ES2746650T3 - Solid forms comprising (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione, compositions thereof, and uses thereof - Google Patents

Abstract

A solid form comprising the enantiomerically pure compound of formula (I): ** Formula ** having an X-ray powder diffraction pattern comprising its characteristic peaks at 7.5, 11.3, 16.4, 17 , 8 and 26.4 degrees 2θ ± 0.2 degrees 2θ measured using Cu Kα radiation at 1.54 Å; and having a differential scanning calorimetry graph comprising an endothermic event with an onset temperature of about 138 ° C while heating a sample at a rate of about 10 ° C / min.

Description

DESCRIPTION

Solid forms comprising (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione, compositions thereof, and uses thereof

1. Field of the invention

Provided herein is the solid form C of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione, compositions comprising the forms solid, methods of making the solid form and uses for the treatment of various diseases and / or disorders.

2. Background of the invention

Tumor necrosis factor alpha (TNF-a) is a cytokine that is mainly released by mononuclear phagocytes in response to immunostimulators. TNF-a is capable of enhancing most cellular processes, such as differentiation, recruitment, proliferation, and proteolytic degradation. At low levels, TNF-a confers protection against infectious agents, tumors and tissue injury. However, TNF-a also has a role in many diseases. When administered to a patient, TNF-a causes or aggravates inflammation, fever, cardiovascular effects, bleeding, coagulation, and acute phase responses similar to those seen during acute infections and shock states. Enhanced or unregulated production of TNF-a has been implicated in various diseases and medical conditions, for example, cancers, such as solid tumors and blood-borne tumors; heart disease, such as congestive heart failure; and viral, genetic, inflammatory, allergic, and autoimmune diseases.

3 ', 5'-cyclic adenosine monophosphate (cAMP) also has a role in many diseases and conditions, such as, but not limited to, asthma and inflammation and other conditions (Lowe and Cheng, Drugs of the Future, 17 (9) , 799-807, 1992). Elevation of cAMP in inflammatory leukocytes has been shown to inhibit its activation and subsequent release of inflammatory mediators, including TNF-a and NF-kB. Increased cAMP levels also lead to relaxation of smooth muscle in the airways.

The main cellular mechanism for cAMP inactivation is believed to be the breakdown of cAMP by a family of isoenzymes called cyclic nucleotide phosphodiesterases (PDE) (Beavo and Reitsnyder, Trends in Pharm., 11, 150-155, 1990 ). There are eleven known PDE families. It is recognized, for example, that inhibition of type IV PDE is particularly effective in both inhibiting inflammatory mediator release and relaxing smooth muscle in the airways (Verghese, et al., J. Pharm. Exper. Therapeut., 272 (3), 1313-1320, 1995). Thus, compounds that specifically inhibit PDE4 (PDE IV), can inhibit inflammation and aid relaxation of smooth muscle in the airways with minimal unwanted side effects, such as cardiovascular or antiplatelet effects. Currently used PDE4 inhibitors lack selective action at acceptable therapeutic doses.

Cancer is a particularly devastating disease, and increases in blood levels of TNF-a are implicated in the risk and spread of cancer. Normally, in healthy subjects, cancer cells cease to survive in the circulatory system, one of the reasons being that the lining of blood vessels acts as a barrier to extravasation of tumor cells. However, increased levels of cytokines have been shown to substantially increase adhesion of cancer cells to the endothelium in vitro. One explanation is that cytokines, such as TNF-a, stimulate biosynthesis and expression of a cell surface receptor called ELAM-1 (leukocyte adhesion molecule to the endothelium). ELAM-1 is a member of a family of calcium-dependent cell adhesion receptors, known as LEC-CAM, which includes LECAM-1 and GMP-140. During an inflammatory response, ELAM-1 on endothelial cells functions as a "targeted migration receptor" for leukocytes. Recently, ELAM-1 on endothelial cells has been shown to mediate increased adherence of colon cancer cells to the endothelium treated with cytokines (Rice et al., 1989, Science 246: 1303-1306).

Inflammatory diseases such as arthritis, related conditions (eg, osteoarthritis and rheumatoid arthritis), inflammatory bowel disease (eg, Crohn's disease and ulcerative colitis), sepsis, psoriasis, atopic dermatitis, contact dermatitis, chronic obstructive pulmonary disease , and chronic inflammatory lung diseases are also widespread and problematic ailments. TNF-a plays a major role in the inflammatory response and the administration of its antagonists blocks chronic and acute responses in animal models of inflammatory disease.

Enhanced or unregulated production of TNF-a has been implicated in viral, genetic, inflammatory, allergic, and autoimmune diseases. Examples of such diseases include, but are not limited to: HIV; hepatitis; adult respiratory distress syndrome; bone resorption diseases; chronic obstructive pulmonary diseases; chronic inflammatory lung diseases; asthma; dermatitis; cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; postischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection; autoimmune disease; spondylitis rheumatoid; arthritic conditions, such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lupus erythematosus; ENL in leprosy; radiation damage; asthma; and alveolar injury from hyperoxia. Tracey et al., 1987, Nature 330: 662-664 and Hinshaw et al., 1990, Circ. Shock 30: 279-292 (endotoxic shock); Dezube et al., 1990, Lancet, 335: 662 (cachexia); Millar et al., 1989, Lancet 2: 712-714 and Ferrai-Baliviera et al., 1989, Arch. Surg. 124: 1400-1405 (adult respiratory distress syndrome); Bertolini et al., 1986, Nature 319: 516-518, Johnson et al., 1989, Endocrinology 124: 1424-1427, Holler et al., 1990, Blood 75: 1011-1016, and Grau et al., 1989, N. Engl. J. Med. 320: 1586-1591 (bone resorption diseases); Pignet et al., 1990, Nature, 344: 245-247, Bissonnette et al., 1989, Inflammation 13: 329-339 and Baughman et al., 1990, J. Lab. Clin. Med. 115: 36-42 (chronic inflammatory lung diseases); Elliot et al., 1995, Int. J. Pharmac.

17: 141-145 (rheumatoid arthritis); von Dullemen et al., 1995, Gastroenterology, 109: 129-135 (Crohn's disease); Duh et al., 1989, Proc. Nat. Acad. Sci. 86: 5974-5978, Poll et al., 1990, Proc. Nat. Acad. Sci. 87: 782-785, Monto et al., 1990, Blood 79: 2670, Clouse et al., 1989, J. Immunol. 142, 431-438, Poll et al., 1992, AIDS Res. Hum. Retrovirus, 191 197, Poli et al. 1990, Proc. Natl. Acad. Sci. 87: 782-784, Folks et al., 1989, PNAS 86: 2365-2368 (HIV and opportunistic infections resulting from HIV).

Pharmaceutical compounds that can block the activity or inhibit the production of certain cytokines, including TNF-a, can be beneficial therapeutic agents. Many small molecule inhibitors have shown an ability to treat or prevent inflammatory diseases implicated by TNF-a (for a review, see Lowe, 1998 Exp. Opin. Ther. Patents 8: 1309-1332). One such class of molecules is the substituted phenethylsulfones described in United States Patent No. 6,020,358.

The preparation and selection of a solid form of a pharmaceutical compound is complex, since a change in the solid form can affect a variety of physical and chemical properties, which can provide benefits or drawbacks in processing, formulation, stability and bioavailability, among other important pharmaceutical characteristics. Potential pharmaceutical solids include crystalline solids and amorphous solids. Amorphous solids are characterized by a lack of long-range structural order, while crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends on the specific application; amorphous solids are sometimes selected on the basis of, for example, an improved dissolution profile, while crystalline solids may be desirable for properties such as, for example, physical or chemical stability (see, for example, SR Vippagunta et al., Adv. Drug. Deliv. Rev., (2001) 48: 3-26; L. Yu, Adv. Drug. Deliv. Rev., (2001) 48: 27-42).

Whether crystalline or amorphous, potential solid forms of a pharmaceutical compound include single-component and multi-component solids. Single-component solids consist essentially of the pharmaceutical compound in the absence of other compounds. Diversity among single-component crystalline materials can potentially arise, for example, from the phenomenon of polymorphism, where multiple three-dimensional arrangements exist for a particular pharmaceutical compound (see, for example, SR Byrn et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). The case of ritonavir, an HIV protease inhibitor that was formulated as soft gelatin capsules, underscored the importance of studying polymorphs. Approximately two years after product launch, unanticipated precipitation of a new less soluble polymorph in the formulation required the product to be withdrawn from the market until a more consistent formulation could be developed (see SR Chemburkar et al., Org. Process Res Dev., (2000) 4: 413-417).

Additional diversity among the potential solid forms of a pharmaceutical compound may arise, for example, from the possibility of multi-component solids. Crystalline solids comprising two or more ionic species can be referred to as salts (see, for example, Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, Eds., (2002), Wiley, Weinheim). Additional types of multi-component solids that may offer other property improvements for a pharmaceutical compound or a salt thereof, include, for example, hydrates, solvates, co-crystals and clathrates, among others (see, for example, SR Byrn et al ., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). Furthermore, multi-component crystal forms can potentially be susceptible to polymorphism, where a given multi-component composition may exist in more than one three-dimensional crystal arrangement. The preparation of solid forms is of great importance in the development of a safe, effective, stable and marketable pharmaceutical compound.

Embodiments are provided herein that address the need for solid forms of the chemically named compound (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3- diona ("Compound A"), which was described in US Application. No. 10 / 392,195, filed March 19, 2003 (issued as US Patent No. 6,962,940), as well as US Provisional Applications. with Serial No. 60 / 366,515, filed on March 20, 2002 and 60 / 438,450, filed on January 7, 2003.

3. Summary of the invention

This invention relates to methods of treating diseases and disorders using an enantiomer of a substituted phenethylsulfone compound and pharmaceutically acceptable solvates, hydrates, co-crystals, clathrates, prodrugs, and polymorphs thereof, and methods of reducing the level of cytokines and their precursors in mammals. The invention also relates to pharmaceutical compositions comprising Form C of the 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione enantiomer and a pharmaceutically acceptable carrier. The invention further relates to Form C of the 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione enantiomer substantially free of its enantiomer ( -).

This invention is particularly concerned with Form C of the (+) enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione. This compound is believed to have higher potency and other benefits compared to its racemate, 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione.

The invention includes the use of Form C of the (+) enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione to treat or prevent diseases or disorders enhanced by inhibition of TNF-α production in mammals. In certain embodiments, this treatment includes the reduction or avoidance of adverse effects. Such disorders include, but are not limited to, cancers including, but not limited to, head, thyroid, neck, eye, skin, mouth, throat, esophagus, chest, bone, blood, lung, colon, sigmoid, rectum , stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart, adrenal, subcutaneous tissue, lymph nodes, heart, and combinations thereof. Specific cancers that can be treated by this method are multiple myeloma, malignant melanoma, malignant glioma, leukemia, and solid tumors.

The invention also includes the use of Form C of the (+) enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione in the treatment or prevention of heart disease, including, but not limited to, congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.

The invention also includes the use of Form C of the (+) enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione to treat diseases or disorders enhanced by PDE4 inhibition. For example, the compounds and compositions of the invention may be useful in treating or preventing viral, genetic, inflammatory, allergic, and autoimmune diseases. Examples of such diseases include, but are not limited to: HIV; hepatitis; adult respiratory distress syndrome; bone resorption diseases; chronic obstructive pulmonary diseases; chronic inflammatory lung diseases; dermatitis; inflammatory skin disease, atopic dermatitis; cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; postischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection, including graft-versus-host disease; autoimmune disease; rheumatoid spondylitis; arthritic conditions, such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lupus erythematosus; erythema nodosum leprosum (ENL) in leprosy; radiation damage; asthma; and alveolar injury from hyperoxia.

In yet another embodiment, Form C of the stereomerically pure (+) enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione is also useful in the treatment or prevention of microbial infections or symptoms of microbial infections, including, but not limited to, bacterial infections, fungal infections, malaria, mycobacterial infection, and opportunistic infections resulting from HIV.

The invention further includes pharmaceutical compositions and single unit dosage forms comprising Form C of the 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3 enantiomer. -dione and pharmaceutically acceptable polymorphs, prodrugs, hydrates, clathrates, and solvates thereof.

In a separate embodiment, the invention includes Form C of the 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione enantiomer.

In a further embodiment, the invention includes a method of producing Form C of the stereomerically pure (+) enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3 -dione comprising contacting 1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethylamine with a chiral amino acid, and contacting the product of the first step with N- (1,3-Dioxo -1,3-dihydro-isobenzofuran-4-yl) -acetamide. A chiral salt of 1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethylamine is also described.

Embodiments herein provide solid forms comprising Form C of the chemically named compound (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3- diona ("Compound A"). Compound A can be synthesized or obtained according to any method apparent to those skilled in the art based on the teachings herein, including the methods described in the Examples below. Compound A can also be prepared according to the methods described in US Pat. No. 6,962,940, issued on November 8, 2005.

In certain embodiments, the solid forms are single-component crystalline forms of Form C of Compound A. In certain embodiments, the solid forms are multi-component crystalline forms, including, but not limited to, crystals and / or solvates (including hydrates) comprising Form C of Compound A. In other aspects described, the solid forms are single-component amorphous forms of Compound A. In other aspects described, the solid forms are multi-component amorphous forms. Without pretending to stay Limited by any particular theory, certain novel solid forms provided herein have particular advantageous physical and / or chemical properties that make them useful, for example, for the manufacture, processing, formulation and / or storage, while possessing particularly advantageous biological properties, such as, for example, bioavailability and / or biological activity.

In particular embodiments, the solid forms provided herein include solid forms comprising Compound A, including, but not limited to, single-component and multi-component solid forms comprising Form C of Compound A. In certain embodiments, the Solid forms provided herein include polymorphs, solvates (including hydrates) and co-crystals comprising Form C of Compound A. Certain embodiments herein provide methods for preparing, isolating, and / or characterizing the solid forms provided herein. .

The solid forms provided herein are useful as active pharmaceutical ingredients for the preparation of formulations for use in patients. Therefore, the embodiments herein include the use of these solid forms as a final drug product. Certain embodiments provide useful solid forms for preparing final dosage forms with improved properties, for example, powder flow properties, compaction properties, tabletting properties, stability properties, and excipient compatibility properties, among others, which are necessary for the manufacture, processing, formulation and / or storage of final pharmacological products. Certain embodiments herein provide pharmaceutical compositions comprising a single component crystalline form, and / or a multi component crystalline form comprising Form C of Compound A and a pharmaceutically acceptable diluent, excipient, or vehicle. The solid forms and final drug products provided herein are useful, for example, for the treatment, prevention, or management of diseases and disorders provided herein.

Certain embodiments herein provide methods that use the solid forms provided herein to treat, prevent, or control diseases or disorders enhanced by inhibition of TNF-α production in mammals, such as HIV; hepatitis; adult respiratory distress syndrome; bone resorption diseases; chronic obstructive pulmonary diseases; chronic inflammatory lung diseases; asthma; dermatitis; cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; postischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection; autoimmune disease; rheumatoid spondylitis; arthritic conditions, such as psoriatic arthritis, rheumatoid arthritis, and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lupus erythematosus; cutaneous lupus erythematosus; pulmonary sarcoidosis; ENL in leprosy; radiation damage; asthma; and alveolar injury from hyperoxia. Such disorders also include, but are not limited to, cancers, including, but not limited to, head, thyroid, neck, eye, skin, mouth, throat, esophagus, chest, bone, blood, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart, adrenal, subcutaneous tissue, lymph nodes, heart, and combinations thereof. Specific cancers that can be treated by this method are multiple myeloma, malignant melanoma, malignant glioma, leukemia, and solid tumors. In certain embodiments, methods using the solid forms provided herein include reducing or avoiding certain adverse effects.

Certain embodiments herein provide methods of using the solid forms provided herein in the treatment or prevention of heart disease, including, but not limited to, congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, myocarditis acute viral, rejection of heart allograft and myocardial infarction.

Certain embodiments herein provide methods of using the solid forms provided herein to treat diseases or disorders improved by PDE4 inhibition. For example, the solid forms provided herein may be useful in treating or preventing viral, genetic, inflammatory, allergic, and autoimmune diseases. Examples of such diseases include, but are not limited to: HIV; hepatitis; adult respiratory distress syndrome; bone resorption diseases; chronic obstructive pulmonary diseases; chronic inflammatory lung diseases; dermatitis; inflammatory skin disease; atopic dermatitis; cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; postischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection including graft-versus-host disease; autoimmune disease; rheumatoid spondylitis; arthritic conditions, such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lupus erythematosus; erythema nodosum leprosum (ENL) in leprosy; radiation damage; asthma; and alveolar injury from hyperoxia.

Certain embodiments herein provide methods of using the solid forms provided herein in the treatment or prevention of microbial infections or symptoms of microbial infections including, but not limited to, bacterial infections, fungal infections, malaria, mycobacterial infection, and opportunistic infections resulting from HIV.

Particular embodiments herein provide methods of using the solid forms provided herein in the treatment or prevention of diseases including: psoriasis; psoriasic arthritis; rheumatoid arthritis; chronic skin sarcoid; giant cell arteritis; Parkinson's; nodular prurigo; lichen planus; complex aptosis; Behcet's disease; lupus; hepatitis; uveitis; Sjogren's disease; depression (including major depression); interstitial cystitis; vulvodynia; prostatitis; osteoarthritis; diffuse large B lymphocyte lymphoma; polymysoitis; dermatomyositis; inclusion body myositis; erosive osteoarthritis; interstitial cystitis; hepatitis; endometriosis; radiculopathy; and gangrenous pyoderma.

Certain embodiments herein provide unique pharmaceutical compositions and unit dosage forms comprising one or more solid forms provided herein.

3.1. Brief description of the figures

FIG. 1 provides a representative X-ray powder diffraction pattern ("XRPD") for Form A of Compound A.

Fig. 2 provides a representative differential scanning calorimetry ("DSC") graph of Form A of Compound A.

Fig. 3 provides a representative thermogravimetric analysis ("TGA") graph of Form A of Compound A.

Fig. 4 provides a representative dynamic vapor absorption ("DVS") graph of Form A of Compound A.

