WO 2010/132538 and WO 2010/122162. Specific examples of HCV NS5A inhibitors include: EDP-239 (developed by Enanta); ACH-2928 (developed by Achillion); PPI-1301 (developed by Presido Pharmaceuticals); PPI-461 (developed by Presido Pharmaceuticals); AZD-7295 (developed by AstraZeneca); GS-5885 (developed by Gilead); BMS-824393 (developed by Bristol-Myers Squibb); BMS-790052 (developed by Bristol-Myers Squibb); (Gao M. et al, Nature, 465 , 96-100 (2010); nucleoside or nucleotide polymerase inhibitors such as PSI-661 (developed by Pharmasset), PSI-938 (developed by Pharmasset), PSI- 7977 (developed by Pharmasset), INX-189 (developed by Inhibitex), JTK-853 (developed by Japan Tobacco), TMC-647055 (Tibotec Pharmaceuticals), RO-5303253 (developed by Hoffmann-La Roche) and IDX-184 ( Developed by Idenix Pharmaceuticals).

The term "viral helicase inhibitor" as used herein means an agent that is effective to inhibit the function of a viral helicase, including a Flaviviridae helicase, in a mammal.

As used herein, "immunomodulatory agent" means an agent that is effective to enhance or potentiate the immune system response in a mammal. Immunomodulators include, for example, class I interferons (such as alpha interferon, beta interferon, delta interferon and omega interferon, x interferon, complex interferon and asialo interferon), class II interferons (such as gamma interference) And pegylated interferon.

Exemplary immunomodulatory agents include, but are not limited to, thalidomide; IL-2; erythropoietin; IMPDH inhibitors, such as Merimepod (Vertex Pharmaceuticals Inc.); interferon, Including natural interferons (such as OMNIFERON, Viragen and SUMIFERON, Sumitomo, a blend of natural interferons), natural interferon alpha (ALFERON, Hemispherx Biopharma, Inc.), interferon alpha n1 from lymphoblastoid cells (WELLFERON) , Glaxo Wellcome), oral alpha interferon, pegylated interferon, pegylated interferon alpha 2a (PEGASYS, Roche), recombinant interferon alpha 2a (ROFERON, Roche), inhaled interferon alpha 2b (AERX) , Aradigm), pegylated interferon alpha 2b (ALBUFERON, Human Genome Sciences/Novartis, PEGINTRON, Schering), recombinant interferon alpha 2b (INTRON A, Schering), pegylated interferon alpha 2b (PEG-INTRON) , Schering, VIRAFERONPEG, Schering), interferon beta-1a (REBIF, Serono, Inc. and Pfizer), interferon alpha (INFERGEN, Valeant Pharmaceutical), interferon gamma-1b (ACTIMMUNE, Intermune, Inc.), unpolymerized Ethylene glycolated interferon alpha, alpha interferon, and analogs thereof; and synthetic thymosin alpha 1 (ZADAXIN, SciClone Pharmaceuticals Inc.).

The term "class I interferon" as used herein means an interferon selected from the group of interferons that all bind to a type 1 receptor. It includes Class I interferons produced naturally and synthetically. Examples of class I interferons include alpha interferon, beta interferon, delta interferon and omega interferon, tau interferon, co-interferon, and asialo interferon. The term "class II interferon" as used herein means an interferon selected from the group of interferons that all bind to a type II receptor. Examples of class II interferons include gamma interferon.

Antisense agents include, for example, ISIS-14803.

Specific examples of HCV NS3 protease inhibitors include BILN-2061 (Boehringer Ingelheim) SCH-6 and SCH-503034/Schering-Plough, VX-950/Vertex and ITMN-B ( InterMune), GS9132 (Gilead), TMC-435350 (Tibotec/Medivir), ITMN-191 (InterMune), MK-7009 (Merck).

Internal ribosome entry site (IRES) inhibitors include ISIS-14803 (ISIS Pharmaceuticals) and their compounds described in WO 2006019831 (PTC therapeutics).

In one embodiment, other active agents for use in the compositions and combinations include, for example, ribavirin, amantadine, metoprrol, levovirin, Viramidine and maxamine.

In one embodiment, the other active agents are interferon alpha, ribavirin, silybum marianum, interleukine-12, amantadine, ribonuclease, thymosin, N-acetylcysteine Or cyclosporine.

In one embodiment, the other active agent is interferon alpha 1A, interferon alpha 1B, interferon alpha 2A or interferon alpha 2B. Interferons can be obtained in PEGylated and non-PEGylated forms. Pegylated interferons include PEGASYS ^TM and Peg-intron ^TM.

The recommended dose of PEGASYS ^TM for monotherapy of chronic hepatitis C was administered subcutaneously by abdomen or thighs once with 180 mg (1.0 mL vial or 0.5 mL prefilled syringe) per week for 48 weeks.

When used in combination with ribavirin in chronic hepatitis C as the recommended dose of PEGASYS ^TM weekly 180 mg (1.0 mL vial or 0.5 mL prefilled syringe).

Ribavirin is typically administered orally, and ribavirin lozenges are currently commercially available. A typical standard daily dose of a viral azole tablet (e.g., about 200 mg of a tablet) is from about 800 mg to about 1200 mg. For example, a viral azole tablet is administered at about 1000 mg for a system weighing less than 75 kg, or about 1200 mg for a system having a body weight greater than or equal to 75 kg. However, the methods or combinations of the invention are not limited to any particular dosage form or regimen herein. Typically, ribavirin can be administered according to the dosage regimen described in its commercial product label.

The recommended dose of PEG-lntron ^TM therapy weekly subcutaneously 1.0 mg / kg, for one year. This dose should be administered on the same day of the week.

When administered in combination with ribavirin, the recommended dose of PEG-lntron is 1.5 micrograms per kilogram per week.

Combinations of the above mentioned may suitably be presented for use in the form of a pharmaceutical formulation, and thus a pharmaceutical formulation comprising a combination as defined above and a pharmaceutically acceptable carrier thus constitutes another aspect of the invention. The individual components used in the methods of the invention or combinations of the invention may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations.

In one embodiment, the other agent is interferon alpha 1A, interferon alpha 1B, interferon alpha 2A or interferon alpha 2B and optionally ribavirin.

When compound ( 1 ) is used in combination with at least one second therapeutic agent that is active against the same virus, the dose of each compound may be the same as or different from when the compound is used alone. Those skilled in the art will readily appreciate the appropriate dosage.

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are hereby incorporated by reference in their entirety. In case of conflicts, the present specification (including definitions) shall prevail. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

illustration Example 1: XRPD and C ¹³ General method for solid state NMR measurement

SSNMR experiment:

Solid state nuclear magnetic spectroscopy (SSNMR) was obtained on a Bruker 400 MHz proton frequency wide aperture spectrometer. Form A was obtained on a Bruker 500 MHz spectrometer. The longitudinal relaxation time ( ¹ HT ₁ ) of proton relaxation is determined by fitting the detected proton saturation recovery data with an exponential function before obtaining the carbon spectrum. This value is used to set the optimal recirculation delay for the carbon cross-polarization magic angle rotation experiment ( ^13C CPMAS), which is typically set between 1.2 x ¹ HT ₁ and 1.5 x ¹ HT ₁ . The carbon spectrum was obtained with a 2 millisecond contact time using a linear amplitude ramp (50% to 100%) on the proton channel and a 100 kHz SPINAL-64 decoupling. The typical magic angle rotation (MAS) speed is 12.5 kHz. To limit frictional heat generation due to rapid rotation, the probe temperature was maintained at 275 K. The carbon spectrum was externally referenced by setting the high field resonance of the adamantane solid phase sample to 29.5 ppm. Using this procedure, the carbon spectrum is indirectly referenced to 0 ppm tetramethyl decane.

Bruker D8 Discover XRPD experimental details.

The XRPD pattern was obtained in a reflective mode at room temperature using a Bruker D8 Discover diffractometer (asset tag V012842) equipped with a sealed tube source and a Hi-Star area detector (Bruker AXS, Madison, WI). The X-ray generator operates at a voltage of 40 kV and a current of 35 mA. The powder sample was placed in an aluminum reservoir. Both boxes were each recorded with an exposure time of 120 seconds. The data was then integrated in steps of 0.02° in the range of 4° to 40° 2θ and combined into one continuous pattern.

Example 2: Formation of Compound (1):

Method A:

Compound ( 1 ) can be prepared as described in WO 2008/058393:

5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexylcarbonyl)-amino]- Preparation of thiophene-2-carboxylic acid

Step I

Treatment of 3-amino-5-bromo-thiophene-2- with 1,4-cyclohexanedione monoethylene ketal (11.3 mg, 72.0 mmol) and dibutyltin dichloride (1.098 g, 3.6 mmol) A suspension of methyl formate (17.0 g, 72.0 mmol) in dry THF (21 mL). After 5 minutes, phenyl decane (9.74 mL, 79.2 mmol) was added and the mixture was stirred at room temperature overnight. After concentration, the residue was dissolved in EtOAc, washed successively with NaHCO ₃ and brine. The organic layer was separated, dried over Na ₂ SO _4, filtered and concentrated. The crude material was diluted in hexanes (500 mL). After filtration, the mother liquor was evaporated to dryness to give methyl 5-bromo-3-(1,4-dioxo-spiro[4.5]dec-8-ylamino)thiophene-2-carboxylate (24.79 g, 92% yield rate).

References: WO 2004/052885

Step II

Preparation of trans-4-methylcyclohexylcarboxylic acid chloride:

Ethyl dichloromethane (2 M in DCM, 117 mL) was added dropwise to a mixture of <RTI ID=0.0> The mixture was stirred at room temperature for 3 hours. The DCM was removed under reduced pressure and the residue was evaporated with DCM. The residue was dissolved in toluene to prepare a 1 M solution.

Preparation of B-target compound:

Adding a solution of 1 M of trans-4-methylcyclohexylcarboxylic acid chloride to 5-bromo-3-(1,4-dioxo-spiro[4.5]dec-8-ylamino)-thiophene-2- A solution of methyl formate (24.79 g, 65 mmol) in toluene (25 mL) was then added pyridine (5.78 mL, 71.5 mmol). The resulting mixture was then stirred under reflux for 16 hours. The reaction mixture was diluted with toluene (60 mL) and cooled to 5 °C. After adding pyridine (12 mL) and MeOH (5.6 mL), the mixture was stirred at 5 ° C for 2 hr. The white suspension was filtered off and toluene was added to the mother liquor. The organic phase was washed with 10% citric acid, washed with saturated aqueous NaHCO _3, dried (Na ₂ SO ₄₎ and concentrated. The residue was triturated in boiling hexane (1500 mL). The reaction mixture was allowed to cool to room temperature. The reaction flask was immersed in an ice bath and stirred for 30 min; a white solid was filtered and washed with cold hexane The solid was purified by hydrazine column chromatography using 20% EtOAc:hexanes eluting to afford the final compound 5-bromo-3-[(1,4-dioxo-spiro[4.5] 癸-8-yl)- Methyl (trans-4-methyl-cyclohexylcarbonyl)-amino]-thiophene-2-carboxylate (10.5 g, 32%).

Step III

5-Bromo-3-[(1,4-dioxo-spiro[4.5]dec-8-yl)-(trans-4-methylcyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid The methyl ester (8.6 g, 17 mmol) was dissolved in EtOAc (EtOAc) (EtOAc) The reaction was stirred at 40 ° C for 3 hours. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO _3. The organic layer was separated, dried over Na ₂ SO _4, filtered, and concentrated to give as a solid of 5-bromo-3 - [(trans-4-methyl - cyclohexyl-carbonyl) - (4-oxo - cyclohexyl) Methylamino-thiophene-2-carboxylate (7.4 g, 95%).

Step IV

To 5-bromo-3-[(trans-4-methyl-cyclohexylcarbonyl)-(4-o-oxy-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester under N ₂ atmosphere ( 5.9 g, 12.9 mmol) NaBH ₄ (250 mg, 6.4 mmol) was added portionwise (about 30 min) in 50 mL MeOH in cold (0 ° C). After the addition was completed and the reaction was completed by TLC (hexane:EtOAc 1:1), 10 mL of 2% HCl was added and stirred for 15 minutes. The reaction mixture was concentrated to dryness under vacuum. The reaction mixture was reconstituted with water (25 mL) and extracted withEtOAc. The combined organic phases were dried and concentrated and dried to MgSO _4. The residue was purified by hydrazine gel column chromatography using EtOAc:hexane (1:1) as eluting solvent to afford 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)- Methyl 4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylate (4.5 g, 77% yield).

Step V

To the compound methyl 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexylcarbonyl)-amino]-thiophene-2-carboxylate (500 mg, 1.09 mmol And 3,3-dimethyl-but-1-yne (385 mg, 4.69 mmol) in DMF (0.5 mL) was added triethylamine (1.06 mL) and bis(diphenylmethyleneacetone) dipalladium (0) (70 mg, 0.08 mmol), and the reaction mixture was stirred under reflux for 16 hours under a N ₂ atmosphere. DMF and triethylamine were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was separated, dried (Na ₂ SO _4), concentrated, and the residue was purified by column chromatography using ethyl acetate and hexane (1: 2) was purified from the agent as a solvent, to obtain 330 mg (66%) as a solid 5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexylcarbonyl)-amino group ]-Methylthiophene-2-carboxylate.

