JP2014114308A - Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof - Google Patents

Abstract

Disclosed are compounds capable of treating and / or preventing disorders that are ameliorated by reducing TNF-α levels or inhibiting PDE4, and compositions containing the compounds.
(+)-2- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione represented by the following formula: A solid form comprising and a composition comprising the solid form.

[Selection figure] None

Description

1. TECHNICAL FIELD Provided herein are (+)-2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3- A solid form comprising dione, a composition comprising the solid form, a method of producing the solid form, and methods of use thereof for the treatment of various diseases and / or disorders.

2. BACKGROUND ART Tumor necrosis factor α (TNF-α) is a cytokine that is released primarily by mononuclear phagocytes in response to immunostimulants. TNF-α can promote most cellular processes such as differentiation, mobilization, proliferation, and proteolysis. At low levels, TNF-α provides protection against infectious agents, tumors and tissue damage. However, TNF-α also plays a role in many diseases. When administered to a patient, TNF-α causes or exacerbates an acute phase response similar to that seen during inflammation, fever, cardiovascular effects, bleeding, coagulation, and acute infection and shock conditions. Enhanced or unregulated TNF-α production is found in, for example, cancers such as solid tumors and hematological tumors; heart diseases such as congestive heart failure; and viral diseases, genetic diseases, inflammatory diseases, allergic diseases, and self It has been implicated in a number of diseases and medical conditions, such as immune diseases.

Adenosine 3 ′, 5′-cyclic monophosphate (cAMP) is also, but not limited to, asthma and inflammation, and other conditions (Lowe and Cheng, D
rugs of the Future, Volume 17 (9), 799-807, 1992
Plays a role in many diseases and conditions such as Increased cAMP in inflammatory leukocytes has been shown to suppress these activations and subsequent release of inflammatory mediators including TNF-α and NF-κB. Increased cAMP levels also result in relaxation of airway smooth muscle.

The main cellular mechanism for inactivation of cAMP is thought to be the degradation of cAMP by a family of isozymes called cyclic nucleotide phosphodiesterases (PDEs) (Beavo and Reitsnyder, Trends in Pha).
rm. 11, 150-155, 1990). There are 11 known PDE families. For example, inhibition of PDE type IV has been recognized to be particularly effective in inhibiting both release of inflammatory mediators and relaxation of airway smooth muscle (Verghese et al., J
. Pharm. Exper, Therapeut. 272 (3), 1313-13
20 pages, 1995). Thus, compounds that specifically inhibit PDE4 (PDE IV) can minimize unwanted side effects such as cardiovascular or antiplatelet effects, suppress inflammation and help relax airway smooth muscle. Currently used PDE4 inhibitors lack selective action at acceptable therapeutic doses.

Cancer is a particularly devastating disease, and increased levels of TNF-α in the blood are involved in cancer risk and spread. Normally, in healthy subjects, cancer cells cannot survive in the circulatory system, but one of these reasons is that the lining of blood vessels acts as a barrier to tumor cell extravasation. However, due to increased cytokine levels, in vitro
Has been shown to substantially increase the adhesion of cancer cells to the endothelium. One explanation is that cytokines such as TNF-α stimulate the biosynthesis and expression of a cell surface receptor called ELAM-1 (endothelial leukocyte adhesion molecule). ELAM-1 is LEC
-A member of the family of calcium-dependent cell adhesion receptors known as CAM, which includes LECAM-1 and GMP-140. During the inflammatory reaction
ELAM-1 on endothelial cells functions as a “homing receptor” for leukocytes. Recently, ELAM-1 on endothelial cells has been shown to mediate increased adhesion of colon cancer cells to cytokine-treated endothelium (Rice et al., 1989, Science 246).
Volume: 1303-1306).

Arthritis, related arthritic symptoms (eg osteoarthritis and rheumatoid arthritis), inflammatory bowel disease (eg Crohn's disease and ulcerative colitis), sepsis, psoriasis, atopic dermatitis, contact dermatitis, chronic obstructive Inflammatory diseases such as lung disease and chronic inflammatory lung disease are also generalized and problematic diseases. TNF-α plays a central role in inflammatory responses, and administration of these antagonists blocks chronic and acute responses in animal models of inflammatory diseases.

Enhanced or unregulated TNF-α production has been implicated in viral diseases, genetic diseases, inflammatory diseases, allergic diseases, and autoimmune diseases. Examples of such diseases include, but are not limited to, HIV; hepatitis; adult respiratory distress syndrome; bone resorption disease; chronic obstructive pulmonary disease; chronic pulmonary inflammatory disease; asthma; dermatitis; cystic fibrosis; Shock; Sepsis; Endotoxin shock; Hemodynamic shock; Septic syndrome; Post-ischemic reperfusion injury; Meningitis; Psoriasis; Fibrous disease; Cachexia; Graft rejection; Autoimmune disease; Arthritic symptoms 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; Includes cell damage. Tracey et al., 1987, Nat
ure 330: 662-664 and Hinshaw et al., 1990, Circ.
Shock 30: 279-292 (endotoxin shock); Dezube et al., 1990.
Year, Lancet, 335: 662 (cachexia); Millar et al., 1989, La
ncet 2: 712-714 and Ferrai-Baliviera et al., 198
9 years, Arch. Surg. 124: 1400-1405 (adult respiratory distress syndrome);
Bertolini et al., 1986, Nature 319: 516-518, Jo.
honson et al., 1989, Endocrinology 124: 1424-142.
7, Holler et al., 1990, Blood 75: 1011-1016, and Grau et al., 1989, N.A. Engl. J. et al. Med. 320: 1586-1591
(Bone resorption disease); Pignet et al., 1990, Nature, 344: 245-2.
47, Bissonnette et al., 1989, Inflammation 13:
329-339 and Baughman et al., 1990, J. MoI. Lab. Clin. Me
d. 115: 36-42 (chronic pulmonary inflammatory disease); Elliot et al., 1995, In
t. J. et al. Pharmac. 17: 141-145 (Rheumatoid Arthritis); von Dul
lemen et al., 1995, Gastroenterology, 109: 129-1.
35 (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. MoI. 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 (opportunistic infection caused by HIV and HIV).

Pharmaceutical compounds that can block the activity of certain cytokines or inhibit their production, including TNF-α, can be beneficial therapies. Many small molecule inhibitors are TN
Proven ability to treat or prevent inflammatory diseases associated with F-α (for review, see Lowe, 1998 Exp. Opin. Ther. Patent.
s 8: see pages 1309-1332. One such molecular class is the substituted phenethyl sulfone described in US Pat. No. 6,020,358.

The preparation and selection of solid forms of pharmaceutical compounds is complex given that changes in solid form can affect various physical and chemical properties. These properties can provide advantages or disadvantages of processing, formulation, stability and bioavailability, among other important pharmaceutical characteristics. Potential solid formulations include crystalline solids and amorphous solids. Amorphous solids are characterized by a lack of long-range structural order, and crystalline solids are characterized by structural periodicity. The desired class of solid formulation depends on the particular application; the amorphous solid may be selected based on, for example, an enhanced dissolution profile, while
Crystalline solids may be desirable for properties such as physical or chemical stability, for example (
For example, S.M. R. Vippagunta et al., Adv. Drug. Deliv. Rev. ,
(2001) 48: 3-26; Yu, Adv. Drug. Deliv. Rev
. (2001) 48: 27-42).

Regardless of whether they are crystalline or amorphous, potential solid forms of pharmaceutical compounds include single-component and multi-component solids. Single component solids consist essentially of pharmaceutical compounds free of other compounds. Differences in single-component crystalline materials can potentially arise from, for example, polymorphism present in certain pharmaceutical compounds where there are multiple three-dimensional arrays (eg, S
. R. Byrn et al., Solid State Chemistry of Drugs,
(1999) See SSCI, West Lafayette). The importance of studying polymorphism was emphasized by the case of ritonavir, an HIV protease inhibitor formulated as a soft gelatin capsule. About two years after the product was launched, a new, insoluble polymorph unexpected precipitation in the formulation forced the product to withdraw from the market until a more stable formulation could be developed ( S. R. Chemburkar et al.
Org. Process Res. Dev. (2000) 4: 413-417).

Additional diversity among potential solid forms of pharmaceutical compounds can arise, for example, from the possibility of multi-component solids. Crystalline solids containing more than one ionic species are sometimes referred to as salts (eg, Handbook of Pharmaceutical Salts: Pr
operations, Selection and Use, P.M. H. Stahl and C
. G. (See Wermuth, (2002), Wiley, Weinheim). Additional types of multi-component solids that can potentially provide other property improvements to pharmaceutical compounds or salts thereof include, for example, hydrates, solvates, co-crystals and clathrates, among others. Included (eg, SR Byrn et al., Solid State Chemistr
y of Drugs, (1999) SSCI, see West Lafayette). In addition, the multi-component crystal forms are potentially polymorphic. In the case of polymorphism, a given multi-component composition can be present in two or more three-dimensional crystal arrays. The preparation of the solid form is
It is very important in developing safe, effective, stable and highly marketable pharmaceutical compounds.

Provided herein are (+)-2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione and Embodiments addressing the need for a solid form of a chemically named compound (“Compound A”), which is US patent application Ser. No. 10/392, filed Mar. 19, 2003.
195 (issued as US Pat. No. 6,962,940), and March 2, 2002
U.S. Provisional Application No. 60 / 366,515, filed 0 days, and U.S. Provisional Application No. 60 / 438,450, filed Jan. 7, 2003.

The present invention utilizes the enantiomers of substituted phenethyl sulfone compounds and pharmaceutically acceptable solvates, hydrates, co-crystals, clathrates, prodrugs and polymorphs to treat diseases and disorders. The present invention relates to methods and methods for reducing levels of cytokines and their precursors in mammals. The present invention also provides 2- [1- (3-ethoxy-4-methoxyphenyl)-
2-Methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione The (+)-enantiomer and a pharmaceutically acceptable carrier. The present invention further provides 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3 substantially free of its (−) enantiomer.
-Relates to the (+) enantiomer of dione.

The invention particularly relates to the (+) enantiomer of 2- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione. This compound is a racemic 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1
, 3-dione is believed to have increased potency and other benefits.

The present invention relates to 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl for treating or preventing diseases or disorders that ameliorate by inhibiting TNF-α production in mammals. ] Use of the (+) enantiomer of -4-acetylaminoisoindoline-1,3-dione. In some embodiments, the treatment includes reducing or avoiding adverse effects. Such disorders include, but are not limited to, head, thyroid, neck, eye, skin, mouth, pharynx, esophagus, chest, bone, blood, bone marrow, lung, colon, sigmoid colon, rectum, stomach, prostate, Cancers include but are not limited to breast, ovary, kidney, liver, pancreas, brain, intestine, heart, adrenal gland, subcutaneous tissue, lymph nodes, heart cancer, 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 treats heart diseases including, but not limited to, congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction. Or 2- [1- (3-ethoxy-4-methoxyphenyl) in prevention
2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione (+) enantiomer use.

The invention also provides for treating a disease or disorder that ameliorates by inhibition of PDE4.
[1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-
Includes the use of the (+) enantiomer of acetylaminoisoindoline-1,3-dione.
For example, the compounds and compositions of the invention can be useful for treating or preventing viral diseases, genetic diseases, inflammatory diseases, allergic diseases, and autoimmune diseases. Examples of such diseases include, but are not limited to, HIV; hepatitis; adult respiratory distress syndrome; bone resorption disease; chronic obstructive pulmonary disease; chronic pulmonary inflammatory disease; dermatitis; inflammatory skin disease, atopic dermatitis Septic shock; sepsis; endotoxin shock; hemodynamic shock; septic syndrome; reperfusion injury after ischemia; meningitis; psoriasis; fibrotic disease; cachexia; Autoimmune disease; rheumatoid spondylitis; arthritic symptoms such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; Includes lupus erythematosus; leprosy nodular erythema (ENL) in leprosy; radiation injury; asthma; and hyperoxic alveolar injury.

In another embodiment, the stereoisomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione is pure (+ ) Enantiomers also treat or treat microbial infections or symptoms of microbial infections, including but not limited to bacterial infections, fungal infections, malaria, mycobacterial infections, and opportunistic infections resulting from HIV Useful for prevention.

The present invention relates to the (+) enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione and pharmaceutically Further encompassed are pharmaceutical compositions and single dose formulations, including acceptable polymorphs, prodrugs, hydrates, clathrates, and solvates thereof.

In a separate embodiment, the present invention provides 2- [1- (3-ethoxy-4-methoxyphenyl)
2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione (+) enantiomer.

In a further embodiment, the invention provides 1- (3-ethoxy-4-methoxy-phenyl)-
Contacting 2-methanesulfonyl-ethylamine with a chiral amino acid and the product of the first step is N- (1,3-dioxo-1,3-dihydro-isobenzofuran-4-
Yl) -acetamide and contacting with 2- [1- (3-ethoxy-4-
Methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione as a stereoisomer includes a method for producing a pure (+) enantiomer. In a related embodiment, the invention provides 1- (3-ethoxy-4-methoxy-phenyl)
Includes chiral salts of -2-methanesulfonyl-ethylamine.

Embodiments herein include (+)-2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-
A solid form comprising a compound chemically named dione ("Compound A") is provided. Compound A can be synthesized or obtained according to any method apparent to one of ordinary skill in the art based on the teachings herein, including the methods described in the Examples below. Compound A is 2
It can also be prepared according to the method described in US Pat. No. 6,962,940 issued Nov. 8, 005, which is incorporated herein by reference in its entirety.

In some embodiments, the solid form is a single component crystalline form of Compound A. In some embodiments, the solid form is a multi-component crystalline form that includes, but is not limited to, a co-crystal comprising Compound A and / or a solvate (including hydrates). In other embodiments, the solid form is a single component amorphous form of Compound A. In other embodiments, the solid form is a multi-component amorphous form. Without being limited by any particular theory, some novel solid forms provided herein are particularly advantageous which make them useful, for example, for manufacturing, processing, formulating and / or storage. Physical properties and / or chemical properties, while also having particularly advantageous biological properties such as, for example, bioavailability and / or biological activity.

In specific embodiments, solid forms provided herein include, but are not limited to, solids comprising Compound A, including single component and multiple component solid forms comprising Compound A. Includes form. In some embodiments, solid forms provided herein include polymorphs comprising Compound A, solvates (including hydrates) and co-crystals. Some embodiments herein provide methods for making, isolating and / or characterizing the solid forms provided herein.

The solid form provided herein is a drug substance (ac) that prepares a formulation for use in a patient.
tive pharmaceutical ingredients). Accordingly, embodiments herein include the use of these solid forms as final formulations. Some embodiments are necessary, for example, for manufacturing, processing, formulating and / or storing the final formulation, among others, the flow properties, compression properties, tableting properties, stability properties, and additives of the powder To improve the properties, such as the compatibility properties, and to provide a solid form useful to produce the final dosage form. Some embodiments herein include single component crystalline forms, multiple component crystalline forms, single component amorphous comprising Compound A and a pharmaceutically acceptable excipient, additive or carrier. Pharmaceutical compositions comprising a quality form and / or a multi-component amorphous form are provided. The solid forms and final formulations provided herein are useful, for example, for the treatment, prevention or management of the diseases and disorders provided herein.

Some embodiments herein include HIV; hepatitis; adult respiratory distress syndrome; bone resorption disease; chronic obstructive pulmonary disease; chronic pulmonary inflammatory disease; asthma; dermatitis; cystic fibrosis; Sepsis; Endotoxin shock; Hemodynamic shock; Septic syndrome; Reperfusion injury after ischemia; Meningitis; Psoriasis; Fibrous disease; Cachexia; Graft rejection; Autoimmune disease;
Arthritic symptoms 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; Solids provided herein for treating, preventing or managing diseases or disorders that ameliorate by inhibiting TNF-α production in a mammal, such as radiation damage; asthma; and hyperoxia alveolar damage A method using a form is provided. Such disorders further include, but are not limited to, head, thyroid, neck, eye, skin, mouth, pharynx, esophagus, chest, bone, blood, bone marrow, lung, colon, sigmoid colon,
Cancers include, but are not limited to, rectal, stomach, prostate, breast, ovary, kidney, liver, pancreas, brain, intestine, heart, adrenal gland, subcutaneous tissue, lymph node, heart cancer and combinations thereof. Specific cancers that can be treated by this method are multiple myeloma, malignant melanoma, malignant glioma, leukemia and solid tumors. In some embodiments, the methods using solid forms provided herein include reducing or avoiding some adverse effects.

Some embodiments herein include, but are not limited to, congestive heart failure,
Using the solid form provided herein in the treatment or prevention of heart disease including cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction Provide a method.

Some embodiments herein provide methods of using the solid form provided herein to treat a disease or disorder that ameliorates by inhibition of PDE4. For example, the solid forms provided herein can be useful for treating or preventing viral diseases, genetic diseases, inflammatory diseases, allergic diseases, and autoimmune diseases. Examples of such diseases include, but are not limited to, HIV; hepatitis; adult respiratory distress syndrome; bone resorption disease; chronic obstructive pulmonary disease; chronic pulmonary inflammatory disease; dermatitis; inflammatory skin disease; ;
Cystic fibrosis; septic shock; sepsis; endotoxin shock; hemodynamic shock; septic syndrome; reperfusion injury after ischemia; meningitis; psoriasis; fibrosis; cachexia; Included graft rejection; autoimmune disease; rheumatoid spondylitis; arthritic symptoms such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; Leprosy nodular erythema (ENL) in leprosy; radiation damage;
Asthma; and hyperoxic alveolar injury.

Some embodiments herein include microbial infections or symptoms of microbial infections including but not limited to bacterial infections, fungal infections, malaria, mycobacterial infections, and opportunistic infections resulting from HIV. Methods of using the solid forms provided herein in treatment or prevention are provided.

Specific embodiments herein include: psoriasis; psoriatic arthritis; rheumatoid arthritis; chronic cutaneous sarcoid; giant cell arteritis; Parkinson's disease; nodular rash; Behcet's disease; lupus; hepatitis; uveitis; Sjogren's disease; depression (including major depression); interstitial cystitis; vulvar pain; prostatitis; Cell lymphoma; polymysoitis; dermatomyositis;
Solids provided herein in the treatment or prevention of diseases including inclusion body myositis; erosive osteoarthritis; interstitial cystitis; hepatitis; endometriosis; radiculopathy; and pyoderma gangrenosum A method of using a form is provided.