Fig 5 provides a representative XRPD pattern of Form B of Compound A.

Fig 6 provides a representative DSC plot of Form B of Compound A.

Fig 7 provides a representative TGA graph of Form B of Compound A.

Fig 8 provides a representative DVS graph of Form B of Compound A.

Fig 9 provides a representative XRPD pattern of Form C of Compound A.

Fig 10 provides a representative DSC graph of Form C of Compound A.

Fig 11 provides a representative TGA plot of Form C of Compound A.

Fig 12 provides a representative DVS graph of Form C of Compound A.

Fig 13 provides a representative XRPD pattern of Form D of Compound A.

Fig 14 provides a representative DSC plot of Form D of Compound A.

Fig 15 provides a representative TGA plot of Form D of Compound A.

Fig 16 provides a representative DVS graph of Form D of Compound A.

Fig 17 provides a representative XRPD pattern of Form E of Compound A.

Fig 18 provides a representative DSC plot of Form E of Compound A.

Fig 19 provides a representative TGA graph of Form E of Compound A.

Fig 20 provides a representative DVS graph of Form E of Compound A.

Fig 21 provides a representative XRPD pattern of Form F of Compound A.

Fig 22 provides a representative DSC plot of Form F of Compound A.

Fig 23 provides a representative TGA graph of Form F of Compound A.

Fig 24 provides a representative DVS graph of Form F of Compound A.

Fig 25 provides a representative XRPD of Form G of Compound A.

Fig. 26 provides a representative DSC graph of Form G of Compound A.

Fig. 27 provides a representative TGA graph of Form G of Compound A.

Fig. 28 provides a representative DVS graph of Form G of Compound A.

Fig. 29 illustrates a preparation of the 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione enantiomer.

Fig. 30 illustrates the effect of Compound A on LPS-induced neutrophilia in the lungs of conscious ferrets.

Fig. 31 illustrates the percentage change in epidermal thickness among the 15 subjects on Day 29 in a clinical study evaluating Compound A in patients with severe plaque-type psoriasis.

Fig. 32 illustrates the change in mean iNOS (normalized to hARP) in lesion skin biopsy samples on Day 29 in a clinical study evaluating Compound A in patients with severe plaque-type psoriasis.

Fig. 33 illustrates the percentage change in total psoriasis area score and severity index (PASI) among patients evaluable from baseline on Day 29 in a clinical study evaluating Compound A in patients with severe plaque-type psoriasis. .

3.2. Definitions

As used herein, the term "Compound A" refers to (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione enantiomerically pure exiting an HPLC column at approximately 25.4 minutes when that column is a 150mm x 4.6mm Ultron Chiral ES-OVS (Agilent Technology) chiral HPLC column, eluent is 15:85 of ethanol: 20 mM KH ² PO ⁴ at pH 3.5, and the observation wavelength is 240 nm. The 1H NMR spectrum of Compound A is substantially as follows: ⁸ (CDCla); 1.47 (t, 3H); 2.26 (s, 3H); 2.87 (s, 3H); 3.68-3.75 (dd, 1H); 3.85 (s, 3H); 4.07-4.15 (q, 2H); 4.51-4.61 (dd, 1H); 5.84-5.90 (dd, 1H); 6.82 to 8.77 (m, ^6H); 9.46 (s, 1H). The 13C NMR spectrum of Compound A is substantially as follows: ⁸ (DMSO-d ⁶ ); 14.66; 24.92; 41.61; 48.53; 54.46; 55.91; 64.51; 111.44; 112.40; 115.10; 118.20; 120.28; 124.94; 129.22; 131.02; 136.09; 137.60; 148.62; 149.74; 167.46; 169.14; 169.48. Compound A dissolved in methanol rotates the plane of polarized light in the (+) direction.

Without being limited by theory, Compound A is believed to be S- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione}, which has the following structure:

As used herein, the term "patient" refers to a mammal, particularly a human.

As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including bases or acids inorganic and organic bases or acids.

As used herein, and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, derivatives and metabolites of Compound A including biohydrolyzable moieties, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Prodrugs can normally be prepared using well-known methods, such as those described in 1 Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995).

As used herein, and unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureido", "biohydrolysable phosphate" mean amide, ester, carbamate, carbonate, ureido or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but may confer to that compound advantageous properties in vivo, such as absorption, duration of action o start of action; or 2) it is biologically inactive, but is converted in vivo to the biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxycyloxy esters, alkyl acylamino alkyl esters, and choline esters. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

As used herein, and unless otherwise indicated, the term "stereomerically pure" means a composition that comprises a stereoisomer of a compound and that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having a chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereoisomers of the compound. A typical stereomerically pure compound comprises more than about 80% by weight of a stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably more than about 90% by weight of a stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and much more preferably more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.

As used herein, and unless otherwise indicated, the term "enantiomerically pure" means a stereomerically pure composition of a compound having a chiral center.

As used herein, the term "adverse effects" includes, but is not limited to, gastrointestinal, kidney, and liver toxicities, leukopenia, increased bleeding times due to, for example, thrombocytopenia, and prolonged pregnancy, nausea , vomiting, drowsiness, asthenia, dizziness, teratogenicity, extrapyramidal symptoms, akathisia, cardiotoxicity including cardiovascular disorders, inflammation, male sexual dysfunction, and elevated serum liver enzyme levels. The term "gastrointestinal toxicities" includes, but is not limited to, gastric and intestinal erosions and ulcers. The term "renal toxicity" includes, but is not limited to, conditions such as papillary necrosis and chronic interstitial nephritis.

As used herein, and unless otherwise stated, the phrases "reduce or avoid adverse effects" and "that reduce or avoid adverse effects" mean the reduction in the severity of one or more adverse effects, as defined in this document.

It should be noted that if there is a discrepancy between a represented structure and a name given to that structure, more weight is given to the represented structure. Furthermore, if the stereochemistry of a structure or a portion of a structure is not indicated, for example, by bold or dashed lines, the structure or portion of the structure should be interpreted to include all of its stereoisomers.

As used herein, and unless otherwise specified, the terms "solid form" and related terms refer to a physical form that is not predominantly in a liquid or gaseous state. As used herein and, unless otherwise specified, the term "solid form" and related terms, when used herein to refer to Compound A, refer to a physical form comprising the Compound A that is not predominantly in a liquid or gaseous state. Solid forms can be crystalline, amorphous, or mixtures thereof. In particular embodiments, the solid forms can be liquid crystals. A "single component" solid form comprising Compound A consists essentially of Compound A. A "multiple component" solid form comprising Compound A comprises a significant amount of one or more additional species, such as ions and / or molecules inside the solid form. For example, in particular embodiments, a multi-component crystalline solid form comprising Compound A further comprises one or more non-covalently linked species at regular positions in the crystal lattice. Multicomponent solid forms comprising Compound A include co-crystals, solvates (eg, hydrates) and clathrates of Compound A. In particular embodiments, the term "solid form comprising Compound A" and related terms include solid component forms single and multiple components comprising Compound A. In particular embodiments, "solid forms comprising Compound A" and related terms, include crystalline forms comprising Compound A, amorphous forms comprising Compound A, and mixtures thereof.

As used herein and, unless otherwise specified, the term "crystalline" and related terms used herein, when used to describe a compound, substance, modification, material, component, or Product, unless otherwise specified, means that the compound, substance, modification, material, component, or product is substantially crystalline as determined by X-ray diffraction. See, for example, Remington: The Science and Practice of Pharmacy. , 21st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23rd ed., 1843-1844 (1995).

As used herein and, unless otherwise specified, the term "crystalline forms", and related terms herein, refer to solid forms that are crystalline. Crystalline forms include single-component crystal forms and multi-component crystal forms, and include, but are not limited to, polymorphs, solvates, hydrates, and / or other molecular complexes. In certain embodiments, a crystalline form of a substance can be substantially free of amorphous and / or other crystalline forms. In certain embodiments, a crystalline form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20 %, 25%, 30%, 35%, 40%, 45% or 50% of one or more amorphous and / or other crystalline forms on a weight basis. In certain embodiments, a crystalline form of a substance can be physically and / or chemically pure. In certain embodiments, a crystalline form of a substance can be approximately 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% physically and / or chemically pure. .

As used herein, and unless otherwise specified, the terms "polymorphs," "polymorphic forms," and related terms herein, refer to two or more crystalline forms consisting of essentially the same molecule. , molecules and / or ions. Like different crystal forms, different polymorphs may have different physical properties such as, for example, melting temperature, heat of fusion, solubility, dissolution properties and / or vibrating spectra, as a result of the arrangement or shaping of the molecules and / or ions in the crystal lattice. Differences in physical properties can affect pharmaceutical parameters, such as storage stability, compressibility and density (important in product formulation and manufacture), and dissolution rate (an important factor in bioavailability). Differences in stability may be the result of changes in chemical reactivity (for example, differential oxidation, such that a dosage form fades more rapidly when it is made up of one polymorph than when it is made up of another polymorph) or mechanical changes (For example, tablets are crumbled in storage as a kinetically favored polymorph becomes a more thermodynamically stable polymorph), or both (for example, tablets of a polymorph are more susceptible to decomposition at high humidity). As a result of solubility / dissolution differences, in the extreme case, some solid state transitions may result in lack of power or, at the other extreme, toxicity. Furthermore, physical properties may be important in processing (for example, a polymorph may be more prone to solvate formation or it may be difficult to filter and wash without impurities, and the shape of the particles and the size distribution may be different between polymorphs).

As used herein, and unless otherwise specified, the terms "solvate" and "solvate" refer to a crystalline form of a solvent-containing substance. The terms "hydrate" and "hydrated" refer to a solvate in which the solvent comprises water. "Solvate polymorphs" refers to the existence of more than one crystal form for a particular solvate composition. Similarly, "hydrate polymorphs" refers to the existence of more than one crystal form for a particular hydrate composition. The term "powdered solvate", as used herein, refers to a crystalline form of a substance that can be prepared by removing the solvent from a solvate.

As used herein, and unless otherwise specified, the term "amorphous,""amorphousform," and related terms used herein, mean that the substance, component, or product in question does not it is substantially crystalline as determined by X-ray diffraction. In particular, the term "amorphous form" describes a disordered solid form, that is, a solid form that lacks a long-range crystalline order. In certain embodiments, an amorphous form of a substance can be substantially free of other amorphous forms and / or crystalline forms. In other embodiments, an amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40 %, 45% or 50% of one or more amorphous and / or crystalline forms on a weight basis. In certain embodiments, an amorphous form of a substance can be physically and / or chemically pure. In certain embodiments, an amorphous form of a substance can be approximately 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% physical and / or chemically pure.

Techniques for characterizing crystalline and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, vibrational spectroscopy, for example, Raman and infrared (IR) spectroscopy, solution and solid state nuclear magnetic resonance (NMR) spectroscopy, light microscopy, hot stage light microscopy, scanning electron microscopy (SEM), electron crystallography, and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility measurements, dissolution measurements, elemental analysis and Karl Fischer analysis. The characteristic parameters of the unit cells can be determined using one or more techniques such as, but not limited to, X-ray diffraction and neutron diffraction, including single crystal diffraction and powder diffraction. Useful techniques for analyzing powder diffraction data include profile refinement, such as Rietveld refinement, which can be used, for example, to analyze diffraction peaks associated with a single phase in a sample comprising more than one phase. solid. Other useful methods for analyzing powder diffraction data include unit cell indexing, which enables a person skilled in the art to determine unit cell parameters from a sample comprising crystalline powder.

As used herein and, unless otherwise specified, the term "approximately", when used in conjunction with a numeric value or range of values that is provided to characterize a particular solid form, eg a specific temperature or temperature range, such as, for example, that which describes a thermal event by DSC or TGA, including, for example, melting, dehydration, desolvation, or glass transition events; a change in mass, such as, for example, a change in mass as a function of temperature or humidity; a solvent or water content, in terms of, for example, mass or a percentage; or a peak position, such as, for example, in IR or Raman or XRPD spectroscopy analysis; indicate that the value or range of values may deviate to an extent deemed reasonable to one skilled in the art while describing the particular solid form. For example, in particular embodiments, the term "approximately", when used in this context and, unless otherwise specified, indicates that the numerical value or range of values may vary within 25%, 20%, 15% , 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the value or range of mentioned values.

As used herein and, unless otherwise specified, a sample comprising a particular crystalline form or an amorphous form that is "substantially pure", eg, substantially free of other solid forms and / or other chemical compounds, contains, in particular embodiments, less than about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, 0.75%, 0.5%, 0.25% or 0.1% weight percent of one or more solid forms and / or other chemical compounds.

As used herein and, unless otherwise specified, a sample or composition that is "substantially free" of one or more solid forms and / or other chemical compounds means that the composition contains, in particular embodiments, less of about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5 %, 0.25%, or 0.1% weight percent of one or more solid forms and / or other chemical compounds.

As used herein, and unless otherwise indicated, the terms "treat", "treating" and "treatment" refer to the eradication or improvement of a disease or disorder, or of one or more associated symptoms with the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a patient with such disease or disorder. In some embodiments, the terms refer to the administration of a compound provided herein, with or without another additional active agent, after the onset of symptoms of the particular disease.

As used herein, and unless otherwise specified, the terms "prevent," "preventing," and "prevention" refer to preventing the onset, recurrence, or spread of a disease or disorder, or of one. or more symptoms of it. In certain embodiments, the terms refer to treatment with or administration of a compound provided herein, with or without another additional active compound, prior to the onset of symptoms, particularly to patients at risk for diseases or disorders provided therein. present document. Terms include inhibition or reduction of a particular disease symptom. Patients with a family history of a particular disease are candidates for preventive regimens in certain embodiments. Furthermore, patients with a history of recurring symptoms are also potential candidates for prevention. In this regard, the term "prevention" can be used interchangeably with the term "prophylactic treatment".

As used herein, and unless otherwise specified, the terms "manage,""manage," and "manage" refer to preventing or delaying the advancement, spread, or worsening of a disease or disorder, or of one or more symptoms of it. Often the beneficial effects a patient obtains from a prophylactic and / or therapeutic agent do not result in a cure for the disease or disorder. In this regard, the term "management" includes the treatment of a patient who has suffered from the particular disease in an attempt to prevent or minimize the recurrence of the disease.

As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment or management of the disease or disorder. The term "therapeutically effective amount" can include an amount that improves overall therapy, reduces or avoids the symptoms or causes of the disease or disorder, or increases the therapeutic efficacy of another therapeutic agent.

As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or disorder, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, that provides prophylactic benefit in preventing disease. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or improves the prophylactic efficacy of another prophylactic agent.

The term "composition" as used herein, is intended to include a product that comprises the specified ingredients (and in the specified amounts, if indicated), as well as any product that is the result, directly or indirectly, of the combination of the specified ingredients in the specified quantities. By "pharmaceutically acceptable" is meant that the diluent, excipient, or vehicle must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

4. Detailed description of the invention

This invention relates to Form C of the stereomerically pure Compound A, which is the (+) enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3- dione, substantially free of its (-) enantiomer, as well as novel methods of use, and compositions comprising Form C of Stereomerically pure Compound A and / or solid forms comprising Form C of Compound A. For example, the present Invention includes the in vitro and in vivo use of Form C of Compound A, and the incorporation of Form C of Compound A in pharmaceutical compositions and single unit dosage forms, useful in the treatment and prevention of a variety of diseases and disorders. Diseases and disorders that are ameliorated by lowering TNF-a levels or inhibiting PDE4 are well known in the art and are described herein. The specific methods of the invention reduce or avoid the adverse effects associated with compounds used as TNF-a inhibitors. Other specific methods of the invention reduce or avoid the adverse effects associated with the use of racemic 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione.

Specific methods of the invention include methods of treating or preventing diseases and disorders, including, but not limited to, solid tumors, blood-borne tumors, and inflammatory diseases.

Dosage and dosage forms of the invention, comprising Form C of Compound A or a pharmaceutically acceptable polymorph, prodrug, clathrate, solvate, or hydrate thereof (where particular embodiments include solid forms comprising Compound A as described in herein) can be used in the methods of the invention.

Without being limited by theory, it is believed that Compound A, which includes solid forms comprising Compound A, can inhibit TNF-a production. Accordingly, a first aspect of the invention relates to a method of inhibiting TNF-a production comprising contacting a cell displaying abnormal TNF-a production with an effective amount of Form C of Compound A stereomerically neat, or a pharmaceutically acceptable prodrug, metabolite, solvate, hydrate, or clathrate thereof (where particular embodiments include solid forms comprising Compound A as described herein). In a particular embodiment, the invention relates to a method of inhibiting TNF-a production comprising contacting a mammalian cell displaying abnormal production of TNF-a with an effective amount of Form C of Compound A stereomerically neat, or a pharmaceutically acceptable prodrug, metabolite, solvate, hydrate, or clathrate thereof (where particular embodiments include solid forms comprising Compound A as described herein).

The invention also relates to Form C for use in the treatment, prevention or management of disorders that improve with the reduction of TNF-a levels in a patient, comprising administering to a patient in need of such treatment or prevention, a therapeutically or prophylactically effective amount of Form C of the stereomerically pure Compound A or a pharmaceutically acceptable polymorph, salt, solvate or hydrate thereof (where the particular embodiments include solid forms comprising Compound A as described herein). In particular embodiments, diseases or disorders that are ameliorated by inhibition of mammalian TNF-a production include, but are not limited to: HIV; hepatitis; adult respiratory distress syndrome; bone resorption diseases; chronic obstructive pulmonary diseases; diseases chronic lung inflammations; asthma; dermatitis; cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; postischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection; autoimmune disease; rheumatoid spondylitis; arthritic conditions, such as psoriatic arthritis, rheumatoid arthritis, and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lupus erythematosus; cutaneous lupus erythematosus; pulmonary sarcoidosis; erythema nodosum leprosum (ENL) in leprosy; radiation damage; asthma; and alveolar injury from hyperoxia. Such disorders also include, but are not limited to, cancers, including, but not limited to, head, thyroid, neck, eye, skin, mouth, throat, esophagus, chest, bone, blood, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart, adrenal, subcutaneous tissue, lymph nodes, heart, and combinations thereof. Specific cancers that can be treated by this method are multiple myeloma, malignant melanoma, malignant glioma, leukemia, and solid tumors.