Step VI

5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexylcarbonyl)-amino] -Methyl thiophene-2-carboxylate (0.10 g, 0.22 mmol) dissolved in THF:MeOH:H ₂ O 3:2:1 mixture (5.0 mL) with 1 N LiOH.H ₂ O solution (0.65 mL) , 0.65 mmol) treatment. After stirring at 60 ° C for 2 hours, the reaction mixture was concentrated under reduced pressure on a rotary evaporator. The mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified using 0.1 N HCl. EtOAc layer was separated and dried over Na ₂ SO _4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator, followed by purification by column chromatography using methanol and dichloromethane (1:9) as a solvent to afford 30 mg (30%) as solid. 5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexylcarbonyl)-amino]- Thiophene-2-carboxylic acid. ESI ^- (MH): 444.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 0.58 (m, 1H), 0.74 (q, J = 6.53 Hz, 1H), 0.81 (ddd, J = 12.86, 12.49, 3.19 Hz, 1H), 1.18 ( m,5H), 1.28 (s, 3H), 1.42 (m, 1H), 1.55 (m, 3H), 1.61 (m, 1H), 1.73 (m, 2H), 1.81 (m, 2H), 3.19 (m) , 1H), 4.26 (m, 1H), 4.49 (bs, 1H), 7.14 (s, 1H), 13.45 (bs, 1H).

Method B

5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexylcarbonyl)-amino]- Preparation of thiophene-2-carboxylic acid

Step I

Treatment of methyl 3-amino-thiophene-2-carboxylate with 1,4-cyclohexanedione monoethylene ketal (5.0 g, 32.05 mmol) and dibutyltin dichloride (482 mg, 1.59 mmol) A suspension of 5.0 g, 31.85 mmol) in dry THF (9 mL). After 5 minutes, phenyl decane (4.3 mL, 34.96 mmol) was added and the mixture was stirred at room temperature overnight. After concentration, the residue was dissolved in EtOAc and washed successively with NaHCO ₃ and brine. The organic layer was separated, dried (Na ₂ SO _4), filtered and concentrated. The residue was purified by column chromatography using 30% ethyl acetate in hexanes as eluting solvent to afford 3-(1,4-dioxo-spiro[4.5]indole-8-ylamino)-thiophene- Methyl 2-formate (4.5 g, 47% yield).

Alternative program:

Methyl 3-amino-thiophene-2-carboxylate (1 equivalent) was dissolved in dichloromethane, then dissolved in 1,4-cyclohexanedione monoethylene acetal (2 equivalents) to give a slightly yellow Solution. This solution was added to a suspension of NaBH(OAc) ₃ (2.2 eq.) in dichloromethane. Acetic acid (2.4 eq.) was added dropwise over 15 minutes. The resulting suspension was stirred under N ₂ at 20 ° C to 25 ° C for 24 hours. The reaction was quenched by the addition of water and stirred for 1 hour. The dichloromethane layer was separated, treated with water and stirred for additional 1 hour. The dichloromethane layer was separated and added to a saturated NaHCO ₃ solution and stirred at 20 ° C to 25 ° C for 20 min. The solid was filtered and some white residue, and the organic layer was separated, dried (Na ₂ SO ₄₎ and evaporated. Methanol was added to the residue and evaporated to dryness. The residue was taken into methanol and stirred at 0 ° C for 2 h. The suspension was vacuum filtered and the resulting filter cake was washed with cold methanol. The white solid was dried under vacuum at 35 ° C to 40 ° C for about 20 hours to give the title compound.

Step II

A. Preparation of trans-4-methylcyclohexylcarboxylic acid chloride

Add oxalyl chloride (2 M in dichloromethane, 17 mL) dropwise to EtOAc-EtOAc (EtOAc (EtOAc) In the suspension in). The reaction mixture was stirred at room temperature for 3 hours. The volatiles were removed under reduced pressure to give crude acid chloride which was used directly for next.

B. Add trans-4-methylcyclohexylcarboxylic acid chloride to methyl 3-(1,4-dioxo-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylate (2.4 g, 8.08 mmol) in a solution of toluene (18 mL) followed by pyridine (0.7 mL). The resulting mixture was then stirred under reflux for 16 hours. The reaction mixture was diluted with toluene (7 mL) and cooled to 5 °C. After adding pyridine (1.5 mL) and MeOH (0.8 mL), the mixture was stirred at 5 ° C for 2 hr. The white solid was filtered and washed with toluene. The filtrate was washed with 10% citric acid, washed with saturated aqueous NaHCO _3, dried (Na ₂ SO ₄₎ and concentrated. The solid was purified by hydrazine column chromatography using 20% EtOAc:hexanes eluting to afford 3-[(1,4-dioxo-spiro[4.5] 癸-8-yl)- Methyl-cyclohexylcarbonyl-amino]-thiophene-2-carboxylate (2.3 g, 68%).

Alternative program:

Anhydrous DMF was added to a solution of trans-4-methylcyclohexylcarboxylic acid (1.8 eq.) in toluene under nitrogen. The reaction mixture was stirred and sulfinium chloride (2.16 equivalents) was added over 3 minutes to 5 minutes. The mixture was then stirred at room temperature for 3 hours. When the reaction was completed, toluene was added to the reaction mixture. The solution is then evaporated to half its volume under reduced nitrogen pressure. The solution was dissolved in toluene to obtain a 1 N acid chloride solution.

Add methyl 3-(1,4-dioxo-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylate (1 equivalent) and pyridine (2 equivalents) to acid chloride (1 N) In solution. The reaction mixture was stirred under reflux for 15 hours. Once the reaction was completed, the reaction mixture was cooled to room temperature, and then methanol and toluene were added thereto. The reaction mixture was stirred for 1 hour at room temperature, and saturated aqueous solution of NaHCO _3. The organic layer was separated, dried (Na ₂ SO ₄₎ and evaporated to about 4 parts by volume of solvent. 4 parts by volume of heptane was added to the solution while stirring. The reaction flask was immersed in an ice bath and stirred for 120 minutes; the beige solid was filtered and washed with cold heptane and then dried in vacuo oven overnight to afford title compound.

Step III

n-BuLi (2 equivalents) was added dropwise to a cold (-40 ° C) solution of diisopropylamine (1 eq.) in dry THF over 10 min. The reaction mixture was stirred at the same temperature for 30 minutes. Then 3-[(1,4-dioxo-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene was added dropwise (35 min) A solution of methyl 2-carboxyformate (1 equivalent) in THF maintained at an internal temperature of about -40 °C. The reaction mixture was stirred for 30 minutes and a solution of iodine (2 eq.) in THF was added dropwise and stirred at the same temperature for 30 min, then a saturated solution of NH ₄ Cl was added. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with a 5% sodium thiosulfate solution. The organic layer was separated, dried (Na ₂ SO ₄₎ and evaporated to the suspension, followed by the addition of heptane. The suspension was stirred at 0 ° C for 30 minutes, filtered and washed with heptane to give 3-[(1,4-dioxo-spiro[4.5] 癸-8-yl)-(trans-4methyl-cyclohexanecarbonyl) )-Amino]-5-iodo-thiophene-2-carboxylic acid methyl ester. MS experimental value (electrospray): (M+H): 548.21.

Step IV

3-[(1,4-Dioxo-spiro[4.5]癸-8-yl)-(trans-4-methyl-cyclohexylcarbonyl)-amino]-5 was added to 25 mL of RBF under nitrogen Methyl iodo-thiophene-2-carboxylate (1 equivalent), cuprous iodide (0.025 equivalent) and bis(dibenzylideneacetone) dipalladium (0) (0.01 equivalent). DMF, triethylamine (2.5 eq.) and 3,3-dimethyl-but-1-yne (2 eq.) were added, and the reaction mixture was stirred at 40 ° C under N ₂ atmosphere for 2 hr. The reaction mixture was filtered on celite and washed with ethyl acetate. The solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed 3 times with water. The organic layer was separated, dried (Na ₂ SO _4), evaporated to approximately 2 mL, followed by addition of 8 mL of heptane. It was evaporated to 2 mL to 4 mL and cooled in an ice bath. The white solid formed was filtered, washed with heptane and dried in an oven to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(1,4-dioxo- snail) [4.5] Methyl-8-yl)-(trans-4-methyl-cyclohexylcarbonyl)-amino]-thiophene-2-carboxylate.

Step V

5-(3,3-Dimethyl-but-1-ynyl)-3-[(1,4-dioxo-spiro[4.5]dec-8-yl)-(trans-4-methyl- Methyl cyclohexylcarbonyl)-amino]-thiophene-2-carboxylate (1 eq.) was dissolved in tetrahydrofuran and treated with 3.6 N HCl solution. The reaction was stirred at 40 ° C for 5 hours. Water was then added and the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×, 50 mL). The combined extracts were washed with 25 mL of saturated aqueous NaHCO ₃ and 2 × 50 mL of water. The organic layer was concentrated to a thick oil and 50 mL heptane was added to mixture to precipitate the desired compound, which was filtered to afford 5-(3,3-dimethyl-but-1-ynyl)-3- [(Ret-4-methyl-cyclohexylcarbonyl)-(4-o-oxy-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester.

Step VI

5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexylcarbonyl)-(4-o-oxy-cyclohexyl)-amino] A solution of methyl thiophene-2-carboxylate (1 eq.) in THF. Water was added to the reaction mixture and cooled to -25 °C. NaBH ₄ (0.5 eq.) was added portionwise, maintaining the temperature below -20 °C. The mixture was stirred at -25 °C for 2 hours, then 2 N HCl was added and the solution was warmed to room temperature. The phases were separated and the aqueous layer was washed with EtOAC. The organic phases were combined and washed with brine and dried over Na ₂ SO ₄ and concentrated to dryness to give isomer was 93: 7 in the form of a mixture of 5- (3,3-dimethyl - 1-ynyl) - Methyl 3-[(4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexylcarbonyl)-amino]-thiophene-2-carboxylate. The crude cis/trans mixture was recrystallized from methanol to give >99% of the trans isomer.

Step VII

Subsequent procedures similar to those previously reported (Method A, Step VI) were carried out to obtain 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)- (trans-4-methyl-cyclohexylcarbonyl)-amino]-thiophene-2-carboxylic acid. MS experimental value (electrospray): (MH): 444.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 0.58 (m, 1H), 0.74 (q, J = 6.53 Hz, 1H), 0.81 (ddd, J = 12.86, 12.49, 3.19 Hz, 1H), 1.18 ( m,5H), 1.28 (s, 3H), 1.42 (m, 1H), 1.55 (m, 3H), 1.61 (m, 1H), 1.73 (m, 2H), 1.81 (m, 2H), 3.19 (m) , 1H), 4.26 (m, 1H), 4.49 (bs, 1H), 7.14 (s, 1H), 13.45 (bs, 1H).

The above method A and method B produce a compound ( 1 ) methanol solvate as a final product after column chromatography (step VI of Route A) using methanol and dichloromethane (1:9) as a dissolving agent.

Method C

1. Step 1

Compound J (50.0 g, 1.0 eq.), compound K (52.2 g, 1.05 eq.) and NaBH(OAc) ₃ (118.0 g, 1.75 eq.) were then charged to the reactor, followed by the addition of toluene (600 mL, 12 parts by volume) . The stirring was started and then the internal temperature was adjusted to 0 ° C to 5 ° C. The mixture was a heterogeneous suspension of a white solid. A solution of trichloroacetic acid (TCA, 52.0 g, 1.0 eq.) in toluene (150 mL, 3 parts by volume) was then added to the stirred mixture over 1 hour while maintaining the internal temperature between 0 ° C and 5 ° C. between. The reaction mixture is warmed to 20 ° C to 25 ° C, followed by stirring at 20 ° C to 25 ° C for 2 hours to 4 hours under a nitrogen atmosphere. The progress of the reaction was monitored by HPLC.

After completion of the reaction, the reaction mixture was transferred to a solution of K ₂ CO ₃ (307.7 g, 7.0 eq.) in deionized water (375 mL, 7.5 parts by volume). The two phase mixture was stirred and the phases were separated. Washed with an aqueous solution of the organic phase with _{K 2 CO 3 (175.9 g,} 4.0 equiv.) In deionized water (375 mL, 7.5 vol) of, followed by NaCl (20.4 g, 1.1 equiv.) In deionized water (375 mL, 7.5 The aqueous solution in part by volume is washed. The organic phase is separated. Reduce the volume of the batch by distillation (on the rotary evaporator) It was reduced to 250 mL (5 parts by volume) at a bath temperature of 40 ° C, and the resulting crude solution of Compound G in toluene was used in the next step (HPLC: 98.29% AUC chemical purity). Compound G : ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.45 (m, 2H), 1.64 (m, 4H), 1.88 (m, 2H), 3.56 (m, 1H), 3.72 (s, 3H) , 3.87 (m, 4H), 6.70 (d, J = 6.8 Hz, 1H), 6.90 (d, J = 4.4 Hz, 1H), 7.70 (d, J = 4.4 Hz, 1H).

2. Step 2

2.1. Step 2b: Use of trans-methylcyclohexylcarbonyl chloride (Compound F)

To a solution of the compound G in toluene (94.6 g, 250 mL, 5.0 parts by volume) obtained from the previous step was added toluene (410 mL, 8.2 vol.) and pyridine (64.0 mL, 2.5 eq.). Stirring was started and the internal temperature was adjusted to 20 ° C to 25 ° C. Compound F (102.2 g, 2.0 eq.) was added over 0.5 h. Once the addition is complete, the batch is heated to 95 ° C to 100 ° C. The progress of the reaction was monitored by HPLC. After the reaction was completed, the batch was cooled to 30 ° C to 35 ° C, followed by the addition of methanol (189 mL, 3.8 parts by volume) over 45 minutes and the batch was stirred for 1 hour to 2 hours. Deionized water (189 L, 3.8 parts by volume) was added to the batch at 30 ° C to 35 ° C, followed by stirring at 60 ° C to 70 ° C for 1 hour to 2 hours. The mixture was heated to 55 ° C to 60 ° C and then stirred for 1 hour.