Some embodiments herein provide pharmaceutical compositions and single dose formulations comprising one or more solid forms provided herein.

FIG. 5 provides a representative powder X-ray diffraction (“XRPD”) pattern of Form A of Compound A. FIG. 10 provides a representative differential scanning calorimetry (“DSC”) plot of Form A of Compound A. 2 provides a representative thermogravimetric analysis (“TGA”) plot of Form A of Compound A. FIG. 2 provides a representative dynamic vapor sorption (“DVS”) plot of Form A of Compound A. FIG. FIG. 6 provides a representative XRPD pattern of Compound A Form B. FIG. 7 provides a representative DSC plot of Compound A Form B. FIG. 5 provides a representative TGA plot of Compound A Form B. FIG. 3 provides a representative DVS plot of Compound A Form B. FIG. 5 provides a representative XRPD pattern of Compound A Form C. FIG. 5 provides a representative DSC plot of Form A of Compound A. FIG. 7 provides a representative TGA plot of Compound A Form C. FIG. 7 provides a representative DVS plot of Compound A Form C. FIG. 5 provides a representative XRPD pattern of Compound A Form D. FIG. 6 provides a representative DSC plot of Compound A Form D. FIG. 7 provides a representative TGA plot of Compound A Form D. FIG. 6 provides a representative DVS plot of Form A of Compound A. FIG. 7 provides a representative XRPD pattern of Compound A Form E. FIG. 5 provides a representative DSC plot of Form A of Compound A. FIG. 5 provides a representative TGA plot of Form A of Compound A. FIG. 5 provides a representative DVS plot of Form A of Compound A. FIG. 10 provides a representative XRPD pattern of Form A of Compound A. FIG. 7 provides a representative DSC plot of Compound A Form F. FIG. 7 provides a representative TGA plot of Compound A Form F. FIG. 7 provides a representative DVS plot of Compound A Form F. FIG. 6 provides a representative XRPD of Compound A Form G. FIG. 6 provides a representative DSC plot of Form A of Compound A. FIG. 7 provides a representative TGA plot of Form A of Compound A. FIG. 5 provides a representative DVS plot of Compound A Form G. FIG. 2 shows the preparation of the (+) enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione. It is a figure which shows the effect on LPS induced neutropenia of the compound A in the lung of an awakening ferret. FIG. 10 shows the percentage change in epidermal thickness of all 15 subjects on Day 29 of a clinical trial evaluating Compound A in patients with severe plaque type psoriasis. FIG. 6 shows the change in mean iNOS (standardized for hARP) in a damaged skin biopsy specimen on Day 29 of a clinical trial evaluating Compound A in patients with severe plaque type psoriasis. Shows the percent change in Psoriasis Area and Severity Index (PASI) scores of patients that can be evaluated on Day 29 from the baseline clinical trial evaluating Compound A in patients with severe plaque-type psoriasis FIG.

3.2. Definitions As used herein, the term “Compound A” means that the column is 150 mm × 4.6.
mm Ultron Chiral ES-OVS chiral HPLC column (Agilen
t Technology), and the eluent is 15:85 ethanol: 20 with a pH of 3.5.
When it is mM KH ₂ PO ₄ and the observation wavelength is 240 nm, it is HPLC in about 25.4 minutes.
The enantiomers obtained from the column are pure (+)-2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione. means. The ¹ H NMR spectrum of Compound A is substantially as follows: δ (CDCl ₃ ); 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). The ¹³ C NMR spectrum of Compound A is substantially as follows: δ (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 polarization in the (+) direction.

Without being limited by theory, Compound A has S- {2-
[1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-
Acetylaminoisoindoline-1,3-dione}.

  As used herein, the term “patient” means a mammal, particularly a human.

As used herein, the term “pharmaceutically acceptable salts” is prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Means salt.

As used herein, unless otherwise indicated, the term “prodrug”
To provide the compound under biological conditions (in vitro or in vivo
Means a derivative of a compound that can be hydrolyzed, oxidized or otherwise reacted. Examples of prodrugs include, but are not limited to, biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs Derivatives and metabolites of Compound A that contain biohydrolyzable moieties such as the body are included. Prodrugs are usually 1 Burge
r's Medicinal Chemistry and Drug Discover
ry, pages 172-178, pages 949-982 (Manfred E. Wolff, Ed.
Can be prepared using well-known methods, such as the method described in US Pat.

As used herein, unless otherwise indicated, “biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzable carbamate”, “biohydrolyzable carbonate”,
The terms “biohydrolyzable ureido” and “biohydrolyzable phosphate” do not interfere with the biological activity of the compound, but give beneficial properties to the compound in vivo, such as uptake, duration of action or onset of action Or 2) biologically inert but in
Means an amide, ester, carbamate, carbonate, ureido, or phosphate, respectively, of a compound that is converted in vivo to a biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkylacylaminoalkyl 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 alkyl amines, substituted ethylene diamines, amino acids, hydroxyalkyl amines, heterocyclic and heteroaromatic amines, and polyether amines.

As used herein, unless otherwise indicated, the term “stereoisomerically pure” includes one stereoisomer of a compound and other stereoisomers of the compound are substantially free. Means a composition not present in For example, a stereomerically pure composition of a compound having one asymmetric center is substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two asymmetric centers is substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomer of the compound, more preferably one of the compounds More than about 90% by weight of stereoisomers and about 10% by weight of other stereoisomers of the compound
Less than, 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 stereoisomer of the compound, most preferably about one stereoisomer of the compound. Contains more than 97 wt% and less than about 3 wt% of other stereoisomers of the compound.

As used herein, unless otherwise indicated, the term “enantiomerically pure” means a stereomerically pure composition of a compound having one asymmetric center.

As used herein, the term “adverse effect” includes, but is not limited to, gastrointestinal toxicity, nephrotoxicity and hepatotoxicity, leukopenia, eg, increased bleeding time due to thrombocytopenia, and pregnancy period. Includes prolonged, nausea, vomiting, somnolence, asthenia, dizziness, teratogenicity, extrapyramidal symptoms, akathisia, cardiotoxicity including cardiovascular disorders, inflammation, male sexual dysfunction, and elevated serum liver enzyme levels . The term “gastrointestinal toxicity” includes, but is not limited to, gastric and intestinal ulceration and erosion. The term “nephrotoxicity” includes, but is not limited to, conditions such as renal papillary necrosis and chronic interstitial nephritis.

As used herein, unless otherwise indicated, the phrases “reducing or avoiding adverse effects” and “reducing or avoiding adverse effects” refer to one or more of the terms defined herein. It means a reduction in the severity of adverse effects.

Note that if there is a discrepancy between the indicated structure and the name given to that structure, the indicated structure will be emphasized. Further, where a structural stereochemistry or part of a structure is not shown, for example, in bold or dotted lines, the structure or part of a structure is to be interpreted as encompassing all stereoisomers thereof.

As used herein, unless otherwise indicated, the term “solid form” and related terms refer to physical forms that are not primarily in a liquid or gaseous state. As used herein, unless otherwise indicated, the term "solid form" and related terms are
As used herein to mean Compound A, it means a physical form comprising Compound A that is not primarily in a liquid or gaseous state. The solid form can be crystalline, amorphous or a mixture thereof. In a specific embodiment, the solid form can be a liquid crystal. The “single component” solid form comprising Compound A consists essentially of Compound A. "Multiple components" containing Compound A
The solid form of the present includes a significant amount of one or more additional species, such as ions and / or molecules, within the solid form. For example, in a specific embodiment, the crystalline multi-component solid form comprising Compound A further comprises one or more species that are non-covalently bonded at normal positions in the crystal lattice. Multiple component solid forms comprising Compound A include co-crystals, solvates (eg, hydrates) and inclusion bodies of Compound A. In a specific embodiment, the term “solid form comprising Compound A” and related terms include single component and multiple component solid forms comprising Compound A. In a specific embodiment, “solid form comprising Compound A” and related terms include crystalline forms comprising Compound A, amorphous forms comprising Compound A, and mixtures thereof.

As used herein, “crystalline” as used herein, unless otherwise indicated.
The terms and related terms, when used to describe a compound, substance, modified form, material, component or product, refer to that compound, substance, modified form, material, component or product unless otherwise indicated. Determining by X-ray diffraction means substantially crystalline. For example, Remington: The Science and Practice of
Pharmacy, 21st edition, Lippincott, Williams and Wi
lkins, Baltimore, MD (2005); US Pharmacopeia, 23rd edition, 18
See pages 43-1844 (1995).

As used herein, unless otherwise indicated, the “crystalline form”, “
The term “crystalline form” and related terms mean a solid form that is crystalline. Crystal forms include, but are not limited to, single-component and multi-component crystal forms,
Polymorphs, solvates, hydrates, and / or other molecular complexes are included. In some embodiments, the crystalline form of the material may be substantially free of amorphous and / or other crystalline forms. In some embodiments, the crystalline form of the material is about 1%, 2% on a weight basis.
%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 3%
Less than 0%, 35%, 40%, 45% or 50% of one or more amorphous forms and / or
Or other crystal forms may be included. In some embodiments, the crystalline form of the material can be physically and / or chemically pure. In some embodiments, the crystalline form of the substance is
About 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 9
It may be 0% physically and / or chemically pure.

As used herein, unless otherwise indicated, the terms “polymorph”, “polymorphic form” and related terms herein are the same molecule, the same plurality of molecules, and / or the same By two or more crystal forms consisting essentially of ions. Different polymorphs, such as different crystal forms, result from the arrangement or conformation of molecules and / or ions in the crystal lattice, for example, melting temperature, heat of fusion, solubility, elution properties and / or vibrational spectra, etc. May have different physical properties. Differences in physical properties can affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacture), and dissolution rate (an important factor in bioavailability). Differences in stability can be due to changes in chemical reactivity (eg, differential oxidation such that the dosage form changes color more quickly when it is composed of one polymorph than when it is composed of other polymorphs) or machine. Changes (eg, tablets break up on storage because kinetically favored polymorphs are converted to thermodynamically more stable polymorphs) or both (eg, one polymorphic tablet is May be susceptible to collapse at high humidity). As a result of solubility / elution differences, in extreme cases, some solid state transitions can result in lack of efficacy, or in other extreme cases, lack of toxicity. In addition, physical properties can be important in processing (e.g., one polymorph may be more likely to form a solvate or may be difficult to filter and wash to remove impurities, particle shape and Size distribution may vary between polymorphs).

As used herein, unless otherwise indicated, the terms “solvate” and “solvated” refer to a crystalline form of a substance comprising a solvent. "Hydrate" and "Hydrated"
The term means a solvate wherein the solvent comprises water. “Solvate polymorph” means the presence of more than one crystalline form of a particular solvate composition. Similarly, a “hydrate polymorph” is
It means the presence of more than one crystal form of a particular hydrate composition. As used herein, the term “desolvated solvate” means a crystalline form of a substance that can be prepared by removing a solvent from a solvate.

As used herein, unless otherwise indicated, the terms “amorphous”, “amorphous form” and related terms used herein refer to the substance, component or product of interest. This means that the object is not substantially crystalline as determined by X-ray diffraction. In particular, the term “amorphous form” refers to a disordered solid form, ie, a solid form lacking long-range crystalline order. In some embodiments, the amorphous form of the material may be substantially free of other amorphous and / or crystalline forms. In other embodiments, the amorphous form of the material is
Approximately 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 3% on a weight basis
It may comprise less than 0%, 35%, 40%, 45% or 50% of one or more other amorphous and / or crystalline forms. In some embodiments, the amorphous form of the material can be physically and / or chemically pure. In some embodiments, the amorphous form of the material is about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 9
1% or 90% physically and / or chemically pure.

Techniques that characterize crystalline and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopy Methods such as infrared (IR) and Raman spectroscopy, solid state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (
SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility measurement,
Includes elution measurement, elemental analysis and Karl Fischer analysis. Characteristic unit cell parameters 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. Techniques useful for analyzing powder diffraction data include profile precision such as the Rietveld method that can be used to analyze diffraction peaks associated with a single phase in a sample containing more than one solid phase. Included. Other methods useful for analyzing powder diffraction data include unit cell indexing, which allows one skilled in the art to determine unit cell parameters from a sample containing crystalline powder.

As used herein, unless otherwise indicated, the terms “about” and “approximately” refer to a numerical value or range of values provided to characterize a particular solid form, such as a particular temperature. Or a temperature range such as, for example, representing a DSC or TGA thermal event, including melting, dehydration, desolvation or glass transition events; mass change, eg, mass change as a function of temperature or humidity; Or water content, eg expressed in weight or percentage; or peak position, eg IR or Raman spectroscopy or XRPD
When used in connection with such as in the analysis according to the above, while still representing the specific solid form, it indicates that the value or range of values may deviate as deemed appropriate to one skilled in the art. For example, in specific embodiments, the terms “about” and “approximately” are used in this context and unless otherwise indicated, a numerical value or range of numerical values is 25 of the listed value or range of values. %, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,
It is shown that it can vary within the range of 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25%.

As used herein and unless otherwise indicated, “substantially pure”, eg, certain crystalline or amorphous forms substantially free of other solid forms and / or other chemical compounds In a specific embodiment, the sample comprising about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4% One or more other solid forms of less than 1 wt%, 3 wt%, 2 wt%, 1 wt%, 0.75 wt%, 0.5 wt%, 0.25 wt% or 0.1 wt% And / or other chemical compounds.

As used herein and unless otherwise indicated, a sample or composition that is “substantially free of one or more other solid forms and / or other compounds” In typical embodiments, about 25%, 20%, 15%, 10%, 9%, 8%
%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0%
. It is meant to contain less than 75%, 0.5%, 0.25% or 0.1% by weight of one or more other solid forms and / or other compounds.

As used herein, unless otherwise indicated, “treat”, “treating”
The term “treatment” means eradication or amelioration of a disease or disorder, or eradication or amelioration of one or more symptoms associated with a disease or disorder. In some embodiments, these terms minimize the spread or worsening of a disease or disorder caused by administration of one or more prophylactic or therapeutic agents to a patient with such a disease or disorder. Means. In some embodiments, these terms refer to administering a compound provided herein with or without other additional effective agents after the occurrence of symptoms of a particular disease. .

As used herein, unless otherwise indicated, “prevent”, “prevent”
And the term “prevention” means prevention of the occurrence, recurrence or spread of a disease or disorder or one or more of those symptoms. In some embodiments, these terms may be used in patients at risk of a disease or disorder provided herein, with or without other additional active compounds prior to the onset of symptoms. It means treating with or administering to a compound provided herein. These terms encompass the suppression or reduction of symptoms of a particular disease. Specifically, patients with a family history of disease are candidates for prevention regimens in some embodiments. In addition, patients with a history of recurrent symptoms are also potential candidates for prevention. From this point of view, the term “prevention” can be used synonymously with the term “prophylactic treatment”.

As used herein, unless otherwise indicated, “manage”, “manage”
And the term “management” means preventing or delaying the progression, spread or worsening of a disease or disorder or of one or more of those symptoms. Often, the beneficial effects that patients obtain from prophylactic and / or therapeutic agents do not result in cure of the disease or disorder. In this regard, the term “managing” encompasses treating a patient suffering from a particular disease in an attempt to prevent or minimize the recurrence of the disease.

As used herein, unless otherwise indicated, a “therapeutically effective amount” of a compound provides a therapeutic benefit in the treatment or management of a disease or disorder, or is associated with a disease or disorder An amount sufficient to delay or minimize multiple symptoms. A therapeutically effective amount of a compound means the amount of the 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"
An amount that improves the overall therapy, reduces or avoids the symptoms or causes of the disease or disorder, or enhances the therapeutic effect of other therapeutic agents can be included.

As used herein, unless otherwise indicated, 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 the therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing disease. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of other prophylactic agents.

As used herein, the term “composition” refers to a product comprising a specified component (in a specified amount, if indicated), as well as a specified amount, either directly or indirectly. Any product resulting from the combination of the ingredients described is intended to be included. “Pharmaceutically acceptable” means that the excipient, additive or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. To do.

Mode for carrying out the invention

4). Detailed Description of the Invention The present invention relates to 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylamino which is substantially free of its (-) enantiomer. Stereoisomerically pure compound A which is the (+) enantiomer of isoindoline-1,3-dione and the novel process used and the stereoisomerically pure compound A and / or compound A containing compound A It relates to a composition comprising a form. For example, the invention encompasses single dose formulations useful for the in vitro and in vivo use of Compound A, the incorporation of Compound A into pharmaceutical compositions, and the treatment and prevention of various diseases and disorders. Diseases and disorders that ameliorate by reducing TNF-α levels or inhibiting PDE4 are well known in the art and are described herein. Specific methods of the invention reduce or avoid the adverse effects associated with compounds used as TNF-α inhibitors. Other specific methods of the present invention include racemic 2- [
Reduce or avoid adverse effects associated with the use of 1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione.

Specific methods of the present invention include methods for treating or preventing diseases and disorders including but not limited to solid tumors, hematological tumors and inflammatory diseases.

Compound A or a pharmaceutically acceptable polymorph, prodrug, clathrate, solvate or hydrate thereof (specific embodiments include solid forms comprising Compound A as described herein) The pharmaceutical products and dosage forms of the present invention containing the above can be used in the method of the present invention.

Without being limited by theory, Compound A including a solid form containing Compound A
Is believed to be capable of inhibiting TNF-α production. As a result, the first of the present invention
Embodiments of the invention include a compound A or a pharmaceutically acceptable prodrug, metabolite, polymorph, solvate, hydrate thereof as an effective amount of stereoisomers in cells exhibiting abnormal TNF-α production. ,
Alternatively, specific embodiments relate to a method of inhibiting TNF-α production comprising contacting a clathrate (a specific embodiment includes a solid form comprising Compound A as described herein). In a specific embodiment, the present invention provides a method for treating mammalian cells exhibiting abnormal TNF-α production with an effective amount of stereoisomers as pure Compound A or a pharmaceutically acceptable prodrug, metabolite, TNF-α production comprising contacting the form, solvate, hydrate, or clathrate (in specific embodiments, including solid forms comprising Compound A as described herein) It relates to a method of inhibiting.