A further embodiment of the invention relates to Form C for use in a method of treating or preventing cancer, including, but not limited to, solid tumor, blood-borne tumor, leukemias, and in particular, multiple myeloma in a patient comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of the stereomerically pure Compound A Form C or a pharmaceutically acceptable prodrug, metabolite, solvate, hydrate or clathrate thereof (where the particular embodiments include solid forms comprising Form C of Compound A as described herein); in particular, when the patient is a mammal.

In another embodiment, the invention relates to Form C for use in a method of inhibiting PDE4 comprising contacting PDE4 in a cell (eg, a mammalian cell) with an effective amount of Form C of Compound A stereomerically pure or a pharmaceutically acceptable prodrug, metabolite, solvate, hydrate, or clathrate thereof (where particular embodiments include solid forms comprising Form C of Compound A as described herein).

A further embodiment of the invention relates to Form C for use in a method of treating or preventing diseases or disorders that are ameliorated by PDE4 inhibition in a patient comprising administering to a patient in need of such treatment or prevention an amount therapeutically or prophylactically effective Form C of stereomerically pure Compound A or a pharmaceutically acceptable prodrug, metabolite, solvate, hydrate or clathrate thereof (where particular embodiments include solid forms comprising Form C of Compound A as described herein document). Disorders enhanced by PDE4 inhibition include, but are not limited to, asthma, inflammation (eg, inflammation due to reperfusion), acute or chronic obstructive pulmonary disease, chronic inflammatory lung disease, inflammatory bowel disease, Crohn's disease, Behcet's disease or colitis.

In another embodiment, the invention relates to Form C for use in a method of controlling cAMP levels in a cell comprising contacting a cell with an effective amount of Form C of stereomerically pure Compound A or a prodrug. , metabolite, solvate, hydrate or pharmaceutically acceptable clathrate thereof (where particular embodiments include solid forms comprising Form C of Compound A as described herein). As used herein, the term "controlling cAMP levels" includes preventing or reducing the degradation rate of 3 ', 5'-cyclic adenosine monophosphate (cAMP) in a cell, or increasing the amount of adenosine monophosphate 3 ', 5'-cyclic present in a cell, preferably a mammalian cell, more preferably a human cell. In a particular method, the rate of cAMP degradation is reduced by approximately 10, 25, 50, 100, 200 or 500 percent, compared to the rate in comparable cells that have not been contacted with a compound of the invention.

A further embodiment of the invention relates to Form C for use in a method of treating or preventing depression, asthma, inflammation (eg, contact dermatitis, atopic dermatitis, psoriasis, rheumatoid arthritis, osteoarthritis, inflammatory skin disease, inflammation due to reperfusion), chronic or acute obstructive pulmonary diseases, chronic inflammatory or pulmonary diseases, inflammatory bowel disease, Crohn's disease, Behcet's disease or colitis in a patient, comprising administering to a patient in need of such treatment or prevention, a therapeutically or prophylactically effective amount of stereomerically pure Form C of Compound A or a pharmaceutically acceptable prodrug, metabolite, solvate, hydrate, or clathrate thereof (where particular embodiments include solid forms comprising Form C of Compound A as described in This document); in particular, when the patient is a mammal.

A separate embodiment of the invention includes Form C for use in methods of treating or preventing myelodysplastic syndrome (MDS) which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of the stereomerically pure Form C of the Compound A or a pharmaceutically acceptable solvate, hydrate, clathrate, or prodrug thereof (where the particular embodiments include solid forms comprising Form C of Compound A as described herein). MDS refers to a diverse group of hematopoietic stem cell disorders. MDS is characterized by a cellular marrow with impaired morphology and maturation (dysmyelopoiesis), peripheral blood cytopenias, and a variable risk of progression to acute leukemia, which is the result of ineffective production of blood cells. See The Merck Manual 953 (17th ed. 1999) and List et al., 1990, J. Clin. Oncol. 8: 1424.

A separate embodiment of the invention includes Form C for use in methods for treating or preventing myeloproliferative disease (MPD) which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of Form C of the Stereomerically pure Compound A or a pharmaceutically acceptable solvate, hydrate, clathrate or prodrug thereof (where the particular embodiments include solid forms comprising Form C of Compound A as described herein). A myeloproliferative disease (MPD) refers to a group of disorders characterized by clonal abnormalities of the hematopoietic stem cell. See, for example, Current Medical Diagnosis & Treatment, pgs. 499 (37th ed., Tierney et al., Ed., Appleton & Lange, 1998).

The invention also includes Form C for use in a method of treatment, prevention or management of pain, including, but not limited to, complex regional pain syndrome, which comprises administering to a patient in need of such treatment, prevention or management, a therapeutically or prophylactically effective amount of a stereomerically pure Form C of Compound A or a pharmaceutically acceptable solvate, hydrate, clathrate or prodrug thereof (where the particular embodiments include solid forms comprising Form C of Compound A as described herein document). In a specific embodiment, administration is before, during, or after surgery or physical therapy aimed at reducing or avoiding a symptom of complex regional pain syndrome in the patient.

In particular methods of the invention, Form C of stereomerically pure Compound A or a pharmaceutically acceptable prodrug, solvate, hydrate or clathrate thereof (where particular embodiments include solid forms comprising Form C of Compound A as described herein document), is co-administered with at least one additional therapeutic agent. Examples of additional therapeutic agents include, but are not limited to, anticancer drugs, anti-inflammatories, antihistamines, and decongestants.

4.1. Solid forms comprising compound A

Certain embodiments herein provide solid forms comprising Compound A, which has the chemical structure shown above. Racemic 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione is readily prepared using the methods of US Patent No. 6,020,358. Compound A, which is the (+) enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione, can be prepared according to any obvious method for Skilled in the art, including the methods described in US Patent No. 6,962,940.

Solid forms comprising Compound A include single component and multiple component forms, including crystalline forms and amorphous forms, and including, but not limited to, polymorphs, solvates, hydrates, co-crystals and clathrates where each of said solid forms according to the invention and discussed herein below comprises Form C. The particular embodiments herein provide single component amorphous solid forms of Compound A. The particular embodiments herein provide single component crystalline solid forms of Compound A. Particular embodiments herein provide multi-component crystalline solid forms comprising Compound A. The multi-component solid forms provided herein include solid forms which can be described by the terms salt, co-crystal, hydrate, solvate. , clathrate and / or polymorphic, and include solid forms that can be described by one or more of these terms.

Solid forms comprising Compound A can be prepared by the methods described herein, including the methods described in the Examples below, or by techniques known in the art, including heating, cooling, freeze-drying, lyophilization, annealing. melting, rapid solvent evaporation, slow solvent evaporation, solvent recrystallization, addition of antisolvent, suspension recrystallization, fusion crystallization, desolvation, recrystallization in confined spaces such as, for example, in nanopores or capillaries, surface recrystallization or templates such as, for example, in polymers, recrystallization in the presence of additives, such as, for example, counter-crystal molecules, desolvation, dehydration, rapid cooling, slow cooling, exposure to solvent and / or water, drying, including eg vacuum drying, diffu steam, sublimation, grinding (including, for example, cryogenic grinding, solvent drip grinding, or liquid-assisted grinding), microwave-induced precipitation, sonication-induced precipitation, laser-induced precipitation, and precipitation of a supercritical fluid. The particle size of the resulting solid forms, which can vary (for example, from nanometric to millimeter dimensions), can be controlled, for example, by varying crystallization conditions, such as, for example, the crystallization rate and / or the crystallization solvent system, or by particle size reduction techniques, eg, grinding, milling, micronization, or sonication.

Although not intended to be bound by any particular theory, certain solid forms are characterized by physical properties, eg, stability, solubility, and rate of dissolution, appropriate for pharmaceutical and therapeutic dosage forms. Furthermore, although without wishing to be linked to any particular theory, Certain solid forms are characterized by physical properties (eg, density, compressibility, hardness, morphology, cleavage, adhesion, solubility, water absorption, electrical properties, thermal behavior, solid state reactivity, physical stability, and chemical stability) that affect Particular processes (eg, throughput, filtration, washing, drying, milling, blending, tabletting, flowability, dissolving, formulating, and lyophilizing) that make certain solid forms suitable for the manufacture of a solid dosage form. Such properties can be determined using particular analytical chemical techniques, including solid state analytical techniques (eg, X-ray diffraction, microscopy, spectroscopy, and thermal analysis), as described herein and known in the art.

Certain embodiments herein provide compositions comprising one or more of the solid forms. Certain embodiments provide compositions of one or more solid forms in combination with other active ingredients. Certain embodiments provide methods for using these compositions in the treatment, prevention, or management of diseases and disorders including, but not limited to, the diseases and disorders provided herein.

In addition to the solid forms comprising Compound A, solid forms comprising prodrugs of Compound A are provided herein.

The solid forms provided herein can also comprise unnatural proportions of atomic isotopes at one or more of the atoms in Compound A. For example, the compound can be radiolabeled with radioactive isotopes, such as, for example, tritium (3H ), iodine-125 (125I) sulfur-35 (35S), or carbon-14 (14C). Radiolabelled compounds are useful as therapeutic agents, eg, cancer therapeutics, research reagents, eg, binding assay reagents, and diagnostic agents, eg, in vivo imaging agents. All isotopic variations of Compound A, whether radioactive or not, are intended to be included within the scope of the embodiments provided herein.

4.1.1. Form A of Compound A

Certain embodiments herein provide Form A crystalline form of Compound A. In certain embodiments, Form A of Compound A can be obtained from various solvents, including, but not limited to, solvent systems comprising acetone, ethanol, and mixtures thereof. In certain embodiments, Form A can be obtained using a rapid cooling crystallization process.

In certain embodiments, Form A of Compound A can be characterized by X-ray powder diffraction analysis. A representative XRPD pattern is provided for Form A of Compound A in Fig. 1. In certain embodiments, Form A of Compound A is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve of the following approximate positions: 8.1, 14.4, 15.2, 17 , 4, 18.4, 19.2, 20.5, 22.8, 23.2 23.6, 24.5, 25.1 degrees 20. In certain embodiments, Form A of Compound A is characterized by a XRPD pattern that matches the pattern shown in Fig. 1. In certain embodiments, Form A of Compound A is characterized by an XRPD pattern that has 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks that match the peaks in the representative pattern of Form A provided herein .

In certain embodiments, Form A of Compound A can be characterized by thermal analysis. A representative DSC graph for Form A of Compound A is shown in Fig. 2. In certain embodiments, Form A is characterized by a DSC graph comprising an endothermic event with an onset temperature of approximately 145 ° C. In certain embodiments, Form A is characterized by a DSC graph further comprising an endothermic event with an onset temperature of approximately 155 ° C. A representative TGA graph for Form A of Compound A is shown in Fig. 3. In certain embodiments, Form A is characterized by a TGA graph comprising a loss of mass of less than about 1%, for example , approximately 0.05%, of the total mass of the sample after heating from approximately 25 ° C to approximately 140 ° C. In certain embodiments, Form A of Compound A does not contain substantial amounts of water or other solvent in the crystal lattice. In certain embodiments, Form A is not solvated. In certain embodiments, Form A is anhydrous.

In certain embodiments, Form A of Compound A can be characterized by moisture absorption analysis. A representative graph of moisture absorption isotherms is shown in Fig. 4. In certain embodiments, when the relative humidity ("RH") increases from about 0% to about 95% RH, Form A exhibits a change by mass of less than about 1%, for example, about 0.4%, of the initial mass of the sample. In certain embodiments, the mass gained after adsorption is lost when the RH is again lowered to approximately 0% RH. Accordingly, in certain embodiments, Form A is substantially non-hygroscopic. In certain embodiments, the XRPD pattern of the Form A material does not change substantially after adsorption / desorption analysis. In certain embodiments, Form A is stable with respect to humidity.

In certain embodiments, Form A of Compound A can be characterized by its stability profile. In certain embodiments, the Form A material is stable, for example, its XRPD pattern remains substantially unchanged, after exposure to elevated temperature, after exposure to high humidity, after exposure to one or more solvents, and / or after compression. In certain embodiments, for example, Form A is stable after exposure to an environment of about 40 ° C and about 75% RH environment for about four weeks. In certain embodiments, Form A is stable after exposure to one or more solvent systems comprising, for example, ethanol, water, and / or heptane, at about 40 ° C for at least about four weeks. In certain embodiments, Form A is converted to Form C of Compound A upon exposure to a solvent including, but not limited to, toluene for four weeks. In certain embodiments, Form A is stable upon compression at approximately 2000 psi pressure for approximately one minute.

In certain embodiments, Form A of Compound A can be characterized by particle analysis. In certain embodiments, Form A is characterized as a white powder. In certain embodiments, a Form A sample comprises particles that have a plate-like morphology. In certain embodiments, a sample of Form A comprises particles with a Dgo of less than about 18 pm. (As used herein, the Dgo value represents the 90th percentile of the particle size distribution measured by length; that is, 90% of the particles have a length of this value or less.)

Certain embodiments herein provide Form A as a mixture of solid forms comprising Compound A, including, for example, a mixture comprising Form C and optionally one or more of the following: Forms B, D, E, F, G and an amorphous solid form comprising Compound A as provided herein.

4.1.2. Form B of Compound A

Certain embodiments herein provide Form B crystalline form of Compound A. In certain embodiments, Form B of Compound A can be obtained from various solvents, including, but not limited to, solvent systems comprising 2-propanol, acetone , acetonitrile, ethanol, ethyl acetate, heptane, methanol, methyl ethyl ketone, methyl t-butyl ether, methylene chloride, n-butanol, n-butyl acetate, tetrahydrofuran, toluene, water, and mixtures comprising two or more of the same. For example, in certain embodiments, Form B can be obtained by crystallization from a solvent system comprising 1: 1 ethanol: water, for example, by a process comprising evaporation of the 1: 1 solvent system from ethanol: water at about 25 ° C followed by isolation of Form B. For example, in certain embodiments, Form B can be obtained by crystallization from a solvent system comprising 1: 1 acetone: ethanol, for example, by a process comprising suspending a solid form comprising Compound A in acetone: ethanol 1: 1 at approximately 25 ° C for approximately 2 days, followed by isolation of Form B.

In certain embodiments, Form B of Compound A can be characterized by X-ray powder diffraction analysis. A representative XRPD pattern is provided for Form B of Compound A in Fig. 5. In certain embodiments, Form B of Compound A is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve of the following approximate positions: 10.1, 12.4, 13.5, 15 , 7, 16.3, 18,1,20,7, 22,5, 24,7, 26,2, 26,9, 29,1 degrees 20. In certain embodiments, Form B of Compound A is characterized by an XRPD pattern that matches the pattern shown in Fig. 5. In certain embodiments, Form B of Compound A is characterized by an XRPD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks that match the peaks in the representative pattern of Form B provided herein document.

In certain embodiments, Form B of Compound A can be characterized by thermal analysis. A representative DSC graph for Form B of Compound A is shown in Fig. 6. In certain embodiments, Form B is characterized by a DSC graph comprising an endothermic event with an onset temperature of approximately 154 ° C. A representative TGA graph for Form B of Compound A is shown in Fig. 7. In certain embodiments, Form B is characterized by a TGA graph comprising a loss of mass of less than about 1%, for example , about 0.25%, of the total mass of the sample after heating from about 25 ° C to about 140 ° C. In certain embodiments, Form B of Compound A does not contain substantial amounts of water or other solvent in the crystal lattice. In certain embodiments, Form B is anhydrous. In certain embodiments, Form B is not solvated.

In certain embodiments, Form B of Compound A can be characterized by moisture absorption analysis. A representative graph of moisture absorption isotherms is shown in Fig. 8. In certain embodiments, when the h R increases from about 0% to about 95% RH, Form B exhibits a mass change of less than about 1%, for example, about 0.6%, of the initial mass of the sample. In certain embodiments, the mass gained after adsorption is lost when the RH is again lowered to approximately 0% RH. In certain embodiments, Form B is substantially non-hygroscopic. In certain embodiments, the XRPD pattern of the Form B material does not change substantially after analysis of adsorption / desorption. In certain embodiments, Form B is moisture stable.

In certain embodiments, Form B of Compound A can be characterized by its stability profile. In certain embodiments, the Form B material is stable, for example, its XRPD pattern remains substantially unchanged, after exposure to elevated temperature, after exposure to high humidity, after exposure to one or more solvents, and / or after compression. In certain embodiments, for example, Form B is stable after exposure to an environment of about 40 ° C and about 75% RH environment for about four weeks. In certain embodiments, Form B is stable after exposure to a solvent system comprising, for example, ethanol, water, or heptane, at about 40 ° C for at least about four weeks. In certain embodiments, Form B is converted to Form C of Compound A upon exposure to a solvent system comprising, for example, toluene for approximately four weeks. In certain embodiments, Form B is stable upon compression at approximately 2000 psi pressure for approximately one minute.

In certain embodiments, Form B of Compound A can be characterized by particle analysis. In certain embodiments, Form B is characterized as a white powder. In certain embodiments, a Form B sample comprises particles that have a flake-like morphology. In certain embodiments, a Form B sample comprises particles with a D ⁹⁰ of less than about 12 pm.

Certain embodiments herein provide Form B as a mixture of solid forms comprising Compound A, including, for example, a mixture comprising Form C and optionally one or more of the following: Forms A, D, E, F, G and an amorphous solid form comprising Compound A as provided herein.

4.1.3. Form C of Compound A

Certain embodiments herein provide the Form C crystalline form of Compound A. In certain embodiments, Form C of Compound A can be obtained from various solvent systems, including, but not limited to, solvent systems comprising acetone, acetonitrile , ethanol, heptane, methanol, methyl ethyl ketone, tetrahydrofuran, toluene, water, and mixtures comprising two or more thereof. For example, in certain embodiments, Form C can be obtained by crystallization from a solvent system comprising toluene, for example, by a process comprising the use of toluene as an antisolvent, followed by isolation of Form C.