Separate the phases. Deionized water (189 mL, 3.8 parts by volume) was added at 55 ° C to 60 ° C, followed by stirring for 1 hour. The toluene phase was concentrated by distillation. The batch is heated to 78 ° C to 83 ° C (eg 80 ° C), then n-heptane (473 mL, 9.5 parts by volume) is added to the toluene solution over 1 hour to 3 hours, followed by stirring at 90 ° C to 95 ° C Batch for 2 hours. The batch was cooled to 20 ° C to 25 ° C over 5 hours, followed by stirring at 20 ° C to 25 ° C for 1 hour to 12 hours. Filter the solids. The filter cake was washed with n-heptane (190 mL, 3.8 parts by volume) and dried under vacuum at 40 ° C to 45 ° C for 10 to 20 hours. The isolated Compound E was analyzed by HPLC, GC and Karl Fischer titration. The total yield of steps 1 and 2 was 113.5 g, 84.1%. HPLC: 99.39% AUC chemical purity (typical purity > 98.0%). Compound ^{E: 1 H NMR (400 MHz} , DMSO- d 6) δ 0.48 (m, 1H), 0.63 (m, 1H), 0.74 (d, J = 6.4 Hz, 3H), 0.98 (m, 1H), 1.22 (m, 2H), 1.36 (m, 1H), 1.52-1.67 (m, 10H), 1.77 (m, 2H), 3.75-3.78 (m, 4H), 3.76 (s, 3H), 4.44 (m, 1H) ), 7.11 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 5.2 Hz, 1H).

2.2. Step 2a: Using trans-methylcyclohexanecarboxylic acid (Compound H)

Under N ₂ atmosphere, Compound H (633 g, 2.0 equiv) was fed into the reactor 1. Toluene (1.33 L, 3.8 parts by volume) was then added to the reactor followed by the addition of DMF (1.73 mL, 0.01 eq.) followed by stirring. SOCl ₂ (325 mL, 2.0 eq.) was added slowly over 30 min. The internal temperature is adjusted to 33 ° C to 37 ° C (for example, 35 ° C). The solution was stirred at 33 ° C to 37 ° C for 2 hours. The mixture was cooled to 20 ° C to 25 ° C, transferred to a rotary evaporator, and then concentrated to 3.8 parts by volume (about 1.3 L). Toluene (665 mL, 1.9 parts by volume) was then added to the concentrate and the resulting batch was concentrated to 3.8 parts by volume (about 1.3 L).

Compound G (662 g, 1.75 L, 5.0 parts by volume) in toluene was fed into the reactor 2 under a N ₂ atmosphere. Toluene (4.97 L, 14.2 parts by volume) and pyridine (448 mL, 2.5 equivalents) were added to Reactor 2. Stirring was started and the internal temperature was adjusted to 20 ° C to 25 ° C.

A solution of Reactor 1 (acid chloride obtained above) in toluene was added to Reactor 2 over 1 hour. Once the addition has been completed, the reaction mixture is heated to 95 ° C to 105 ° C. IPC samples were taken after 24 hours to 30 hours and analyzed for compound G consumption by HPLC.

The reaction mixture is then cooled to 25 ° C to 30 ° C. MeOH (665 mL, 1.9 parts by volume) was added to the reaction mixture over 45 min. Deionized water (1.33 L, 3.8 parts by volume) was then added to the reaction mixture at 25 °C to 30 °C. The mixture was heated to 55 ° C to 60 ° C and then stirred for 1 hour. Stirring was stopped and the phases were separated for 10 minutes. The upper organic layer was separated and the aqueous layer was discarded. Deionized water (1.33 L, 3.8 parts by volume) was added to the reaction mixture at 55 ° C to 60 ° C, followed by stirring for 1 hour. Stirring was stopped and the phases were separated for 10 minutes. The upper organic layer was separated and the aqueous layer was discarded. The solution was transferred (while it was maintained at about 60 ° C) to a rotary evaporator and concentrated to 5.7 parts by volume (about 2 L). Heptane (3.3 L, 5.0 parts by volume) was then added to the suspension at about 60 °C. The suspension was cooled to 20 ° C to 25 ° C while stirring for 5 hours. Filter the suspension. The filter cake was washed twice with heptane (665 mL, 1.9 parts). The solid was dried under vacuum on a filter. The total yield of Steps 1 and 2 was 805.2 g (85.8%), which was a white solid. HPLC: 99.15% AUC chemical purity. Compound ^{E: 1 H NMR (400 MHz} , DMSO- d 6) δ 0.48 (m, 1H), 0.63 (m, 1H), 0.74 (d, J = 6.4 Hz, 3H), 0.98 (m, 1H), 1.22 (m, 2H), 1.36 (m, 1H), 1.52-1.67 (m, 10H), 1.77 (m, 2H), 3.75-3.78 (m, 4H), 3.76 (s, 3H), 4.44 (m, 1H) ), 7.11 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 5.2 Hz, 1H).

3. Step 3

Anhydrous THF (1.0 L, 2.0 parts by volume) and anhydrous diisopropylamine (258 mL, 1.55 eq.) were added to Reactor 1. The solution was cooled to -50 ° C to -40 ° C. Once the desired temperature was reached, a 1.6 M solution (1.11 L, 1.50 equivalents) of n-butyllithium in hexane was added at a rate such that the internal temperature was maintained below -40 °C. After the addition was completed, the solution was further stirred at -50 ° C to -40 ° C for 2 hours.

Compound E (500 g, 1.0 equivalent) and anhydrous THF (5.0 L, 10.0 parts by volume) were fed to Reactor 2. The resulting solution was added to the reactor 1 at a rate such that the internal temperature was kept below -40 °C for 1 hour. A solution of iodine (361 g, 1.20 equivalents) in THF (500 mL, 1.0 part by volume) was added to the cold reaction mixture at such a rate that the internal temperature was kept below -40 °C. The reaction mixture was allowed to stand at -50 ° C to -40 ° C for 1 hour. The progress of the reaction was monitored by HPLC.

After the reaction is complete, the batch is warmed to 0 ° C to 5 ° C and transferred to a solution of NaHSO ₃ (617 g, 5.0 eq.) cooled to 0 ° C to 5 ° C in deionized water (2.5 L, 5.0 parts by volume). in. Dichloromethane (1.5 L, 3.0 parts by volume) was added to the suspension. The two phase mixture was stirred for 1 hour while warming to 20 °C to 25 °C. Separate the phases. The aqueous phase was washed with dichloromethane. The combined organic phases were washed twice with an aqueous solution, and washed with NH ₄ Cl (634 g, 10.0 eq.) In deionized water (1.9 L, 5.0 vol) of, followed by washing with water. The batch volume is reduced by distillation. The solvent was converted to toluene: toluene (1.5 L, 3.0 parts by volume) was again added and then concentrated to a volume of 3.0 parts (about 1.5 L). Toluene (5.0 L, 10.0 parts by volume) was then added to the resulting concentrate and the mixture was heated to 95 °C - 100 °C until a homogeneous solution was obtained. Heptane (5.0 L, 10.0 parts by volume) was added to the toluene solution at 95 ° C - 100 ° C, followed by cooling the mixture to 20 ° C to 25 ° C over 6 hours. Filter the suspension. The filter cake was washed twice with heptane (500 mL, 1.0 part volume). The solid was dried under vacuum on a filter. The isolated Compound A was analyzed by HPLC, GC and Kafxti titration. The yield of Step 3 was 520.5 g (80.2%) as a beige solid. HPLC: typically >97.0% AUC chemical purity. Compound ^{A: 1 H NMR (400 MHz} , DMSO- d 6) δ 0.54 (m, 1H), 0.65 (m, 1H), 0.76 (d, J = 6.8 Hz, 3H), 1.00 (m, 1H), 1.22 (m, 2H), 1.30 (m, 1H), 1.44-1.68 (m, 10H), 1.60-1.69 (m, 4H), 1.77 (m, 2H), 3.74 (s, 3H), 3.77 (m, 4H) ), 4.40 (m, 1H), 7.46 (s, 1H).

4. Step 4

A. Method A1

The jacketed 1 L 3-neck reactor was fitted with a nitrogen inlet followed by compound (A) (112.7 g, 205.9 mmol). CuI (1.18 g, 6.18 mmol) and Pd(PPh ₃ ) ₄ (457.9 mg, 0.412 mmol) were added to the reactor. The reactor was purged with a stream of nitrogen followed by anhydrous 2-methyltetrahydrofuran (789 mL). The mixture was stirred at 20 ° C to 25 ° C for 15 minutes. Anhydrous diisopropylamine (52.09 g, 72.15 mL, 514.8 mmol) and a tributyl acetylene (18.59 g, 27.0 mL, 226.5 mmol) were added to the reactor. The mixture was then stirred at 20 ° C to 25 ° C. According to HPLC, complete conversion was achieved after 4 hours of stirring. The mixture was cooled to 10 °C. The organic phase was then washed with a 12.6 wt% aqueous solution of oxalic acid for at least 3 hours, followed by separation of the phases. Activated carbon (22.5 g) was added to the reaction mixture. The suspension is stirred at 20 ° C to 25 ° C for not less than 12 hours. The mixture was filtered through celite. The filter cake was washed with 2-butanone (563.5 mL) and the filtrate was added to the organic phase. HPLC analysis of the organic solution showed that the compound (B) had a purity of 99.56% AUC. This solution is typically used directly in the next step. Compound ( B ): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 0.52-0.59 (m, 1H), 0.61 - 0.70 (m, 1H), 0.76 (d, J = 6.4 Hz, 3H), 0.88- 1.03 (m, 1H), 1.15 - 1.37 (m, 4H), 1.31 (s, 9H), 1.41-1.68 (m, 9H), 1.74-1.85 (m, 2H), 3.75-3.81 (m, 4H), 3.75 (s, 3H), 4.39-4.42 (m, 1H), 7.27 (s, 1H).

B. Method A2

The jacketed 1 L 3-neck reactor was fitted with a nitrogen inlet followed by compound ( A ) (63.94 g). CuI (667.3 mg, 0.03 equivalents) and Pd(PPh ₃ ) ₄ (269.9 mg, 0.002 equivalents) were added to the reactor. The reactor was purged with a stream of nitrogen followed by the addition of methyl tert-butyl ether (MtBE) (7 parts by volume). The mixture was stirred at 20 ° C to 25 ° C for 15 minutes. Anhydrous diisopropylamine (40.9 mL, 2.5 equivalents) was added to the stirred mixture while maintaining the internal temperature between 20 ° C and 25 ° C and stirring the batch for not less than 15 minutes. Ternary butyl acetylene (16.7 mL, 1.2 eq.) was added to the reactor. The mixture was then stirred at 20 ° C to 25 ° C. According to HPLC, complete conversion was achieved after 4 hours of stirring. The mixture was cooled to 10 °C. The organic phase was then washed with 12.6 wt% aqueous oxalic acid dehydrate (383.6 mL, 6 parts by volume) while maintaining the batch temperature below 20 °C to 25 °C. Next, the batch temperature was adjusted to 20 ° C to 25 ° C and the two phase mixture was stirred at this temperature for at least 3 hours. Next, separate the phases for at least 30 minutes. The organic phase was then washed again with an aqueous solution of oxalic acid dehydrate (6 wt%, 383.6 mL, 6 parts by volume) while maintaining the batch temperature below 20 °C to 25 °C. The two phase mixture was stirred at this temperature for at least one hour. The phases are then separated. Activated carbon (6.4 g to 12.8 g, 10 wt% to 20 wt% relative to compound A ) was added to the reaction mixture. The suspension is stirred at 20 ° C to 25 ° C for not less than 12 hours. The mixture was filtered through celite. The filter cake was washed with MtBE (192 mL, 3 parts) and the filtrate was taken to organic. This solution is typically used directly in the next step.

C. Method B

The jacketed 3 L 3-neck reactor was fitted with a nitrogen inlet followed by compound ( A ) (20.00 g, 36.53 mmol). CuI (208.7 mg, 1.096 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (51.28 mg, 0.07306 mmol) were added to the reactor. The reactor was purged with a stream of nitrogen followed by anhydrous 2-methyltetrahydrofuran (140.0 mL). The mixture was stirred at 20 ° C to 25 ° C for 15 minutes. Anhydrous diisopropylamine (9.241 g, 12.80 mL, 91.32 mmol) and tert-butylacetylene (3.751 g, 5.452 mL, 45.66 mmol) were added to the reactor. The mixture was then stirred at 20 ° C to 25 ° C (20.9 ° C) to form a suspension. The mixture was then heated to 45 ° C for 6 hours. HPLC analysis showed a conversion of 99.77%. Heptane (140.0 mL) was added while cooling to 20 °C over 4 hours. Filter the suspension. The filtrate was washed with aqueous oxalic acid dihydrate (120 mL, 15 w/v%, 142.8 mmol). The phases were separated, washed (120 mL, 7 w / w %) and water (120.0 mL) then the organic phase was washed with NH ₄ Cl solution (120 mL, 10 w / v %, 224.3 mmol), NaHCO 3 aq. The residual metal was removed by adding 2.0 g of charcoal (10 wt%, VRT-0921870) and then stirred at 20 ° C to 25 ° C for 5 hours. The suspension was then filtered through celite. The diatomaceous earth bed was washed with 2-methyltetrahydrofuran (40.0 mL). HPLC analysis of the organic solution showed that the compound ( B ) had a purity of 99.47% AUC.