The invention also provides a method of treating, preventing or managing a disorder ameliorating by reducing TNF-α levels in a patient, which comprises a therapeutically effective amount or prophylaxis for a patient in need of such treatment or prevention. A top effective amount of a stereoisomerically pure compound A or a pharmaceutically acceptable prodrug, metabolite, polymorph, solvate, hydrate, or clathrate (specific embodiments are Including a solid form comprising Compound A as described herein). In a specific embodiment, a disease or disorder that is ameliorated by inhibition of TNF-α production in a mammal includes, but is not limited to: HIV; hepatitis;
Adult respiratory distress syndrome; bone resorption disease; chronic obstructive pulmonary disease; chronic lung inflammatory disease; asthma; dermatitis; cystic fibrosis; septic shock; sepsis; endotoxin shock; Subsequent reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; transplant rejection; autoimmune disease; rheumatoid spondylitis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lupus erythematosus; cutaneous lupus erythematosus; pulmonary sarcoidosis; Includes cell damage. Such disorders include, but are not limited to, head, thyroid, neck, eye, skin, mouth, pharynx, esophagus, breast, bone, blood, bone marrow, lung, colon, sigmoid colon, rectum, stomach, prostate, Further included are cancers including but not limited to breast, ovary, kidney, liver, pancreas, brain, intestine, heart, adrenal gland, subcutaneous tissue, lymph nodes, heart cancer, 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 present invention is a method of treating or preventing cancer in a patient, including but not limited to solid tumors, hematologic tumors, leukemias, especially multiple myeloma, wherein such treatment or prevention is required. A therapeutically effective amount of a stereoisomerically pure compound A or a pharmaceutically acceptable prodrug, metabolite, polymorph, solvate, hydrate or inclusion body thereof (a specific embodiment) Includes solid forms containing Compound A as described herein)
In particular, the patient is a mammal.

In other embodiments, the invention is a method of inhibiting PDE4, wherein PDE4 in a cell (eg, a mammalian cell) is pure Compound A or a pharmaceutically acceptable as an effective amount of a stereoisomer. Contacting the prodrug, metabolite, polymorph, solvate, hydrate or clathrate (specific embodiments include solid forms comprising Compound A described herein). Relates to a method comprising:

A further embodiment of the invention is a method of treating or preventing a disease or disorder ameliorated by inhibition of PDE4 in a patient, wherein the patient in need of such treatment or prevention is a therapeutically effective amount or a prophylactically effective amount. Stereoisomerically pure Compound A or a pharmaceutically acceptable prodrug, metabolite, polymorph, solvate, hydrate or clathrate (specific embodiments are described herein) Including a solid form comprising Compound A). Disorders ameliorated by inhibition of PDE4 include, but are not limited to, asthma, inflammation (eg inflammation due to reperfusion), chronic or acute obstructive pulmonary disease,
Includes chronic or acute pulmonary inflammatory disease, inflammatory bowel disease, Crohn's disease, Behcet's disease, or colitis.

In another embodiment, the present invention provides a method of controlling cAMP levels in a cell comprising pure compound A or a pharmaceutically acceptable prodrug, metabolite thereof, with the cell as an effective amount of a stereoisomer, Contacting a polymorph, solvate, hydrate or clathrate (specific embodiments include solid forms comprising Compound A as described herein). As used herein, the term “controls cAMP levels” includes adenosine 3 ′, 5′-cyclic mono in a cell, preferably a mammalian cell, more preferably a human cell. Inhibiting or reducing the rate of phosphate (cAMP) degradation, or increasing the amount of adenosine 3 ′, 5′-cyclic monophosphate present in the cell. In a specific method, the rate of cAMP degradation is about 10, 25, 50, 100, 2 compared to the proportion in similar cells not contacted with a compound of the invention.
Reduced to 00 or 500 percent.

Further embodiments of the invention include depression, asthma, inflammation (eg, contact dermatitis, atopic dermatitis, psoriasis, rheumatoid arthritis, osteoarthritis, inflammatory skin disease, inflammation due to reperfusion), chronic in patients Or acute obstructive pulmonary disease, chronic or pulmonary inflammatory disease, inflammatory bowel disease,
A method of treating or preventing Crohn's disease, Behcet's disease or colitis, wherein a therapeutically effective amount or a prophylactically effective amount of a stereoisomer pure compound A or pharmaceutical for a patient in need of such treatment or prevention Acceptable prodrugs, metabolites, polymorphs, solvates, hydrates or clathrates thereof (specific embodiments include solid forms comprising Compound A described herein) In particular, the patient is a mammal.

Another embodiment of the invention is a method of treating or preventing myelodysplastic syndrome (MDS), wherein a therapeutically effective amount or a prophylactically effective amount of a stereoisomer in a patient in need of such treatment or prevention. As pure Compound A or a pharmaceutically acceptable solvate, hydrate, stereoisomer, clathrate, or prodrug thereof (specific embodiments include Compound A described herein) Including a solid form). MDS
It refers to a diverse group of hematopoietic stem cell disorders. MDS is characterized by various risks of progression to acute leukemia resulting from bone marrow of cells with impaired morphology and maturation (myelopoiesis), peripheral blood cytopenias, and the production of ineffective blood cells. The Merck Manual 95
3 (17th edition 1999) and List et al., 1990, J. MoI. Clin. Onco
l. 8: 1424.

Another embodiment of the invention is a method of treating or preventing myeloproliferative disease (MPD), wherein a therapeutically effective amount or a prophylactically effective amount of a stereoisomer in a patient in need of such treatment or prevention. As pure Compound A or a pharmaceutically acceptable solvate, hydrate, stereoisomer, clathrate, or prodrug thereof (specific embodiments are described in Compound A described herein)
Including a solid form comprising). Myeloproliferative disease (MPD) refers to a group of disorders characterized by clonal abnormalities of hematopoietic stem cells. For example,
Current Medical Diagnosis & Treatment, 49
See page 9 (37th edition, edited by Tierney et al., Appleton & Lange, 1998).

The present invention also treats pain, including but not limited to complex regional pain syndrome,
A method of preventing or managing comprising a therapeutically effective amount or a prophylactically effective amount of a stereoisomer pure compound A or a pharmaceutically acceptable solvate thereof in a patient in need of such treatment, prevention or management Administering a compound, hydrate, stereoisomer, clathrate, or prodrug (specific embodiments include a solid form comprising Compound A described herein). Include. In a specific embodiment, administration is prior to surgery or physical therapy,
The aim is to reduce or avoid symptoms of complex regional pain syndrome in patients during or after construction.

In specific methods of the invention, stereoisomerically pure Compound A or a pharmaceutically acceptable polymorph, prodrug, solvate, hydrate, or clathrate (specific embodiments are Including solid forms comprising Compound A as described herein) is administered adjunctively with at least one additional therapeutic agent. Examples of additional therapeutic agents include, but are not limited to, anticancer drugs, anti-inflammatory drugs, antihistamines and decongestants.

4.1. Solid Forms Comprising Compound A Some embodiments herein provide a solid form comprising Compound A having the chemical structure shown above. Racemic 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione is a US patent incorporated herein by reference. It is easily prepared using the method of 6,020,358. Compound [A], the (+) enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione, is obtained by reference. US Pat. No. 6,962,9 incorporated herein.
It can be prepared according to any method apparent to those skilled in the art including the method described in No. 40.

Solid forms comprising Compound A include crystalline and amorphous forms, and polymorphs,
Single component and multiple component forms are included, including but not limited to solvates, hydrates, co-crystals and inclusion bodies. The specific embodiments herein provide a single component amorphous solid form of Compound A. The specific embodiments herein provide a single component crystalline solid form of Compound A. Specific embodiments herein include compounds A
A multi-component amorphous form comprising The specific embodiments herein provide a multi-component crystalline solid form comprising Compound A. Multi-component solid forms provided herein include solid forms that may be described by the terms salt, co-crystal, hydrate, solvate, clathrate and / or polymorph, Solid forms that may be described by one or more of these terms are included.

The solid form comprising Compound A can be prepared by methods described herein, including those described in the Examples below, or by heating, cooling, freeze drying, lyophilization, quenching of the melt, rapid solvent Evaporation, slow solvent evaporation, solvent recrystallization, antisolvent addition, slurry recrystallization,
Crystallization from a melt, desolvation, eg recrystallization in a limited space such as in nanopores or capillaries, eg recrystallization on a surface such as a polymer or on a template, eg co-crystal versus molecule Recrystallization in the presence of additives such as, desolvation, dehydration, rapid cooling, slow cooling, immersion in solvent and / or water, eg drying including vacuum drying, vapor diffusion, sublimation (eg ,
Known in the art, including grinding (including cryogenic grinding, solvent drop grinding or liquid assisted grinding), microwave induced precipitation, sonication induced precipitation, laser induced precipitation and supercritical fluid precipitation Can be prepared by existing techniques. The particle size of the resulting solid form, which may vary (eg from nanometer to millimeter dimensions), for example, by changing the crystallization state, such as the rate of crystallization and / or the crystallization solvent system, or for example By particle size reduction techniques such as grinding, pulverizing, pulverizing or sonication,
For example, it can be controlled.

Without being bound to any particular theory, some solid forms are characterized by physical properties suitable for pharmaceutical and therapeutic formulations, such as stability, solubility and dissolution rate. In addition, while not wishing to be bound by any particular theory, some solid forms may require certain processes (e.g., some solid forms suitable for the production of solid dosage forms)
Yield, filtration, washing, drying, fine grinding, mixing, tableting, fluidity, elution, blending, and lyophilization)
Physical properties that affect (e.g. density, compressibility, hardness, morphology, cutting, stickiness, solubility, water uptake, electrical properties, thermal behavior, solid state reactivity, physical stability, And chemical stability). Such properties are determined using specific analytical chemistry techniques, including the solid state analytical techniques described herein and well known in the art (eg, X-ray diffraction, microscopy, spectrometry and thermal analysis). Can be determined.

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

In addition to the solid form comprising Compound A, provided herein is a solid form comprising a prodrug of Compound A.

The solid forms provided herein can also include unnatural proportions of atomic isotopes at one or more of the atoms in Compound A. For example, the compound may be radiolabeled with a radioactive isotope such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I), sulfur-35 ( ³⁵ S), or carbon-14 ( ¹⁴ C). Can do. Radiolabeled compounds can be used, for example, for therapeutic agents such as cancer therapeutics, for example, research reagents such as binding test reagents, and for example in vivo.
It is useful as a diagnostic agent such as a vo contrast agent. 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. Compound A Form A
Some embodiments herein provide a Form A crystal form of Compound A. In some embodiments, Form A of Compound A can be obtained from a variety of solvents, including but not limited to solvent systems including acetone, ethanol, and mixtures thereof. In some embodiments, Form A can be obtained using a fast cooling crystallization method.

In some embodiments, Form A of Compound A can be characterized by powder X-ray diffraction analysis. A representative XRPD pattern of Form A of Compound A is provided in FIG. In some embodiments, Form A of Compound A has the following approximate position: 8.1 at 2θ
°, 14.4 °, 15.2 °, 17.4 °, 18.4 °, 19.2 °, 20.5 °, 22
. 8 °, 23.2 °, 23.6 °, 24.5 °, 25.1 ° are 1, 2, 3, 4, 5, 6, 7
, 8, 9, 10, 11, or 12 characterized by XRPD peaks. In some embodiments, Form A of Compound A is characterized by an XRPD pattern that matches the pattern shown in FIG. In some embodiments, Form A of Compound A is 1, 2, 3, 4, 5, 6, 7, 8, consistent with the peaks of the representative Form A pattern provided herein.
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22
Characterized by XRPD patterns with 23, 24 or 25 peaks.

In some embodiments, Form A of Compound A can be characterized by thermal analysis. A representative DSC plot of Form A of Compound A is shown in FIG. In some embodiments, Form A features a DSC plot that includes an endothermic event with an onset temperature of about 145 ° C. In some embodiments, Form A features a DSC plot that further includes an endothermic event with an onset temperature of about 155 ° C. A representative TGA plot of Form A of Compound A is shown in FIG. In some embodiments, Form A is about 25
A mass loss of less than about 1% of the total mass of the sample after heating to from about 0.degree.
. Characterized by a TGA plot with a mass loss of 05%. In some embodiments,
Form A of Compound A does not contain a substantial amount of water or other solvent in the crystal lattice. In some embodiments, Form A is unsolvated. In some embodiments, Form A is anhydrous.

In some embodiments, Form A of Compound A can be characterized by moisture sorption analysis. A representative moisture sorption isotherm plot is shown in FIG. In some embodiments, when the relative humidity (“RH”) is increased from about 0% to about 95% RH, Form A is
It exhibits a mass change of less than about 1% of the starting mass of the sample, for example, a mass change of about 0.4%. In some embodiments, when RH decreases to about 0% of the original RH, the increased mass after absorption is lost. Thus, in some embodiments, Form A is substantially non-hygroscopic. In some embodiments, the XRPD pattern of Form A material is not substantially altered in the adsorption / desorption analysis. In some embodiments, Form A is stable with respect to humidity.

In some embodiments, Form A of Compound A can be characterized by its stability profile. In some embodiments, the Form A material is stable, for example, its XRPD pattern is exposed to elevated temperature, exposed to elevated humidity, exposed to one or more solvents, and / or compressed. Remains substantially unchanged. In some embodiments, for example, Form A is stable to about 4 weeks exposure to an environment of about 40 ° C. and an environment of about 75% RH. In some embodiments, Form A is about 40 ° C. in one or more solvent systems comprising, for example, ethanol, water and / or heptane.
At least about 4 weeks of exposure. In some embodiments, Form A
Converts to Form C of Compound A after 4 weeks exposure to a solvent including but not limited to toluene. In some embodiments, Form A is stable to compression for about 1 minute at about 2000 psi pressure.

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

Some embodiments herein provide Form A of Compound A that is substantially pure. Some embodiments herein can be found, for example, in Form B, provided herein.
Form A of Compound A is substantially free of other solid forms comprising Compound A, including C, D, E, F, G, and / or an amorphous solid form comprising Compound A. Some embodiments herein include, for example, the following forms B, C, D, E, F provided herein:
Form A is provided as a mixture of solid forms comprising Compound A, including mixtures comprising one or more of the amorphous solid forms comprising G, Compound A.

4.1.2. Compound A Form B
Some embodiments herein provide a Form B crystal form of Compound A. In some embodiments, Form A of Compound A is, but is not limited to, 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, heptane, methanol, methyl ethyl ketone, methyl t-butyl ether, methylene chloride, n-butanol , Acetic acid n-
It can be obtained from a variety of solvents, including solvent systems including butyl, tetrahydrofuran, toluene, water and mixtures containing two or more thereof. For example, in some embodiments,
Form B can be obtained by crystallization from a solvent system comprising ethanol: water 1: 1, for example by evaporating the ethanol: water 1: 1 solvent system at about 25 ° C. and then isolating Form B Can be obtained by a method including the step of: For example, in some embodiments, Form B can be obtained by crystallization from a solvent system comprising acetone: ethanol 1: 1, for example, acetone: ethanol 1: 1 at about 25 ° C. for about 2 days. It can be obtained by a process comprising slurrying a solid form comprising Compound A and then isolating Form B.

In some embodiments, Form A of Compound A can be characterized by powder X-ray diffraction analysis. A representative XRPD pattern of Compound A Form B is provided in FIG. In some embodiments, Form B of Compound A has the following approximate positions: 10.
1 °, 12.4 °, 13.5 °, 15.7 °, 16.3 °, 18.1 °, 20.7 °, 2
2.5 °, 24.7 °, 26.2 °, 26.9 °, 29.1 ° are 1, 2, 3, 4, 5, 6
, 7, 8, 9, 10, 11, or 12 characterized by XRPD peaks. In some embodiments, Form B of Compound A is an XRP that matches the pattern shown in FIG.
Characterized by a D pattern. In some embodiments, Form B of Compound A is 1, 2, 3, 4, 5, 6, 7, which matches the peaks of the representative Form B pattern provided herein.
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
Characterized by an XRPD pattern having 22, 23, 24 or 25 peaks.

In some embodiments, Form A of Compound A can be characterized by thermal analysis. A representative DSC plot for Form A of Compound A is shown in FIG. In some embodiments, Form B features a DSC plot that includes an endothermic event with an onset temperature of about 154 ° C. A representative TGA plot of Compound A Form B is shown in FIG. In some embodiments, Form B is a TGA plot that includes a mass loss of less than about 1% of the total mass of the sample after heating to about 25 ° C. to about 140 ° C., eg, a mass loss of about 0.25%. It is characterized by. In some embodiments, Form B of Compound A does not include a substantial amount of water or other solvent in the crystal lattice. In some embodiments, Form B is anhydrous. In some embodiments, Form B is unsolvated.

In some embodiments, Form B of Compound A can be characterized by moisture sorption analysis. A typical moisture sorption isotherm plot is shown in FIG. In some embodiments, when RH increases from about 0% to about 95% RH, Form B exhibits a mass change of less than about 1% of the starting mass of the sample, eg, a mass change of about 0.6%. Show. In some embodiments, when RH decreases to about 0% of the original RH, the increased mass after absorption is lost. In some embodiments, Form B is substantially non-hygroscopic. In some embodiments, the XRPD pattern of Form B material is not substantially altered in the adsorption / desorption analysis. In some embodiments, Form B is stable with respect to humidity.

In some embodiments, Form A of Compound A can be characterized by its stability profile. In some embodiments, the Form B material is stable, for example, its XRPD pattern is exposed to elevated temperature, exposed to elevated humidity, exposed to one or more solvents, and / or compressed. Remains substantially unchanged. In some embodiments, for example, Form B is stable to about 4 weeks of exposure to an environment of about 40 ° C. and an environment of about 75% RH. In some embodiments, Form B is at least about 4 at about 40 ° C. in a solvent system comprising, for example, ethanol, water and / or heptane.
Stable to weekly exposure. In some embodiments, Form B converts to Compound A Form C upon exposure to a solvent system comprising, for example, toluene for about 4 weeks. In some embodiments, Form B is stable to compression for about 1 minute at about 2000 psi pressure.