In certain embodiments, Form C of Compound A can be characterized by X-ray powder diffraction analysis. An XRPD pattern representative of Form C of Compound A is provided in Fig. 9. In certain embodiments, Form C of Compound A is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve of the following approximate positions: 7.5, 11.3, 15.3, 16 , 4, 17.8, 21.4, 22.6, 23.5, 24.8, 25.5, 26.4, 27.6 degrees 20. In certain embodiments, Form C of Compound A is characterized by an XRPD pattern that matches the pattern shown in Fig. 9. In certain embodiments, Form C of Compound A is characterized by an XRPD pattern that has 1,2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks that match the peaks in the representative pattern of Form C provided herein document.

In certain embodiments, Form C of Compound A can be characterized by thermal analysis. A representative DSC graph for Form C of Compound A is shown in Fig. 10. In certain embodiments, Form C is characterized by a DSC graph comprising an endothermic event with an onset temperature of approximately 138 ° C. In certain embodiments, a characteristic Form C DSC graph further comprises one or more additional events, such as, for example, an endothermic event with an onset temperature of approximately 166 ° C. A representative TGA graph for Form C of Compound A is shown in Fig. 11. In certain embodiments, Form C is characterized by a TGA graph comprising a loss of mass of less than about 10%, for example , approximately 5.9%, of the total mass of the sample after heating from approximately 25 ° C to approximately 140 ° C. In certain embodiments, the TGA mass loss event comprises loss of toluene solvent, as indicated, for example, by TG-IR analysis. In certain embodiments, Form C of Compound A is solvated. In certain embodiments, Form C is a toluene solvate. In certain embodiments, the Form C crystal lattice comprises approximately three molar equivalents of toluene per mole of Compound A.

In certain embodiments, Form C of Compound A can be characterized by moisture absorption analysis. A representative graph of moisture absorption isotherms is shown in Fig. 12. In certain embodiments, when the RH increases from about 0% to about 95% RH, Form C exhibits a mass change of less than about 1%, for example, about 0.5%, of the initial mass of the sample. In certain embodiments, the mass gained after adsorption is lost when the RH is again lowered to approximately 0% RH. In certain embodiments, Form C is substantially non-hygroscopic. In certain embodiments, the XRPD pattern of the Form C material does not change substantially after adsorption / desorption analysis. In certain embodiments, Form C is moisture stable.

In certain embodiments, Form C of Compound A can be characterized by its stability profile. In certain embodiments, the Form C material is stable, for example, its XRPD pattern remains substantially unchanged, after exposure to elevated temperature, after exposure to high humidity, after exposure to one or more solvents, and / or after compression. In certain embodiments, for example, Form C is stable after exposure to an environment of about 40 ° C and about 75% RH environment for about four weeks. In certain embodiments, Form C is stable after exposure to a solvent system comprising, for example, ethanol, water, heptane, or toluene, at about 40 ° C for at least about four weeks. In certain embodiments, Form C is stable upon compression at approximately 2000 psi pressure for approximately one minute.

In certain embodiments, Form C of Compound A can be characterized by particle analysis. In certain embodiments, Form C is characterized as a white powder. In certain embodiments, a Form C sample comprises particles that have a plate-like morphology. In certain embodiments, a Form C sample comprises particles with a D ⁹⁰ of less than about 12 pm.

Certain embodiments herein provide Form C of Compound A which is substantially pure. Certain embodiments herein provide Form C of Compound A which is substantially free of other solid forms comprising Compound A including, for example, Forms A, B, D, E, F, G and / or a form amorphous solid comprising Compound A as provided herein. Certain embodiments herein provide Form C as a mixture of solid forms comprising Compound A, including, for example, a mixture comprising one or more of the following: Forms A, B, D, E, F, G and an amorphous solid form comprising Compound A as provided herein.

4.1.4. Form D of Compound A

Certain embodiments herein provide the Form D crystalline form of Compound A. In certain embodiments, Form D of Compound A can be obtained from various solvents, including, but not limited to, solvent systems comprising methylene chloride. For example, in certain embodiments, Form D can be obtained by crystallization from a solvent system comprising methylene chloride, for example, by a process comprising evaporation of methylene chloride, followed by isolation of Form D.

In certain embodiments, Form D of Compound A can be characterized by X-ray powder diffraction analysis. An XRPD pattern representative of Form D of Compound A is provided in Fig. 13. In certain embodiments, Form D of Compound A is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve of the following approximate positions: 7.5, 9.6, 11.3, 13 , 9, 16.3, 17.7, 20.5, 23.2, 24.6, 25.2, 26.0, 28.8 degrees 20. In certain embodiments, Form D of Compound A is characterized by an XRPD pattern that matches the pattern shown in Fig. 13. In certain embodiments, Form D of Compound A is characterized by an XRPD pattern that has 1,2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks that match the peaks in the representative pattern of Form D provided herein document.

In certain embodiments, Form D of Compound A can be characterized by thermal analysis. A representative DSC graph for Form D of Compound A is shown in Fig. 14. In certain embodiments, Form D is characterized by a DSC graph comprising an endothermic event with an onset temperature of approximately 100 ° C. A representative TGA graph for Form D of Compound A is shown in Fig. 15. In certain embodiments, Form D is characterized by a TGA graph comprising a loss of mass of less than about 10%, for example , about 6.5%, of the total mass of the sample after heating from about 25 ° C to about 110 ° C. In certain embodiments, the TGA mass loss event comprises loss of the toluene chloride solvent (i.e., dichloromethane), as indicated, for example, by G-IR t-analysis. In certain embodiments, Form D of Compound A is solvated. In certain embodiments, Form D is a methylene chloride solvate. In certain embodiments, the Form D crystal lattice comprises approximately 2.5 molar equivalents of methylene chloride per mole of Compound A.

In certain embodiments, Form D of Compound A can be characterized by moisture absorption analysis. A representative graph of moisture absorption isotherms is shown in Fig. 16. In certain embodiments, when the h R increases from about 0% to about 95% RH, Form D exhibits a mass change of less than about 3%, for example, about 1.5%, of the initial mass of the sample. In certain embodiments, the mass gained after adsorption is lost when the RH is again lowered to approximately 0% RH. Accordingly, in certain embodiments, Form D is slightly hygroscopic. In certain embodiments, the XRPD pattern of the Form D material does not change substantially after adsorption / desorption analysis. In certain embodiments, Form D is moisture stable.

In certain embodiments, Form D of Compound A can be characterized by its stability profile. In certain embodiments, the Form D material is stable, for example, its XRPD pattern remains substantially unchanged, after compression. For example, in certain embodiments, Form D is stable upon compression at approximately 2000 psi pressure for approximately one minute. In certain embodiments, Form D is stable upon exposure to an environment of approximately 40 ° C and approximately 75% RH environment for approximately four weeks, although, in certain embodiments, the peak intensity resulting from the Form XRPD pattern D is reduced. In certain embodiments, this reduction in the peak intensity of XRPD results from the formation of amorphous material comprising Compound A. In certain embodiments, Form D becomes Form B of Compound A upon exposure to a solvent system. comprising, for example, heptane, ethanol, and / or water at about 40 ° C for about four weeks. In certain embodiments, Form D is converted to Form C of Compound A upon exposure to a solvent system comprising toluene at approximately 40 ° C for approximately four weeks.

In certain embodiments, Form D of Compound A can be characterized by particle analysis. In certain embodiments, Form D is characterized as a white powder. In certain embodiments, a Form D sample comprises particles that have a flake-like morphology. In certain embodiments, a Form D sample comprises particles with a D ⁹⁰ of less than about 18 pm.

Certain embodiments herein provide Form D as a mixture of solid forms comprising Compound A, including, for example, a mixture comprising Form C and optionally one or more of the following: Forms A, B, E, F, G and an amorphous solid form comprising Compound A as provided herein.

4.1.5. Form E of Compound A

Certain embodiments herein provide the Form E crystalline form of Compound A. In certain embodiments, Form E of Compound A can be obtained from various solvents, including, but not limited to, solvent systems comprising acetone, acetonitrile, heptane , methylene chloride and mixtures comprising two or more of them. For example, in certain embodiments, Form E can be obtained by crystallization from a solvent system comprising acetonitrile, for example, by a process comprising evaporation of acetonitrile, followed by isolation of Form E.

In certain embodiments, Form E of Compound A can be characterized by X-ray powder diffraction analysis. A representative XRPD pattern is provided for Form E of Compound A in Fig. 17. In certain embodiments, Form E of Compound A is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve of the following approximate positions: 7.6, 9.2, 11.4, 15 , 5, 16.5, 17.9, 19.6, 20.5, 21.6, 22.8, 23.8, 26.6 degrees 20. In certain embodiments, Form E of Compound A is characterized by an XRPD pattern that matches the pattern shown in Fig. 17. In certain embodiments, Form E of Compound A is characterized by an XRPD pattern that has 1,2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks that match the peaks in the representative pattern of Form E provided herein document.

In certain embodiments, Form E of Compound A can be characterized by thermal analysis. A representative DSC graph for Form E of Compound A is shown in Fig. 18. In certain embodiments, Form E is characterized by a DSC graph comprising an endothermic event with an onset temperature of approximately 95 ° C. A representative TGA graph for Form E of Compound A is shown in Fig. 19. In certain embodiments, Form E is characterized by a TGA graph comprising a loss of mass of less than about 8%, for example , about 4.0%, of the total mass of the sample after heating from about 25 ° C to about 110 ° C. In certain embodiments, the TGA mass loss event comprises loss of the acetonitrile solvent, as indicated, for example, by TG-IR analysis. In certain embodiments, Form E of Compound A is solvated. In certain embodiments, Form E is an acetonitrile solvate. In certain embodiments, the Form E crystal lattice comprises approximately 2.5 molar equivalents of acetonitrile per mole of Compound A.

In certain embodiments, Form E of Compound A can be characterized by moisture absorption analysis. A representative graph of moisture absorption isotherms is shown in Fig. 20. In certain embodiments, when the h R increases from about 0% to about 95% RH, Form E exhibits a mass change of less than about 10%, for example, about 5.1%, of the initial mass of the sample. In certain embodiments, the mass gained after adsorption is lost when the RH is again lowered to approximately 0% RH. In certain embodiments, Form E is hygroscopic. In certain embodiments, the XRPD pattern of the Form E material does not change substantially after adsorption / desorption analysis. In certain embodiments, Form E is stable with respect to moisture.

In certain embodiments, Form E of Compound A can be characterized by its stability profile. In certain embodiments, the Form E material is stable, eg, its XRPD pattern remains substantially unchanged upon compression. For example, in certain embodiments, Form E is stable upon compression at approximately 2000 psi pressure for approximately one minute.

In certain embodiments, Form E of Compound A can be characterized by particle analysis. In certain embodiments, Form E is characterized as a white powder. In certain embodiments, a Form E sample comprises particles having a flake-like morphology. In certain embodiments, a Form E sample comprises particles with a Dgo of less than about 18 pm.

Certain embodiments herein provide Form E as a mixture of solid forms comprising Compound A, including, for example, a mixture comprising Form C and optionally one or more of the following: Forms A, B, D, F, G and an amorphous solid form comprising Compound A as provided herein.

4.1.6. Form F of Compound A

Certain embodiments herein provide the Form F crystalline form of Compound A. In certain embodiments, Form F of Compound A can be obtained from various solvents, including, but not limited to, solvent systems comprising acetone, ethane, water and mixtures comprising two or more thereof. For example, in certain embodiments, Form F may be obtained by crystallization from a solvent system comprising ethanol and / or water, for example, by a process comprising contacting a solid form comprising Compound A with a solvent system comprising ethanol and / or water, followed by isolation of Form F.

In certain embodiments, Form F of Compound A can be characterized by X-ray powder diffraction analysis. An XRPD pattern representative of Form F of Compound A is provided in Fig. 21. In certain embodiments, Form F of Compound A is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve of the following approximate positions: 8.1, 8.6, 15.6, 17 , 3, 19.3, 21.4, 22.8, 24.6, 25.4, 25.9, 26.6, 27.7 degrees 20. In certain embodiments, Form F of Compound A is characterized by an XRPD pattern that matches the pattern shown in Fig. 21. In certain embodiments, Form F of Compound A is characterized by an XRPD pattern that has 1,2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks that match the peaks in the representative pattern of Form F provided herein document.

In certain embodiments, Form F of Compound A can be characterized by thermal analysis. A representative DSC graph for Form F of Compound A is shown in Fig. 22. In certain embodiments, Form F is characterized by a DSC graph comprising an endothermic event with an onset temperature of approximately 145 ° C. A representative TGA graph for Form F of Compound A is shown in Fig. 23. In certain embodiments, Form F is characterized by a TGA graph comprising a loss of mass of less than about 1%, for example , about 0.1%, of the total mass of the sample after heating from about 25 ° C to about 180 ° C. In certain embodiments, Form F of Compound A does not contain substantial amounts of water or other solvent in the crystal lattice. In certain embodiments, Form F is not solvated. In certain embodiments, Form F is anhydrous.

In certain embodiments, Form F of Compound A can be characterized by moisture absorption analysis. A representative graph of moisture absorption isotherms is shown in Fig. 24. In certain embodiments, when the h R increases from about 0% to about 95% RH, Form F exhibits a mass change of less than about 1%, eg about 0.2%, of the initial mass of the sample. In certain embodiments, the mass gained after adsorption is lost when the RH is again lowered to approximately 0% RH. In certain embodiments, Form F is substantially non-hygroscopic. In certain embodiments, the XRPD pattern of the Form F material does not change substantially after adsorption / desorption analysis. In certain embodiments, Form F is stable with respect to humidity.

In certain embodiments, Form F of Compound A can be characterized by its stability profile. In certain embodiments, the Form F material is stable, eg, its XRPD pattern remains substantially unchanged upon compression. For example, in certain embodiments, Form F is stable upon compression at approximately 2000 psi pressure for approximately one minute. In certain embodiments, Form F is stable upon exposure to a solvent system comprising, for example, ethanol, acetone, or mixtures thereof, for approximately two days at approximately 25 ° C.

In certain embodiments, Form F of Compound A can be characterized by particle analysis. In certain embodiments, Form F is characterized as a white powder. In certain embodiments, a Form F sample comprises particles that have a flake-like morphology. In certain embodiments, a sample of Form F comprises particles with a D ⁹⁰ of less than about 18 pm.

Certain embodiments herein provide Form F as a mixture of solid forms comprising Compound A, including, for example, a mixture comprising Form C and optionally one or more of the following: Forms A, B, D, E, G and an amorphous solid form comprising Compound A as provided herein.

4.1.7. Form G of Compound A

Certain embodiments herein provide the Form G crystalline form of Compound A. In certain embodiments, Form G of Compound A can be obtained from various solvents, including, but not limited to, solvent systems comprising ethyl acetate. For example, in certain embodiments, Form G may be obtained by crystallization from a solvent system comprising ethyl acetate, for example, by a process comprising contacting a solid form comprising Compound A with a system of Solvents comprising ethyl acetate, followed by isolation of Form G.

In certain embodiments, Form G of Compound A can be characterized by X-ray powder diffraction analysis. An XRPD pattern representative of Form G of Compound A is provided in Fig. 25. In certain embodiments, Form G of Compound A is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve of the following approximate positions: 7.9, 9.5, 11.7, 15 , 7, 16.8, 18.1, 19.7, 21.8, 22.8, 25.1, 25.8, 26.7 degrees 20. In certain embodiments, Form G of Compound A is characterized by a pattern XRPD that matches the pattern shown in Fig. 25. In certain embodiments, Form G of Compound A is characterized by an XRPD pattern that has 1,2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks that match the peaks in the representative Form G pattern provided herein.

In certain embodiments, Form G of Compound A can be characterized by thermal analysis. A representative DSC graph for Form G of Compound A is shown in Fig. 26. In certain embodiments, Form G is characterized by a DSC graph comprising an endothermic event with an onset temperature of approximately 109 ° C. A representative TGA graph for Form G of Compound A is shown in Fig. 27. In certain embodiments, Form G is characterized by a TGA graph comprising a loss of mass of less than about 8%, for example , about 3.8%, of the total mass of the sample after heating from about 25 ° C to about 110 ° C. In certain embodiments, the TGA mass loss event comprises the loss of the ethyl acetate solvent, as indicated, for example, by TG-IR analysis. In certain embodiments, Form G of Compound A is solvated. In certain embodiments, Form G is an ethyl acetate solvate. In certain embodiments, the Form G crystal lattice comprises approximately three molar equivalents of ethyl acetate per mole of Compound A.

In certain embodiments, Form G of Compound A can be characterized by moisture absorption analysis. A representative graph of moisture absorption isotherms is shown in Fig. 28. In certain embodiments, when the RH increases from about 0% to about 95% RH, Form G exhibits a mass change of less than about 1%, eg about 0.4%, of the initial sample mass. In certain embodiments, the mass gained after adsorption is lost when the RH is again lowered to approximately 0% RH. In certain embodiments, Form G is substantially non-hygroscopic. In certain embodiments, the XRPD pattern of the Form G material does not change substantially after adsorption / desorption analysis. In certain embodiments, Form G is moisture stable.

In certain embodiments, Form G of Compound A can be characterized by its stability profile. In certain embodiments, the Form G material is stable, for example, its XRPD pattern remains substantially unchanged upon compression. For example, in certain embodiments, Form F is stable upon compression at approximately 2000 psi pressure for approximately one minute. In certain embodiments, Form G is converted to Form B upon exposure to a solvent system comprising, for example, ethanol, acetone, or mixtures thereof, for approximately two days at approximately 25 ° C.

In certain embodiments, Form G of Compound A can be characterized by particle analysis. In certain embodiments, Form G is characterized as a white powder. In certain embodiments, a Form G sample comprises particles having a flake-like morphology. In certain embodiments, a Form G sample comprises particles with a D ⁹⁰ of less than about 18 pm.

Certain embodiments herein provide Form G as a mixture of solid forms comprising Compound A, including, for example, a mixture comprising Form C and optionally one or more of the following: Forms A, B, D, E, F, and an amorphous solid form comprising Compound A as provided herein.