D. Method C

Compound (A) [1.0 equivalent], copper catalyst, Pd(PPh ₃ ) ₄ [0.002 equivalent], and MEK [7 parts by volume] were added to a round bottom flask equipped with a mechanical stirring, an N ₂ bubbler and a thermocouple. The reaction solution was stirred at room temperature until dissolved and then i Pr ₂ NH [2.5 eq.] and tert-butyl acetylene [1.1 eq.] were added. The reaction solution was stirred at 20 ° C to 25 ° C. The reaction conversion rate (conversion [%]) was monitored via LC. For copper catalysts, CuI (99.9%), CuI (98%), CuCl and CuBr:CuI (for 99.9% and 98%) were tested: in the case of 0.03 equivalents of CuI, after about 2 hours of reaction time, over 95% conversion Is compound (B); in the case of 0.025 equivalent of CuI, after about 5 hours of reaction time, more than 90% is converted to compound (B); in the case of 0.02 equivalent of CuI, after about 5 hours of reaction time, more than 90% conversion Is compound (B); in the case of 0.015 equivalent of CuI, after about 5 hours of reaction time, more than 90% is converted to compound (B); in the case of 0.01 equivalent of CuI, after about 5 hours of reaction time, more than 75% conversion Is compound (B); CuCl: in the case of 0.03 equivalent of CuCl, after about 2 hours of reaction time, more than 99% is converted to compound (B); in the case of 0.025 equivalent of CuCl, after about 2 hours of reaction time, about 100 % converted to compound (B); in the case of 0.02 equivalents of CuCl, more than 90% is converted to compound (B) after about 2 hours of reaction time; in the case of 0.015 equivalent of CuCl, after about 2 hours of reaction time, over 95 % converted to compound (B); in the case of 0.01 equivalent of CuCl, after about 20 hours of reaction time, about 100% Compound (B); CuBr: in the case of 0.03 equivalent of CuBr, after about 22 hours of reaction time, more than 99% is converted to compound (B); in the case of 0.025 equivalent of CuBr, after about 22 hours of reaction time, 85% is converted to compound (B); in the case of 0.02 equivalent of CuBr, after about 22 hours of reaction time, more than 95% is converted to compound (B); in the case of 0.015 equivalent of CuBr, after about 22 hours of reaction time, 70% is converted to compound (B); in the case of 0.01 equivalent of CuBr, after about 22 hours of reaction time, more than 80% is converted to compound (B).

5. Step 5

A. Method A

A jacketed 1 L 4-neck reactor was charged with a nitrogen inlet followed by a solution of compound ( B ) (22.9 g, 45.65 mmol) in 2-butanone (about 250 mL), followed by heating to 60 °C. The reactor was purged with a stream of nitrogen followed by 2N aqueous HCl (175 mL). The mixture was stirred at 60 ° C for 4 hours. Stop stirring and remove the lower aqueous phase. Stirring was started again followed by the addition of 2 N aqueous HCl in water (175 mL). The mixture was stirred at 60 ° C until the conversion (99% by HPLC) had reached equilibrium (about another 2.5 hours). After cooling to 20 ° C, the lower aqueous phase was removed. Followed by 10 wt% NH ₄ Cl solution and then the organic phase was washed and the phases separated. The organic phase was then distilled to approximately 115 mL. Acetone (115 mL) was added and the batch was concentrated to approximately 115 mL. This procedure of adding acetone followed by distillation was repeated twice more. Water (57.3 mL) was added to the organic phase at 20 ° C, then the mixture was stirred for 2 hours. Water was added to the organic phase at 20 ° C for 2 hours, and then the mixture was further stirred for 1 hour. The solid was filtered and washed with 1:1 MeOH / H ₂ O (25 mL) and then dried at 60 <0>C in a micro-flow nitrogen vacuum oven for 24 hours to afford 19.8 g (95% yield) of compound ( C ). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 0.56-0.68 (m, 2H), 0.76 (d, J = 6.4 Hz, 3H), 1.19-1.30 (m, 4H), 1.30 (s, 9H), 1.46-1.60 (m, 6H), 1.83-1.89 (m, 2H), 2.05-2.18 (m, 3H), 2.47-2.55 (m, 1H), 3.76 s, 3H), 4.77-4.85 (m, 1H) , 7.30 (s, 1H).

B. Method B

The jacketed 1 L 4-neck reactor was charged with a nitrogen inlet followed by compound ( B ) (103.3 g, 1.0 equivalent in 100% yield in step 4) on 2-butanone (about 1.03 L, In a solution of about 10 parts by volume total batch volume), it is then heated to 57 ° C to 62 ° C (eg 60 ° C). The reactor was purged with a stream of nitrogen, followed by the addition of 2 N aqueous HCl (723 mL, 7 parts by volume of 103.3 g of compound ( B )) over about 10 minutes while maintaining the batch temperature between 57 ° C and 62 ° C (eg 60 ° C). The mixture was stirred at 57 ° C to 62 ° C (for example, 60 ° C) for 5 hours. Stop stirring and remove the lower aqueous phase. Stirring was started again followed by the addition of 2 N HCl fresh water (310 mL, 3 parts by volume of 103.3 g of compound ( B )). The mixture is stirred at 57 ° C to 62 ° C (eg 60 ° C) until the conversion (99% according to HPLC) has reached equilibrium (about another 2.5 hours). After cooling to 20 ° C to 25 ° C, the stirring was stopped and the phases were separated for at least 30 minutes. Next was added an aqueous solution of NH _{4 Cl (10 wt%, 517} mL, 5 vol) while the batch temperature was maintained at 20 ℃ to 25 ℃. The two phase mixture is stirred at 20 ° C to 25 ° C for at least 30 minutes. The phases are then separated. The organic phase was then distilled by vacuum distillation to about 471 mL with a maximum jacket temperature of 60 °C. Acetone (471.1 mL) was added and the batch was concentrated to approximately 471 mL. This procedure of adding acetone followed by distillation was repeated twice more. Water (235.6 mL, 2.28 parts by volume) was added to the organic phase at 20 ° C, then the mixture was stirred for 2 hours. Additional water (235.6 mL, 2.28 parts by volume) was added to the organic phase over 2 hours at 20 °C, then the mixture was stirred for an additional hour. The solid was filtered and washed with a 1:1 mixture of acetone/H ₂ O (volume: volume, 103 mL: 103 mL), followed by drying in a microflow nitrogen vacuum oven at 60 ° C for 24 hours to obtain 19.8 g (99.5% yield). Rate) Compound ( C ) having a total purity of 98.0%.

6. Step 6

A. Method A: Using LiAlH (OtBu) ₃

Compound (C) (399 g, 1.0 equiv, the limiting reagent) is fed into the 12 L reactor and purged with N _2. Anhydrous THF (2 L, 5.0 parts by volume) was then fed to the reactor, followed by stirring the mixture. The resulting solution was cooled to -65 ° C to -64 ° C.

LiAlH(O t Bu) ₃ (960 ml, 1 M in THF, 2.40 parts by volume or 1.1 equivalents) was added while maintaining the batch temperature at no higher than -40 °C. The solution was added over 2 hours and 15 minutes. The rate of addition was 1.45 parts per hour.

After the addition of LiAlH(O t Bu) _{3 was} completed, the batch was further stirred at -40 ° C or below -40 ° C for 1 hour. A small amount of IPC sample was collected after 1 hour and immediately quenched with 1 N HCl. Analyze the compound ( C ) consumption of the sample (when the compound ( C ) is relative to the compound ( D ) according to the IPC method The reaction is considered complete at 0.5%).

If the reaction was not completed, the reaction was stirred at -40 ° C for an additional 1 hour. IPC samples were collected and immediately stopped with 1 N HCl. If the reaction is not completed, an additional amount of LiAlH(O t Bu) _{3 is added} (for example, if the 1.0% peak area of the unreacted compound ( C ) remains compared to the product compound ( D ), LiAlH(O t Bu) is added. ₃ % of the initial feed of the solution). The batch is maintained at a temperature of -40 ° C to -50 ° C or below -50 ° C during the reaction. After the addition of LiAlH(OtBu) ₃ , the batch was stirred at -45 ° C to -40 ° C for 1 hour. A small amount of IPC sample was collected after 1 hour and the reaction was immediately quenched with 1 N HCl.

Once the reaction was complete, MTBE (1197 L, 3 parts by volume) was fed into the batch and the batch was then warmed to 0 °C. The resulting solution is added to a mixture of an aqueous solution of oxalic acid (or tartaric acid) over a period of about 10 minutes to 15 minutes by mixing oxalic acid (or tartaric acid) (9 w/ A mixture of w%, 2394 L, 6 parts by volume and MTBE (7 L, 2 parts by volume) was cooled to 8 ° C to 10 ° C to obtain. The batch temperature was adjusted to 15 ° C to 25 ° C and the resulting mixture was stirred for 30 minutes to 60 minutes.

Stop stirring. The upper organic phase was collected. Water (2.8 L, 7 parts by volume) was added to the organic phase. The two phase mixture was stirred at 15 ° C to 25 ° C for 10 minutes. Then stop stirring. The upper organic phase was collected.

Crystallization of the compound ( D ) is carried out by converting the solvent to methanol. The batch volume was reduced to 1.2 L or 3.0 parts by vacuum distillation at <60 °C.

Methanol (4 L, 10 parts by volume) was added to the batch (without adjusting the batch temperature) and the batch volume was reduced to 1.2 L or 3.0 parts by vacuum distillation at <60 °C. Repeat this step. Next, the batch volume was adjusted to 3.0 parts by adding 479 mL.

A small amount of IPC sample of the slurry was collected. The solid was filtered and analyzed by gas chromatography to determine the residual THF and MTBE relative to methanol. If the solvent is completely converted to methanol, the batch is heated to 60 ° C to 65 ° C and stirred at this temperature until all solids are dissolved. 2 parts by volume of a 50% by volume methanol/water solution was added, and the temperature was maintained at not lower than (NLT) 50 °C. Next, adjust the temperature to 47 ° C to 53 ° C (for example, 50 ° C), and maintain the temperature of 4 The hour is such that the solid begins to crystallize. The remaining 2 volumes of 50 vol% methanol/water solution were then added to the batch. The batch was then cooled to 15 ° C to 25 ° C at about 5 ° C per hour and held at not less than (NLT) for 4 hours at 15 ° C to 25 ° C. The filter cake was washed with 1 part by volume (based on the amount of compound 5 fed) of 50% by volume of methanol/water.

The material was dried under a microflow of nitrogen vacuum at 55 ° C to 65 ° C for at least 12 hours.

If necessary, the batch can be recrystallized by feeding dry compound ( D ) (1 equivalent) and methanol (2 parts by volume, relative to compound ( D ) feed) to the reactor and batching Heat to 60 ° C to 65 ° C until all solids are dissolved. The batch was then cooled to -20 °C over a period of 3 hours. The resulting solid was filtered and dried under a microflow of nitrogen vacuum at 55 ° C to 65 ° C for at least 12 hours. Compound D : ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 0.52-0.69 (m, 2H), 0.75 (d, 6.4 Hz, 3H), 0.76-0.86 (m, 1H), 1.11-1.24 (m, 5H), 1.31 (s, 9H), 1.43-1.57 (m, 6H), 1.73-1.83 (m, 4H), 3.17-3.18 (m, 1H), 3.75 (s, 3H), 4.24-4.30 (m, 1H), 4.49 (d, J = 4.4 Hz, 1H), 7.23 (s, 1H).

B. Method B: In addition to LiAlH (OtBu) ₃ Reducing agent other than

The reducing agent other than LiAlH(OtBu) ₃ which mainly produces the desired isomer is: LiAlH(O i Bu) ₂ (O tBu ) ₃ , DiBAlH, LiBH ₄ , NaBH ₄ , NaBH(OAc) ₃ , Bu ₄ NBH ₄ , ADH005 MeOH/KRED recycle mixture A, KRED-130 MeOH/KRED recycle mixture A, Al(O i -Pr) ₃ / i -PrOH and ( i -Bu) ₂ AlO i Pr.

7. Step 7

Compound ( D ) and Me-THF (5 parts by volume, based on the amount of compound 6 fed) were added to the reactor. An aqueous NaOH solution (2 N, 4.0 parts by volume, 3.7 equivalents) was added to the solution at 15 ° C to 25 ° C. The batch is heated to 68 ° C to 72 ° C and stirred at this temperature for 8 hours to 16 hours. The progress of the reaction was monitored by LC. The batch was cooled to 0 ° C to 5 ° C after completion. A precipitate formed. An aqueous citric acid solution (30% by weight, 3.7 equivalents) was added over 15 minutes to 30 minutes while maintaining the batch temperature below 25 °C. Separate the phases. Water (5 parts by volume, based on the amount of compound 6 fed) was added to the organic layer. Separate the phases. The batch volume was reduced to 3 parts by volume (at compound ( D ) feed) by vacuum distillation at a maximum temperature of 35 °C. Anhydrous Me-THF (3 parts by volume, based on the amount of compound ( D ) fed) was then added. The water content was determined by Kafiel titration. If residual water 1.0% considered the batch to be dry.

The final product of Compound ( 1 ) can be recrystallized from a mixture of EtOAc or nBuOAc and acetone via a solvent as described below to form Form M of Compound ( 1 ):

A: Recrystallization in a mixture of nBuOAc and acetone:

The solvent was first converted from 2-Me-THF to nBuOAc by first reducing the batch volume by vacuum distillation at a maximum temperature of 45 ° C to 2 parts by volume to 3 parts by volume (based on the amount of compound ( D ) fed). . Add nBuOAc (3 parts by volume, based on the amount of compound ( D ) fed), and reduce the volume of the batch to 2 parts by volume to 3 parts by vacuum distillation at a maximum temperature of 45 ° C (feed with compound ( D ) Meter). The batch volume was then adjusted to a total of 5 parts by volume to 6 parts by adding nBuOAc. The residual 2-Me-THF content in nBuOAc in the solution was analyzed. This cycle was repeated until less than 1% of 2-Me-THF remained relative to nBuOAc as determined by GC analysis. Once the residual 2-Me-THF IPC criteria are met and the total batch volume is ensured to be 6 (based on compound ( D ) feed), the batch temperature is adjusted to 40 °C to 45 °C. Next, acetone was fed into the batch to have about 10 wt% acetone in the solvent. The batch temperature was adjusted to 40 ° C to 45 ° C. Compound 1 seed crystals (1.0% by weight, based on the total target weight of Compound ( 1 )) were added. The batch was stirred at 40 ° C to 45 ° C for 4 hours to 8 hours. The recrystallization process was monitored by X-ray powder diffraction (XRPD). If the spectrogram matches the spectrogram of the desired form, the batch is cooled from 40 ° C to 45 ° C to 30 ° C to 35 ° C (preferably about 35 ° C) at a rate of 5 ° C per hour. The batch was held at about 35 ° C for at least one hour, then filtered and the filter cake was washed with a 9:1 wt:wt mixture of nBuOAc/acetone (1 part by volume). The material was dried in a microfluidic nitrogen vacuum at no higher than 45 ° C for 12 hours to 24 hours. Starting from compound ( D ), the expected separation molar yield of compound ( 1 ) (Form M) is from 80% to 85%. Compound ^{(1): 1 H NMR (} 400 MHz, DMSO- d 6) δ 0.58 (m, 1H), 0.74 (q, J = 6.53 Hz, 1H), 0.81 (ddd, J = 12.86,12.49,3.19 Hz, 1H), 1.18 (m, 5H), 1.28 (s, 3H), 1.42 (m, 1H), 1.55 (m, 3H), 1.61 (m, 1H), 1.73 (m, 2H), 1.81 (m, 2H) ), 3.19 (m, 1H), 4.26 (m, 1H), 4.49 (bs, 1H), 7.14 (s, 1H), 13.45 (bs, 1H).