In some embodiments, Form A of Compound A can be characterized by particle analysis. In some embodiments, Form B is characterized as a white powder. In some embodiments, the Form B sample comprises particles having a flake-like morphology. In some embodiments, the Form B sample comprises particles having a D ₉₀ of less than about 12 μm.

Some embodiments herein provide Form B of Compound A that is substantially pure. Some embodiments herein can be found, for example, in Form A, provided herein.
Form A of Compound A is substantially free of other solid forms comprising Compound A, including C, D, E, F, G, and / or an amorphous solid form comprising Compound A. Some embodiments herein include, for example, the following forms A, C, D, E, provided herein:
Form B is provided as a mixture of solid forms comprising Compound A, including mixtures comprising one or more of the amorphous solid forms comprising F, G and Compound A.

4.1.3. Compound A Form C
Some embodiments herein provide a Form C crystal form of Compound A. In some embodiments, Form A of Compound A is a solvent that includes, but is not limited to, acetone, acetonitrile, ethanol, heptane, methanol, methyl ethyl ketone, tetrahydrofuran, toluene, water, and mixtures comprising two or more thereof. It can be obtained from a variety of solvent systems, including systems. For example, in some embodiments, Form C can be obtained by crystallization from a solvent system comprising toluene, such as using toluene as an antisolvent and then isolating Form C. Can be obtained by:

In some embodiments, Form A of Compound A can be characterized by powder X-ray diffraction analysis. A representative XRPD pattern of Form A of Compound A is provided in FIG. In some embodiments, Form C of Compound A has the following approximate position: 7.5 at 2θ
°, 11.3 °, 15.3 °, 16.4 °, 17.8 °, 21.4 °, 22.6 °, 23
. 5 °, 24.8 °, 25.5 °, 26.4 °, 27.6 ° are 1, 2, 3, 4, 5, 6,
Characterized by XRPD peaks located at 7, 8, 9, 10, 11, or 12. In some embodiments, Form A of Compound A is an XRPD that matches the pattern shown in FIG.
Characterized by a pattern. In some embodiments, Form A of Compound A is 1, 2, 3, 4, 5, 6, 7, 8 that matches the peak of the representative Form C pattern provided herein.
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 2
Characterized by an XRPD pattern having 2, 23, 24, or 25 peaks.

In some embodiments, Form A of Compound A can be characterized by thermal analysis. A representative DSC plot of Form A of Compound A is shown in FIG. In some embodiments, Form C includes an endothermic event with an onset temperature of about 138 ° C.
Features a plot. In some embodiments, the characteristic Form C DSC plot further includes one or more additional events, eg, an endothermic event with an onset temperature of about 166 degrees Celsius. A representative TGA plot of Form A of Compound A is shown in FIG. In some embodiments, Form C has a TGA plot that includes a mass loss of less than about 10% of the total mass of the sample after heating to about 25 ° C. to about 140 ° C., eg, a mass loss of about 5.9%. Features. In some embodiments, the TGA mass loss event is, for example, T
As shown by G-IR analysis, it includes the loss of solvent toluene. In some embodiments, Form C of Compound A is solvated. In some embodiments, Form C
Is a toluene solvate. In some embodiments, the crystal lattice of Form C comprises about 3 molar equivalents of toluene per mole of Compound A.

In some embodiments, Form A of Compound A can be characterized by moisture sorption analysis. A typical moisture sorption isotherm plot is shown in FIG. In some embodiments, when RH increases from about 0% to about 95% RH, Form C exhibits a mass change of less than about 1% of the starting mass of the sample, eg, a mass change of about 0.5%. Show. In some embodiments, when RH decreases to about 0% of the original RH, the increased mass after absorption is lost. In some embodiments, Form C is substantially non-hygroscopic. In some embodiments, the XRPD pattern of Form C material remains substantially unchanged after adsorption / desorption analysis. In some embodiments, Form C is stable with respect to humidity.

In some embodiments, Form A of Compound A can be characterized by its stability profile. In some embodiments, the Form C material is stable, for example, its XRPD pattern is exposed to elevated temperature, exposed to elevated humidity, exposed to one or more solvents, and / or compressed. Remains substantially unchanged. In some embodiments, for example, Form C is stable for about 4 weeks of exposure to an environment of about 40 ° C. and an environment of about 75% RH. In some embodiments, Form C is at least about 4 at about 40 ° C. in a solvent system comprising, for example, ethanol, water, heptane or toluene.
Stable to weekly exposure. In some embodiments, Form C is about 2000 p.
Stable to compression for about 1 minute at si pressure.

In some embodiments, Form A of Compound A can be characterized by particle analysis. In some embodiments, Form C is characterized as a white powder. In some embodiments, the Form C sample comprises particles having a plate-like morphology. In some embodiments, the Form C sample comprises particles having a D ₉₀ of less than about 12 μm.

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

4.1.4. Compound A Form D
Some embodiments herein provide a Form D crystal form of Compound A. In some embodiments, Form A of Compound A can be obtained from a variety of solvents, including but not limited to solvent systems including methylene chloride. For example, in some embodiments, Form D can be obtained by crystallization from a solvent system comprising methylene chloride,
For example, it can be obtained by a method comprising the steps of evaporating methylene chloride and then isolating form D.

In some embodiments, Form A of Compound A can be characterized by powder X-ray diffraction analysis. A representative XRPD pattern of Form A of Compound A is shown in FIG. In some embodiments, Form A of Compound A has the following approximate position: 7.5 at 2θ
°, 9.6 °, 11.3 °, 13.9 °, 16.3 °, 17.7 °, 20.5 °, 23.
2 °, 24.6 °, 25.2 °, 26.0 °, 28.8 ° are 1, 2, 3, 4, 5, 6, 7
, 8, 9, 10, 11, or 12 characterized by XRPD peaks. In some embodiments, Form A of Compound A is an XRPD that matches the pattern shown in FIG.
Characterized by a pattern. In some embodiments, Form A of Compound A is 1, 2, 3, 4, 5, 6, 7, 8 that matches the peak of the representative Form D pattern provided herein.
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 2
Characterized by an XRPD pattern having 2, 23, 24, or 25 peaks.

In some embodiments, Form A of Compound A can be characterized by thermal analysis. A representative DSC plot of Form A of Compound A is shown in FIG. In some embodiments, Form D includes an endothermic event with an onset temperature of about 100 ° C.
Features a plot. A representative TGA plot of Compound A Form D is shown in FIG. In some embodiments, Form D has a TGA plot that includes a mass loss of less than about 10% of the total mass of the sample after heating to about 25 ° C. to about 110 ° C., eg, a mass loss of about 6.5%. Features. In some embodiments, the TGA mass loss event is, for example,
As indicated by TG-IR analysis, it includes the loss of the solvent methylene chloride (ie, dichloromethane). In some embodiments, Form A of Compound A is solvated. In some embodiments, Form D is a methylene chloride solvate. In some embodiments, the crystal lattice of Form D comprises about 2.5 molar equivalents of methylene chloride per mole of Compound A.

In some embodiments, Form A of Compound A can be characterized by moisture sorption analysis. A representative moisture sorption isotherm plot is shown in FIG. In some embodiments, when RH increases from about 0% to about 95% RH, Form D exhibits a mass change of less than about 3% of the starting mass of the sample, eg, a mass change of about 1.5%. Show. In some embodiments, when RH decreases to about 0% of the original RH, the increased mass after absorption is lost. Thus, in some embodiments, Form D is slightly hygroscopic. In some embodiments, the XRPD pattern of Form D material is not substantially altered in the adsorption / desorption analysis. In some embodiments, Form D is stable with respect to humidity.

In some embodiments, Form A of Compound A can be characterized by its stability profile. In some embodiments, the Form D material is stable, for example, its XRPD pattern remains substantially unchanged upon compression. For example, in some embodiments, Form D is stable to compression for about 1 minute at about 2000 psi pressure. In some embodiments, Form D has an environment of about 40 ° C. and about 75% RH.
Although stable to about 4 weeks of exposure to the environment, in some embodiments, Form D XR
The resulting peak intensity of the PD pattern decreases. In some embodiments, XRPD
The decrease in peak intensity is caused by the formation of an amorphous material containing Compound A. In some embodiments, Form D converts to Compound A Form B upon exposure to a solvent system comprising, for example, heptane, ethanol and / or water at about 40 ° C. for about 4 weeks. In some embodiments, Form D converts to Compound A Form C upon exposure to a solvent system comprising toluene at about 40 ° C. for about 4 weeks.

In some embodiments, Form A of Compound A can be characterized by particle analysis. In some embodiments, Form D is characterized as a white powder. In some embodiments, the Form D sample comprises particles having a flake-like morphology. In some embodiments, Form D samples comprise particles having a D ₉₀ of less than about 18 μm.

Some embodiments herein provide Form D of Compound A that is substantially pure. Some embodiments herein can be found, for example, in Form A, provided herein.
Form A of Compound A substantially free of other solid forms comprising Compound A, including amorphous solid forms comprising Compound A, B, C, E, F, G and / or Compound A . Some embodiments herein include, for example, the following forms A, B, C, E, provided herein:
Form D is provided as a mixture of solid forms comprising Compound A, including mixtures comprising one or more of the amorphous solid forms comprising F, G and Compound A.

4.1.5. Form A of Compound A
Some embodiments herein provide a Form E crystal form of Compound A. In some embodiments, Form E of Compound A is obtained from a variety of solvents, including but not limited to solvent systems including acetone, acetonitrile, heptane, methylene chloride, and mixtures comprising two or more thereof. be able to. For example, in some embodiments, Form E
Can be obtained by crystallization from a solvent system containing acetonitrile, for example,
It can be obtained by a method comprising the steps of evaporating acetonitrile and then isolating Form E.

In some embodiments, Form A of Compound A can be characterized by powder X-ray diffraction analysis. A representative XRPD pattern of Form A of Compound A is provided in FIG. In some embodiments, Form E of Compound A has the following approximate position:
6 °, 9.2 °, 11.4 °, 15.5 °, 16.5 °, 17.9 °, 19.6 °, 20
. 5 °, 21.6 °, 22.8 °, 23.8 °, and 26.6 ° are 1, 2, 3, 4, 5, 6,
Characterized by XRPD peaks located at 7, 8, 9, 10, 11, or 12. In some embodiments, Form E of Compound A is an XRP that matches the pattern shown in FIG.
Characterized by a D pattern. In some embodiments, Form E of Compound A is 1, 2, 3, 4, 5, 6, 7, which matches the peak of the representative Form E pattern provided herein.
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
Characterized by an XRPD pattern having 22, 23, 24 or 25 peaks.

In some embodiments, Form A of Compound A can be characterized by thermal analysis. A representative DSC plot for Form A of Compound A is shown in FIG. In some embodiments, Form E features a DSC plot that includes an endothermic event with an onset temperature of about 95 ° C. A representative TGA plot of Form E of Compound A is shown in FIG. In some embodiments, Form E has a TGA plot that includes a mass loss of less than about 8% of the total mass of the sample after heating to about 25 ° C. to about 110 ° C., eg, a mass loss of about 4.0%. Features. In some embodiments, the TGA mass loss event is, for example, TG-I
As shown by R analysis, it includes the loss of the solvent acetonitrile. In some embodiments, Form E of Compound A is solvated. In some embodiments, Form E
Is an acetonitrile solvate. In some embodiments, the crystal lattice of Form E is
Contains about 2.5 molar equivalents of acetonitrile per mole of Compound A.

In some embodiments, Form E of Compound A can be characterized by moisture sorption analysis. A typical moisture sorption isotherm plot is shown in FIG. In some embodiments, when RH increases from about 0% to about 95% RH, Form E exhibits a mass change of less than about 10% of the starting mass of the sample, eg, a mass change of about 5.1%. Show. In some embodiments, when RH decreases to about 0% of the original RH, the increased mass after absorption is lost. In some embodiments, Form E is hygroscopic. In some embodiments, the XRPD pattern of Form E material is not substantially altered in the adsorption / desorption analysis. In some embodiments, Form E is stable with respect to humidity.

In some embodiments, Form E of Compound A can be characterized by its stability profile. In some embodiments, the Form E material is stable, for example, its XRPD pattern remains substantially unchanged upon compression. For example, in some embodiments, Form E is stable to compression for about 1 minute at about 2000 psi pressure.

In some embodiments, Form E of Compound A can be characterized by particle analysis. In some embodiments, Form E is characterized as a white powder. In some embodiments, the Form E sample comprises particles having a flake-like morphology. In some embodiments, Form E samples comprise particles having a D ₉₀ of less than about 18 μm.

Some embodiments herein provide Form E of Compound A that is substantially pure. Some embodiments herein can be found, for example, in Form A, provided herein.
Form A of Compound A substantially free of other solid forms comprising Compound A, including amorphous solid forms comprising Compound A, B, C, D, F, G and / or Compound A . Some embodiments herein include, for example, Forms A, B, C, D, F provided below
Form E as a mixture of solid forms comprising Compound A, including mixtures comprising one or more of the amorphous solid forms comprising G, Compound A.

4.1.6. Compound A Form F
Some embodiments herein provide a Form F crystal form of Compound A. In some embodiments, Form A of Compound A can be obtained from a variety of solvents including, but not limited to, solvent systems including acetone, ethanol, water, and mixtures comprising two or more thereof. . For example, in some embodiments, Form F can be obtained by crystallization from a solvent system comprising ethanol and / or water, for example, a solid form comprising Compound A comprises ethanol and / or water. It can be obtained by a method comprising contacting a solvent system and then isolating Form F.

In some embodiments, Form A of Compound A can be characterized by powder X-ray diffraction analysis. A representative XRPD pattern of Form A of Compound A is shown in FIG. In some embodiments, Form A of Compound A has the following approximate position: 8.1 ° at 2θ,
8.6 °, 15.6 °, 17.3 °, 19.3 °, 21.4 °, 22.8 °, 24.6 °
25.4 °, 25.9 °, 26.6 °, 27.7 ° are 1, 2, 3, 4, 5, 6, 7, 8
, 9, 10, 11, or 12 characterized by XRPD peaks. In some embodiments, Form A of Compound A is characterized by an XRPD pattern that matches the pattern shown in FIG. In some embodiments, Form A of Compound A is 1, 2, 3, 4, 5, 6, 7, 8, 9 that matches the peaks of the representative Form F pattern provided herein.
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
Characterized by an XRPD pattern having 23, 24 or 25 peaks.

In some embodiments, Form A of Compound A can be characterized by thermal analysis. A representative DSC plot of Form A of Compound A is shown in FIG. In some embodiments, Form F features a DSC plot that includes an endothermic event with an onset temperature of about 145 ° C. A representative TGA plot of Form A of Compound A is shown in FIG.
In some embodiments, Form F is characterized by a TGA plot that includes a mass loss of less than about 1% of the total mass of the sample after heating to about 25 ° C. to about 180 ° C., eg, about 0.1%. To do. In some embodiments, Form A of Compound A does not include a substantial amount of water or other solvent in the crystal lattice. In some embodiments, Form F is unsolvated. In some embodiments, Form F is anhydrous.

In some embodiments, Form A of Compound A can be characterized by moisture sorption analysis. A representative moisture sorption isotherm plot is shown in FIG. In some embodiments, when RH is increased from about 0% to about 95% RH, Form F exhibits a mass change of less than about 1% of the starting mass of the sample, eg, a mass change of about 0.2%. Show. In some embodiments, when RH decreases to about 0% of the original RH, the increased mass after absorption is lost. In some embodiments, Form F is substantially non-hygroscopic. In some embodiments, the XRPD pattern of Form F material is not substantially altered in the adsorption / desorption analysis. In some embodiments, Form F is stable with respect to humidity.

In some embodiments, Form A of Compound A can be characterized by its stability profile. In some embodiments, the Form F material is stable, for example, its XRPD pattern remains substantially unchanged upon compression. For example, in some embodiments, Form F is stable to compression for about 1 minute at about 2000 psi pressure. In some embodiments, Form F is stable to exposure to about 2 days at about 25 ° C. in a solvent system comprising, for example, ethanol, acetone or mixtures thereof.

In some embodiments, Form A of Compound A can be characterized by particle analysis. In some embodiments, Form F is characterized as a white powder. In some embodiments, the Form F sample comprises particles having a flake-like morphology. In some embodiments, Form F samples comprise particles having a D ₉₀ of less than about 18 μm.

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

4.1.7. Compound A Form G
Some embodiments herein provide a Form G crystal form of Compound A. In some embodiments, Form G of Compound A can be obtained from a variety of solvents, including but not limited to solvent systems including ethyl acetate. For example, in some embodiments, Form G can be obtained by crystallization from a solvent system comprising ethyl acetate, for example, contacting a solid form comprising Compound A with a solvent system comprising ethyl acetate, It can then be obtained by a method comprising the step of isolating Form G.

In some embodiments, Form A of Compound A can be characterized by powder X-ray diffraction analysis. A representative XRPD pattern of Form A of Compound A is provided in FIG.
In some embodiments, Form A of Compound A has the following approximate position: 7.9 ° at 2θ
9.5 °, 11.7 °, 15.7 °, 16.8 °, 18.1 °, 19.7 °, 21.8
°, 22.8 °, 25.1 °, 25.8 °, 26.7 ° are 1, 2, 3, 4, 5, 6, 7,
Characterized by an XRPD peak located at 8, 9, 10, 11, or 12. In some embodiments, Form A of Compound A is characterized by an XRPD pattern that matches the pattern shown in FIG. In some embodiments, Form A of Compound A is 1, 2, 3, 4, 5, 6, 7, 8, consistent with the peaks of the representative Form G pattern provided herein.
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22
Characterized by XRPD patterns with 23, 24 or 25 peaks.