4.2. Treatment methods

The invention includes Form C for use in methods of treatment, prevention, and management of diseases or disorders that are ameliorated by reducing TNF-a levels in a patient comprising administering to a patient in need of such treatment, prevention, or I handle a therapeutically or prophylactically effective amount of Form C and optionally one or more solid forms comprising Compound A, such as, for example, Form A of Compound A, Form B of Compound A, Form D of Compound A , Form E of Compound A, Form F of Compound A, Form G of Compound A, or an amorphous form of Compound A, as provided herein.

Disorders that improve with TNF-a inhibition include, but are not limited to: heart disease, such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction ; solid tumors, including, but not limited to, sarcoma, carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing tumor, leiomyosarcoma, rhabdomyomas, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, carcinoma of the sweat glands, carcinoma of the sebaceous glands, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma , bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonic carcinoma, Wilms tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, carcinoma of bladder, epithelial carcinoma, glioma, astrocytoma, med uloblastoma, craniopharyngioma, ependymoma, Kaposi's sarcoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma; and blood-borne tumors including, but not limited to, "ALL" acute lymphoblastic leukemia, B lymphocyte acute lymphoblastic leukemia, T lymphocyte acute lymphoblastic leukemia, "AML" acute myeloblastic leukemia, "APL" acute lymphocytic leukemia, erythroleukemia acute, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia "CML", chronic lymphocytic leukemia "CLL", multiple myeloma, and acute and chronic leukemias, for example, lymphoblastic, myelogenous, lymphocytic, and myelocytic leukemia.

The specific methods of the invention further comprise the administration of an additional therapeutic agent (ie, a therapeutic agent other than Compound A). Examples of additional therapeutic agents include, but are not limited to, anticancer drugs such as, but not limited to: alkylating agents, nitrogen mustards, ethyleneimines, methylmelamines, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, pyrimidine analogs, analogs purine, vinca alkaloids, epipodophyllotoxins, antibiotics, topoisomerase inhibitors and cancer vaccines.

Specific additional therapeutic agents include, but are not limited to: acivycin; aclarubicin; acodazole hydrochloride; acronin; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropyrimine; busulfan; cactinomycin; calusterone; caracemide; carbetimero; carboplatin; carmustine; Carrubicin Hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; chrysnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diazicuone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; promate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; ethanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; phostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmophosin; interleukin II (including recombinant interleukin II or rIL2), interferon alfa-2a; interferon alfa-2b; alpha-n1 interferon; alpha-n3 interferon; interferon beta-I a; gamma-I b interferon; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; sodium methotrexate; metoprine; meturedepa; mitindomide; mitocarcin; mitochromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxysuran; paclitaxel; pegaspargasa; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobromano; piposulfan; pyroxantrone hydrochloride; plicamycin; plomestane; sodium porfimer; porphyromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprin; rogletimide; safingol; safingol hydrochloride; semustina; simtrazeno; sodium sparphosphate; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; theoxyrone; testolactone; thiamiprine; thioguanine; thiotepa; thiazofurin; tirapazamina; toremifene citrate; trestolone acetate; tricyribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinrelrelin tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. Other anticancer drugs include but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecipenol; adozelesin; aldesleukina; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrografolida; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalization morphogenetic protein 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azathyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoyl staurosporine; beta-lactam derivatives; beta-aletine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinyl spermine; bisnafide; bistratene A; bizelesin; breflato; bropyrimine; Budotitan butionin sulfoximine; calcipotriol; calfostina C; camptothecin derivatives; IL-2 from canarian smallpox; Capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest m 3; CARN 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorines; chloroquinoxaline sulfamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; colismicin A; colismicin B; combretastatin A4; combretastatin analog; conagenine; crambescidin 816; chrysnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentantraquinones; cycloplatam; cypemycin; Cytarabine Ophosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diazicuone; didemnin B; didox; diethylnorespermine; dihydro-5-azacitidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselene; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristerida; estramustine analog; estrogen agonists; estrogen antagonists; ethanidazole; etoposide phosphate; exemestane; fadrozol; fazarabine; fenretinide; filgrastim; finasteride; flavopyridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; phostriecin; photemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; herregulin; hexamethylene bisacetamide; hypericin; Ibandronic acid; idarubicin; idoxifene; idramanthone; ilmophosin; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin-like growth factor receptor 1 inhibitor; interferon agonists; interferons; interleukins; iobenguano; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladin; isobengazol; isohomohalicondrina B; itasetron; jasplaquinolide; kahalalida F; lamelarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte interferon alpha; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analog; lipophilic disaccharide peptide; lipophilic platinum compounds; lysoclinamide 7; lobaplatin; earthworm; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysophylline; lithic peptides; maytansine; Manostatin A; marimastat; masoprocol; maspina; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; Unpaired double-stranded RNA; mitoguazone; mitolactol; mitomycin analogs; mitonaphid; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A + sk from Mycobacterium cell wall; mopidamol; multi-drug resistance gene inhibitor; multiple tumor suppressor-based therapy-1; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone pentazocine; napavine; nafterpina; nartograstim; nedaplatin; nemorrubicin; neidronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrulline; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogs; paclitaxel derivatives; palauamine; palmitoylrizoxine; pamidronic acid; panaxitriol; panomifene; parabactin; pazeliptina; pegaspargasa; peldesina; pentosan sodium polysulfate; pentostatin; pentrozole; perflubron; perfosfamide; perilyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pyrarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinotriamine complex; sodium porfimer; porphyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A based immunomodulator; protein kinase C inhibitor; protein kinase C inhibitor, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; glitters; pyrazoloacridine; pyridoxylated hemoglobin-polyoxyethylene conjugate; RAF antagonists; raltitrexed; ramosetron; RAS farnesyl protein transferase inhibitors; RAS inhibitor; RAS-GAP inhibitor; demethylated reteliptin; rhenium etidronate Re 186; rhizoxine; ribozymes; retinamide RII; rogletimide; rohitucina; romurtida; roquinimex; rubiginone B1; ruboxil; safingol; saintopin; SarCNU; sarcophitol A; sargramostim; Sdi 1 mimetics; semustina; inhibitor 1 derived from senescence; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermina; sparphosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; inhibitors of stem cell division; stymiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramine; swainsonin; synthetic glycosaminoglycans; talimustine; Tamoxifen Method; tauromustine; tazarotene; tecogalan sodium; tegafur; telurapyrilium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; taliblastin; thiocoraline; thrombopoietin; thrombopoietin mimetic; thimafalsine; thymopoietin receptor agonist; timotrinan; thyroid stimulating hormone; tin ethyl ethiopurine; tirapazamina; titanocene dichloride; topsentina; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; tricyribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tryphostins; UBC inhibitors; ubenimex; growth inhibitory factor derived from the urogenital sinus; urokinase receptor antagonists; vapreotide; varioline B; vector system, erythrocyte gene therapy; velaresol; veramine; verdinas; verteporfin; vinorelbine; vinxaltin; vitaxine; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin estimalomer.

Embodiments herein include a method of treating or preventing diseases or disorders that are ameliorated by PDE4 inhibition in a patient comprising administering to a patient in need of such treatment or prevention one or more solid forms comprising Compound A. Disorders ameliorated by PDE4 inhibition includes, but is not limited to, asthma, inflammation, chronic or acute obstructive pulmonary disease, chronic or acute inflammatory lung disease, inflammatory bowel disease, Crohn's disease, Behcet's disease, colitis, ulcerative colitis, and arthritis or inflammation due to reperfusion. In a preferred embodiment, the disease or disorder to be treated or prevented is chronic obstructive pulmonary disease.

Specific methods of the invention may comprise the administration of an additional therapeutic agent such as, but not limited to, anti-inflammatory, antihistamine and decongestant drugs. Examples of such additional therapeutic agents include, but are not limited to: antihistamines including, but not limited to, ethanolamines, ethylenediamines, piperazines, and phenothiazines; anti-inflammatory drugs; NSAIDs, including, but not limited to, aspirin, salicylates, acetominophen, indomethacin, sulindac, etodolac, phenamates, tolmetin, ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, pyroxicam, pyroxicam, melody and steroids including but not limited to cortical steroids and adrenal corticosteroids.

The specific methods of the invention avoid or reduce drug interactions and other adverse effects associated with agents used in the treatment of such disorders, including racemic substituted phenylethylsulfones. Without being bound by theory, certain solid forms comprising Compound A can provide an overall improved therapeutic efficacy, or a therapeutic index, on 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] - Racemic 4-acetylaminoisoindolin-1,3-dione, including solid forms thereof.

As noted above, certain solid forms comprising Compound A can be used in the treatment or prevention of a wide range of diseases and conditions. The magnitude of a prophylactic or therapeutic dose of a particular active ingredient of the invention in the acute or chronic management of a disease or condition may vary with the nature and severity of the disease or condition and the route by which the principle is administered. active. The dose, and perhaps the frequency of the dose, also varies according to the age, body weight and response of each patient. Appropriate dosage regimens can be easily selected by those skilled in the art, taking these factors into consideration. In general, the recommended daily dose range for the conditions described herein is within the range of about 1 mg to about 1000 mg per day, given as a single once-daily dose, preferably as divided doses at throughout a day. More specifically, the daily dose is administered twice a day in equally divided doses. Specifically, a daily dose range can be from about 5 mg to about 500 mg a day, more specifically, from about 10 mg to about 200 mg a day. Specifically, the daily dose can be administered in 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg or 100 mg dosage forms. In patient management, therapy should be started at a lower dose, perhaps from about 1 mg to about 25 mg, and increased if necessary to as low as about 200 mg to about 1000 mg daily in a single or divided dose, depending on the general response of the patient. Alternatively, the daily dose is from 0.01 mg / kg to 100 mg / kg.

It may be necessary to use dosages of the active ingredient outside the ranges described herein in some cases, as will be apparent to those skilled in the art. In addition, it is noted that the GP or clinician will know how and when to interrupt, adjust, or end therapy along with each patient's response.

The terms "therapeutically effective amount", "prophylactically effective amount" and "therapeutically or prophylactically effective amount", as used herein, include the dosage amounts described above and the dose frequency guidelines. Different therapeutically effective amounts may be applicable for different diseases and conditions, as is readily known to those skilled in the art. Similarly, sufficient amounts to treat or prevent such disorders, but insufficient to cause, or sufficient to reduce the adverse effects associated with 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4- Racemic acetylaminoisoindolin-1,3-dione are also included in the dosage amounts described above and the dose frequency guidelines.

4.3. Pharmaceutical compositions

Pharmaceutical compositions and unit dosage forms comprising Form C and optionally one or more solid forms comprising Compound A are provided herein. Methods for preparing pharmaceutical compositions and single unit dosage forms are also provided herein. comprising one or more solid forms comprising Form C of Compound A. For example, in certain embodiments, individual dosage forms comprising a solid form provided herein or prepared using the solid form provided herein may be suitable for oral, mucosal (including rectal, nasal or vaginal administration), parenteral (including subcutaneous, intramuscular, bolus, intra-arterial or intravenous), sublingual, transdermal, buccal or topical administration.

In certain embodiments, the pharmaceutical compositions and dosage forms provided herein comprise Form C and optionally one or more solid forms comprising Compound A. Certain embodiments herein provide pharmaceutical compositions and dosage forms. comprising a solid form comprising Form C of Compound A, where the solid form comprises substantially pure Compound A. Certain embodiments herein provide pharmaceutical compositions and dosage forms comprising a mixture of solid forms comprising Form C of Compound A, including, for example, a mixture comprising Form C and optionally one or more of the following: Forms A, B, D, E, F, and an amorphous solid form comprising Compound A as provided herein. The pharmaceutical compositions and dosage forms provided herein typically also comprise one or more pharmaceutically acceptable excipients, diluents, or carriers.

A particular pharmaceutical composition included by this embodiment comprises one or more solid forms comprising Form C of Compound A and at least one additional therapeutic agent. Examples of additional therapeutic agents include, but are not limited to: anticancer drugs and inflammation therapies including, but not limited to, those provided herein.

The single unit dosage forms of the invention are suitable for oral, mucosa (eg, nasal, sublingual, vaginal, buccal, or rectal), parenteral (eg, subcutaneous, intravenous, bolus, intramuscular, or intra-arterial) administration or transdermal administration. to a patient. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; seals; troches lozenges; dispersions; suppositories; ointments; poultices (plasters); pasta; powder; dressings; creams; plasters; solutions; patches; sprays (for example, nasal sprays or inhalers); gels; Liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or liquid water-in-oil emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (eg, crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

The composition, form and type of dosage forms of the invention will typically vary depending on their use. For example, a dosage form used in the acute treatment of inflammation or a related disorder may contain greater amounts of one or more of the active ingredients that it comprises than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form can contain smaller amounts of one or more of the active ingredients that comprise an oral dosage form used to treat the same disease or disorder. These and other ways in which the specific dosage forms included by this invention will vary from each other will be apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).

Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the industry, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors already known in the art, including, but not limited to, how the dosage form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suitable for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients of the dosage form.

The lactose-free compositions of the invention may comprise excipients that are well known in the art and are listed, for example, in the US Pharmacopeia. (USP) SP (XXI) / NF (XVI). In general, lactose-free compositions comprise an active ingredient, a binder / filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Preferred lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

This invention further includes anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water may facilitate the degradation of some compounds. For example, the addition of water (eg, 5%) is widely accepted in pharmaceutical techniques as a means of simulating long-term storage to determine characteristics such as shelf life or stability of formulations over time. . See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2nd Ed., Marcel Dekker, NY, NY, 1995, pgs. 379-80. In fact, water and heat speed up the decomposition of some compounds. Therefore, the effect of water on a formulation can be of great significance since steam and / or moisture are normally encountered during the formulation working, handling, packaging, storage, transportation and use.

The anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture ingredients and low humidity or low humidity conditions. The pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine are preferably anhydrous if substantial contact with steam and / or moisture is expected during manufacture, packaging and / or storage.

An anhydrous pharmaceutical composition must be prepared and stored so that its anhydrous nature is maintained. Accordingly, the anhydrous compositions are preferably packaged using materials known to prevent exposure to water so that they can be included in suitable formulation kits. Examples of suitable packages include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (eg, vials), blister packs, and strip packs.

The invention further includes pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate at which an active ingredient will decompose. Such compounds, referred to herein as "stabilizers", include, but are not limited to, antioxidants, such as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the specific amounts and types of the active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is administered to patients. However, the typical dosage forms provided herein are within the range of about 1 mg to about 1,000 mg daily, administered as a single once-daily dose in the morning, but preferably as divided doses throughout the day. More specifically, the daily dose is administered twice a day in equally divided doses. Specifically, a daily dose range can be from about 5 mg to about 500 mg a day, more specifically, from about 10 mg to about 200 mg a day. In patient management, therapy can be started at a lower dose, perhaps from about 1 mg to about 25 mg, and increased if necessary to as high as about 200 mg to about 1000 mg daily in a single dose or divided doses, depending on the general response of the patient.

4.3.1. Oral dosage forms

The pharmaceutical compositions of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but not limited to, tablets (eg, chewable tablets), caplets, capsules, and liquids (eg, flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and can be prepared by pharmaceutical methods well known to those skilled in the art. See generally Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).

The typical oral dosage forms of the invention are prepared by combining the active ingredient (s) in an intimate mixture with at least one excipient according to conventional pharmaceutical composition techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in liquid or aerosol oral dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (eg, powders, tablets, capsules, or caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents. .

Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid excipients are employed. If desired, the tablets can be coated by conventional aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the pharmaceutical methods. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the active ingredients with liquid carriers, finely divided solid supports, or both, and then shaping the product into the desired presentation, if necessary.

For example, a tablet can be made by compression or molding. Compression-formed tablets can be prepared by compressing the active ingredients in a suitable compressor in a fluid form such as a powder or granules, optionally mixed with an excipient. The moldable tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Examples of excipients that can be used in the oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth. pulverized, guar gum, cellulose and its derivatives (for example, ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose (for example, No. 2208, 2906, 2910), cellulose , and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms described herein include, but are not limited to, talc, calcium carbonate (eg, granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol. , silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in the pharmaceutical compositions of the invention is typically present from about 50 to about 99 weight percent of the composition pharmaceutical or dosage form.

Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL-PH-101 ™, AVICEL-PH-103 ™, AVICEL RC-581 ™, AVICEL-PH-105 ™ (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581 ™. Suitable low moisture or anhydrous excipients or additives include AVICEL-PH-103 ™ and Starch 1500 LM ™.

Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under desired conditions. Therefore, to form the solid oral dosage forms of the invention a sufficient amount of disintegrant should be used which is neither too high nor too little to adversely alter the release of the active ingredients. The amount of disintegrant used will vary based on the type of formulation and is easily discernible by one of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent disintegrant, specifically from about 1 to about 5 weight percent disintegrant.

Disintegrants that can be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, starch of potato or tapioca, pregelatinized starch, other starches, clays, other algin, other cellulose, gums, and mixtures thereof.

Lubricants that can be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, mild mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, acid stearic, sodium lauryl sulfate, talc, hydrogenated vegetable oil (for example, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, oleate ethyl, ethyl laurate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL 200 ™, manufactured by WR Grace Co. of Baltimore, MD), a synthetic silica coagulated aerosol (available from Degussa Co. of Plano, TX), CAB- O-SIL ™ (a pyrogenic silicon dioxide product marketed by Cabot Co. of Boston, MA) and mixtures thereof. When used, lubricants are typically used in an amount of less than about one percent by weight of the pharmaceutical compositions or dosage forms in which they are incorporated.

4.3.2. Delayed Release Dosage Forms

Solid forms comprising Form C of Compound A as provided herein can be administered by controlled release or by administration devices that are well known to those skilled in the art. Examples include, but are not limited to, those described in US Pat. No.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active substances of the invention. Therefore, the invention includes unit dosage forms appropriate for oral administration, such as, but not limited to, tablets, capsules, gelatin coated tablets, and caplets that are adapted for controlled release.

All controlled-release pharmaceuticals have a common goal to improve drug therapy over that achieved by their uncontrolled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of pharmacological substance used to cure or control the condition in a minimal amount of time. The benefits of controlled-release formulations include prolonged drug activity, reduced dosing frequency, and increased patient acceptance. In addition, controlled release formulations can be used to influence the time of onset of action or other characteristics, such as blood levels of the drug, and thus may influence the presence of side effects (eg, adverse).