B: Recrystallization from EtOAc:

The solvent was converted from 2-Me-THF to n EtOAc by first reducing the batch volume to 2 parts by volume to 3 parts by volume (based on compound ( D ) feed) by vacuum distillation at a maximum temperature of 35 °C. . EtOAc was added (10 parts by volume, based on the amount of compound ( D ) fed), and the volume of the batch was reduced to 2 parts by volume to 3 parts by vacuum distillation at a maximum temperature of 35 ° C (feeding with compound ( D ) Meter). The residual 2-Me-THF content in EtOAc in the solution was analyzed. This cycle was repeated until less than 1% of 2-Me-THF remained relative to EtOAc as determined by GC analysis. Once the residual 2-Me-THF IPC criteria are met and the total batch volume is guaranteed to be 10 (based on compound ( D ) feed), the batch temperature is adjusted to 40 °C to 45 °C. Compound 1 seed crystals (1.0% by weight, based on the total target weight of Compound ( 1 )) were added. The batch was stirred at 40 ° C to 45 ° C for 12 hours. A flat bottom reactor (non-conical) should be used. The recrystallization process was monitored by X-ray powder diffraction (XRPD). If the spectrogram matches the spectrogram of the desired form, the batch is cooled from 40 ° C to 45 ° C to 11 ° C to 14 ° C at a rate of 5 ° C per hour. The batch was filtered and the filter cake was washed with EtOAc (1 part by volume) previously cooled to 11-14 °C. The material was dried in a microfluidic nitrogen vacuum at no higher than 45 ° C for 12 hours to 24 hours. Starting from compound ( D ), the expected separation molar yield of compound ( 1 ) (Form M) is from 80% to 85%.

Example 3: Formation of polymorphic form A and polymorphic form M of compound (1)

3A: Formation of polymorphic form A of compound (1)

Polymorphic Form A of Compound ( 1 ) can be prepared by following the procedures described below:

10 g of compound ( 1 ) was fed into the reactor. 20 g of methanol was then fed into the reactor. The reactor was heated to 60 ° C to dissolve the compound ( 1 ). The reactor was then cooled to 10 ° C and allowed to stand until a solid of compound ( 1 ) was formed. The solid of compound ( 1 ) was filtered. 20 g of acetone was added to the solid of compound ( 1 ) at 25 °C. A mixture of acetone and compound ( 1 ) was stirred for 1 hour and the resulting solid was filtered. The filtered solid was dried at 75 ° C for 12 hours.

Form of Compound (1) of the A: XRPD data and C compound (1) of Form A ¹³ solid state NMR data are shown in FIGS. 1 and 2. Some representative XRPD peaks and DSC endotherms (°C) for Form A of Compound ( 1 ) are summarized in Table 1 below.

3B: Formation of polymorphic form M of compound (1)

1. Method A

The polymorphic form M of compound ( 1 ) can be prepared by following the procedures described below:

10 g of compound ( 1 ) was fed into the reactor. 50 g of ethyl acetate was then fed into the reactor. The reactor was heated to 45 ° C and the mixture was stirred for 1 day to 2 days until Form M was observed. The reactor was then cooled to 25 ° C and allowed to stand until a solid of compound ( 1 ) was formed. The solid of compound ( 1 ) was filtered and the filtered solid was dried at 35 °C for 24 hours.

2. Method B

The polymorphic form M of compound ( 1 ) can also be prepared in a similar manner as described above for Process A, but using the solvent system listed in Table 2A below and in the respective temperature ranges listed in Table 2A in the solvent. The compound ( 1 ) is stirred in the system.

Compound (1) in the form of M: Compound (1) The XRPD data of the form M and C ¹³ solid state NMR data are shown in FIG. 4 and FIG. Some representative XRPD peaks and DSC endotherms (°C) for Form M of Compound ( 1 ) are summarized in Table 2B below.

Example 4: Formation of the amine salt of the compound (1)

10 g of compound ( 1 ) was dissolved in 100 g of IPA (isopropanol). A stock solution of 1 equivalent of tromethamine in water (2.72 g of tromethamine and 6.34 g of water) was prepared. 0.5 g of the tromethamine stock solution was added to the solution of the compound ( 1 ). The mixture was kept for 1 hour, and as it was, a seed of the tromethamine salt of the compound ( 1 ) was used. The resulting slurry was filtered and washed with IPA. The filtered wet cake was dried at 70 °C. The yield was 58%.

Example 5: Preparation of a capsule comprising polymorph Form A of Compound (1)

Two different oral dosage formulations of Form A of Compound ( 1 ) were prepared as shown in Tables 3a and 3b.

A. Wet granulation and capsule composition

200 mg Form A capsules were prepared as follows. 50 mg Form A capsules were prepared in a similar manner as described below for the 200 mg capsules. Formulation compositions for wet granulation and capsule blends for active capsules are described in Tables 4a and 4b.

The actual weight of each component in the final capsule blend of the 200 mg capsule strength batch can be determined based on the yield calculation of the wet granulation (internal phase). The sample is calculated as follows:

B. Overview of wet granulation and capsule preparation (200 mg)

a) High shear wet granulation process

1. Weighed (10%) of the compound ( 1 ) in polymorphic form A, crystalline cellulose PH-101, lactose monohydrate, poloxamer 188, sodium lauryl sulfate and povidone K29/32 .

2. Excess compound ( 1 ), crystalline cellulose PH-101, lactose monohydrate, poloxamer 188 and povidone K29/32 at 70% speed using a co-mill with #20 mesh. Screened.

3. Weigh the required amount of "screened" compound ( 1 ), crystalline cellulose PH-101, lactose monohydrate, poloxamer 188, sodium lauryl sulfate and povidone K29/32 and transfer to V In a barrel blender (PK 1 cube).

4. Blend the material for 5 minutes at a set speed (typically 25 RPM).

5. The bulk wet granulation blend was placed in a high shear granulator (Vector GMX.01).

6. Granulate the blend.

7. Once the granulation end point is reached, the material (wet granulation blend) is transferred to a suitable container and dried.

8. Grind all dry particles using a co-mill with #20 mesh.

b) Capsule manufacturing process flow

9. Weighed (10%) amount of crystalline cellulose PH-102, lactose monohydrate, croscarmellose sodium and magnesium stearate.

10. Excess crystalline cellulose PH-102, monohydrated lactose, croscarmellose sodium and magnesium stearate were sieved at 70% speed using a co-mill with #20 mesh.

11. Weigh the required amount of "screened" crystalline cellulose PH-102, lactose monohydrate, croscarmellose sodium, magnesium stearate and ground granules, and remove magnesium stearate The material was transferred to a V-cylinder blender (PK 1 cube).

12. The material is blended in a V-cylinder blender.

13. Magnesium stearate is then added to the V-cylinder blender and the mixture is blended.

14. Encapsulation of the final blend.

Example 6: Preparation of a tablet containing the polymorphic form M of compound (1)

A. Lozenge A

Wet granulation and lozenge composition

Formulation compositions for wet granulation and lozenge blends for active lozenges are described in Tables 5a and 5b. The total composition specifications of the tablets are described in Table 5c. The wet granulation process flow chart and manufacturing flow chart of Form M Lozenge A are shown in Figures 5 and 6, respectively.

a) High shear wet granulation process

1. Weighed (10%) amount of compound ( 1 ), crystalline cellulose PH-101, lactose monohydrate, poloxamer 188, sodium lauryl sulfate, povidone K12 and crosslinked carboxymethyl fiber Sodium.

2. Using a co-mill with a 813 μm mesh, excess compound ( 1 ), crystalline cellulose PH-101, lactose monohydrate, poloxamer 188, sodium lauryl sulfate, povidone K12 and The croscarmellose sodium was sieved at 30% speed. Place the screened material in individual bags or containers.

3. Weigh the required amount of "screened" compound ( 1 ), crystalline cellulose PH-101, lactose monohydrate, poloxamer 188, sodium lauryl sulfate, povidone K12 and crosslinked carboxymethyl Cellulose sodium.

4. Set the V-cylinder blender and transfer the material from step 3 to the blender.

5. Blend the material in a V-cylinder blender at a set speed (typically 25 RPM) for 5 minutes.

6. Pour the contents of the V-cylinder blender into a LDPE bag (bulk wet granulation blend).

7. Set a high shear granulator (Vector GMX.01) with a 1 L granulator tank.

8. The bulk wet granulation blend is then transferred to a 1 L granulator tank.

9. Granulation of the blend according to the specified wet granulation parameters (Table 6)

Stage 1: The use of 77% of the total amount of water required for wet granulation granulates the material under specified process parameters. Once the water addition is complete, the granulation is stopped. The wall of the high shear granulator, the impeller and the chopper are scraped and the particles are inspected to determine if the visual end point is reached. If yes, proceed to step 10, otherwise proceed to phase 2.

Stage 2: Add the remaining 23% water and pelletize the material under the specified process parameters. Once the water is added, stop the granulation and scrape the wall of the high shear granulator, the impeller and the chopper and test The particles are used to determine if the visual end point is reached. If yes, proceed to step 10, otherwise continue granulation with 2 ml of water per the previous process parameters until the end point is reached.

10. Once the granulation end point is reached, even the material (wet granulation blend) is passed through a #20 (850 μm) mesh and the sieved material is transferred to a suitable container.

11. Dry the screen material of step 10 in an oven according to the specified drying parameters (total drying temperature: 30 ° C to 45 ° C).

12. All dry granules were ground at 30% speed using a co-mill with a 813 μm mesh. (Any material left in the co-mill is manually passed through a #20 (850 μm) mesh and the ground particles and sieved particles are combined). The weight of the ground particles is measured and the material is packaged in a bag.

b) Lozenge manufacturing process flow

1. Weighed (10%) amount of crystalline cellulose PH-102, monohydrated lactose, croscarmellose sodium and magnesium stearate.

2. Excess crystalline cellulose PH-102, lactose monohydrate, croscarmellose sodium and magnesium stearate were sieved at 30% speed using a co-mill with a 813 μm mesh.

3. Weigh the required amount of "screened" crystalline cellulose PH-102, lactose monohydrate, croscarmellose sodium, magnesium stearate, and ground granules.

4. Transfer materials other than magnesium stearate to a V-cylinder blender.

5. Place the material in a V-cylinder blender at a set speed (typically 25 RPM) blended for 10 minutes.

6. Magnesium stearate is then added to the V-cylinder blender.

7. Blend the material in a V-cylinder blender at a set speed (typically 25 RPM) for 1 minute.

8. Pour the contents of the V-cylinder blender into the bag.

9. Set up a GlobePharma ingot machine with a modified caplet tool (size 0.30" x 0.60").

10. Compress the final blend to form a tablet.

B. Lozenges B

The formulation composition of the pre-granulation blend is provided in Table 7a . Table 7b provides the composition of the granulation binder solution. The theoretical compression blend composition is provided in Table 7c . The composition and approximate batch size of the coated suspension (including 50% excess for line priming and pump calibration) are provided in Table 7d . The general specifications for the composition of tablet B are summarized in Table 7e . The target amount of the envelope is 3.0 w/w% of the weight of the core tablet. The wet granulation process flow chart and manufacturing flow chart of Form M Lozenges B are shown in Figures 7 and 8, respectively.

A. Wet granulation

a) Preparation of adhesive solution

The binder solution includes povidone, SLS, and poloxamer. The solution was prepared based on the 9 w/w% water content of the final dry granules. Preparation excess 100% For pump calibration, pilot piping, etc.

1. Weigh the required amount of poloxamer 188, sodium lauryl sulfate, povidone K12, and purified (deionized) water.

2. Add povidone K12 to deionized water with constant stirring and stir the resulting mixture. Poloxamer 188 and sodium lauryl sulfate were added to a tank containing deionized water and dissolved povidone K12. The rate of agitation is then lowered after the addition of the surfactant so that only partial vortexes are formed.

3. Stir the solution until all solids present are completely dissolved.

4. The solution is then allowed to stand for at least 2 hours until the bubbles in the solution disappear. Alternatively, a partial vacuum can be drawn from the solution tank for one hour to degas the solution.

b) Wet granulation process

1. Weighing compound ( 1 ), croscarmellose sodium, crystalline cellulose PH-101, and lactose monohydrate.

2. Using the U5 or U10 co-grinder equipped with a 32R sieve and a circular impeller, weigh the extracted compound ( 1 ), lactose and crystalline cellulose at UHP in 4000 rpm or in U10 at 2800 rpm. , enter the bag or directly into the 200 L Meto blender.

3. Transfer material from step 2 to a 200 L Meto box blender.

4. Blend the material for 15 minutes at 10 RPM.

5. Feed the material directly from the blending barrel to a loss-in-weight powder feeder or LDPE bag.

6. Set the required barrel and screw configuration as specified in Table 8a and Table 8b Leistritz 27 mm twin screw extruder.