In some embodiments, Form A of Compound A can be characterized by thermal analysis. A representative DSC plot for Form A of Compound A is shown in FIG. In some embodiments, Form G features a DSC plot that includes an endothermic event with an onset temperature of about 109 ° C. A representative TGA plot of Compound A Form G is shown in FIG. In some embodiments, Form G is a TGA plot comprising a mass loss of less than about 8% of the total mass of the sample after heating to about 25 ° C. to about 110 ° C., eg, a mass loss of about 3.8% It is characterized by. In some embodiments, the TGA mass loss event is, for example, TG-
As indicated by IR analysis, it includes the loss of the solvent ethyl acetate. In some embodiments, Form G of Compound A is solvated. In some embodiments, Form G is an ethyl acetate solvate. In some embodiments, the crystal lattice of Form G comprises about 3 molar equivalents of ethyl acetate per mole of Compound A.

In some embodiments, Form A of Compound A can be characterized by moisture sorption analysis. A typical moisture sorption isotherm plot is shown in FIG. In some embodiments, when RH increases from about 0% to about 95% RH, Form G exhibits a mass change of less than about 1% of the starting mass of the sample, eg, a mass change of about 0.4%. Show. In some embodiments, when RH decreases to about 0% of the original RH, the increased mass after absorption is lost. In some embodiments, Form G is substantially non-hygroscopic. In some embodiments, the XRPD pattern of Form G material is not substantially altered in the adsorption / desorption analysis. In some embodiments, Form G is stable with respect to humidity.

In some embodiments, Form A of Compound A can be characterized by its stability profile. In some embodiments, the Form G material is stable, for example, its XRPD pattern remains substantially unchanged upon compression. For example, in some embodiments, Form F is stable to compression at about 2000 psi pressure for about 1 minute. In some embodiments, Form G converts to Form B upon exposure to a solvent system comprising, for example, ethanol, acetone or mixtures thereof at about 25 ° C. for about 2 days.

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

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

4.2. Methods of Treatment The present invention is a method of treating, preventing or managing a disease or disorder that ameliorates by reducing TNF-α levels in a patient, for example, Form A of Compound A as provided herein, Compound A, such as Compound A Form B, Compound A Form C, Compound A Form D, Compound A Form E, Compound A Form F, Compound A Form G, or Amorphous Form of Compound A Including a method comprising administering a therapeutically effective amount or prophylactically effective amount of one or more solid forms comprising to a patient in need of such treatment, prevention or management.

Disorders ameliorated by inhibition of TNF-α include, but are not limited to: congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and Heart disease such as myocardial infarction; sarcoma, cancer, fibrosarcoma, myxosarcoma, liposarcoma,
Chondrosarcoma, osteogenic sarcoma, chordoma, hemangiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic endothelial sarcoma, synovial, mesothelioma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer Breast cancer, ovarian cancer, prostate cancer, squamous cell cancer, basal cell cancer, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary cancer, papillary adenocarcinoma, cystadenocarcinoma, medullary cancer, bronchogenic lung cancer, Renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, fetal cancer, Wilms tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrology Cell tumor, medulloblastoma, craniopharyngioma, ependymoma, Kaposi's sarcoma, pineal tumor,
Solid tumors including but not limited to hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma; and acute lymphoblastic Leukemia "ALL", acute lymphoblastic B cell leukemia, acute lymphoblastic T cell leukemia, acute myeloblastic leukemia "AML", acute promyelocytic leukemia "APL", acute monoblastic leukemia, Acute erythrocytic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute undifferentiated leukemia, chronic myelogenous leukemia “CML”, chronic lymphocytic leukemia “CLL”, hairy cell Examples include leukemias, multiple myeloma, and acute and chronic leukemias such as hematologic tumors including but not limited to lymphoblastic, myeloid, lymphocytic, and myelocytic leukemia.

Specific methods of the invention further include 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, alkylating agents, nitrogen mustard, ethyleneimine, methylmelamine, alkyl sulfonates, nitrosourea, triazene, folic acid analogs, pyrimidine analogs, purine analogs, Anti-cancer drugs such as, but not limited to, vinca alkaloids, epipodophyllotoxins, antibiotics, topoisomerase inhibitors and anti-cancer vaccines are included.

Specific additional therapeutic agents include but are not limited to acivicin; aclarubicin;
Acodazole hydrochloride; acronin; adzelesin; aldesleukin; altretamine; ambomycin; amethanetron acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase;
Azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafidodimesylate (bisna)
fide dimesylate); bicerecin; bleomycin sulfate; brequinal sodium; bropirimine; busulfan; cactinomycin; carsterone; caracemide;
Carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate (crisn)
atol mesylate); cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexolmaplatin; deazaguanin
e); dezaguanine mesylate; diaziquone
Docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; ephlornitine hydrochloride; elsamitrucin; enloplatin
Enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorbicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate;
Fazarabine hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; hosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; gemcitabine hydrochloride; hydroxyurea; Interleukin II (including recombinant interleukin II or rIL2), interferon α
-2a; interferon α-2b; interferon α-n1; interferon α-
n3; interferon β-Ia; interferon γ-Ib; iproplatin (ipropl
atine); irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; riarozole hydrochloride; lometrexol sodium; lomustine; rosoxantrone hydrochloride; mazoprocol; maytansine; mechlorethamine hydrochloride; Purine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocrimin; Mitocromin; Mitogillin; Santron; Mycophenolic acid; Nocodazole; Nogaramycin; Ormaplatin; Oxythran; Paclitaxel; Peguas Rugaze; Perio clarithromycin (
pelimycin); pentamustine; pepromycin sulfate; perphosphamide; pipobroman; piposulphane; pyroxanthrone hydrochloride; prikamycin;
Porfimer sodium; Porphyromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazofurin; Pyrazofurin; Ribopurine; Logretimide; Saphingol; Safingol hydrochloride; Semustine; Simtrazene; Sart Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Sulofenur; Talysomycin; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride; Temoporfin; Thioguanine; thiotepa; thiazofurin; tirapazamine; toremifene citrate; trestron acetate; Silybin; trimetrexate; glucuronate trimetrexate; triptorelin; hydrochloride Tsuburozoru; uracil mustard;
Uredepa; vapleotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate
Binleurosin sulfate; Vinorelbine tartrate; Vinrosidin sulfate; Vinzolidine sulfate; Borozol; Zeniplatin; Dinostatin; Zorubicin hydrochloride. Other anti-cancer drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adesipenol; adzelesin; aldesleukin;
Antagonists; altretamine; ambamustine; amidox
dox); amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; antarelix;
Antiandrogen, Prostate cancer; Antiestrogen; Antineoplaston; Antisense oligonucleotide; Aphidicolin glycinate; Apoptosis gene modulator; Apoptosis regulator; Apric acid; Ara-CDP-DL-PTBA; Asulacrine); Atamestan; Atristine; Axinastatin 1; Axinastatin 2; Axinastatin 3; Azasetron; Azatoxin; Azatyrosine; Baccatin III derivatives; Ballanol; Batimastat; );
β-lactam derivatives; β-alletin; betaclamicin B; betulinic acid; bFGF inhibitor;
Bicalutamide; bisantren; bisaziridinylspermine; bisnafide
); Bistratene A; biselesin; breflate; bropirimine; budotitanium; buthionine sulphoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; CARN 700; cartilage-derived inhibitor; calzeresin; casein kinase inhibitor (ICOS); castanospermine; cecropin B
Chlorinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analog; clotrimazole; chorismycin A; chorismycin B; combretastatin A4; combretastatin analog; Krysnatol; Cryptophysin 8; Cryptophycin A derivative; Classin A; Cyclopentanetraquinone; Cycloplatam; Cypemycin; Cytarabine ocphosphate; Cytolytic factor; Cytostatin; Dacliximab; Decitabine; Dexrazoxane; Dexverapamil; Diaziquan; Didemnin B; Zidox; Diethylnorspermine; Dihydro-5 Azacitidine; 9-dihydro-taxol; dioxacarboxylic mycin; diphenylspiro Mus Chin; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;
Ecomustine; Edelfosin; Edrecolomab; Eflorolnitin; Elemene; Emitefur; Epirubicin; Epristeride; Estramustine analogues; Estrogen agonists; Flavopiridol; frzelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; hotemustine; gadolinium texaphyrin; gallium nitrate; Inhibitors;
Hepsulfame; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramanton; ilmofosin; ilomasterat; imidazoacridone; imiquimod; immunostimulating peptide; Interferon; Interleukin; Iobuguan; Iododoxorubicin; 4-Ipomeanol; Iropract; Irsogladine; Isobengazole;
ondrin B); itasetron; jaspraquinolide; kahalalide F; lamellarin-N triacetate; lanreotide; reinamycin; lenograstim; lentinan sulfate; leptorstatin;
Estrogen + progesterone; leuprorelin; levamisole; riarosol; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; rissoclinamide 7; lovasplatin; lombricin; Phyllin; lysophylline; soluble peptide; mayansin (maitansine); mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitor;
Menogalil; Melvalon; Meterelin; Methioninase; Metoclopramide; MIF inhibitor; Mifepristone; Miltefosin; Milimostim; Mismatched double-stranded RNA; Mitguazone; Mitactol; Mitomycin analog; Mofaroten; morulamostim; human chorionic gonadotropin monoclonal antibody; monophosphoryl lipid A + myobacterium (
myobacterium) cell wall sk; mopidamol; multidrug resistance gene inhibitor; multiple tumor suppressor 1 based therapy; mustard anticancer agent; micaperoxide B; mycobacterial cell wall extract; myriapolone; N-acetyldinarine; Nafarelin; nagrestip; naloxone + pentazocine; napabin; naphterpine;
Narutograstim; nedaplatin; nemorubicin; neridronate; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulator; nitroxide antioxidant;
Onitrile; O6-Benzylguanine; Octreotide; Oxenone; Oligonucleotide; Onapristone; Ondansetron; Ondansetron; Oracin; Oral cytokine inducer; Ormaplatin; Osaterone; Oxaliplatin; Oxaunomycin; Derivatives; Palauamine (palauami
ne); palmitoyl lysoxin; pamidronic acid; panaxitriol; panomiphene; parabactin; parazectin; pegaspargase; perdesin; sodium pentosan polysulfate; pentostatin; pentrozole; Phenazinomycin; phenyl acetate; phosphatase inhibitor; picibanil; pilocarpine hydrochloride; pirarubicin;
Plastin A; prasetin B; plasminogen activator inhibitor; platinum complex; platinum compound; platinum-triamine complex; porfimer sodium; porphyromycin; prednisone; propylbisacridone; prostaglandin J2; Protein kinase C inhibitor; microalgae protein kinase C inhibitor; protein tyrosine phosphatase inhibitor; purine nucleoside phosphorylase inhibitor; purpurin; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene complex; raf antagonist; raltitrexed Ramosetron; ras farnesyl protein transferase inhibitor; ras inhibitor; ras-GAP inhibitor; Chin; etidronate rhenium Re 186; rhizoxins; ribozymes; RII
Rotinit; Rokinimex; Rubimex; Rubiginon B1; Rubixil; Safingoles; Signon; SarCNU; Sarcophytol A; Sargramostim; Sdi1 mimetic; Semustine; Senescence-derived inhibitor 1; Inhibitors; Signaling modulators; Single-chain antigen-binding proteins; Schizophyllan; Sobuzoxane; Sodium borocaptate
sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sonfomin acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; Stipiamide; stromelysin inhibitor; sulfinosine; superactive vasoactive intestinal peptide antagonist; suraista; suramin; swainsonine; synthetic glycosaminoglycan; talimustine; tamoxifen methiodide; tauromustine; Tegafur; tellurapyryl
telomerase inhibitor; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; taliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; Tilapazamine; titanocene dichloride; topcentin; toremifene; totipotent stem cell factor; translation inhibitor; tretinoin; triacetyluridine; tricitrebin; trimethrexate; triptorelin; tropisetron; tyrosteride; Urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonist; bapleutide;
Varioline B; vector system, erythrocyte gene therapy; veralesol; veramine;
rdin); verteporfin; vinorelbine; vinxaltine; vitaxin; borozole; zanoterone; xeniplatin; dilascorb; and dinostatin stimamarer.

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

Specific methods of the invention can include the administration of additional therapeutic agents such as, but not limited to, anti-inflammatory agents, antihistamines and decongestants. Examples of such additional therapeutic agents include, but are not limited to, ethanolamine, ethylenediamine, piperazine, and phenothiazine; antihistamines; anti-inflammatory agents;
Contains salicylate, acetominophen, acetominophen, indomethacin, sulindac, etodolac, fenamic acid, tolmetine, ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam, pyrazolone derivatives NSAI is not limited to
DS; and steroids including but not limited to cortical steroids and corticosteroids.

The specific methods of the present invention avoid or reduce other adverse effects associated with drugs used to treat such disorders, including drug interactions and racemic substituted phenylethyl sulfones. Without being limited by any theory, some solid forms, including Compound A, are racemic 2- [1- (3-ethoxy-4-methoxyphenyl), including their solid forms. ) -2-Methylsulfonylethyl] -4-acetylaminoisoindoline-1
, 3-dione may further result in an overall improved therapeutic efficacy or therapeutic index.

As noted above, some solid forms comprising Compound A can be used for the treatment or prevention of a wide range of diseases and conditions. The magnitude of a prophylactic or therapeutic amount of a particular active ingredient of the present invention in the acute or chronic management of a disease or condition can vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. The dose, and possibly the frequency of administration, will also vary according to age, weight and individual patient response. Appropriate dosing regimens can be readily selected by those skilled in the art in view of such factors. In general, the recommended daily dose range for the conditions described herein is from about 1 mg to about 1 per day, given a single daily dose, preferably divided doses throughout the day. , 000 mg.
More specifically, the daily dose is administered twice daily at equally divided doses. Specifically, the daily dose range is from about 5 mg to about 500 mg per day, more specifically from about 10 mg per day to
It can be about 200 mg. Specifically, the daily dose is 5 mg, 10 mg, 15 mg, 20
It can be administered in dosage forms of mg, 25 mg, 50 mg, or 100 mg. In patient management, therapy is initiated at a low dose, perhaps about 1 mg to about 25 mg, and about 200 mg to about 1 per day as a single or divided dose, if necessary, depending on the patient's overall response.
The dose should be increased to 1,000 mg. Alternatively, the daily dose is 0.01 mg / kg to 1
00 mg / kg.

As will be apparent to those skilled in the art, in some cases it may be necessary to use dosages of the active ingredient outside the ranges disclosed herein. In addition, the clinician or treating physician
Note that we know how and when to stop, adjust or terminate treatment in conjunction with individual patient response.

As used herein, the phrases “therapeutically effective amount”, “prophylactically effective amount” and “therapeutically or prophylactically effective amount” encompass the above doses and dosing frequency schedule. Different therapeutically effective amounts may be applicable to different diseases and conditions, as will be readily apparent to those skilled in the art. Similarly, an amount sufficient to treat or prevent such a disorder, but 2
-[1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4
-Amounts that are not sufficient to cause the adverse effects associated with the racemic form of acetylaminoisoindoline-1,3-dione or that are sufficient to reduce the adverse effects associated therewith are also encompassed by the dose and dosing frequency schedule. The

4.3. Pharmaceutical compositions Pharmaceutical compositions comprising one or more solid forms comprising Compound A and single dose formulations are:
Provided herein. Also provided herein are methods for preparing pharmaceutical compositions and single dose formulations comprising one or more solid forms comprising Compound A. For example, in some embodiments, an individual dosage form comprising a solid form provided herein or an individual dosage form prepared using a solid form provided herein is orally, Suitable for mucosal (including rectal, nasal, or vaginal), parenteral, sublingual, transdermal, buccal, or topical administration (including subcutaneous, intramuscular, bolus injection, intraarterial, or intravenous) obtain.

In some embodiments, the pharmaceutical compositions and dosage forms provided herein comprise one or more solid forms comprising Compound A. Some embodiments herein are:
For example, a pharmaceutical composition comprising a solid form comprising Compound A, such as Form A, B, C, D, E, F, G provided herein, or an amorphous solid form comprising Compound A, and A dosage form is provided, wherein the solid form comprises substantially pure Compound A. Some embodiments herein include Compound A, such as, for example, Form A, B, C, D, E, F, G provided herein, or an amorphous solid form comprising Compound A. Pharmaceutical compositions and dosage forms comprising solid forms comprising, for example, comprising Form A, B, C, D, E, F, G and / or Compound A provided herein There are substantially no other solid forms comprising Compound A, including amorphous solid forms. Some embodiments herein include, for example, one of the following amorphous solid forms comprising Form A, B, C, D, E, F and Compound A provided herein: Pharmaceutical compositions and dosage forms are provided that comprise a mixture of solid forms comprising Compound A, including mixtures comprising species or plurality. The pharmaceutical compositions and dosage forms provided herein typically also include one or more pharmaceutically acceptable additives, excipients or carriers.

The specific pharmaceutical composition encompassed by this embodiment comprises one or more solid forms comprising Compound A and at least one additional therapeutic agent. Examples of additional therapeutic agents include, but are not limited to, anti-cancer drugs and anti-inflammatory therapies, including but not limited to those provided herein.

The single dose formulation of the present invention can be administered to a patient orally (eg, nasal, sublingual, vaginal, buccal, or rectal), parenteral (eg, subcutaneous, intravenous, bolus injection, intramuscular, Or suitable for transdermal administration to a patient. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules such as soft elastic gelatin capsules; cachets;
Lozenges; lozenges; dispersions; suppositories; ointments; poultices (poultices); pasta agents; powders; bandages; creams; plasters; Oral or mucosal administration to patients including suspensions (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs And sterile solids (eg, crystalline or amorphous solids) that can be reconstituted to provide a liquid dosage form suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention will typically vary depending on their use.
For example, a dosage form used for acute treatment of inflammation or related disorders may contain one or more active ingredients it contains in higher amounts than used for chronic treatment of the same disease. Similarly, a parenteral dosage form may contain one or more active ingredients it contains in lesser amounts than an oral dosage form used to treat the same disease or disorder. These and other ways in which specific dosage forms encompassed by this invention will vary from one another will be readily apparent to those skilled in the art. For example, Re
minton's Pharmaceutical Sciences, 18th edition, M
See ack Publishing, Easton PA (1990).