Most controlled-release formulations are designed to initially release one amount of drug (active ingredient) that immediately produces the desired therapeutic effect and gradually and continuously release the other amounts of drug to maintain this level of therapeutic or prophylactic effect. over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug that is metabolized and excreted from the body. The controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, and other physiological conditions or compounds.

4.3.3. Parenteral dosage forms

Parenteral dosage forms can be administered to patients by various routes, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically avoids the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, injection ready solutions, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, injection ready suspensions and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: USP Water for Injection; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose Injection and Sodium Chloride, and Lactate Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the active ingredients described herein can also be incorporated into the parenteral dosage forms of the invention.

4.3.4. Transdermal, topical and mucous dosage forms

The transdermal, topical, and mucous dosage forms of the invention include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one skilled in the art. See, eg, Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 &1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucous tissues within the oral cavity can be formulated as mouth rinses or as oral gels. Furthermore, transdermal dosage forms include "depot-type" or "matrix-type" patches, which can be applied to the skin and used for a specific period of time to allow the penetration of a desired amount of active ingredients.

Suitable excipients (eg, vehicles and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms included in this invention are well known to those skilled in the pharmaceutical art, and depend on the particular tissue to which A certain pharmaceutical composition, or dosage form, will be applied. With this in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to create lotions. , tinctures, creams, emulsions, gels or ointments, which are non-toxic and pharmaceutically acceptable. If desired, moisturizing or moisturizing creams may also be added to the pharmaceutical compositions and dosage forms. Examples of such additional ingredients are well known in the art. See, eg, Remington's Pharmaceutical Sciences, 16a and ^{1 8} eds., Mack Publishing, Easton PA (1980 and 1990).

Depending on the specific tissue to be treated, additional components can be used before, together with, or after treatment with active ingredients of the invention. For example, penetration enhancers can be used to aid in the administration of the active substances into the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethylsulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (povidone, polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 ™ (polysorbate 80) and Span 60 ™ (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, can also be adjusted to improve the administration of one or more active ingredients. Similarly, the polarity of a solvent vehicle, its ionic strength, or tonicity can be adjusted to improve administration. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients to improve administration. In this regard, stearates can serve as a lipid vehicle

4.3.5. Kits

This invention includes kits that, when used by the clinician, can simplify the administration of appropriate amounts of active ingredients to a patient.

A typical kit of the invention comprises a unit dosage form of Compound A, or a solid or pharmaceutically acceptable prodrug thereof, and a unit dosage form of a second active ingredient. Examples of second active ingredients include, but are not limited to, those mentioned herein.

The kits of the invention may further comprise devices that are used to administer the active ingredient (s). Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.

The kits of the invention may further comprise pharmaceutically acceptable carriers that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form to be reconstituted for parenteral administration, the kit may comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a sterile, particle-free solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to: USP Water for Injection; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose Injection and Sodium Chloride, and Lactate Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

5. Examples

The present application explicitly refers to the entirety of US Pat. No. 6,962,940 (issued on November 8, 2005), including the examples provided therein.

5.1. Example 1: Synthesis of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoidolin-1,3-dione

A stirred solution of 1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethylamine (1.0g, 3.7mmol) and 3-acetamidophthalic anhydride (751mg, 3.66mmol) in acetic acid (20ml ) heated at reflux for 15 h. The solvent was removed in vacuo to produce an oil. Chromatographic analysis of the resulting oil produced the product as a yellow solid (1.0 g, 59% yield): mp, 144 ° C; 1H NMR (CDCh) 8: 1.47 (t, J = 7.0 Hz, 3H, CH ³ ), 2.26 (s, 3H, CH ³ ), 2.88 (s, 3H, CH ³ ), 3.75 (dd, J = 4.4, 14.3 Hz, 1H, CH), 3.85 (s, 3H, CH3), 4.11 (q, J = 7 Hz, 2H, CH ² ), 5.87 (dd, J = 4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar ), 7.47 (d, J = 7 Hz, 1H, Ar), 7.64 (t, J = 8 Hz, 1H, Ar), 8.74 (d, J = 8 Hz, 1H, Ar), 9.49 (bs, 1H, NH); 13C NMR (CDCla) 8: 14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11 , 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal. calc. for C ²² H ²⁴ NO ⁷ S: C, 57.38; H, 5.25; N, 6.08. Observed: C, 57.31; H, 5.34; N, 5.83.

5.2. Example 2: Synthesis of (+) 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione

Preparation of 3-aminophthalic acid

10% Pd / C (2.5 g), 3-nitrophthalic acid (75.0 g, 355 mmol) and ethanol (1.5 l) were charged into a 2.5 l Parr hydrogenator under a nitrogen atmosphere . Hydrogen was charged to the reaction vessel up to 55 psi. The mixture was stirred for 13 hours, keeping the hydrogen pressure between 50 and 55 psi. Hydrogen was released and the mixture was purged with nitrogen 3 times. The suspension was filtered through a celite pad and rinsed with methanol. The filtrate was concentrated in vacuo. The resulting solid was resuspended in ether and isolated by vacuum filtration. The solid was dried under vacuum at a constant weight, providing 54 g (84% yield) of 3-aminophthalic acid as a yellow product. 1H NMR (DMSO-d6) 8: 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t, 1H), 8-10 (a , s, 2H); 13C NMR (DMSO-d6) 8: 112.00, 115.32, 118.20, 131.28, 135.86, 148.82, 169.15, 170.09.

Preparation of 3-acetamidophthalic anhydride

A 1 L 3-neck round bottom flask was equipped with a mechanical stirrer, a thermometer, and a condenser, and charged with 3-aminophthalic acid (108g, 596mmol) and acetic anhydride (550ml). The reaction mixture was heated under reflux for 3 hours and cooled to about 25 ° C and further to 0-5 ° C for an additional 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried under vacuum at room temperature at a constant weight, giving 75 g (61% yield) of 3-acetamidophthalic anhydride as a white product. 1H NMR (CDCh) 8: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H ).

Resolution of 2- (3-ethoxy-4-methoxyphenyl-1- (methylsulfonyl) -et-2-ylamine

A 3 L 3 neck round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2- (3-ethoxy-4-methoxyphenyl) -1- (methylsulfonyl) -et-2- ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 l). The stirred suspension was heated under reflux for 1 hour. The stirred mixture was allowed to cool. at room temperature and stirring was continued for an additional 3 hours at room temperature. The suspension was filtered and washed with methanol (250 l). The solid was air dried and then vacuum dried at room temperature at a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 ml) were refluxed for 1 hour, cooled to room temperature and stirred for a further 3 hours at room temperature. The suspension was filtered and the filter cake was washed with methanol (200 ml). The solid was air dried and then vacuum dried at 30 ° C at a constant weight, yielding 49.6 g (90% recovery) of (S) -2- (3-ethoxy-4-methoxyphenyl) salt - 1- (methylsulfonyl) -et-2-ylamine-N-acetyl-L-leucine (98.4% ee). Chiral HPLC (1/99 EtOH / KH ² PO ⁴ 20mM pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150mm x 4.6mm, 0.5ml / min, at 240nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%).

Preparation of Compound A

A 500 ml 3-neck round bottom flask was equipped with a mechanical stirrer, a thermometer, and a condenser. The reaction vessel was charged with (S) -2- (3-ethoxy-4-methoxyphenyl) -1- (methylsulfonyl) -et-2-yl amine N-acetyl-L-leucine (25g, 56mmol, 98% ee), 3-acetamidophthalic anhydride (12.1g, 58.8mmol), and glacial acetic acid (250ml). The mixture was refluxed overnight and then cooled to <50 ° C. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 ml x 2), saturated aqueous NaHCO ³ (250 ml x 2), brine (250 ml x 2), and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was recrystallized from a binary solvent containing ethanol (150 ml) and acetone (75 ml). The solid was isolated by vacuum filtration and washed with ethanol (100 ml x 2). The product was dried in vacuo at 60 ° C at a constant weight, providing 19.4 g (75% yield) of S- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] - 4-acetamidoisoindolin-1,3-dione} with 98% chiral HPLC ee (15/85 EtOH / KH ² PO ⁴ 20mM pH 5, Ultron Chiral ES-OVS from Agilent Technology, 150mm x 4.6 mm, 0.4 ml / min, at 240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%). 1H NMR (CDCla) ⁸ : 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07 4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8, 77 (m, ^6H), 9.46 (s, 1H); 13C NMR (DMSO-d ⁶ ) ⁸ : 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.

A reaction scheme illustrating a preparation of the (+) enantiomer of Compound A is provided as in Fig. 29.

5.3. Example 3: TNF-a inhibition

LPS-induced TNF-a assay in human whole blood

The ability of the compounds to inhibit LPS-induced TNF-a production by human whole blood was measured essentially as described below for the LpS-induced TNF-a assay in human PBMC, except that fresh whole blood was used. extracted instead of PBMC. (Muller et al., 1999, Bioorg. & Med. Chem. Lett., 9: 1625-1630.) IC ⁵⁰ of TNF-a induced by whole human blood LPS = 294 nM for Compound A.

LPS-induced serum TNF-a inhibition in mouse

Compounds in this animal model were tested according to previously described methods (Corral et al., 1996, Mol. Med., 2: 506-515). Mouse LPS-induced serum TNF-a inhibition (mouse ED ⁵⁰ , mg / kg, po) = 0.05 for Compound A.

LPS-induced TNF-a production

Lipopolysaccharide (LPS) is an endotoxin produced by gram-negative bacteria such as E. coli that induces the production of many proinflammatory cytokines, including TNF-a. In peripheral blood mononucleated cells (PBMC), TNF-a produced in response to LPS is obtained from monocytes, which comprise approximately 5-20% of total PBMC. Compounds were tested for the ability to inhibit LPS-induced TNF-a production from PBMC as previously described (Muller et al., 1996, J. Med. Chem., 39: 3238). PBMCs from normal donors were obtained by Ficol1Hypaque density centrifugation (Pharmacia, Piscataway, NJ, USA). Cells were grown in RPMI (Life Technologies, Grand Island, NY, USA) supplemented with 10% AB ± human serum (Gemini Bio-products, Woodland, CA, USA), 2mM L-glutamine, 100 U / ml penicillin and 100 pg / ml streptomycin (Life Technologies).

Placed in PBMC plates (2 x 105 cells) in 96-well flat-bottom Costar tissue culture plates (Corning, NY, USA) in triplicate. Cells were stimulated with LPS (Sigma, St. Louis, MO, USA) at 100 ng / ml in the absence or presence of compounds. Compounds (Celgene Corp., Warren, NJ, USA) were dissolved in DMSO (Sigma) and additional dilutions were made in culture medium immediately prior to use. The final DMSO concentration in all samples was 0.25%. Compounds were added to cells one hour prior to LPS challenge. Cells were incubated for 18-20 hours at 37 ° C in 5% CO ^2, and then the supernatants were collected, diluted with culture medium, and assayed for levels of TNF-a by ELISA (Endogen, Boston, MA, USA). IC ⁵⁰ of TNF-a induced by LPS = 77 nM for Compound A.

IL-1p-induced TNF-a production

During the course of inflammatory diseases, TNF-a production is often stimulated by cytokine 1L-1p, rather than by LPS obtained from bacteria. Compounds were tested for the ability to inhibit IL-1p-induced TNF-a production of human PBMC as described above for LPS-induced TNF-a production, except that PBMCs were isolated from units of leukocytes of origin (Sera-Tec Biologicals, North Brunswick, NJ, USA) by centrifugation on Ficoll-Paque Plus (Amersham Pharmacia, Piscataway, NJ, USA), were plated on tissue culture plates 96-well at 3 x 105 cells / well in RPMI-1640 medium (Bio Whittaker, Walkersville, Maryland, USA) containing 10% thermoactivated fetal bovine serum (Hyclone), 2 mM L-glutamine, 100 U / ml of penicillin and 100 mg / ml of streptomycin (complete medium), were pretreated with compounds at 10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064, and 0 pM, in duplicate, at a final DMSO concentration of 0.1% at 37 ° C, in an incubator humidified with 5% CO ² for one hour, then stimulated with 50 ng / ml IL-1 recombinant human p (Endogen) for 18 hours. IC ⁵⁰ of TNF-a induced by IL-p = 83 nM for Compound A.

5.4. Example 4: PDE selectivity

PDE1, 2, 3, 5, and 6 enzyme assays

The specificity of the compounds for PDE4 was tested by testing a single concentration (10 pM) against bovine PDE1, human PDE2, PDE3, and human platelet PDE5 (Hidaka and Asano 1976, Biochem. Biophys. Acta, 429: 485, and Nicholsen et al., 1991, Trends Pharmaco. Sci., 12:19), and PDE6 of external segments of bovine retina rods (Baehr et al. 1979, J. Biol. Chem., 254: 11669, and Gillespie et al. 1989, Mol. Pharm., 36: 773). The results are listed in Table 1.

PDE7 enzyme assay

PDE7 is a cAMP-selective PDE expressed primarily in T lymphocytes and skeletal muscle. Cytokines obtained from T lymphocytes such as IL-2 and IFN-y are potentially regulatable through PDE7 inhibition. PDE7 was purified from Hut78 human T lymphocytes by anion exchange chromatography as previously described (Bloom and Beavo, 1996, Proc. Natl. Acad. Sci. USA, 93: 14188-14192). Compounds were tested against the PDE7 preparation in the presence of 10 nM cAMP as described for PDE4 in Table 1.

5.5. Example 5: pde4 inhibition

PDE4 enzyme assay (derived from U937 cells)

The PDE4 enzyme was purified from U937 human monocytic cells by gel filtration chromatography as previously described (Muller et al., 1998, Bioorg. & Med. Chem. Lett. 8: 2669-2674). Phosphodiesterase reactions were performed in 50 mM Tris HCl pH 7.5, 5 mM MgCh, 1 pM cAMP, 10 nM [3H] -cAMP for 30 min at 30 ° C, boiled off, treated with 1 mg / ml of snake venom, and separated using AG-1XS ion exchange resin (BioRad) as described (Muller et al., 1998, Bioorg. & Med. Chem. Lett. 8: 2669-2674). The reactions consumed less than 15% of the available substrate. The results are listed in Table 1.

Table 1. Specificity of PDE

5.6. Example 6: Human T lymphocyte assays

IL-2 and IFN-y production induced by BSE

Staphylococcal enterotoxin B (BSE) is a superantigen derived from the gram-positive bacteria Staphylococcus aureus. BSE provides the convenient physiological stimulus specific for T lymphocytes expressing Vp chains of the particular T lymphocyte receptor. Human PBMCs (consisting of approximately 50% T lymphocytes) were isolated from leukocyte units of origin as described above and plated in 96-well tissue culture plates at 3 x 105 cells / well in complete medium, were pretreated with compounds at 10, 2, 0.4, 0.08, 0.0l6, 0.0032, 0.00064, and 0 | jM in duplicate at a final DMSO concentration of 0.1% at 37 ° C in a humidified 5% CO ² incubator for 1 hour, then stimulated with 100 ng / ml BSE (Sigma Chemical Co., St. Louis, MO, USA) for 18 hours. IL-2 and IFN-y levels were measured by ELISA (R&D Systems, Minneapolis, MN, USA). IC ⁵⁰ of IL-2 = 291 nM for Compound A. IC ⁵⁰ of IFN-y = 46 nM for Compound A.

5.7. Example 7: cAMP elevation tests

PGE 2- induced cAMP elevation

Prostaglandin E ² (PGE ² ) binds to prostanoid receptors on monocytes, T lymphocytes, and other leukocytes, and consequently elevates intracellular levels of cAMP, resulting in inhibition of cellular responses. The combination of PGE ² and a PDE4 inhibitor synergistically elevates cAMP levels in these cell types, and the elevation of cAMP in PBMC produced by PDE4 inhibitors in the presence of PGE ² is proportional to the inhibitory activity of that PDE4 inhibitor. Intracellular cAMP was measured in human PBMC as follows. PBMC were isolated as described above and plated in 96-well plates at 1 x 10 6 cells per well in RPMI-1640. Cells were pretreated with compounds at 100, 10, 1, 0.1, 0.01 and 0 jM in a final concentration of 2% DMSO, in duplicate, at 37 ° C, in a humidified 5% incubator of CO ² for one hour. The cells were then stimulated with PGE ² (10 jM) (Sigma) for 1 hr. Cells were lysed with HCl, 0.1 N final concentration, to inhibit phosphodiesterase activity and the plates were frozen at -20 ° C. The produced cAMP was measured using the cAMP Immunoassay Kit (R&D Systems) (at low pH). The EC ⁵⁰ of PBMC cAMP for the racemate is 3.09 jM. The EC ⁵⁰ of PBMC cAMP for Compound A is 1.58 jM.

The elevation of cAMP in human neutrophils was measured as follows. PBMC were removed from the leukocytes of origin (Sera-Tec Biologicals) by centrifugation in Ficoll-Paque Plus (Amersham Pharmacia). The resulting erythrocyte / polymorphonuclear cell (PMN) pellet was resuspended in Hank's balanced salt solution (Bio Whittaker) and mixed with an equal volume of 3% Dextran T-500 (Amersham Pharmacia) in 0 saline solution , 9%. The erythrocytes were allowed to settle for 20 minutes, and the PMNs were removed and centrifuged at 120 rpm for 8 minutes at 4 ° C. The remaining erythrocytes were lysed in cold 0.2% saline for 30 seconds, and the cells were restored to isotonicity by adding an equal volume of 1.6% saline. The PMNs were spun at 1200 rpm for 8 minutes at 4 ° C, then resuspended in RPMI-1640 and assayed for cAMP elevation as described for the PBMC above. The PMNs were found to be approximately neutrophilic with 74% CD18 / CD11b +, 71% CD16 + CD9 + by flow cytometry on a FACSCalibur (Becton Dickinson, San Jose, CA, USA). Results are shown in table 2.