7. Feed the dry blend to the extruder using a K-Tron loss-in-weight feeder.

8. Use a calibrated K-Tron pump to inject the binder fluid into the extruder. The pump is calibrated using actual fluid prior to operation.

9. The blend is then granulated.

10. The weight ratio of solution feed rate to powder feed rate was 0.215 to obtain a suitable final composition. To obtain a predetermined powder feed 167.00 g min ^-1, the solution feed rate of 35.91 g min ^-1.

11. Wet the wet granules from the twin screw at 1000 rpm using an in-line U5 co-mill with a square 4 mm screen and round bar impeller.

12. Collect and dry the wet abrasive particles. The water content is not more than 3.0%.

B. Extragranular blending and compression process

1. Weigh the amount of extragranular excipients based on the composition of the compressed blend.

2. The granules and Cab-O-Sil were added directly to a 200 L Meto box blender and blended for 8 minutes at 15 RPM.

3. The blend was then passed directly into a 600 L Meto box blender or double LDPE bag through a U10 co-mill with a 40 G screen and round bar impeller at 600 rpm.

4. Using a U10 co-mill with a 32R sieve and a round bar impeller at 600 rpm, the approximate amount of crystalline cellulose PH-101 and Ac-Di-Sol are sieved and directly into the 600 L Meto box blend. Machine or double LDPE bag.

5. Manually pass #50 of stearylsulfonate (SSF) into a suitable container. A portion of the extragranular blend equal to about 10 times the mass of the SSF calculated in step one was placed in a container with SSF and blended for 30 seconds, and then the mixture was added to a box blender.

6. Blend the mixture for 10 minutes at 15 rpm.

7. Compress the final blend.

8. Measure the individual and average tablet weight, hardness and thickness during the compression process.

C. Coating process

The film coat was applied to the core lozenge in a Vector VPC 1355 pan coater in the form of an aqueous suspension of 20 wt% Opadry II White #85F18378. The target coating is 3.0 w/w% by weight of the core tablet and the acceptable range is 2.5% to 3.5%. To achieve this, spraying is equivalent to a 3.2% by weight increase in the amount of coating suspension, assuming a coating efficiency of 95% would result in a 3.0% coating. The coating process is as follows:

1. Calculate the disk load by dividing the tablet yield by 3 (or 2, if there is less than 75 kg of core tablet) and calculate the amount of coating suspension required (based on 3.2% coating), including 50 % excess for pipeline priming, pump rate testing, and coating wall.

2. Prepare a coating suspension by slowly adding Opadry II #85F18378 powder to an appropriate amount of deionized water while continuously stirring the fluid with an overhead stirrer to ensure adequate wetting of the powder. Once all Opadry was added to the water, stirring was continued for 60 minutes at a lower rpm. The maximum hold time for spraying the suspension is 24 hours.

3. Pre-coat the tray with Opadry by spraying the coating suspension for 5 minutes to 10 minutes. Dry the plate for 1 minute to 2 minutes after spraying.

4. Load the calculated amount of the tablet into the coating pan.

5. Preheat the pan to the desired bed temperature while shaking the pan.

The tablet weight gain was calculated and the coating amount was determined to be between 2.5% and 3.5%. Once the spray reaches this amount, the spray is stopped. When the amount of coating is sufficient, the tablet is dried for another 5 minutes. The heating is stopped and the tablet is cooled while shaking the disk. When the bed temperature reaches 35 ° C (± 1 ° C), the process is stopped. The coating pan door remains closed during the cooling period.

Example 7: Lozenges of the tromethamine salt of the compound (1)

Formulation compositions for wet granulation and lozenge blends for active lozenges are described in Tables 9a and 9b. The general specifications for the tromethamine salt tablets are described in Table 9c. The wet granulation process flow chart and manufacturing flow diagram of the tromethamine salt tablet are shown in Figures 9 and 10, respectively.

The actual weight of each component in the final tablet blend of the 250 mg tablet strength batch can be determined based on the yield calculation of the wet granulation (internal phase). The sample is calculated as follows:

a) High shear wet granulation process

1. Weighed (10%) of the compound ( 1 ) of tromethamine salt, crystalline cellulose PH-101, lactose monohydrate, poloxamer 188, sodium lauryl sulfate, povidone K12 and Cross-linked sodium carboxymethyl cellulose.

2. Using a co-grinder (or manual sieving) equipped with a #20 mesh, an excess of the compound ( 1 ) of the tromethamine salt, crystalline cellulose PH-101, lactose monohydrate, poloxamer 188. Sodium lauryl sulfate, povidone K12 and croscarmellose sodium were sieved at 70% speed.

3. Weigh the required amount of "screened" compound ( 1 ) of tromethamine salt, crystalline cellulose PH-101, lactose monohydrate, poloxamer 188, sodium lauryl sulfate, povidone K12 And croscarmellose sodium.

4. Transfer the material from step 3 to a V-cylinder blender.

5. Blend the material in a V-cylinder blender at a set speed (typically 25 RPM) for 5 minutes.

6. Pour the contents of the V-cylinder blender into a LDPE bag (bulk wet granulation blend).

7. Place the bulk wet granulation blend of step 6 into a high shear granulator (Vector GMX.01) with a 1 L granulator tank.

8. Granulate the blend. The wet granulation process is carried out in two stages:

Stage 1: The use of 77% of the total amount of water required for wet granulation granulates the material under specified process parameters. Once the water addition is complete, the granulation is stopped and the walls of the high shear granulator, the impeller and the chopper are scraped and the granules are inspected to determine if the visual end point is reached. If yes, proceed to step 10, otherwise proceed to phase 2.

Stage 2: Add the remaining 23% water and pelletize the material. Once the water addition is complete, the granulation is stopped and the walls of the high shear granulator, the impeller and the chopper are scraped and the granules are inspected to determine if the visual end point is reached.

Stage 3: Use only impellers and shredders to pellet the material for approximately 30 seconds under the specified process parameters. The granulation is stopped and the walls of the high shear granulator, the impeller and the chopper are scraped and the granules are inspected to determine if the visual end point is reached. If yes, proceed to the next step, otherwise continue to granulate with 2 ml of water per the previous process parameters until the end point is reached. Once the granulation end point is reached, even the material (wet granulation blend) passes through the #10 mesh and is transferred through the sieve material to a suitable container.

9. The material is then dried.

10. Once the material is confirmed to be dry, all dry granules are manually screened using a #20 (850 μm) mesh.

b) Lozenge manufacturing process flow

11. Weighed (10%) amount of crystalline cellulose PH-102, croscarmellose sodium and magnesium stearate.

12. Using a co-grinder (or manual sifter) with a 813 μm mesh, will Excess crystalline cellulose PH-102, croscarmellose sodium and magnesium stearate were sieved at 30% speed and placed through a sieve material in individual bags or containers.

13. Weigh the required amount of "screened" crystalline cellulose PH-102, croscarmellose sodium, magnesium stearate, and ground granules.

14. Transfer material other than magnesium stearate from the previous step to a V-cylinder blender.

15. Blend the material in a V-cylinder blender at a set speed (typically 25 RPM) for 5 minutes.

16. Magnesium stearate is then added to the V-cylinder blender.

17. The resulting material was blended for 1 minute at a set speed (typically 25 RPM) in a V-cylinder blender.

18. Compress the final blend using a GlobePharma ingot machine according to the specified tablet compression process parameters. Individual and average lozenge weight, hardness, thickness and brittleness are monitored during the compression process.

19. At the end of the operation, remove all the tablets and place them in the bottle.

Example 8: Compound IV of Compound (1)

A flow chart for the manufacture of a pharmaceutical intravenous solution is shown in FIG. A description of the manufacturing process is provided below.

1. Sterilize all equipment and components to be used in the process.

2. Preparation of 10% phosphoric acid and 1 M sodium hydroxide solution for pH adjustment

a. 10% phosphoric acid (86%):

Approximately 250 mL of water for injection (WFI) was added to the 500 mL volumetric flask. Then 59 mL of phosphoric acid was slowly added to the bottle. The mixture is then mixed.

b. 1 M sodium hydroxide:

Add approximately 250 mL of WFI to the 500 mL volumetric flask. Then 20 g of sodium hydroxide was slowly added to the bottle. The mixture is then mixed.

3. Preparation of 70 mM phosphate buffer -12 L with dextrose

a. Weigh the required amount of dextrose, sodium dihydrogen phosphate and disodium hydrogen phosphate.

b. Add about 10 L of cold WFI (15-30 °C) to the compounding vessel.

c. The mixture is then mixed.

d. Add the weighed amount of dextrose, sodium dihydrogen phosphate, and disodium hydrogen phosphate to the container. The mixture is then mixed until the solution is clear.

e. Take a 10 mL sample to check the pH. The pH was adjusted to pH 7.4 (range: 7.2 to 7.6) with 10% phosphoric acid or 1 M sodium hydroxide solution as needed.

f. Make up to 12 L (12.2 kg at a density of 1.013 g/mL) with an appropriate amount of WFI (15 ° C to 30 ° C). Mix for not less than 5 minutes.

4. Preparation of compound ( 1 ) / HPβCD solution

a. Weigh the desired amount of HPβCD and the form M of compound ( 1 ).

b. Add about 9 kg of phosphate/dextrose buffer (15 ° C to 30 ° C) to the mixing vessel with the stir bar.

c. Add the weighed HPβCD to the buffer solution and stir the mixture for not less than 5 minutes until the solution becomes clear.

d. Compound ( 1 ) is then added to the compounding vessel. The vessel wall above the fluid is rinsed with 50 mL to 100 mL of buffer solution to wash away any residual drug that may be on the side. The resulting mixture was then mixed for not less than 2 hours until the solution became clear.

e. Take a 10 mL sample and check the pH. The pH was adjusted to pH 7.0 (range: 7.0 to 7.4) with 10% phosphoric acid or 1 M sodium hydroxide solution as needed.

f. Make up to 10 L (10.2 kg at a density of 1.0218 g/ml) with an appropriate amount of phosphate/dextrose buffer (15 ° C to 30 ° C). Mix for not less than 5 minutes.

5. Using a peristaltic pump, the bulk solution was filtered through a series of 2 Millipak 200 0.22 micron filters into a 20 L Flexboy sterile bag.

6. Place the solution in the vial using a Flexicon peristaltic filling machine. The filled vials are stored at 15 ° C to 30 ° C.

Example 9: Dissolution data

The dissolution profile of Form M Lozenge A, Form M Lozenges B, Form A Capsules and Tris Lozenges is in FESSIF (Feeding State Simulated Intestinal Fluid) (Figure 12) and at 0.4% SLS (Lauryl) Obtained in sodium sulphate (Figure 14):

Dissolved in FESSIF:

Stirring paddle: USP II

Stirring paddle speed: 50 rpm

Volume: 900 mL

Media: FeSSIF

Temperature: 37 ° C

Dissolved in 0.4% SLS:

Stirring paddle: USP II

Stirring paddle speed: 50 rpm

Volume: 900 mL

Medium: 0.4% SLS in citrate buffer, pH 4.8

Temperature: 37 ° C.

Example 10: Simulation of area under the curve (AUC) ratio of tablet B of compound (1)

Each tablet and capsule comprises 200 mg of compound ( 1 ).

An example of a FESSIF used to obtain a dissolution profile is shown in Table 12.

The rate of dissolution of the formulation in the specified medium is a fundamental property of the formulation. In vitro dissolution rates can be correlated with parameters derived from observed in vivo pharmacokinetic data (eg, AUC, _Cmax, etc.). For each particular drug, specific in vitro conditions need to be developed to establish in vitro and in vivo correlations. The rate of in vivo dissolution of Compound ( 1 ) in the human body was found to correlate with the rate of dissolution of Compound ( 1 ) formulation in simulated human intestinal fluid medium. The correlation is based on the human plasma concentration-time curve of Form M capsule, Form A capsule and tromethamine salt tablet in the form of Compound ( 1 ) and its dissolution rate in simulated human intestinal medium. The in vitro and in vivo dissolution profiles are represented by the following formula: Where M is the mass of the active drug dissolved, M ₀ is the initial mass of the active drug, t is the dissolution time, C _s is the solubility of the drug in the dissolution medium, V is the volume of the dissolution medium, and z is the dissolution rate constant. z represents the mass transfer property of the drug in the specified medium.

Compound (1) formulations in vivo z value vivo person based software used by fitting Gastroplus ^TM human plasma concentration - time profiles obtained. In vitro z-values were obtained by fitting the dissolution profile in a simulated human intestinal medium using Mathematica software. The correlation between in vitro z and in vivo z is shown in Figure 13.

In the case where correlation has been established, the dissolution rate constant z of the compound ( 1 ) formulation in the simulated human intestinal medium is suitable for predicting the in vivo plasma concentration-time curve of the compound ( 1 ) formulation. Therefore, the z value determined in the simulated human intestinal medium is an important property related to the in vivo efficacy of the compound ( 1 ) formulation.

The Form M formulation of Compound ( 1 ) exhibited a z value of 0.0631 ml/mg per minute in simulated human intestinal fluid. The AUC ratio of the solid formulation of Compound ( 1 ) in the simulated human intestinal fluid having a dissolution rate factor z value in the range of 0.025 ml/mg/min to 100.0 ml/mg/min is expected to be in the range of 0.8 to 1.1. (When the solution is administered, the upper limit of the dissolution rate factor z is infinite. The upper limit of the z value shown here represents the theoretical value of spherical drug particles having a molecular weight of 445.63 D and a radius of 1 nm and a diffusion layer thickness of 1 nm. The AUC ratio is estimated based on a cross-designed virtual test simulation of 36 individuals. It is assumed that the CV% of the inter-individual variability is 20% for the clearance rate, the distribution volume, the permeability, and the in vivo dissolution rate factor z. In vivo variability is negligible. The estimated AUC ratio (90% confidence interval) for the formulation with the assumed z value and the reference formulation is provided in Table 13 below. Formulations with in vitro z values ranging from 0.025 ml/mg/min to 93.3 ml/mg/min are expected to meet the bioequivalence criteria based on the AUC ratio and the reference formulation.