Typical pharmaceutical compositions and dosage forms comprise one or more additives. Suitable additives are
Non-limiting examples of suitable additives that are well known to those skilled in the pharmaceutical arts are provided herein. Whether a particular additive is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, methods of administering the dosage form to a patient. For example, oral dosage forms such as tablets can contain additives that are not suitable for use in parenteral dosage forms. The suitability of a particular additive can also depend on the particular active ingredient in the dosage form.

The lactose-free composition of the present invention can include additives well known in the art, such as listed in the United States Pharmacopeia (USP) SP (XXI) / NF (XVI). Yes. In general, a composition that is free of lactose comprises the active ingredient, binder / filler, and lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Preferred dosage forms that do not contain lactose are:
Contains active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (eg, 5%) is widely accepted in the pharmaceutical arts as a means of facilitating long-term storage to determine properties such as shelf life or stability of the formulation over time. For example, Jens T. Carstensen, Drug
Stability: Principles & Practice, 2nd edition, Mar
cel Dekker, NY, NY, 1995, pages 379-80. In practice, water and heat accelerate the decomposition of some compounds. Therefore, the effect on water formulation is
During manufacturing, handling, packaging, storage, transportation, and use of the formulation, moisture and / or humidity generally occurs and can be of great importance.

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

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

The invention further encompasses pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by 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 buffer, or salt buffer.

Like the amount and type of additive, the amount and specific type of active ingredient in the dosage form can vary depending on factors such as, but not limited to, the route of administration to the patient. However, typical dosage forms provided herein are single daily doses in the morning, preferably about 1 mg to about 1. mg / day, preferably divided daily doses. Within the range of 000 mg. More specifically, the daily dose is administered twice daily at equally divided doses. In particular,
The daily dose range can be about 5 mg to about 500 mg per day, more specifically about 10 mg to about 200 mg per day. In managing the patient, the therapy is a low dose, perhaps about 1 m.
Starting at g to about 25 mg and depending on the patient's overall response, the dose can be increased from about 200 mg to about 1,000 mg daily as a single or divided dose, if necessary.

4.3.1. Oral dosage forms Pharmaceutical compositions of the present invention suitable for oral administration include, but are not limited to, tablets (eg, chewable tablets), caplets, capsules, liquids (eg, flavored syrups), and the like Can be provided as separate dosage forms. Such dosage forms contain predetermined amounts of active ingredients and can be prepared by pharmaceutical methods well known to those skilled in the art. In general, Remington's Pharmaceutical Sciences, 18th.
See Edition, Mack Publishing, Easton PA (1990).

A typical oral dosage form of the present invention is prepared by combining at least one additive and one (or more) active ingredients in a homogeneous mixture according to conventional pharmaceutical mixing techniques. Additives can take a wide variety of forms depending on the form of preparation desired for administration. For example, suitable additives for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of suitable additives for use in solid oral dosage forms (eg, powders, tablets, capsules, and caplets) include, but are not limited to, starch, sugar, microcrystalline cellulose, excipients, Granulating agents, lubricants, binders, and disintegrants are included.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid additives are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms mix the active ingredient uniformly and homogeneously with a liquid carrier, a finely divided solid carrier, or both,
Then, if necessary, it is prepared by shaping the product to the desired appearance.

For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with additives. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid excipient.

Examples of additives that can be used in the oral dosage form of the present 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, gum arabic, sodium alginate, alginic acid, other alginate, tragacanth powder, Natural and synthetic gums such as guar gum, cellulose and derivatives thereof (eg, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose (eg,
No. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

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

Suitable forms of microcrystalline cellulose include, but are not limited to (FMC Corpo
relation, American Viscose Division, Avicel
AVICEL-PH-10 (available from Salees, Marcus Hook, PA)
1 ™, AVICEL-PH-103 ™, AVICEL RC-581 ™, AVICEL-PH-105 ™, and materials sold as mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581 ™. Suitable anhydrous or low moisture additives 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 containing excess disintegrant may disintegrate during storage, while those containing too little disintegrant may not disintegrate at the desired rate or in the desired state. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredient should be used to form the solid oral dosage form of the present invention. The amount of disintegrant used will vary based on the type of formulation and is readily identifiable to those skilled in the art. A typical pharmaceutical composition comprises from about 0.5 to about 15 weight percent of the disintegrant, specifically from about 1 to about 1 of the disintegrant.
About 5 percent by weight.

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

Lubricants that can be used in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light oil, glycerin,
Sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate,
Includes ethyl oleate, ethyl laurate, agar, and mixtures thereof. Additional lubricants include, for example, syloid silica gel (Baltimore)
MD W.M. R. Grace Co. AEROSIL 200 (manufactured by
™), a solidified aerosol of synthetic silica (sold by Degussa Co., Plano, TX), CAB-O-SIL ™ (Cab, MA, Boston, MA)
ot Co. Exothermic silicon dioxide products sold by the company), and mixtures thereof. If used at all, lubricants are usually used in an amount of less than about 1 weight percent of the pharmaceutical composition or dosage form into which they are incorporated.

4.3.2. Delayed Release Dosage Forms Solid forms comprising Compound A provided herein can be administered by controlled release means or by delivery devices well known to those skilled in the art. Examples include, but are not limited to, U.S. Pat. Nos. 3,845,770; 3,916,899;
536,809; 3,598,123; and 4,008,719, 5,6
74,533, 5,059,595, 5,591,767, 5,120,5
48, 5,073,543, 5,639,476, 5,354,556,
And those described in US Pat. No. 5,733,566, each of which is incorporated herein by reference. Such dosage forms are for example hydropropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres to provide the desired release profile at varying rates. ,
Or a combination thereof can be used to provide slow or controlled release of one or more active ingredients. Suitable controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the present invention. Accordingly, the present invention encompasses single dose formulations suitable for oral administration such as, but not limited to, tablets, capsules, gel caps and caplets that are adapted for controlled release.

All controlled release pharmaceutical products have a common goal of improving the drug treatment achieved by the uncontrolled equivalent. Ideally, the use of optimally designed controlled release formulations in medical treatment is characterized by the use of minimal drug substance to cure or control the condition in a minimum amount of time And Advantages of controlled release formulations include widespread drug activity, reduced dosing frequency, and increased patient compliance. In addition, controlled release formulations can be used to affect other properties such as the onset time of action or the blood level of the drug, and thus can affect the occurrence of side effects (eg, adverse effects). is there.

Most controlled release formulations initially release the amount of drug (active ingredient) that quickly provides the desired therapeutic effect, and other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. Is designed to release gradually or continuously. In order to maintain such a constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of active ingredients can be stimulated by a variety of conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

4.3.3. Parenteral dosage forms Parenteral dosage forms can be administered to a patient by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. In order to avoid patient's natural defenses against contaminants by these administrations, parenteral dosage forms are preferably sterile or can be sterilized prior to administration to the patient. Examples of parenteral dosage forms include, but are not limited to, ready-to-use solutions, dry products that can be readily dissolved or suspended in pharmaceutically acceptable injectable vehicles, and ready-to-use suspensions. Suspending agents and emulsions are included.

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, US Pharmacopoeia water for injection; including but not limited to sodium chloride injection, Ringer's injection, glucose injection, glucose and sodium chloride injection, and lactated Ringer's injection Aqueous vehicles; water-soluble vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and, but not limited to, corn oil,
Non-aqueous vehicles such as cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate are included.

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

4.3.4. Transdermal, topical, and mucosal dosage forms The transdermal, topical, and mucosal dosage forms of the present invention include, but are not limited to, eye drops, sprays, aerosols, creams, lotions, ointments, gels. , Solutions, emulsions, suspensions, or other forms known to those skilled in the art. For example, Remington's
Pharmaceutical Sciences, 16th and 18th editions, Mack
Publishing, Easton PA (1980 and 1990); and Introduction to Pharmaceutical Dosage Fo
See rms, 4th edition, Lea & Febiger, Philadelphia (1985). A dosage form suitable for treating mucosal tissue in the oral cavity can be formulated as a mouthwash or as an oral gel. Furthermore, transdermal dosage forms can be applied to the skin and can be worn for a specific period of time to penetrate the desired amount of active ingredient.
Patches of “reservoir type” or “matrix type” are included.

Suitable additives (eg, carriers and excipients) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed by the present invention are well known to those of ordinary skill in the pharmaceutical arts. It is known and depends on the particular tissue to which a given pharmaceutical composition or dosage form is applied.
With this fact in mind, typical additives include non-toxic and pharmaceutically acceptable lotions, tinctures, creams, emulsions, gels or ointments, only This includes, but is not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof.
Moisturizers or wetting agents can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. For example, Remington's P
hereditary sciences, 16th and 18th editions, Mack
See Publishing, Easton PA (1980 and 1990).

Depending on the particular tissue to be treated, additional components can be used prior to, in conjunction with, or after treatment with the active ingredients of the present invention. For example, penetration enhancers can be used to assist in delivering the active ingredients to the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; Kollidon grade (Povidone, Polyvidone); Urea; and Tween 80 ™ (polysorbate 80) and Span 60 ™ (
Various water-soluble or insoluble sugar esters such as sorbitan monostearate) are included.

The pH of the pharmaceutical composition or dosage form, or the pH of the tissue to which the pharmaceutical composition or dosage form is applied, can also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. 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 delivery. From this point of view, stearate can act as a lipid vehicle for the formulation, as an emulsifier or surfactant, and as a delivery enhancer or penetration enhancer. Different solid forms containing the active ingredient can be used to further adjust the properties of the resulting composition.

4.3.5. Kits The present invention includes kits that, when used by a physician, can simplify the administration of an appropriate amount of an active ingredient to a patient.

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

The kit of the present invention can further comprise a device used to administer one (or more) active ingredients. Examples of such devices include, but are not limited to, syringes, infusion bags, patches, and inhalers.

The kit of the present invention further comprises a pharmaceutically acceptable vehicle that can be used to administer one or more active ingredients. For example, if the active ingredient is provided as a solid form that must be reconstituted for parenteral administration, the kit forms a sterile solution free of microparticles where the active ingredient is suitable for parenteral administration. In order to contain a suitable vehicle sealed container which can be dissolved. Examples of pharmaceutically acceptable vehicles include, but are not limited to, US Pharmacopoeia water for injection; but are not limited to sodium chloride injection, Ringer's injection, glucose injection, glucose and sodium chloride injection, And aqueous vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, Non-aqueous vehicles such as ethyl oleate, isopropyl myristate, and benzyl benzoate are included.

5. EXAMPLES This application incorporates by reference the entirety of US Pat. No. 6,962,940 (issued Nov. 8, 2005), including the examples provided in the specification below.

5.1. Example 1 Synthesis of 2- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione 1- (3-Ethoxy-4- Methoxyphenyl) -2-methylsulfonylethylamine (
1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.6
A stirred solution of 6 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to produce an oil. Chromatography of the resulting oil gave the product as a yellow solid (1.0 g, 59% yield): melting point, 144 ° C .; ¹ H NMR (CDCl
₃ ) δ: 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), 7.4
7 (d, J = 7 Hz, 1H, Ar), 7.64 (t, J = 8 Hz, 1H, Ar), 8.74 (d, J = 8 Hz, 1H, Ar), 9.
49 (br s, 1H, NH); ¹³ C NMR (CDCl ₃ ) δ: 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; calculated for elemental analysis C ₂₂ H ₂₄ NO ₇ S: C, 5
7.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.

5.2. Example 2: Synthesis of (+) 2- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-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 to a 2.5 L Parr hydrogenator in a nitrogen atmosphere. Hydrogen was charged to the reaction vessel to 55 psi. The mixture was shaken for 13 hours while maintaining a hydrogen pressure of 50-55 psi. Hydrogen was released and the mixture was purged with nitrogen three times.
The suspension was filtered through a celite layer and rinsed with methanol. The filtrate was concentrated in vacuo. The resulting solid was re-slurried in ether and isolated by vacuum filtration. The solid was dried in vacuo to a constant weight to give 54 g of 3-aminophthalic acid (84% yield) as a yellow product. ¹ H-NMR (DMSO-d6) δ: 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t,
1H), 8-10 (br, s, 2H); ¹³ C-NMR (DMSO-d6) δ: 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 equipped with a mechanical stirrer, thermometer and condenser was charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). .
The reaction mixture was heated to reflux for 3 hours, cooled to about 25 ° C., and further cooled to 0-5 ° C. for an additional hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacuo to a constant weight at ambient temperature and 75 g of 3-acetamidophthalic anhydride (yield 6
1%) was obtained as a white product. ¹ H-NMR (CDCl ₃ ) δ: 2.21 (s, 3H), 7.76 (d, 1H), 7
.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).

2- (3-Ethoxy-4-methoxyphenyl-1- (methylsulfonyl) -eth-2-
Ilamine Separation A 3 L 3-neck round bottom flask is equipped with a mechanical stirrer, thermometer, and cooler, and 2- (
3-Ethoxy-4-methoxyphenyl) -1- (methylsulfonyl) -eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300
mmol), and methanol (1.0 L) were charged. The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for an additional 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air dried and then dried to constant weight in vacuo at ambient temperature to give 109.5 g (98% yield) of 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 an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). Air dry the solid, then 3 in vacuo
Dry to a constant weight at 0 ° C., and (S) -2- (3-ethoxy-4-methoxyphenyl)-
1- (methylsulfonyl) -eth-2-ylamine-N-acetyl-L-leucine salt (9
8.4% ee) was obtained 49.6 g (90% recovery). Chiral HPLC (Agilent T
1/99 EtOH / 20 mM KH ₂ PO ₄ , pH 7 from technologies
. 0, Ultra Chiral ES-OVS, 150 mm x 4.6 mm, 0.5 m
L / min, 240 nm): 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, thermometer, and condenser. (S) -2- (3-Ethoxy-4-methoxyphenyl) -1- (methylsulfonyl) -eth-2-ylamine N-acetyl-L-leucine salt (25 g, 56 mmol)
, 98% ee), 3-acetamidophthalic anhydride (12.1 g, 58.8 mmol), and glacial acetic acid (250 mL). 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 (25
0 mL × 2), saturated aqueous NaHCO ₃ (250 mL × 2), brine (250 mL × 2)
And dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was ethanol (
150 mL) and acetone (75 mL) and recrystallized from a binary solvent. The solid was isolated by vacuum filtration and washed with ethanol (100 mL × 2). The product is dried in vacuo to a constant weight at 60 ° C., and S- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetamidoisoindoline-1, 3-dione} 19.4 g (yield 75%) was obtained with 98% ee. Chiral HPLC (Agilent
15/85 EtOH / 20 mM KH ₂ PO ₄ , pH from Technology
5, Ultron Chiral ES-OVS, 150 mm x 4.6 mm, 0.4 mL
/ Min, 240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%). ¹ H-NMR (CDCl ₃ ) δ: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.6
8-3.75 (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); ¹³ C-NMR (DMSO-d6) δ: 14.66, 24.92, 4
1.61, 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 the preparation of the (+) enantiomer of Compound A is provided as FIG.

5.3. Example 3: TNF-α inhibition Human whole blood LPS-induced TNF-α assay LP with human whole blood except that freshly collected whole blood was used instead of PBMC
The ability of compounds to inhibit S-induced TNF-α production is essentially related to LP in human PBMC.
Measured as described below for the S-induced TNF-α assay (Muller et al., 1
999, Bioorg. & Med. Chem. Lett. 9: 1625-1630
page). Compound A human whole blood LPS-induced TNF-αIC ₅₀ = 294 nM.

Mouse LPS-induced serum TNF-α inhibition.
The compounds were tested in this animal model according to the method described above (Corral et al., 1996, Mol. Med., 2: 506-515). Mouse LPS-induced serum TN of Compound A
F-α inhibition (ED ₅₀ , mg / kg, po) = 0.05.

LPS-induced TNF-α production Lipopolysaccharide (LPS) is an endotoxin produced by gram-negative bacteria such as E. coli that induces the production of many pro-inflammatory cytokines, including TNF-α. is there. TNF-α produced in response to LPS in peripheral blood mononuclear cells (PBMC)
Derived from monocytes containing approximately 5-20% of BMC. The compounds were tested for their ability to inhibit LPS-induced TNF-α production obtained from human PBMC as described above (Muller et al., 1996, J. Med. Chem., 39: 3238). PBMCs obtained from normal donors were converted into Ficoll Hyperpaque (Pharmacia, Piscataw).
ay, NJ, USA) obtained by density centrifugation. Cells were treated with 10% AB ± human serum (Gemi
ni Bio-products, Woodland, CA, USA), 2 mM L-glutamine, 100 U / ml penicillin, and 100 μg / ml streptomycin (L
RPMI (Life Technologies) supplemented with if Technologies
gees, Grand Island, NY, USA).

PBMC (2 × 10 ⁵ cells) in 96 well flat bottom Costar tissue culture plates (Cor
ning, NY, USA) in triplicate. Cells were treated with 100 ng / ml LPS (Sigma, St. Louis, MO, USA in the absence or presence of compound.
) Stimulated. The compound (Celgene Corp., Warren, NJ, USA) was dissolved in DMSO (Sigma) and further diluted in the culture medium immediately before use. The final DMSO concentration in all samples was 0.25%. Compounds were added to cells 1 hour prior to LPS stimulation. Cells are incubated for 18-20 hours at 37 ° C. with 5% CO ₂ , then
The supernatant is collected and diluted with culture medium and ELISA (Endogen, Boston, MA)
USA) and TNF-α levels were assayed. LPS-induced TNF-αIC of Compound A
₅₀ = 77 nM.

IL-1β-induced TNF-α production During the course of inflammatory diseases, TNF-α production is often stimulated by the cytokine IL-1β rather than by bacterially derived LPS. The compound was obtained from human PBMC I
For the ability to inhibit L-1β-induced TNF-α production, leukocyte units originating from PBMC (Sera-Tec Biologicals, North Brunswick)
, NJ, USA) to Ficoll-Paque Plus (Amersham Pha)
RPMI- containing 10% fetal calf serum (Hyclone), heat-inactivated, 2 mM L-glutamine, 100 U / ml penicillin, and 100 mg / ml streptomycin (complete medium) isolated by centrifugation of rmacia, Piscataway, NJ, USA) 1
640 medium (BioWhittaker, Walkersville, Marylan
d, USA), seeded in 96-well tissue culture plates at 3 × 10 ⁵ cells / well, CO ₂
10 μM, 2 μl at a final DMSO concentration of 0.1% in an incubator humidified at 5% for 1 hour at 37 ° C.
M, 0.4 μM, 0.08 μM, 0.016 μM, 0.0032 μM, 0.00064 μ
LPS-induced TNF-, except that it was pre-treated in duplicate with M and 0 μM compound and then stimulated with 50 ng / ml recombinant human IL-1β (Endogen) for 18 hours.
α production was tested as described above. IL-β induced TNF-αIC _{50 of} compound A = 8
3 nM.