Production of fMLF-induced LTB4

N-formyl-methionine-leucine-phenylalanine (fMLF) is a bacterially derived peptide that activates neutrophils to degrade, migrate, and rapidly adhere to endothelial cells and release leukotriene LTB4, a product of arachidonic acid metabolism and itself a neutrophil chemoattractant. Compounds were tested for the ability to block fMLF-induced neutrophil LTB4 production as previously described (Hatzelmann and Schudt, 2001, J. Pharm. Exp. Ther., 297: 267-279), with the following modifications. Neutrophils were isolated as described above and resuspended in calcium or magnesium-free phosphate buffered saline (BioWhittaker) containing 10mM HEPES pH 7.2, and placed in 96-well tissue culture plates at a concentration of 1.7 x 106 cells / well. Cells were treated with thimerosal 50 pM (Sigma) / CaCl ² 1 mM / MGCH 1 mM for 15 minutes at 37 ° C 5% CO ^2, then treated with compounds at 1000, 200, 40, 8, 1, 6, 0.32, 0.064, and 0 nM at a final DMSO concentration of 0.01% in duplicate for 10 minutes. Neutrophils were stimulated with 1 pM fLMF for 30 minutes, then lysed by the addition of methanol (20% final concentration) and frozen in a dry ice / isopropanol bath for 10 minutes. Lysates were stored at -70 ° C until LTB4 content was measured by competitive LTB4 ELISA (R&D Systems). Results are shown in table 2.

Zymosan-induced IL-8 production

Zymosan A, or Saccharomyces cerevisiae from thermally destroyed yeast, binds to the Mac-1 adhesion molecule on the neutrophil surface and activates phagocytosis, cell activation, and IL-8 production. Zymosan-induced IL-8 production was measured as previously described (Au et al., 1998, Brit. J. Pharm.

123: 1260-1266) with the following modifications. Human neutrophils were purified as described above, plated in 96-well tissue culture plates at 3 x 105 cells / well in complete medium, treated with compounds at 10, 2, 0.4, 0.08, 0.016 , 0.0032, 0.00064 and 0 pM, in duplicate, at a final DMSO concentration of 0.1%, for 1 hour at 37 ° C, at 5% CO ² . Neutrophils were then stimulated with boiled, non-opsonized Zymosan A (Sigma) at 2.5 x 105 particles / well for 18 hours. Supernatants were collected and assayed for IL-8 by ELISA (R&D Systems). Results are shown in table 2.

FMLF-induced CD18 / CD11b expression

The expression of CD18 / CD11b (Mac-1) on neutrophils was measured as previously described (Derian et al., 1995, J. Immunol., 154: 308-3 17) with the following modifications. Neutrophils were isolated as described above, then resuspended in complete medium at 1 x 10 6 cells / ml, pretreated with compounds at 10, 1, 0.1, 0.01 and 0 pM, in duplicate, at a final DMSO concentration of 0.1%, for 10 minutes at 37 ° C, at 5% CO ² . The cells were then stimulated with 30 nM fMLF for 30 minutes and then cooled to 4 ° C. Cells were treated with rabbit IgG (Jackson ImmunoResearch Labs, West Grove, PA, USA) (10 pg / 1x106 cells) to block Fc receptors, stained with CD18-FITC and CD11b-PE (Becton Dickinson ) and analyzed by flow cytometry on a FACSCalibur. Expression of CD18 / CD11b (mean fluorescence) in the absence of stimulation was subtracted from all samples to obtain inhibition curves and calculate IC ⁵⁰ values. Results are shown in table 2.

FMLF-induced adhesion to HUVEC

Human umbilical vein endothelial cells (HUVEC) were used as the substrate for neutrophil adhesion as previously described (Derian et al., 1995, J. Immunol., 154: 308-317) with the following modifications. HUVEC cells were obtained from Anthrogenesis (Cedar Knolls, NJ, USA), and neutrophils were not treated with cytochalasin B. Cells were treated with compounds at 10, 1, 0.1, 0.01, 0.001, and 0 pM, at a final DMSO concentration of 0.1%, in duplicate, for 10 minutes, were stimulated with 500 nM fMLF for 30 minutes, and washed twice with s Tf before measuring fluorescence in a plate reader FLX800 (Bio-Tek Instruments, Winooski, VT, USA). Results are shown in table 2.

Table 2. Results of the tests.

5.8. Example 8: aqueous solubility

Equilibrium solubilities were measured in aqueous buffer at pH 7.4. Buffer at pH 7.4 was prepared by adjusting the pH of a NaH ² PO ⁴ 0.07 MA 7.4 solution with 10N NaOH. The ionic strength of the solution was 0.15. At least 1 mg of powder was combined with 1 ml of buffer to make a mixture> 1 mg / kg. These samples were shaken for> 2 hours and allowed to stand overnight at room temperature. The samples were then filtered through from a 0.45 | jm nylon syringe filter that was first saturated with the sample. The filtrate was sampled twice, consecutively. The filtrate was tested by HPLC against standards prepared in 50% methanol. Compound A had 3.5 times greater aqueous solubility than the racemic mixture. Solubility of Custom Compound = 0.012 mg / ml; racemic mixture = 0.0034 mg / ml.

5.9. Example 9: LPS-induced lung neutrophilia ferret model

The conscious ferret model has been used to investigate the anti-inflammatory, emetic, and behavioral effects of PDE4 inhibitors when administered orally (p.o.). From these experiments, a therapeutic index (TI) can be determined for each PDE4 inhibitor. TI has been calculated by dividing the threshold dose to produce emetic episodes and behavioral changes by the anti-inflammatory dose (dose that produces 50% inhibition of LPS-induced neutrophilia).

Animal husbandry

Male ferrets (Mustela Pulorius Euro, weight 1-2 kg). Ferrets were supplied by Bury Green Farm or Misay Consultanci. After transport, the animals were allowed to acclimatize in the holding chambers for a period of not less than seven days. The diet comprised SDS diet granulated food C given at discretion with Whiskers ™ cat food given three times per week. The water was pasteurized animal quality drinking water and was changed every day.

Dosing with PDE4 inhibitor

PDE4 inhibitors were administered orally (po), at doses initially of 1-10 g / kg, but subsequently up to 30 mg / kg in order to establish whether the TI was 10 or higher, and / or lower doses for set the minimum dose to produce 50% neutrophilia inhibition. Ferrets were fasted overnight but were allowed free access to water. Animals were orally dosed with vehicle or PDE4 inhibitor using a 15 cm dosing needle passed below the back of the throat into the esophagus. After dosing, the animals were returned to the holding cages equipped with Perspex doors to allow observation, and were given free access to water. After dosing, the animals were constantly observed and any emesis or changes in behavior were recorded. Animals were allowed access to food 60 to 90 minutes after p.o.ss dosing.

LPS exposure

Thirty minutes after dosing p.o. With the control compound or vehicle, ferrets were placed in sealed Perspex containers and exposed to an aerosol of LPS (100 jg / µl) for 10 minutes. LPS aerosols were generated by a nebulizer (De Vilbiss, USA) and this was directed into the Perspex exposure chamber. After a 10 minute exposure period, the animals were returned to the holding cages and were given free access to water and, at a later stage, to food. Observation was continued for a period of at least 2.5 hours after dosing p.o. and emetic episodes and behavioral changes were recorded.

Bronchoalveolar lavage

Six hours after LPS exposure animals were sacrificed by overdose of pentobarbitone sodium administered intraperitoneally. A cannula was then inserted into the trachea with a polypropylene tube and the lungs were washed twice with 20 ml of heparinized phosphate buffered saline (STF) (10 units / ml).

Blood sampling / tissue removal

A terminal blood sample (10 ml) was drawn by transthoracic cardiac puncture. The blood was centrifuged at 2,500 rpm for 15 minutes and the plasma was withdrawn and stored at -20 ° C. The brain was also removed and frozen at -20 ° C for analysis of compound content.

Cell count

Samples from the bronchoalveolar lavage (BAL) were centrifuged at 1,500 rpm for 5 minutes. The supernatant liquid was removed and the resulting cell pellet was resuspended in 1 ml STF. A cell smear of the resuspended fluid was prepared and stained with Leishmans stain to allow differential cell counting. A total cell count was made using the remaining resuspended sample. From this, the total number of neutrophils in the BAL was determined.

Measured parameters

1.% inhibition of LPS-induced pulmonary neutrophilia.

2. Emetic episodes - the number of vomiting and nausea was counted.

3. Behavioral changes - The following behavioral effects were noted: salivation, gasps, scratches in the mouth, squashed posture, ataxia, arched back, and backward gait. Any change in behavior was semiquantified by applying a severity assessment (mild, moderate or severe).

4. TI was calculated as the highest dose found that did not produce emetic episodes, divided by the lowest dose found that inhibited pulmonary neutrophilia by 50% or more.

The effect of Compound A on LPS-induced neutrophilia in the lungs of conscious ferrets is shown in Fig. 30.

Emesis and behavior changes

After dosing p.o. of PDE4, ferrets were observed for at least two hours and emetic episodes (vomiting and nausea) and behavioral changes were recorded.

No emetic episodes (nausea or vomiting) were observed in ferrets pretreated p.o. with the relevant vehicle (acetone / cremophor / distilled water). In a small proportion of the control treated animals (7/22), slight behavioral changes (lip licking and reverse running) were seen.

Compound A (0.1-3 mg / kg, p.o.) did not produce emetic episodes (nausea and vomiting). Some behavioral changes (squashed posture, lip-licking, and backward movement) were observed and classified as mild. At 10 mg / kg in 2/6 ferrets, some nausea was observed but not marked emesis along with salivation and behavioral changes (valued as mild or moderate). At the highest dose tested (30 mg / kg) moderate to marked emesis was observed in 3/4 animals along with pronounced behavioral changes. These data are summarized in Table 3.

Table 3. Conscious Ferret: Emetic Episodes and Behavioral Changes After Oral Administration of Compound A

Animals were observed up to three hours after dosing. The numbers in parentheses refer to the number of animals that responded. The number of animals in each group varies from 4 to 22.

Therapeutic index calculation

From these experiments, a therapeutic index (TI) for each compound was determined by dividing the threshold dose to induce emetic episodes by the value of ED ⁵⁰ to inhibit pulmonary neutrophilia. The calculation of the TI is summarized in Table 4. Compound A had a TI of 12, producing no emetic episodes at an anti-inflammatory dose of 1 mg / kg.

Table 4. Summary of effective doses (ED ⁵⁰ ) for the inhibition of LPS-induced pulmonary neutrophilia and the induction of emesis and the therapeutic index derived from these values.

5.10. Example 10: Biological activity of Compound A in patients with severe plaque-type psoriasis

Compound A is a novel oral agent that negatively regulates the production of proinflammatory cytokines in human cell models. Compound A has been shown to decrease production of TNF-a, IL-12, and IFN-Y, as well as increase production of IL-10. Psoriasis is strongly associated with dysregulation of cytokines and chemokines, allowing for possible therapies with immunomodulatory compounds. This open-label, single-arm, phase 2 pilot study was designed to assess the biological activity of Compound A in patients with severe plaque-type psoriasis. Additional evaluations of clinical outcomes were performed to assess the potential efficacy of Compound A in the treatment of severe plaque-type psoriasis.

Compound A was administered 20 mg orally daily for 29 days with an additional observation period of 28 days for patient safety. Skin prick biopsy samples (6 mm) were obtained from target plates at the start of the study on Day l5 and Day 29. An uninjured skin biopsy was also taken at the start of the study. The primary pharmacodynamic endpoint was the percent change from baseline in epidermal thickness on Day 29. Skin epidermal thickness measurements and immunohistochemical analysis were performed by a blind reviewer to assess CD11c, CD83, K16, ICAM-1, HLA -DR and filaggrin. Biopsy samples were analyzed by RT-PCR to determine: TNF-a, p40-IL12 / IL23, IL-10, IFN-y, IP10, IL-2, IL-8, iNOS, p19-IL23, K16, CD 83, and hARP. PASI, PGA, and BSA measurements were performed to explore clinical efficacy during the 29-day treatment phase of the study. Adverse event reporting, clinical laboratory evaluations, physical exams, ECG, and vital sign measurements assessed safety. A total of 19 patients were included: 15 patients had complete evaluable biopsy sets and 17 patients had complete efficacy evaluations.

Assessment of change in epidermal thickness was the primary endpoint in this study. Nineteen patients were included in the study, of whom 15 had complete sets of evaluable biopsies at baseline and Day 29. Seventeen of the 19 subjects had clinical efficacy parameters measured at baseline and Day 29. Eight (53.3%) of the 15 patients with evaluable biopsies at baseline and on Day 29 demonstrated a 20% reduction in epidermal skin thickness. The mean reduction in epidermal thickness among the 15 subjects with evaluable biopsies at baseline and Day 29 was 20.5% (p = 0.015). Fig. 31 shows the change in epidermal thickness from baseline to Day 29 among subjects with evaluable biopsies.

Key inflammatory markers including epidermal and dermal T lymphocytes, CD83 + and CD11c cells were evaluated in biopsy samples. The results of 8 responding patients showed a decrease in epidermal and dermal T lymphocytes by 42.56% and 28.79% respectively in responders (> 20% reduction in epidermal thickness). The mean reductions from baseline in CD83 + epidermal and dermal cells were 32.50% and 25.86%, respectively, in responders. CD11c cells were reduced by 40.16% in the epidermis and by 18.50% in the dermis in the responders. Table 5 lists the reductions in key inflammatory skin biopsy markers in responders and non-responders. In addition, one patient with abnormal K16 at baseline had normal K16 on Day 29. Three patients with abnormal ICAM-1 at baseline had normal ICAM-1 on Day 29. Two patients with abnormal HLA-DR had normal HLA-DR on Day 29, and three patients with abnormal filaggrin at baseline had normal filaggrin on Day 29.

Table 5. Percentage reduction of key inflammatory markers on Day 29

Biopsy samples were evaluated to determine the expression of the key inflammatory marker mRNA gene by RT-PCR including: TNFa, p40-IL12 / IL23, IL-10, IFNy, IP10, IL-2, IL-8, iNOS, p19-IL23, K16 and CD83.

INOS mRNA expression was reduced by 66.5% (p = 0.025) in injured skin after 29 days of treatment with Compound A. Reductions and increases in mRNA expression of other inflammatory markers showed general trends of improvement. Fig. 32 graphically shows the change in iNOS expression during the study.

A total of 17 of the 19 included subjects completed the 29-day treatment phase and had complete clinical efficacy evaluations. Fourteen (73.7%) of the 19 included subjects demonstrated an improvement in their PASI with 3 (15.8%) of these patients who showed a> 50% reduction from baseline in their total Psoriasis Area score and Index of severity (PASI) on Day 29. Fig. 33 shows the percentage change in PASI scores among evaluable patients from baseline on Day 29. In addition, 9 (52.9%) of the 17 evaluable patients demonstrated an improvement in Global static physician assessment (sPGA) and 10 (58.8%) of the 17 evaluable patients showed a reduction from baseline in their body surface area (BSA) of psoriasis after 29 days of treatment with Compound A. Safety was assessed during the treatment and follow-up phases through monitoring of adverse events, ECG, laboratory tests, physical exams and vital signs. No deaths were reported and no patient discontinued the study prematurely due to an adverse event. The most common treatment-related adverse events included headache (26.3%) and nausea (15.8%).

In this clinical study, Compound A 20 mg p.o. QD for 29 days was safe in subjects with severe plaque-type psoriasis. The primary end point was reached with 8 (53.3%) of 15 subjects achieving a 20% reduction in epidermal thickness on Day 29. Reductions of key inflammatory markers were observed in skin biopsies, including dermal and epidermal T lymphocytes, CD83 + and CD11c cells. RT-PCR analysis revealed a statistically significant 66.5% reduction in iNOS mRNA in skin biopsies on Day 29. A positive clinical efficacy signal was observed after 29 days of treatment with Compound A. 73 , 7% of the included patients demonstrated an improvement in their psoriasis symptoms, 15.8% of these patients showing a reduction> 50% of the initial value in their PASI score on Day 29. 47.4% of the included patients showed an improvement in their sPGA and 52.6% of the included patients showed a reduction of the initial value in their body surface area (BSA) with psoriasis on Day 29.

5.11. Example 11: A phase 2 study demonstrating the efficacy and safety of Compound A in subjects with moderate to severe psoriasis

This phase 2, randomized, double-blind, placebo-controlled, parallel group, dose-comparison study evaluated the efficacy and safety of Compound A in subjects with moderate to severe plaque psoriasis who were candidates for systemic therapy. .

This study included a 12-week treatment phase followed by a 4-week observational follow-up phase. A total of 260 subjects were randomized to receive Compound A 20 mg BID, Compound A 20 mg QD, or placebo for 12 weeks. The primary endpoint for this study was the proportion of subjects treated with Compound A who achieved a 75% reduction in Psoriasis Area score and Severity Index ("PASI-75") at week 12 / last treatment in reference to the initial visit. The last treatment is defined as the last PASI evaluation completed during the 12-week treatment phase.

At week 12 / last treatment, a significantly higher proportion of subjects treated with 20 mg BID (24%) achieved a PASI-75 compared to the placebo group (10%; P = 0.023). Of subjects receiving 20 mg BID or placebo, 57% vs. 23% achieved pAs I-50 at week 12 / last treatment, respectively; while 14% compared to 6% achieved PASI-90, respectively. At week 12 / last treatment, subjects achieved an average decrease of 52% versus 17% in PASI from baseline in the 20 mg BID versus placebo groups, respectively. Subjects who received Compound A continued to improve over time, showing the largest mean percentage reduction in PASI score at week 12. Overall, adverse event profiles were similar in all three treatment groups. Most of the reported adverse events were minor. No serious drug related adverse events were reported in this study. No subject in the 20 mg IDB group experienced an outbreak of psoriasis during the observational follow-up period.

In this clinical study, Compound A was shown to be well tolerated and safe in subjects with moderate to severe plaque psoriasis. The proportions of subjects achieving 50%, 75%, and 90% improvement in PASI demonstrate the clinical activity of Compound A after 12 weeks of treatment.

5.12. Example 12: screening studies for solid forms

5.12.1. Experimental methodology

Solubility studies. A weighed sample of Compound A (approximately 100 mg) was treated with approximately 2 ml of the test solvent. The solvents used were reactive or HPLC grade. The resulting mixture was stirred for at least 24 hours at approximately 25 ° C. When all solids were dissolved by visual inspection, the estimated solubilities were calculated. The solubilities were estimated from these experiments based on the total volume of solvent used to give a solution. Actual solubilities may be higher than calculated due to the use of a large amount of solvent or a slow dissolution rate. If dissolution did not occur during the experiment, the solubility was measured gravimetrically. A known volume of filtrate was evaporated to dryness and the weight of the residue was measured.