Example 11: Preparation of other tablets containing the polymorphic form M of compound (1)

A. Lozenges C

Rolling and lozenge composition

The total composition specifications of the tablets are described in Table 14. The lozenge formulation was prepared in a manner similar to that described above in Example 6, but using a roll press instead of a twin screw wet granulation process. A manufacturing flow chart for tablet C is shown in FIG. In short, the manufacturing process includes:

Compound ( 1 ) (Form M), microcrystalline cellulose, and croscarmellose sodium were individually sieved, added to a blender, and blended. Magnesium stearate was individually sieved, added to the above blend and further blended. The blend is then dry granulated and ground into granules using a roller press. The granules are then further blended with individual sieved microcrystalline cellulose, croscarmellose sodium, and stearic acid stearate. The final blend is then compressed into a tablet. The final tablet contains 400 mg of compound ( 1 ). After compression, the release of the SDD tablet was tested and packaged.

B. Lozenge D

Wet granulation and lozenge composition

A lozenge formulation was prepared in a manner similar to that described for Formulation B in Example 6 above using a Consigma 1 twin screw granulator with a fluid bed dryer. For HPC 2.25%, the total composition of the compound ( 1 ) particles of the tablet is provided in Tables 19a and 19b.

The formulation and batch size for the pre-granulation blend are provided in Table 20a. Table 20b, Table 20c, Table 20d, Table 20e, Table 20f, and Table 20g provide the composition and batch size of the granulation binder solution. The batch size of the binder solution includes 100% excess for pump calibration and priming solution lines.

a) Preparation of binder solution (HPC 1.5% to 2.5%)

The binder solution includes an HPC binder. The solution was prepared based on 48 w/w%, 53 w/w%, and 58 w/w% water content of the final dry granules. An excess of 100% is prepared for pump calibration, priming lines, and the like.

1. Weigh out the required amount (Table 20b, Table 20c, Table 20d, Table 20e, Table 20f, and Table 20g) of HPC and purified (deionized) water.

2. Add HPC-SL to deionized water with constant agitation and stir until completely dissolved. Lower the agitation rate so that only local vortices are formed Swirling.

3. Stir the solution until all solids present are completely dissolved.

4. Cover the solution and let it stand for 2 hours to 4 hours until the bubbles in the solution have disappeared. Alternatively, a partial vacuum can be drawn from the solution tank for one hour to degas the solution.

b) Wet granulation process

1. Weigh the correct amount of compound ( 1 ), croscarmellose sodium, crystalline cellulose PH-101, and lactose monohydrate according to Table 20a.

2. Using a U5 or U10 co-grinder equipped with a 32R sieve and a circular impeller, the extracted compound ( 1 ), lactose and crystalline cellulose were deblocked in U5 at 4000 rpm or at U800 in 2800 rpm. , enter the bag or go directly into the blender.

3. Set the blender and transfer the material from step 2 to the blender if the material is deblocked into the bag.

4. Blend the material for 5 minutes at 23 RPM. The blender should be 59% to 74% full based on the bulk density of 0.4 g cc ^-1 to 0.5 g cc ^-1 .

5. Take two 1.0 g samples, one for the Kafir (KF) test and the other for the LOD test. These samples do not have to be taken with a sampler.

6. Feed the 5 kg pre-granulation blend directly into the loss-in-weight powder feeder from the blending cylinder. The remaining blender contents are poured into a labeled LDPE bag or fed directly from the blending drum to a loss-in-weight feeder.

7. Set up a Consigma 1 twin screw granulator with a standard screw configuration as specified in Table 21.

8. Feed the dry blend to the extruder using the Barbender loss-in-weight feeder in.

9. Inject the binder fluid into the granulator using a calibrated liquid pump.

10. Granulate the blend according to the experimental design shown in Table 22.

11. Granulation of approximately 4 kg of material for Experiments 1 through 4 (1 kg per experiment) and pelletization of approximately 6 kg of material for Experiment 5 and Experiment 6 (3 kg per experiment).

12. The weight ratio of solution feed rate to powder feed rate varied between experiments (see the solution combinations for all experiments in Table 21 when the powder federel remained constant at 167 g/min).

13. The particles from each experiment were collected into separate LDPE bags.

c) Fluidized bed drying process

14. Feed approximately 1 kg of pellets into a fluid bed dryer and dry according to the parameters shown in Table 22.

15. Collect dry granules into separate LDPE bags.

All references provided herein are hereby incorporated by reference in their entirety. All abbreviations, symbols, and conventions as used herein are consistent with those used in contemporary scientific literature. See, for example, Janet S. Dodd, The ACS Style Guide: A Manual for Authors and Editors , Second Edition, Washington, DC: American Chemical Society, 1997.

It is to be understood that the scope of the invention is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following patent application.

10‧‧‧System

11‧‧‧ computer

20‧‧‧Central Processing Unit/CPU

22‧‧‧ working memory

24‧‧‧ Mass storage memory/CD-ROM drive or disk drive

26‧‧‧Display terminal

28‧‧‧ keyboard

30‧‧‧ input line

32‧‧‧Data machine

34‧‧‧Telephone line or dedicated data line

36‧‧‧Input hardware/input device

40‧‧‧output line

42‧‧‧Printer

46‧‧‧ Output hardware/output device

50‧‧‧System sinking

100‧‧‧Magnetic data storage media

101‧‧‧Substrate

102‧‧‧ coating

110‧‧‧Data storage media

111‧‧‧Substrate

112‧‧‧Coating

113‧‧‧ pits

114‧‧‧Protective coating

Figure 1 shows an XRPD pattern of polymorphic Form A of Compound ( 1 ).

Figure 2 shows the compound (1) C A polymorphic forms of as much as ¹³ solid state NMR spectrum.

Figure 3 shows an XRPD pattern of the polymorphic form M of compound ( 1 ).

Figure 4 shows the compound (1) in crystalline form as much as M is C ¹³ solid state NMR spectrum.

Figure 5 shows a flow chart of a wet granulation process for Form M Tablet A.

Figure 6 shows a flow chart for the manufacture of a Form M tablet.

Figure 7 shows a flow chart of a wet granulation process for Form M Tablet B.

Figure 8 shows a flow chart of the blending, compression and coating process of Form M Tablet B.

Figure 9 is a flow chart showing the wet granulation process of the tromethamine salt tablet of Compound ( 1 ).

Figure 10 shows a flow chart for the manufacture of a tromethamine salt tablet.

Figure 11 shows a process flow diagram for the manufacture of a drug IV (intravascular) solution.

Figure 12 shows the dissolution data of Form A capsules, Form M lozenges A, Form M Lozenges B, and Tris salt lozenges in FeSSIF (fed state simulated intestinal fluid).

Figure 13 shows the correlation between in vitro z and in vivo z of compound ( 1 ) formulations.

Figure 14 shows the dissolution data of Form A capsules, Form M Tablets A, Form M Tablets B, and Tris salt lozenges in 0.4% SLS (sodium lauryl sulfate).

15 shows a diagram of a system for executing instructions encoded by the storage medium of FIGS. 16 and 17.

Figure 16 shows a cross section of a magnetic storage medium.

Figure 17 shows a cross section of an optically readable data storage medium.

Figure 18 is a flow chart showing the wet granulation process of Form M Lozenges C.

Claims (90)