5.4. Example 4: PDE Selectivity PDE 1, 2, 3, 5, and 6 Enzyme Assays Specificity of compounds to PDE 4 was determined from bovine PDE 1, human P obtained from human platelets.
DE2, PDE3, and PDE5 (Hidaka and Asano, 1976,
Biochem. Biophys. Acta, 429: 485, and Nichol.
sen et al., 1991, Trends Pharmaco. Sci. , 12:19)
And PDE6 obtained from segments of the bovine retinal rod outer segment (Baehr et al., 1979, J. Biol. Chem. 254: 11669, and Gillespie et al.,
1989, Mol. Pharm. 36: 773) at a single concentration (10 μM)
). The results are shown in Table 1.

PDE7 Enzyme Assay PDE7 is a cAMP selective PDE that is expressed primarily in T cells and in skeletal muscle. IL
T cell-derived cytokines such as -2 and IFN-γ can potentially be modulated by PDE7 inhibition. PDE7 was purified by anion exchange chromatography as described above.
Purified from ut78 human T cells (Bloom and Beavo, 1996, Pr.
oc. Natl. Acad. Sci. USA, 93: 14188-14192). The compound was tested against PDE7 preparation in the presence of 10 nM cAMP as described in Table 1 for PDE4.

5.5. Example 5: PDE4 inhibition PDE4 (U937 cell derived) enzyme assay PDE4 enzyme was purified from U937 human mononuclear cells by gel filtration chromatography as previously described (Muller et al., 1998, Bioorg. & Med. Chem.
. Lett. 8: 2669-2675). Phosphodiesterase reaction is carried out at pH 7.5
50 mM Tris HCl, 5 mM MgCl ₂ , 1 μM cAMP, 10 nM [ ³ H] −
Performed in cAMP at 30 ° C. for 30 minutes, stopped by boiling, treated with 1 mg / ml snake venom and separated using AG-IXS ion exchange resin (BioRad) as described (Muller et al., 1998 Bioorg. & Med.Chem.Lett.8
Volume: 2669-2675). The reaction consumed less than 15% of the available substrate. The results are shown in Table 1.

5.6. Example 6: Human T cell assay SEB-induced IL-2 and IFN-γ production Staphylococcal enterotoxin B (SEB) is a gram-positive staphylococcus aureus (Staphy
lococcus aureus). SEB is a specific T cell receptor Vβ
Provides a convenient physiological stimulus specific to T cells expressing the chain. Human PBMC (consisting of approximately 50% T cells) is isolated from the source leukocyte unit as described above, seeded in 96-well tissue culture plates at 3 × 10 ⁵ cells / well in complete medium, and CO _2. 5
10 μM, 2 μM at a final DMSO concentration of 0.1% for 1 hour at 37 ° C.
0.4 μM, 0.08 μM, 0.016 μM, 0.0032 μM, 0.00064 μM,
And 0 μM compound in duplicate and then 100 ng / ml SEB
Stimulated with (Sigma Chemical Co., St. Louis, MO, USA) for 18 hours. IL-2 and IFN-γ levels were measured by ELISA (R & D Systems,
Minneapolis, MN, USA). IL-2 IC of Compound A
₅₀ = 291 nM. IFN-γ IC ₅₀ of compound A = 46 nM.

5.7. Example 7: cAMP Elevation Assay PGE ₂ Induced cAMP Elevation Prostaglandin E ₂ (PGE ₂ ) binds to prostanoid receptors on monocytes, T cells and other leukocytes, resulting in intracellular cAMP levels. Increase, resulting in inhibition of cellular responses. The combination of PGE ₂ and a PDE4 inhibitor, cAMP in these cell types
P synergistically increases and P induced by PDE4 inhibitors in the presence of PGE ₂
The increase in cAMP in BMC is proportional to the inhibitory activity of this PDE4 inhibitor. Intracellular cAM
P was measured in human PBMC as follows. PBMCs are isolated as described above and RP
96-well plates were seeded at 1 × 10 ⁶ cells per well in MI-1640. Cells were pretreated with 100 μM, 10 μM, 1 μM, 0.1 μM, 0.01 μM, and 0 μM compound at a final DMSO concentration of 2% at 37 ° C. for 1 hour in an incubator humidified with 5% CO ₂ in duplicate. Cells were then stimulated with PGE ₂ (10 μM) (Sigma) for 1 hour. Cells are lysed with 0.1N final concentration of HCl to inhibit phosphodiesterase activity,
Plates were frozen at -20 ° C. The produced cAMP was measured using a cAMP (low pH) immunoassay kit (R & D Systems). Racemic PBMC cAMP
EC ₅₀ is 3.09 μM. Compound A PBMC cAMP EC ₅₀ is 1.58
μM.

The increase in cAMP in human neutrophils was measured as follows. PBMC is obtained from white blood cells (Sera-Tec Biologicals) as the source of generation, Ficoll-Paque Pl.
The cells were removed by centrifugation with us (Amersham Pharmacia). The resulting red blood cell / polymorphonuclear cell (PMN) pellet was used as Hank's Balanced Salt S.
resuspended in solution (BioWhittaker) and mixed with an equal volume of 3% Dextran T-500 (Amersham Pharmacia) in 0.9% saline. Red blood cells were allowed to settle for 20 minutes, PMN was removed and centrifuged at 120 rpm for 8 minutes at 4 ° C. The remaining red blood cells were lysed in 0.2% cold saline for 30 seconds and the cells were made isotonic by the addition of an equal volume of 1.6% saline. The PMN was centrifuged at 1200 rpm for 8 minutes at 4 ° C. and then resuspended in RPMI-1640 and assayed for cAMP elevation as described for PBMC above. PMN is a FACSCalibur (Becton Dickinson,
San Jose, CA, USA) approximately 74% CD by flow cytometry
18 / CD11b ⁺ , 71% CD16 ⁺ CD9 ⁺ neutrophils were found. The results are shown in Table 2.

fMLF-induced LTB4 production N-formyl-methionine-leucine-phenylalanine (fMLF) is a bacterial-derived peptide that activates neutrophils to rapidly degranulate, migrate, attach to endothelial cells and release leukotriene LTB4. Yes, it is a product of arachidonic acid metabolism and itself a chemoattractant for neutrophils. The compounds were modified as described above (Hatzelmann) with the following modifications:
and Schudt, 2001, J. Am. Pharm. Exp. Ther. 297: 267-279) The ability to block fMLF-induced neutrophil LTB4 production was tested. Neutrophils are isolated as described above and resuspended in phosphate buffered saline without calcium or magnesium (BioWhittaker) with 10 mM HEPES at pH 7.2 and a concentration of 1.7 × 10 ⁶ cells / well. In 96-well tissue culture plates.
Cells 50μM thimerosal _{(Sigma) / 1mM CaCl 2 /} 1mM MgCl 2
For 15 minutes at 37 ° C. with 5% CO ₂ and then 100% at a final DMSO concentration of 0.01%.
Treatment with 0 nM, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0.064 nM and 0 nM compounds in duplicate for 10 minutes. Neutrophils were stimulated with 1 μM fMLF for 30 minutes, then dissolved by adding methanol (final concentration 20%) and frozen in a dry ice / isopropanol bath for 10 minutes. LTB4 ELI competitive with LTB4 content
Lysates were stored at −70 ° C. until measured by SA (R & D Systems). The results are shown in Table 2.

Zymosan-induced IL-8 production Zymosan A or heat-sterilized yeast Saccharomyces cerevisiae (Sacch)
aromyces cerevisiae) binds to the adhesion molecule Mac-1 on the neutrophil surface and induces phagocytosis, cell activation and IL-8 production. Zymosan-induced IL-8 production was as previously described with the following modifications (Au et al., 1998, Brit. J. Pharm.
123: 1260-1266). Human neutrophils are purified as described above, seeded in 96-well tissue culture plates at 3 × 10 ⁵ cells / well in complete medium, and final DM
10 μM, 2 μM, 0.4 μM, 0.08 μM, 0.016 μM, 0 at SO concentration of 0.1%
. CO ₂ 5 at 37 ° C. with 0032 μM, 0.00064 μM, and 0 μM compound for 1 hour
% In duplicate. Neutrophils were then stimulated with non-opsonized boiled zymosan A (Sigma) at 2.5 × 10 ⁵ particles / well for 18 hours. Supernatants were collected and tested for IL-8 by ELISA (R & D Systems). The results are shown in Table 2.

fMLF-induced CD18 / CD11b expression CD18 / CD11b (Mac-1) expression on neutrophils was as described above (Derian et al., 1995, J. Immunol., 154: 308-317 with the following modifications).
Page) measured. Neutrophils are isolated as described above and then 1 × 10 ⁶ cells / well in complete medium.
10 μM, 1 μM, 0.1 μM, 0.01 at a final DMSO concentration of 0.1%
Pretreated with 10 μM and 0 μM compound in duplicate for 10 minutes at 37 ° C. with 5% CO ₂ . Cells were then stimulated with 30 nM fMLF for 30 minutes and then cooled to 4 ° C.
Cells were treated with rabbit IgG (Jackson ImmunoRe to block Fc receptors.
search Labs, West Grove, PA, USA) (10 μg / 1 × 10
⁶ cells), CD18-FITC and CD11b-PE (Becton Dic
Kinson) and analyzed by FACSCalibur flow cytometry. Inhibition curves were obtained by subtracting unstimulated CD18 / CD11b expression (average fluorescence) from all samples, and IC ₅₀ values were calculated. The results are shown in Table 2.

FMLF-induced adhesion to HUVEC Human umbilical vein endothelial cells (HUVEC) were prepared as described above (Deria) with the following modifications.
n et al., 1995, J. Am. Immunol. 154: 308-317), used as a substrate for neutrophil adhesion. HUVEC cells were obtained from Anthrogenesis (Ce
dar Knolls, NJ, USA) and neutrophils were not treated with cytochalasin B. Cells were 10 μM, 1 μM, 0.1 μM, 0.0 at a final DMSO concentration of 0.1%.
Treat in duplicate with 1 μM, 0.001 μM and 0 μM compounds for 10 minutes, 50
Stimulate with 0 nM fMLF for 30 minutes, wash in duplicate with PBS, then FLX8
00 plate reader (Bio-Tek Instruments, Winooski,
The fluorescence was measured with VT, USA). The results are shown in Table 2.

5.8. Example 8: Water solubility Equilibrium solubility was measured in an aqueous buffer at pH 7.4. 0.07M pH 7.4 buffer
It was prepared by adjusting the pH of the NaH ₂ PO ₄ solution to 7.4 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> 1 mg / ml mixture. These samples were shaken for> 2 hours and allowed to stand overnight at room temperature. The sample was then first 0.45 μm Nylon saturated with the sample.
It filtered with the syringe filter. The filtrate was sampled continuously in duplicate. The filtrate was assayed by HPLC against a standard prepared with 50% methanol. Compound A
Has a solubility in water that is 3.5 times greater than the racemic mixture. Measured solubility Compound A = 0.012 mg / mL; racemic mixture = 0.0034 mg / mL.

5.9. Example 9: LPS-induced pulmonary neutropenia ferret model Investigating the effects of anti-inflammatory, emetic and behavioral effects of PDE4 inhibitors when administered by the oral (po) route using an arousal ferret model doing. From these experiments, each PD
The therapeutic index (TI) of an E4 inhibitor can be determined. TI determines the threshold dose for inducing emetic episodes and behavioral changes as an anti-inflammatory dose (50 for LPS-induced neutropenia).
% Of the dose that causes% inhibition).

Animal breeding Male ferret (Mustella Pullorius Euro, body weight 1-2 kg). Ferrets are Bury Green Farm or Misay Consultant.
supplied by y. After transport, the animals were allowed to acclimatize for more than 7 days in the holding room. The diet consisted of freely fed food pelleted SDS diet C and Whiskers ™ cat food fed 3 times a week. The water was pasteurized animal drinking water and was changed daily.

Administration with PDE4 inhibitors PDE4 inhibitors were initially administered orally (po) at a dose of 1-10 g / kg, followed by 30 mg to establish whether the TI is 10 or higher. Orally up to / kg and / or orally at low doses to establish a minimal dose that causes 50% inhibition of neutropenia. Ferret fasted all night, but made water freely available. Animals were orally dosed with vehicle or PDE4 inhibitor using a 15 cm dosing needle that passed through the back of the pharynx and into the esophagus. After dosing, the animals were observed back in a holding cage with a Perspex door, allowing free access to water. After dosing, the animals were continuously observed and any vomiting or behavioral changes were recorded. Animals are p. o
. Food was made available 60-90 minutes after dosing.

Exposure to LPS p. With compound or vehicle control. o. 30 minutes after administration, Pe with sealed ferret
Placed in rspex container and exposed to LPS (100 μg / ml) aerosol for 10 minutes. An LPS aerosol was generated by a nebulizer (DeVilbiss, USA) and directed into the Perspex exposure chamber. After a 10 minute exposure time, the animals were returned to the holding cage to have free access to water and at a later stage to have free access to food. Observation is p. o. Evoking episodes and behavioral changes were recorded for at least 2.5 hours after dosing.

Bronchoalveolar lavage examination Six hours after LPS exposure, animals were killed by an overdose of pentobarbitone sodium administered intraperitoneally. The trachea was then cannulated with polypropylene tubing and the lungs were lavaged in duplicate with 20 ml heparinized (10 units / ml) phosphate buffered saline (PBS).

Blood sampling / tissue removal Terminal blood samples (10 ml) were removed by transthoracic heart puncture. 2,50 blood
Spin for 15 minutes at 0 rpm, remove plasma and store at -20 ° C. The brain was also removed and frozen at −20 ° C. for compound content analysis.

Cell count Bronchoalveolar lavage test (BAL) samples were centrifuged at 1,500 rpm for 5 minutes. The supernatant was removed and the resulting cell pellet was resuspended in 1 ml PBS. Resuspended liquid cell smears were prepared and stained with Leishmann staining to allow different cell counts. Total cell number was counted using the remaining resuspended sample. This determined the total number of neutrophils in the BAL.

Parameter measurement % Inhibition of LPS-induced pulmonary neutropenia.
2. Emetic episodes-The number of vomiting and retching was counted.
3. Behavioral changes-The following behavioral effects were shown. That is, fluency, gasping breathing, mouse crowing, flattened posture, ataxia, arched back and backward walking. Behavioral changes were semi-quantified by applying a severity assessment (mild, moderate or severe).
4). TI was calculated as the highest dose found not to cause an emetic episode divided by the lowest dose found to suppress lung neutropenia by 50% or more.

FIG. 30 shows the effect of awakening ferret of Compound A on LPS-induced neutropenia in the lung.
Demonstrate with

Vomiting and behavioral changes PDE4 p. o. After administration, the ferret is observed for at least 2 hours, and an emetic episode (
Vomiting and retching) and behavioral changes were recorded.

P. In the relevant vehicle (acetone / cremophor / distilled water). o. No emetic episodes (retching or vomiting) were observed in ferrets pretreated with. A small percentage of control animals-treated animals (7/22) showed mild behavioral changes (lip licking and receding).

Compound A (0.1-3 mg / kg, po) did not cause emetic episodes (retching and vomiting). Several behavioral changes (down position, licking and receding lips) were observed and classified as mild. At 10 mg / kg, some retching but not obvious vomiting was observed in 2/6 ferrets with drooling and behavioral changes (scored as mild or moderate). At the highest dose tested (30 mg / kg), moderate to severe vomiting was observed in 3/4 animals with significant behavioral changes. Such data is summarized in Table 3.

Animals were observed for up to 3 hours after dosing. The number in parenthesis means the number of animals that reacted.
The number of animals in each group ranges from 4-22.

Calculation of therapeutic index From these experiments, the therapeutic index (TI) was determined by dividing the threshold dose that elicits an emetic episode for each compound by the ED ₅₀ value that inhibits pulmonary neutropenia. TI calculations are summarized in Table 4. Compound A had a TI of 12 and did not cause an emetic episode at an anti-inflammatory dose of 1 mg / kg.

5.10. Example 10: Biological activity of Compound A in patients with severe plaque-type psoriasis Compound A is a novel oral agent that down-regulates pro-inflammatory cytokine production in a human cell model. With Compound A, TNF-α, IL-12 and IFN-γ
It has been shown to decrease production as well as increase production of IL-10.
Psoriasis is strongly associated with dysregulation of cytokines and chemokines that allow potential therapy with immunomodulatory compounds. This phase 2, open-label, group, pilot study was designed to assess the biological activity of Compound A in patients with severe plaque-type psoriasis. An additional assessment of clinical outcome was performed to assess the potential efficacy of Compound A to treat severe plaque-type psoriasis.

Compound A was orally administered 20 mg daily for 29 days with an additional 28-day observational follow-up period for patient safety. Skin punch biopsy specimen obtained from target plaque (6
mm) was obtained on days 15 and 29 at baseline. Non-injury skin biopsy was also taken at baseline. The primary pharmacodynamic endpoint was the percentage change in epidermis thickness at day 29 from baseline. Measurement of epidermal thickness and immunohistochemical analysis were performed using CD
Performed by a blinded examiner to assess 11c, CD83, K16, ICAM-1, HLA-DR, and filaggrin. A biopsy sample was obtained from TNF-α, p40-IL1.
2 / IL23, IL-10, IFN-γ, IP10, IL-2, IL-8, iNOS, p
19-IL23, K16, CD83, and hARP were analyzed by RT-PCR. PASI, PGA, and BSA measurements were performed to explore clinical efficacy during the 29-day treatment phase of the study. Safety was assessed by reported adverse events, evaluation of laboratory values, physical examination, ECG and vital sign measurements. A total of 19 patients were enrolled: 15 patients completed the set of evaluable biopsies and 17 patients completed the efficacy assessment.