Solution evaporation studies. Evaporation of the solution was performed for solvents in which the solubility of Compound A was greater than about 50 mg / ml, such as acetone, acetonitrile, methylene chloride, and tetrahydrofuran. Solid samples were obtained by slowly evaporating the solvents at about 25 ° C or about 50 ° C in an open vial under a nitrogen atmosphere.

Balance studies. The equilibrium experiments were performed by adding an excess of Compound A to approximately 2 ml of a test solvent. The resulting mixture was stirred for at least 24 hours at about 25 ° C or about 50 ° C. Upon reaching equilibrium, the saturated solution was removed and allowed to slowly evaporate in an open vial under a nitrogen atmosphere at about 25 ° C or about 50 ° C, respectively. The resulting equilibrium suspension was filtered and air dried.

Cooling crystallization studies. Cooling crystallization studies were performed. The solid was dissolved in a solvent at an elevated temperature, about 65 ° C, and allowed to cool to about 25 ° C. Samples that did not crystallize at approximately 25 ° C were placed in a refrigerator (approximately 0-5 ° C). The solids were isolated by decantation and allowed to air dry.

Solvent / antisolvent precipitation studies. Precipitations were carried out using solvent / anti-solvent combinations. The solid was dissolved in a solvent in which Compound A had a relatively high solubility, and then a selected solvent in which Compound A had a relatively low solubility (ie, an antisolvent) was added to the solution. A precipitate formed immediately in some solvent / anti-solvent systems. If precipitation did not occur immediately, the resulting mixture was allowed to cool in a refrigerator (approximately 0-5 ° C) until a precipitate formed. The precipitate was then isolated by decantation and allowed to air dry.

Interconversion studies. Interconversion experiments were performed by making suspensions of a solid form in a saturated solvent. The suspensions were shaken for at least 2 days at approximately 25 ° C. The saturated solution was removed by filtration and the solid was air dried.

Compression studies. Compression tests were performed by pressing the sample under a 2000 psi force for at least one minute with the Carver Mini C compressor. The sample was then analyzed by XRPD.

Hygroscopicity studies. The hygroscopicity of various solid forms was studied using a DVS instrument from Surface Measurement Systems. Typically, a sample size of between about 10-50 mg was loaded into the sample container of the DVS instrument and the sample was analyzed on a DVS automatic absorption analyzer at approximately 25 ° C. Relative humidity was increased in increments of about 10% from about 0% to about 95% RH. Thereafter, the relative humidity was lowered similarly to achieve a complete adsorption / desorption cycle. The mass was recorded at periodic intervals throughout the experiment.

5.12.2. Characterization methodology

Samples generated as described in screening the solid form were typically analyzed by X-ray powder diffraction (XRPD). XRPD was performed on a Thermo ARL X'TRA ™ X-ray powder diffractometer using Cu Ka radiation at 1.54 A. The instrument was equipped with a fine focus X-ray tube. The voltage and amperage of the X-ray generator were set at 45 kV and 40 mA, respectively. Divergence cuts were adjusted to 4mm and 2mm and measurement cuts were adjusted to 0.5mm and 0.2mm. The diffracted radiation was detected using a Peltier cooled Si (Li) solid state detector. Typically, a continuous theta-two theta scan was used at 2.40 ° / min (0.5 s / 0.02 ° step) from 1.5 ° 20 to 40 ° 20. A sintered alumina standard was used to verify the maximum position. In general, the positions of the XRPD peaks are expected to vary individually on a measure-by-measure basis by approximately ± 0.2 ° 20. In general, as understood in the art, two XRPD patterns coincide with each other if the characteristic peaks of the first pattern are in approximately the same positions as the characteristic peaks of the second pattern. As understood in the art, determining whether two XRPD patterns match, or whether the individual peaks in two XRPD patterns match, may require consideration of individual variables and parameters such as, but not limited to, preferred orientation, phase impurities, degree of crystallinity, particle size, variation in the configuration of the diffractometer instrument, variation in the XRPD data collection parameters and / or variation in the XRPD data processing, among others. Determining whether two patterns match can be done visually and / or by computer analysis. Examples of XRPD patterns collected and analyzed using these methods and parameters are provided herein, for example, as Fig. 1, Fig. 5, Fig. 9, Fig. 13, Fig. 17, Fig. 21 and the Fig. 25.

Differential scanning calorimetry (DSC) analyzes were performed on a TA Instruments Q1000 ™. Approximately 5 mg of sample was placed in a tared DSC container and the weight of the sample was accurately recorded. Typically, the sample was heated in a nitrogen atmosphere at a rate of about 10 ° C / min from about 25 ° C to a final temperature of about 200 ° C. Typically, thermal events were reported as extrapolated starting temperatures. Examples of DSC thermograms collected and analyzed using these methods and parameters are provided herein, for example, as Fig. 2, Fig. 6, Fig. 10, Fig. 14, Fig. 18, Fig. 22 and the Fig. 26.

Thermal gravimetric analysis (TGA) was performed on a TA Instruments Q500 ™. Calcium oxalate was used for the calibration. Approximately 10 mg of sample was placed on a tray, accurately weighed, and loaded into the TGA oven. The sample was heated in a nitrogen atmosphere at a rate of about 10 ° C / min from about 25 ° C to a final temperature of about 200 ° C. Examples of TGA thermograms collected and analyzed using these methods and parameters are provided herein, for example, as Fig. 3, Fig. 7, Fig. 11, Fig. 15, Fig. 19, Fig. 23 and the Fig. 27.

Solvation solvents were identified and quantified by TG-IR experiments using a TA Instruments Q500 ™ TGA interconnected with a Fourier Thermo Nicolet AEM transform IR spectrophotometer. Typically, a sample size of approximately 20-50 mg was weighed into an aluminum container and heated to approximately 200 ° C. During the TGA run, steam was transferred to the cell through a heated transfer line. The temperature of both the transfer line and the cell was adjusted to approximately 225 ° C. IR spectra were collected at each 10 second repetition time. Volatile products were identified from a search in the Aldrich Vapor Phase Spectral Library and the library match results are presented to show the identified vapor.

Morphology and particle size analysis of the samples were performed using an Olympus microscope. The instrument was calibrated to USP standards. D ⁹⁰ values were determined using Image Plus - Material Plus software. The D ⁹⁰ value represents the 90th percentile of the particle size distribution measured by length; that is, 90% of the particles have a length of this value or less.

5.12.3. Results of the screening study for solid forms

Solid forms comprising Compound A that were prepared during solid form screening studies included Forms A, B, C, D, E, F, G and an amorphous form. Representative XRPD patterns, DSC charts, TGA charts, and DVS charts for each of Forms A, B, C, D, E, F, and G are provided herein as Fig. 1 - Fig. 28.

Solubility studies. The approximate solubility of Form B of Compound A in various solvents was determined at approximately 25 ° C. The results are shown in Table 6. Form B was found to be more soluble in acetone, acetonitrile, methylene chloride, methyl ethyl ketone and tetrahydrofuran (greater than about 50 mg / ml) followed by ethyl acetate (about 30, 15 mg / ml). Form B was also found to have low solubility in various solvents, including n-butanol, heptane, 2-propanol, toluene, and water (less than about 1 mg / ml).

Solution evaporation studies. The results of solution evaporation studies conducted at approximately 25 ° C and approximately 50 ° C are summarized in Table 7.

Balance studies. The results of the equilibrium studies performed at approximately 25 ° C and approximately 50 ° C are summarized in Table 8.

Cooling crystallization studies. The results of the cooling crystallization studies are summarized in Table 9. The cooling crystallization studies produced crystalline material from numerous solvents, including acetone, acetonitrile, n-butyl acetate, ethyl acetate, methanol, methylene chloride, methyl ethyl ketone (MEK) and tetrahydrofuran (THF). The crystalline materials obtained were typically characterized by XRPD, DSC, and TGA.

Solvent / antisolvent precipitation studies. The results of the solvent / antisolvent precipitation studies are summarized in Table 10. When heptane, water, and toluene were added to Form B in a THF solution at approximately 40 ° C, precipitates formed immediately. When heptane, methyl t-butyl ether (MTBE), toluene, and water were added to Form B in a separate acetonitrile solution at approximately 25 ° C, a clear solution or mixture was formed. Crystalline material of MTBE / acetonitrile, water / acetonitrile and toluene / acetonitrile was obtained after stirring overnight. However, no crystallization occurred for the heptane / acetonitrile mixture. When water was added to Form B in a methanol solution at about 50 ° C, precipitates formed immediately and when heptane and toluene were added to Form B in methanol solution separately at about 50 ° C, a solution formed transparent or a mix. Crystalline material of toluene / methanol and heptane / methanol was obtained after stirring overnight. When toluene was added to Form B in a methylene chloride solution to at about 25 ° C, precipitates formed immediately, and when MTBE was added to Form B in a methylene chloride solution at about 25 ° C, a clear solution was obtained. Crystalline MTBE / methylene chloride material was obtained after stirring overnight. However, crystallization did not occur when heptane was added to Form B in a methylene chloride solution. When heptane was added to Form B in a MEK solution at about 50 ° C, precipitates formed immediately and when MTBE and toluene were added to Form B in a separate MEK solution at about 50 ° C, solutions were obtained transparent. Crystalline material of MTBE / MEK and toluene / MEK was obtained after stirring overnight. When heptane was added to Form B in a solution of n-butyl acetate at about 50 ° C, precipitates formed immediately and when MTBE and toluene were added to Form B in a separate MEK solution at about 50 ° C , transparent solutions were obtained. Crystalline MTBE / n-butyl acetate and toluene / n-butyl acetate material was obtained after stirring overnight. When water and toluene were added to Form B in a separate acetone solution at approximately 40 ° C, precipitates formed immediately, and when ethanol and 2-propanol were added to Form B in a separate acetone solution at approximately 40 ° C, clear solutions were obtained. Crystalline material of ethanol / acetone and 2-propanol / acetone was obtained after stirring overnight. The crystalline materials obtained were identified by XRPD, DSC, TGA.

Stability studies. The results of the stability study are summarized in Table 11. Stabilities of Forms A, B, C and D were studied by exposing the solid samples to the stress condition of 40 ° C / 75% RH for four weeks. Furthermore, the stabilities of Forms A, B, C and D in different solvents were studied by equilibrium in different solvents at 40 ° C for four weeks. The suspensions were then filtered and air dried. Solid samples obtained from stability experiments were analyzed by XRPD and DSC.

Interconversion studies. The results of the interconversion studies are summarized in Table 12.

Compression studies. Compression tests were performed on Forms A, B, C, D, E, F, and G of Compound A. Each form studied was found to be substantially physically stable as observed by XRPD analysis.

Hygroscopicity studies. Hygroscopicity (moisture absorption / desorption) studies were performed on forms A, B, C, D, E, F, and G. Each of the solid samples was analyzed by XRPD after undergoing a full adsorption / desorption cycle. in the DVS system. The XRPD results indicated that none of the analyzed forms underwent substantial solid state transformation as a result of DVS analysis.

Table 6. Study of solubility in Form B

Table 7. Evaporation studies of solution

Table 8. Balance studies

Table 9. Crystallization studies by cooling

Table 10. Solvent / Antisolvent Precipitation Studies

B MEK Tolueno Forma C B etato de Heptano Forma B butilo

B etato de MtBE Forma B butilo B etato de Tolueno Forma B

butilo B DCM Heptano Forma E

B B DCM MtBE Forma B B DCM Tolueno Forma B B l ethyl cet Heptane Form BB MEK MtBE Form B

B MEK Toluene Form CB Heptane etatate Form B butyl

MtBE B etate Form B butyl Toluene B etate Form B

butyl B DCM Heptane Form E

BB DCM MtBE Form BB DCM Toluene Form B

B Methanol Heptane Form B B Methanol Water Form B B Methanol Toluene Form C

hidrofur

Heptano Forma B B Tetrahidrofurano Agua Forma BB

hydrofur

Heptane Form BB Tetrahydrofuran Water Form B

B Tetrahidrofurano Tolueno

Forma C

B Tetrahydrofuran Toluene

Form C

* Abbreviations: MEK = methyl ethyl ketone; DCM = dichloromethane (ie methylene chloride); MtBE = methyl t-butyl ether

Table 11. Stability studies

Table 12. Interconversion studies

5.13. Example 13: 200 mg dosing capsule

Table 13 illustrates a discontinuous formulation and a single dosage formulation for a single dose unit containing 200 mg of a solid form comprising Compound A, i.e. approximately 40 weight percent, in a capsule of size N .0.

Table 13. Formulation for a 200 mg capsule.

The pregelatinized cornstarch components (SPRESS ™ B-820) and Compound A are passed through a 710 pm screen and then loaded into a Diffusion Mixer with a baffle insert and mixed for 15 minutes. The magnesium stearate is passed through a 210 pm screen and added to the Diffusion Mixer. The mixture is then encapsulated in a size 0.500 mg capsule per capsule (batch size 8400 capsules) using a Dosator type capsule filling machine.

5.14. Example 14: 100 mg oral dosage form

Table 14 illustrates a batch formulation and a single unit dose formulation containing 100 mg of a solid form comprising Compound A.

Table 14. Formulation for a 100 mg tablet

The components of microcrystalline cellulose, croscarmellose sodium and Compound A are passed through a # 30 mesh size screen (approximately 430 j to approximately 655 | j). Pluronic F-68® surfactant (manufactured by JRH Biosciences, Inc. of Lenexa, KS) is passed through a # 20 mesh size screen (about 457 j to about 1041 j). Pluronic F-68® surfactant and 0.5 kg croscarmellose sodium are loaded into a 16 qt twin chamber tumbler mixer. and mix for about 5 minutes. The mixture is then transferred to a 3 cubic foot twin chamber tumbling mixer where the microcrystalline cellulose is added and mixed for approximately 5 minutes. The solid form comprising Compound A is added and mixed for an additional 25 minutes. This pre-mix is passed through a roller compactor with a hammer mill attached to the discharge of the roller compactor and brought back to the tumbler mixer. The remaining croscarmellose sodium and magnesium stearate are added to the tumbling mixer and mixed for approximately 3 minutes. The final mixture is compressed in a rotary tablet press with 250 mg per tablet (batch size 200,000 tablets).

Claims (7)

1. A solid form comprising the enantiomerically pure compound of formula (I):

having an X-ray powder diffraction pattern comprising its characteristic peaks at 7.5, 11.3, 16.4, 17.8, and 26.4 degrees 20 ± 0.2 degrees 20 measured using Cu Ka radiation at 1.54 A; Y having a differential scanning calorimetry graph comprising an endothermic event with an onset temperature of about 138 ° C while heating a sample at a rate of about 10 ° C / min. 2. The solid form of claim 1, having a thermogravimetric analysis graph comprising a loss of mass of less than about 10% when heated from about 25 ° C to about 140 ° C. 3. A mixture comprising the solid form of claim 1 or 2 and one or more solid forms selected from: a solid form comprising the enantiomerically pure compound of formula (I):

having an X-ray powder diffraction pattern comprising its characteristic peaks at approximately 7.5, 11.3, 16.3, 25.2 and 26.0 degrees 20; or having a differential scanning calorimetry graph comprising an endothermic event with an onset temperature of approximately 100 ° C; a solid form comprising the enantiomerically pure compound of formula (I):

having an X-ray powder diffraction pattern comprising its characteristic peaks at approximately 7.6, 9.2, 11.4, 17.9, and 26.6 degrees 20; or having a differential scanning calorimetry graph comprising an endothermic event with an onset temperature of approximately 95 ° C; a solid form comprising the enantiomerically pure compound of formula (I):

that it has an X-ray powder diffraction pattern comprising its characteristic peaks at approximately 8.1, 8.6, 15.6, 17.3 and 25.4 degrees 20; or having a differential scanning calorimetry graph comprising an endothermic event with an onset temperature of approximately 145 ° C; or a solid form comprising the enantiomerically pure compound of formula (I):

having an X-ray powder diffraction pattern comprising its characteristic peaks at approximately 7.9, 11.7, 16.8, 18.1, and 26.7 degrees 20; or it has a differential scanning calorimetry graph comprising an endothermic event with an onset temperature of approximately 109 ° C. 4. A pharmaceutical composition comprising the solid form of claim 1. 5. The solid form of claim 1 for use in a method of treating or preventing a disease or disorder enhanced by inhibition of TNF-α production, wherein the disease or disorder is selected from psoriasis; psoriasis; psoriasic arthritis; rheumatoid arthritis; chronic skin sarcoid; giant cell arteritis; Parkinson's disease; nodular prurigo; lichen planus; complex aptosis; Behcet's disease; lupus; hepatitis; uveitis; Sjogren's disease; depression; interstitial cystitis; vulvodynia; prostatitis; osteoarthritis; diffuse large B lymphocyte lymphoma; polymysoitis; dermatomyositis; inclusion body myositis; erosive osteoarthritis; interstitial cystitis; hepatitis; endometriosis; radiculopathy; and gangrenous pyoderma. 6. The solid form of claim 1 for use in a method of treating or preventing a disease or disorder enhanced by PDE4 inhibition, wherein the disease or disorder is selected from HIV; hepatitis; adult respiratory distress syndrome; bone resorption diseases; chronic obstructive pulmonary diseases; chronic inflammatory lung diseases; dermatitis; inflammatory skin disease; atopic dermatitis; cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; postischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection, including graft-versus-host disease; autoimmune disease; rheumatoid spondylitis; arthritic conditions, such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lupus erythematosus; erythema nodosum leprosy in leprosy; radiation damage; asthma; and alveolar injury from hyperoxia. 7. The solid form for use according to claim 5 or 6, wherein the disease or disorder is selected from the group consisting of psoriatic arthritis, psoriasis, rheumatoid spondylitis, Behcet's disease, rheumatoid arthritis, atopic dermatitis, Crohn's disease and colitis. ulcerative