A pharmaceutical composition comprising: a) a polymorphic form M or a tromethamine salt of the compound ( 1 ) represented by the following structural formula: And b) a filler. The pharmaceutical composition of claim 1, wherein the composition comprises the polymorphic form M of compound ( 1 ). The pharmaceutical composition of claim 1 or 2, wherein the composition comprises: from 25 wt% to 75 wt% of the compound ( 1 ) by weight of the pharmaceutical composition; and 20 wt% by weight of the pharmaceutical composition Up to 75 wt% of the filler. The pharmaceutical composition of claim 3, wherein the composition comprises: 20 wt% to 73 wt% of the filler based on the weight of the pharmaceutical composition. The pharmaceutical composition of claim 3, wherein the composition comprises: 25 wt% to 70 wt% of the compound ( 1 ) by weight of the pharmaceutical composition; and 25 wt% to 70 by weight of the pharmaceutical composition Wt% of the filler. The pharmaceutical composition according to any one of claims 1 to 5, wherein the filler comprises microcrystalline cellulose, lactose, sorbitol, cellulose, calcium phosphate, starch or sugar or any combination thereof. The pharmaceutical composition of claim 6, wherein the filler comprises microcrystalline cellulose and/or lactose. The pharmaceutical composition according to any one of claims 1 to 7, which further comprises a disintegrant. The pharmaceutical composition of claim 8, wherein the composition comprises from 1 wt% to 15 wt% of the disintegrant based on the weight of the composition. The pharmaceutical composition of claim 8 or 9, wherein the disintegrant comprises croscarmellose, crospovidone and/or metal starch glycolate. The pharmaceutical composition of claim 10, wherein the disintegrant comprises croscarmellose sodium. The pharmaceutical composition according to any one of claims 1 to 11, which further comprises a binder. The pharmaceutical composition of claim 12, wherein the binder comprises from 0.5 wt% to 10 wt% of the weight of the pharmaceutical composition. The pharmaceutical composition of claim 13, wherein the binder comprises polyvinylpyrrolidone, starch, saccharide, microcrystalline cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxyethylcellulose, and Any combination. The pharmaceutical composition according to any one of claims 1 to 14, further comprising 0.25 wt% to 10 wt% of a wetting agent based on the weight of the pharmaceutical composition. The pharmaceutical composition of claim 15, wherein the humidifying agent comprises a nonionic surfactant and/or an anionic surfactant, and wherein the nonionic surfactant comprises a copolymer of polyoxypropylene and polyoxyethylene, and wherein Anionic surfactants include sodium lauryl sulfate. The pharmaceutical composition according to any one of claims 1 to 16, wherein the composition comprises: a) from 25 wt% to 70 wt% of the polymorphic form M of the compound ( 1 ) by weight of the pharmaceutical composition. a blood acid amine salt; b) from 1 wt% to 15 wt% of the disintegrant by weight of the pharmaceutical composition; and c) from 25 wt% to 70 wt% of the filler based on the weight of the pharmaceutical composition . The pharmaceutical composition according to any one of claims 1 to 16, wherein the composition comprises: a) from 25 wt% to 70 wt% of the polymorphic form M of the compound ( 1 ) by weight of the pharmaceutical composition. a blood acid amine salt; b) from 0.5 wt% to 10 wt% of the binder of the pharmaceutical composition; c) from 1 wt% to 15 wt% of the disintegrant by weight of the pharmaceutical composition; And d) from 25 wt% to 70 wt% of the filler based on the weight of the pharmaceutical composition. The pharmaceutical composition of claim 1, wherein the composition comprises: a) from 25 wt% to 60 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt; a 0.25 wt% to 10 wt% of the wetener based on the weight of the pharmaceutical composition; c) 0.5 wt% to 10 wt% of the binder by weight of the pharmaceutical composition; d) in the pharmaceutical combination 1% to 15% by weight of the disintegrant; and e) 25 to 70% by weight of the filler based on the weight of the pharmaceutical composition. The pharmaceutical composition of any one of claims 1 to 19, further comprising a lubricant. The pharmaceutical composition of claim 20, wherein the lubricant comprises a metal stearate and/or a metal fumarate. The pharmaceutical composition of claim 21, wherein the lubricant comprises sodium stearyl fumarate and/or magnesium stearate. The pharmaceutical composition of claim 1, wherein the composition comprises: a) from 25 wt% to 60 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt; a polyvinylpyrrolidone of 0.5 wt% to 10 wt% based on the weight of the pharmaceutical composition; c) a copolymer of 0.25 wt% to 10 wt% of polyoxypropylene and polyoxyethylene based on the weight of the pharmaceutical composition And d) from 0.25 wt% to 10 wt% of sodium lauryl sulfate by weight of the pharmaceutical composition; e) from 25 wt% to 70 wt% of microcrystalline cellulose by weight of the pharmaceutical composition; Between 1 wt% and 15 wt% of croscarmellose sodium by weight of the pharmaceutical composition. The pharmaceutical composition of claim 1, wherein the composition comprises: a) from 25 wt% to 60 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt; a polyvinylpyrrolidone of 0.5 wt% to 10 wt% based on the weight of the pharmaceutical composition; c) a copolymer of 0.25 wt% to 10 wt% of polyoxypropylene and polyoxyethylene based on the weight of the pharmaceutical composition And d) from 0.25 wt% to 10 wt% of sodium lauryl sulfate by weight of the pharmaceutical composition; e) from 25 wt% to 70 wt% of microcrystalline cellulose by weight of the pharmaceutical composition; Between 1 wt% and 15 wt% of croscarmellose sodium by weight of the pharmaceutical composition. The pharmaceutical composition of claim 1, wherein the composition comprises: a) from 25 wt% to 70 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt, by weight of the pharmaceutical composition; a polyvinylpyrrolidone of from 0.5 wt% to 10 wt%, based on the weight of the pharmaceutical composition; c) from 0.25 wt% to 5 wt% of the copolymer of polyoxypropylene and polyoxyethylene by weight of the pharmaceutical composition d) 0.25 wt% to 5 wt% sodium lauryl sulfate by weight of the pharmaceutical composition; e) 0.25 wt% to 5 wt% of stearin antibutene based on the weight of the pharmaceutical composition Sodium; (m) 20% to 60% by weight of microcrystalline cellulose by weight of the pharmaceutical composition; g) 0.5% to 15% by weight of lactose by weight of the pharmaceutical composition; and h) The pharmaceutical composition is from 1 wt% to 10 wt% of croscarmellose sodium by weight of the pharmaceutical composition. The pharmaceutical composition of claim 1, wherein the composition comprises: a) from 25 wt% to 70 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt, by weight of the pharmaceutical composition; a hydroxypropylcellulose of from 0.5 wt% to 10 wt%, based on the weight of the pharmaceutical composition; c) from 0.25 wt% to 10 wt% of sodium stearyl fumarate based on the weight of the pharmaceutical composition ; d) from 20 wt% to 60 wt% of microcrystalline cellulose by weight of the pharmaceutical composition; and e) from 0.5 wt% to 15 wt% of lactose by weight of the pharmaceutical composition; and f) The weight of the pharmaceutical composition is from 1 wt% to 15 wt% of croscarmellose sodium. The pharmaceutical composition of claim 1, wherein the composition comprises: a) from 25 wt% to 70 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt, by weight of the pharmaceutical composition; And 0.25 wt% to 10 wt% of magnesium stearate by weight of the pharmaceutical composition; c) from 25 wt% to 70 wt% of microcrystalline cellulose by weight of the pharmaceutical composition; and d) The weight of the pharmaceutical composition is from 1 wt% to 15 wt% of croscarmellose sodium. The pharmaceutical composition according to any one of claims 1 to 27, further comprising a glidant selected from the group consisting of amorphous ceria and talc. The pharmaceutical composition of any one of claims 1 to 28, wherein the composition has a dissolution rate factor z of at least about 0.025 ml/mg/min. The pharmaceutical composition of claim 29, wherein the composition has a dissolution rate factor z in the simulated human intestinal fluid ranging from about 0.025 ml/mg/min to 100 ml/mg/min. The pharmaceutical composition of claim 30, wherein the composition has a dissolution rate factor z in the simulated human intestinal fluid ranging from about 10 ml/mg/min to 100 ml/mg/min. The pharmaceutical composition of claim 1, wherein the composition comprises: a) from 25 wt% to 70 wt% of the polymorphic form M of the compound ( 1 ) by weight of the pharmaceutical composition; and b) the pharmaceutical combination a filler of 25 wt% to 70 wt% by weight, the filler being selected from the group consisting of microcrystalline cellulose, lactose, sorbitol, cellulose, calcium phosphate, starch, and sugar, and any Combination wherein the formulation is in the form of a lozenge or capsule. A pharmaceutical composition comprising a compound of (1) crystalline form as much as M, where the compound (1) represented by the following formula based: Wherein the dissolution rate of the composition is represented by the following formula: Where M is the mass of the initial mass of the solubilized compound (1) of, M ₀ is the compound (1) of, t is the dissolution time, C _s is the compound (1) solubility in simulated intestinal fluid in the fed state, V for the fed state The volume of intestinal fluid is simulated, and z is the dissolution rate factor, wherein the z value of the composition is greater than 0.025 ml/mg/min. The pharmaceutical composition of claim 33, wherein the composition is in a solid state. The pharmaceutical composition of claim 34, wherein the dissolution rate factor z in the simulated human intestinal fluid is in the range of from about 0.025 ml/mg/min to 100 ml/mg/min. The pharmaceutical composition of claim 35, wherein the dissolution rate factor z in the simulated human intestinal fluid is in the range of from about 10 ml/mg/min to 100 ml/mg/min. The pharmaceutical composition according to any one of claims 33 to 36, wherein the composition comprises from 25 wt% to 70 wt% of the compound ( 1 ) by weight of the pharmaceutical composition. A pharmaceutical composition comprising: a) a polymorphic form M or a tromethamine salt of the compound ( 1 ) represented by the following structural formula: b) a complexing agent; and c) a buffering agent. The pharmaceutical composition of claim 38, wherein the composition comprises the polymorphic form M of compound ( 1 ). The pharmaceutical composition of claim 38 or 39, wherein the composition comprises: 1 mg/mL to 20 mg/mL of the compound ( 1 ); and the complex is 1 wt% to 25 wt% based on the weight of the pharmaceutical composition And 0.01 to 0.1 M of the buffer. The pharmaceutical composition of any one of claims 38 to 40, wherein the complexing agent comprises a cyclodextrin. The pharmaceutical composition of claim 41, wherein the complexing agent comprises sulfo-butyl-β-cyclodextrin and/or hydroxypropyl-β-cyclodextrin. The pharmaceutical composition according to any one of claims 38 to 42, wherein the buffer comprises sodium dihydrogen phosphate and/or disodium hydrogen phosphate. The pharmaceutical composition of any one of claims 38 to 43 further comprising dextrose and/or mannitol. A pharmaceutical composition comprising a polymorphic form M or a tromethamine salt of the compound ( 1 ) represented by the following structural formula: Wherein the pharmaceutical composition is prepared by providing a compound ( 1 ) particle comprising 35 wt% to 95 wt% of the polymorphic form M of the compound ( 1 ) or tromethamine as a weight of the particles. a salt and 3 wt% to 60 wt% of a filler; and mixing the compound ( 1 ) particles with an extragranular excipient comprising 10 wt% to 50 wt% of a filler based on the weight of the pharmaceutical composition, A pharmaceutical composition of the compound ( 1 ) is formed. The pharmaceutical composition of claim 45, wherein the compound ( 1 ) particles comprise from 40 wt% to 90 wt% of the polymorphic form M of the compound ( 1 ) or the tromethamine salt and 5 by weight of the particles. a filler of from wt% to 50 wt%; and the extragranular excipients comprise from 15 wt% to 50 wt% of filler by weight of the pharmaceutical composition. The pharmaceutical composition of claim 45 or 46, wherein the compound (1) particles further comprise from 0.5 wt% to 10 wt% of disintegration based on the weight of the particles And wherein the extragranular excipient further comprises from 0.5 wt% to 10 wt% of a disintegrant based on the weight of the pharmaceutical composition. The pharmaceutical composition according to any one of claims 45 to 47, wherein the method of forming the compound ( 1 ) particles comprises: providing a binder solution comprising a binder of 0.5 wt% to 10 wt% based on the weight of the pharmaceutical composition And optionally from 0.25 wt% to 10 wt% of a wetting agent; providing a pre-granulation composition comprising from 25 wt% to 75 wt% of the poly(compound) of the compound ( 1 ) by weight of the pharmaceutical composition Form M or tromethamine salt, 10 wt% to 25 wt% filler, and 0.5 wt% to 5 wt% disintegrant; and mixing the binder solution with the pre-granulation composition to form a compound ( 1 ) granules; and the method of mixing the granules of the compound ( 1 ) with the extragranular excipients, comprising the granules of the compound ( 1 ) and comprising from 15 wt% to 50 wt% based on the weight of the pharmaceutical composition a filler and a particulate external excipient of 0.5 wt% to 10 wt% of a disintegrant are mixed to form a pharmaceutical composition of the compound ( 1 ), wherein the binder solution and the pre-granulation composition are mixed This involves feeding the pre-granulation composition into a twin-screw extruder and introducing the binder solution into the twin-screw extruder. The pharmaceutical composition of claim 48, wherein the binder solution further comprises water in the range of from 5 wt% to 15 wt%, based on the weight of the pharmaceutical composition. The pharmaceutical composition according to any one of claims 45 to 49, wherein the pharmaceutical composition comprises the polymorphic form M of the compound ( 1 ). A method of preparing a pharmaceutical composition, comprising: providing a pharmaceutical composition comprising a mixture comprising a polymorphic form M of compound ( 1 ) or a tromethamine salt and a filler, wherein compound ( 1 ) is derived from the following structural formula Indicates: The method of claim 51, wherein the forming of the mixture of the compound ( 1 ) and the filler comprises: providing the compound ( 1 ) particles comprising: i) 35 wt% to 95 wt% of the polycrystal of the compound ( 1 ) Form M or a tromethamine salt; and ii) an intragranular excipient comprising from 3 wt% to 60 wt% of the filler by weight of the granules; and the granules of the compound ( 1 ) The extragranular excipients of the filler of 10 wt% to 50 wt% of the weight of the pharmaceutical composition are mixed. The method of claim 52, wherein the forming of the mixture of the compound ( 1 ) and the filler comprises: providing the compound ( 1 ) particles comprising: i) 40 wt% to 90 wt% of the polycrystal of the compound ( 1 ) Form M or a tromethamine salt; and ii) an intragranular excipient comprising from 5 wt% to 50 wt% of the filler by weight of the granules; and the granules of the compound ( 1 ) The extragranular excipient of the filler of 15 wt% to 50 wt% of the weight of the pharmaceutical composition is mixed. The method of any one of claims 51 to 53, wherein the mixture further comprises a binder and a disintegrant. The method of any one of claims 51 to 53, wherein the mixture further comprises a binder, a disintegrant, and a wetting agent. The method of any one of claims 51 to 53, wherein the method of forming the mixture of the compound ( 1 ) and the filler comprises: providing a compound ( 1 ) particle comprising the polymorphic form M of the compound ( 1 ) or a blood acid amine salt, a moisturizing agent, a binder, and an intragranular excipient comprising a filler and a disintegrant; and mixing the particles of the compound ( 1 ) with an extragranular excipient including a disintegrant and a filler . The method of claim 56, wherein the intragranular excipients comprise from 3 wt% to 50 wt% of filler and from 0.5 wt% to 5 wt% of disintegrant by weight of the particles, and the particles The external excipients include 15 wt% to 50 wt% of a filler and 0.5 wt% to 10 wt% of a disintegrant based on the weight of the pharmaceutical composition. The method of claim 56 or 57, wherein the method of forming the compound ( 1 ) particles comprises: providing a binder solution comprising the binder and the humidifying agent; providing a pre-granulation composition comprising the compound ( 1 ) a polymorphic form M or a tromethamine salt and the intragranular excipient; the binder solution is mixed with the pre-granulated composition to form the compound ( 1 ) granules. The method of claim 58, wherein the mixing of the binder solution and the pre-granulation composition comprises feeding the pre-granulation composition into a twin-screw extruder, and introducing the binder solution into the twin-screw extruder press. The method of claim 58 or 59, wherein the binder solution comprises from 0.5 wt% to 10 wt% of binder based on the weight of the pharmaceutical composition. The method of claim 60, wherein the binder solution further comprises from 0.25 wt% to 10 wt% of a wetting agent based on the weight of the pharmaceutical composition. The method of claim 60 or 61, wherein the binder solution further comprises water in the range of from 5 wt% to 60 wt%, based on the weight of the pharmaceutical composition. The method of any one of claims 54 to 62, wherein the binder comprises hydroxypropylcellulose or polyvinylpyrrolidone. The method of any one of claims 54 to 62, wherein the wetting agent comprises a nonionic surfactant and/or an anionic surfactant, and wherein the nonionic surfactant comprises a copolymer of polyoxypropylene and polyoxyethylene And wherein the anionic surfactant comprises sodium lauryl sulfate. The method of any one of clauses 51 to 64, wherein the filler comprises microcrystalline cellulose and/or lactose. The method of any one of claims 51 to 65, wherein the disintegrant comprises croscarmellose sodium, crospovidone and/or sodium starch glycolate. The method of any one of claims 51 to 66, wherein the extragranular excipients further comprise a lubricant. The method of claim 67, wherein the lubricant comprises a metal stearate and/or a metal fumarate. The method of claim 68, wherein the lubricant comprises sodium stearyl fumarate and/or magnesium stearate. The method of any one of claims 51 to 69, wherein the extragranular excipients further comprise a glidant. The method of claim 70, wherein the flow aid comprises amorphous ceria and/or talc. The method of claim 71, wherein the humidifying agent comprises a copolymer of polyoxypropylene and polyoxyethylene having a sodium lauryl sulfate and a polyoxypropylene molecular weight of 1,800 g/mol and a polyoxyethylene content of 80%; The binder comprises polyvinylpyrrolidone having an average molecular weight of 3,000 to 5,000; the filler comprises microcrystalline cellulose and lactose monohydrate; the disintegrant comprises croscarmellose sodium; the lubricant comprises stearin Sodium fumarate; and the glidant comprises colloidal cerium oxide. The method of claim 71, wherein: the binder comprises hydroxypropylcellulose; the filler comprises microcrystalline cellulose and, optionally, lactose monohydrate; the disintegrant comprises croscarmellose sodium; And the lubricant includes sodium stearyl fumarate. The method of any one of claims 51 to 73, which further comprises compressing the pharmaceutical composition of compound ( 1 ) into a tablet. A method of inhibiting or reducing HCV polymerase activity in a biologically in vitro sample, comprising administering to the sample an effective amount of the pharmaceutical composition of any one of claims 1 to 50. A method of treating an HCV infection in an individual comprising administering to the individual a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 50. A method of inhibiting or reducing the activity of an HCV polymerase in an individual, comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 50. The method of claim 76 or 77, further comprising co-administering to the individual one or more additional therapeutic agents. The method of claim 78, wherein the other therapeutic agents comprise an anti-HCV drug. The method of claim 79, wherein the anti-HCV drug is an HCV protease inhibitor. The method of claim 80, wherein the HCV protease inhibitor is an HCV NS3 inhibitor. The method of claim 81, wherein the HCV protease inhibitor is VX-950. The method of claim 79, wherein the anti-HCV drug is an HCV NS5A inhibitor. The method of any one of clauses 78 to 83, wherein interferon and/or ribavirin are co-administered. The method of claim 84, wherein the interferon is PEGylated Prime. The method of claim 85, wherein the pegylated interferon is pegylated interferon-α. The method of claim 86, wherein the pegylated interferon is pegylated interferon-α 2a or pegylated interferon-α 2b. The method of any one of items 78 to 83, wherein ribavirin is co-administered. The method of any one of clauses 75 to 88, wherein the HCV is genotype 1. The method of any one of clauses 75 to 89, wherein the HCV is genotype 1a or genotype 1b.