Evaluation of changes in epidermal thickness was the primary endpoint in this study. Nineteen patients were enrolled in the study, 15 of which had a complete set of biopsies that could be evaluated at baseline and on day 29. Seventeen of the 19 subjects had clinical efficacy parameters measured at baseline and on day 29. Eight (53.3%) of the 15 patients with biopsies that were evaluable at baseline and on day 29 demonstrated a 20% reduction in epidermal thickness. The average reduction in epidermal thickness of all 15 subjects with biopsies that could be assessed at baseline and on day 29 was 20.5% (p = 0.015). FIG. 31 shows the change in epidermal thickness from baseline to day 29 between subjects with evaluable biopsies.

Significant inflammatory markers including epidermal and dermal T cells, CD83 + and CD11c cells were evaluated in biopsy specimens. According to the results of the 8 patients who responded, the epidermal and dermal T
-Decrease in cells was shown to be 42.56% and 28.79% in responders, respectively (> 20% reduction in epidermal thickness). The mean decrease from baseline in epidermal and dermal CD83 + cells was 32.50% and 25.86 in responders, respectively.
%Met. CD11c cells were reduced by 40.16% in the responder's epidermis and 18.50% in the dermis. Table 5 shows the reduction of important skin biopsy inflammation 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 were:
On day 29 he had normal ICAM-1. Two patients with abnormal HLA-DR were 29
Patient 3 with normal HLA-DR on day and abnormal filaggrin at baseline
The name had normal filaggrin on day 29.

Biopsy specimens were TNFα, p40-IL12 / IL23, IL-10, IFNγ, IP1
MRNA gene expression of important inflammatory markers, including 0, IL-2, IL-8, iNOS, p19-IL23, K16 and CD83, was assessed by RT-PCR. i
NOS mRNA expression is 66.5 in injured skin 29 days after treatment with Compound A.
% (P = 0.025). Reduced and increased mRNA expression of other inflammatory markers
Overall improvement trend was shown. FIG. 32 illustrates the change in iNOS expression during the study.

Of the 19 enrolled subjects, all 17 completed the 29-day treatment phase and completed the evaluation of clinical efficacy. Of the 19 enrolled subjects, 14 (73.7%) reported that these patients had a Psoriasis Area and Severity Index on the 29th day from baseline.
Severity Index) (PASI) showing a> 50% decrease in overall score (35.8)
%) And demonstrated an improvement in PASI. FIG. 33 shows the percent change in PASI score between patients that can be assessed on day 29 from baseline. In addition, 9 out of 17 evaluable patients (52.9%) received a static Physician's Global As
sessment (sPGA), and 10 out of 17 evaluable patients (58.
8%) showed a decrease from baseline in the body surface area (BSA) of patients with psoriasis after 29 days of treatment with Compound A. During the treatment and follow-up phase, safety was assessed by adverse event monitoring, ECG, clinical examination, physical examination and vital signs. No deaths were reported and none of the patients discontinued due to adverse events. The most well-known treatment-related adverse events included headache (26.3%) and nausea (15.8%).

In this clinical trial, 29 days of Compound A 20 mg p. o. QD was safe in subjects with severe plaque-type psoriasis. The primary end point is 2 days of epidermis thickness on day 29.
This was achieved in 8 (53.3%) of the 15 subjects who achieved a 0% reduction. Decrease in inflammatory markers important in skin biopsies are dermal and epidermal T cells, CD83 + and CD1
One cell was shown. INO in skin biopsy on day 29 by RT-PCR analysis
A statistically significant reduction of 66.5% in S mRNA was revealed. A positive clinical efficacy signal was shown 29 days after treatment with Compound A. 73.7% of enrolled patients demonstrated improvement in their psoriasis symptoms, with 15.8% of these patients showing a> 50% reduction in baseline in the patient's PASI score on day 29. 47.4% of enrolled patients showed improvement in patient sPGA, and 52.6% of enrolled patients showed a decrease from baseline in patient psoriasis body surface area (BSA) on day 29. .

5.11. Example 11: Phase 2 study demonstrating efficacy and safety of Compound A in subjects with moderate to severe psoriasis This phase 2, multicenter, randomized, double blind, placebo controlled, parallel group A dose-comparison study evaluated the efficacy and safety of Compound A in subjects with moderate to severe plaque-type psoriasis who are candidates for systemic treatment.

This study includes a 12-week treatment phase followed by a 4-week observational follow-up phase. A total of 260 subjects were randomized, Compound A 20 mg BID, Compound A 20 mg
QD or placebo was administered for 12 weeks. The primary endpoint of this study was a 12% week / last treatment associated with a baseline visit, achieving a 75% reduction in the psoriasis area and severity index score ("PASI-75"), It was the proportion of subjects treated with Compound A. The last treatment was defined as the last PASI assessment completed during the 12 week treatment phase.

At week 12 / final treatment, a significantly higher proportion (24%) of subjects treated with 20 mg BID achieved PASI-75 (10%; P = 0) compared to the placebo group
. 023). Of subjects receiving 20 mg BID or placebo, 57% vs. 23% achieved PASI-50, respectively, at week 12 / final treatment; 14% vs. 6% each received P
ASI-90 was achieved. At Week 12 / final treatment, subjects achieved an average 52% vs. 17% reduction in PASI from baseline in the 20 mg BID vs. placebo group, respectively.
Subjects receiving Compound A continued to improve over time, with the largest average percent decrease in PASI score at week 12. Overall, the adverse event profile was similar across all three treatment groups. The majority of adverse events reported were mild. No serious drug-related adverse events were reported in this study. Subjects in the 20 mg BID group did not experience redness due to psoriasis during the observational follow-up period.

In this clinical trial, Compound A has been shown to be well tolerated and safe in subjects with moderate to severe plaque-type psoriasis. 50%, 75%, and 9 of PASI
The proportion of subjects who achieved 0% improvement demonstrates the clinical activity of Compound A after 12 weeks of treatment.

5.12. Example 12: Solid form screening test 5.12.1. Experimental methodology Solubility test. A weighed sample of Compound A (about 100 mg) was treated with about 2 mL of test solvent. The solvent used was for reagent or HPLC. At least 2 of the resulting mixture
Stir at about 25 ° C. for 4 hours. When all solids were dissolved by visual inspection, the estimated solubility was calculated. Solubility was estimated from these experiments based on the total volume of solvent used to produce the solution. The actual solubility can be higher than that calculated by the use of large amounts of solvent or the slow rate of dissolution. If no dissolution occurred during the experiment,
Solubility was measured gravimetrically. A filtrate with a known volume was evaporated to dryness, and the weight of the residue was measured.

Solution evaporation test. The solution was evaporated for solvents where 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 solvent at about 25 ° C. or about 50 ° C. in nitrogen in an open vial.

Equilibrium test. Equilibrium experiments were performed by adding an excess of Compound A to about 2 mL of test solvent. The resulting mixture was agitated at about 25 ° C. or about 50 ° C. for at least 24 hours. After achieving equilibrium, the saturated solution is removed and about 25 ° C. or about 5 ° C. in nitrogen in an open vial, respectively.
Slow evaporation by placing at 0 ° C. The slurry obtained from equilibration was filtered and dried in air.

Cooling crystallization test. A cooling crystallization test was conducted. The solid was dissolved in a solvent at a high temperature of about 65 ° C. and allowed to cool to about 25 ° C. Refrigerator (about 0-5 ° C) for samples not crystallized at about 25 ° C
Put it in. The solid was isolated by decantation and allowed to dry in air.

Solvent / antisolvent precipitation test. Precipitation was performed with a solvent / antisolvent combination. Compound A is dissolved in a solvent in which Compound A has a relatively high solubility, and then Compound A has a relatively low solubility (
That is, the selected solvent having a poor solvent) was added to the solution. A precipitate immediately formed with several solvent / antisolvent systems. If precipitation did not occur immediately, the resulting mixture was allowed to cool in the refrigerator (about 0-5 ° C.) until a precipitate formed. The precipitate was then isolated by decantation and left to dry in air.

Interconversion test. Interconversion experiments were performed by making a slurry in solid form in a saturated solvent. The slurry was agitated at about 25 ° C. for at least 2 days. The saturated solution was removed by filtration and the solid was dried in air.

Compression test. The compression test was performed by pressing the sample with a Carver Mini C press at a force of 2000 psi for at least 1 minute. The sample is then XRP
Analyzed by D.

Hygroscopicity test. Surface measurement of hygroscopicity in various solid forms
Tested using a Systems DVS instrument. Typically, a sample size of about 10-50 mg was added to the sample pan of the DVS apparatus and the sample was analyzed at about 25 ° C. with a DVS autosorption analyzer. The relative humidity was increased by about 10% from about RH to about 0% to about 95%. The relative humidity was then lowered in a similar manner to achieve a complete adsorption / desorption cycle. Mass was recorded at regular intervals throughout the experiment.

5.12.2. Characterization Methodology Samples generated as described in the solid form screening were typically analyzed by powder X-ray diffraction (XRPD). XRPD Thermo ARL X'TRA ™
Performed on a powder X-ray diffractometer with 1.54 Å Cu Kα radiation. The apparatus was equipped with a fine focus X-ray tube. The voltage and amperage of the X-ray generator are 45 and 45 respectively.
kV and 40 mA were set. The divergence slice was set to 4 mm and 2 mm, and the measurement slice was set to 0.5 mm and 0.2 mm. Diffracted radiation was detected by a Peltier cooled Si (Li) solid state detector. Usually 2.40 ° / min (0.5 sec / 0
. 1θ-2θ continuous scan from 1.5 ° 2θ to 40 ° 2θ in (02 ° step). The peak position was confirmed using a sintered alumina standard. In general, the position of the XRPD peak was expected to vary individually by about ± 0.2 ° 2θ for each measurement. In general, as understood in the art, two XRPD patterns coincide with each other when the characteristic peak of the first pattern is located at approximately the same position as the characteristic peak of the second pattern. As understood in the art, it is preferred, but not limited, to determine whether two XRPD patterns match or whether individual peaks of two XRPD patterns match. Orientation, phase impurities, degree of crystallinity, particle size, difference in diffractometer set, X
Individual variables and parameters, such as variations in RPD data collection parameters and / or variations in XRPD data processing may need to be considered. The determination of whether two patterns match can be performed by eye and / or computer analysis.
Examples of XRPD patterns collected and analyzed using these methods and parameters are provided herein as, for example, FIG. 1, FIG. 5, FIG. 9, FIG.

Differential scanning calorimetry (DSC) analysis was performed on a TA Instruments Q1000 ™. Approximately 5 mg of sample was placed in a DSC pan of known mass and the sample weight was accurately recorded. Typically, samples are about 10 ° C. per minute in nitrogen at about 25 ° C. to a final temperature of about 200.
Heated to ° C. Usually, thermal events were reported as extrapolated onset temperatures. Examples of DSC thermograms collected and analyzed using these methods and parameters are described herein:
For example, FIG. 2, FIG. 6, FIG. 10, FIG. 14, FIG. 18, FIG.

Thermogravimetric analysis (TGA) was performed on a TA Instruments Q500 ™. Calcium oxalate was used for calibration. Put about 10mg of sample in a dish, weigh accurately,
Added to TGA furnace. Samples in nitrogen at about 10 ° C. per minute from about 25 ° C. to a final temperature of about 2
Heated to 00 ° C. Examples of TGA thermograms collected and analyzed using these methods and parameters are described herein, for example, FIG. 3, FIG. 7, FIG. 11, FIG.
23 and 27 are provided.

Solvating solvents were identified and quantified by TG-IR experiments using a TA Instruments Q500 ™ TGA fitted with a Thermo Nicolet AEM Fourier Transform IR spectrophotometer. Usually, a sample size of about 20-50 mg was weighed with an aluminum pan and heated to about 200 ° C. During TGA operation, steam was transferred to the cells by a heated transfer line. The transfer line and cell temperature were set at about 225 ° C. IR spectra were collected each with a 10 second repetition time. Volatility was identified from a search of the Aldrich gas phase spectral library and presented to indicate the identified vapor from the library match results.

Sample morphology and particle size analysis was performed using an Olympus microscope. U device
Calibrated with SP standard. 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 in length, ie 90% of the particles have a length below this value.

5.12.3. Solid Form Screening Test Results The solid form containing Compound A prepared during the solid form screening test includes Form A
, B, C, D, E, F, G and amorphous forms were included. Form A, B, C, D, E, F
Representative XRPD patterns, DSC plots, TGA plots and DVS plots for each of G and G are provided herein as FIGS.

Solubility test. The approximate solubility of Form A of Compound A in various solvents at about 25 ° C. was determined. The results are shown in Table 6. Form B was found to be most soluble in acetone, acetonitrile, methylene chloride, methyl ethyl ketone and tetrahydrofuran (greater than about 50 mg / mL) followed by solubility in ethyl acetate (about 30.15 mg / mL). Form B consists of n-butanol, heptane, 2-propanol, toluene and water (about 1 mg /
It was also found to be poorly soluble in several solvents, including less than mL).

Solution evaporation test. The results obtained from solution evaporation tests conducted at about 25 ° C. and about 50 ° C. are summarized in Table 7.

Equilibrium test. The results obtained from equilibrium tests performed at about 25 ° C. and about 50 ° C. are summarized in Table 8.

Cooling crystallization test. The results obtained from the cooling crystallization test are summarized in Table 9. In the cold crystallization test, crystalline material was generated from a number of solvents including acetone, acetonitrile, n-butyl acetate, ethyl acetate, methanol, methylene chloride, methyl ethyl ketone (MEK) and tetrahydrofuran (THF). The obtained crystalline material is usually XRPD, DSC.
And characterized by TGA.

Solvent / antisolvent precipitation test. The results obtained from the solvent / antisolvent precipitation test are summarized in Table 10. When heptane, water and toluene were added to Form B in THF solution at about 40 ° C., a precipitate formed immediately. When heptane, methyl t-butyl ether (MTBE), toluene and water were added separately to Form B in acetonitrile solution at about 25 ° C., a clear solution or mixture was formed. The crystalline material obtained from MTBE / acetonitrile, water / acetonitrile and toluene / acetonitrile was obtained after stirring overnight. However, no crystallization occurred with the heptane / acetonitrile mixture. About 50 to Form B in methanol solution
When water was added at 0 ° C., a precipitate formed immediately, and when heptane and toluene were added separately to Form B in methanol solution at about 50 ° C., a clear solution or mixture was formed.
The crystalline material obtained from toluene / methanol and heptane / methanol was obtained after stirring overnight. A precipitate formed immediately when toluene was added to Form B in methylene chloride solution at about 25 ° C., and a clear solution was obtained when MTBE was added to Form B in methylene chloride solution at about 25 ° C. The crystalline material obtained from MTBE / methylene chloride was obtained after stirring overnight. However, crystallization did not occur when heptane was added to Form B in methylene chloride solution. When heptane was added to Form B in MEK solution at about 50 ° C., a precipitate formed immediately, and MTBE and toluene were added separately to Form B in MEK solution at about 50 ° C. to give a clear solution. Obtained. The crystalline material obtained from MTBE / MEK and toluene / MEK was obtained after stirring overnight. When heptane was added to Form B in n-butyl acetate solution at about 50 ° C., a precipitate formed immediately and clear when MTBE and toluene were separately added to Form B in MEK solution at about 50 ° C. Solution was obtained. MTBE / n-butyl acetate and toluene /
Obtained after stirring the crystalline material from n-butyl acetate overnight. Water and toluene,
When added separately to Form B in acetone solution at about 40 ° C., a precipitate formed immediately and clear when ethanol and 2-propanol were added separately to Form B in acetone solution at about 40 ° C. A solution was obtained. The crystalline material obtained from ethanol / acetone and 2-propanol / acetone was obtained after stirring overnight. The obtained crystalline material was converted into XRPD, DSC, T
Identified by GA.

Stability test. The results of the stability test are summarized in Table 11. The stability of Forms A, B, C and D was tested by exposing solid samples to harsh conditions of 40 ° C./75% RH for 4 weeks. In addition, the stability of Forms A, B, C and D in different solvents was tested by equilibration of different solvents at 40 ° C. for 4 weeks. The slurry was then filtered and dried in air. Solid samples obtained from stability experiments were analyzed by XRPD and DSC.

  Interconversion test. Table 12 summarizes the results obtained from the interconversion test.

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

Hygroscopicity test. Hygroscopicity (moisture sorption / desorption) for forms A, B, C, D, E, F and G
The test was conducted. After undergoing a complete adsorption / desorption cycle in the DVS system, each solid sample was analyzed by XRPD. XRPD results showed that none of the analyzed forms had substantial solid state conversion as a result of DVS analysis.

5.13. Example 13: 200 MG Dose Capsule Table 13 shows a batch formulation and a single dose for a single dosage unit containing 200 mg of solid form containing Compound A, ie about 40 weight percent, in a 0 size capsule. The formulation is illustrated.

Pregelatinized corn starch (SPRESS ™ B-820) and Compound A
The construct was passed through a 710 μm sieve and then added to a diffusion mixer with a baffle insert and mixed for 15 minutes. Magnesium stearate was passed through a 210 μm sieve and added to the diffusion mixer. The mixture was then encapsulated at 500 mg per capsule (8400 capsule batch size) into 0 size capsules using a Dosator type capsule filler.

5.14. Example 14 100 MG Oral Dosage Form Table 14 illustrates a batch formulation containing 100 mg of solid form containing Compound A and a single dose unit formulation.

Microcrystalline cellulose, croscarmellose sodium, and Compound A construct are passed through a No. 30 mesh sieve (about 430 μ to about 655 μ). (Lenexa, KS JRH B
iossciences, Inc. The Pluronic F-68® surfactant (manufactured by) is passed through a No. 20 mesh sieve (about 457 μ to about 1041 μ). Pl
ronic F-68® surfactant and croscarmellose sodium 0.5
kg was added to a 16 quart V-shaped tumble blender and mixed for about 5 minutes. The mixture is then transferred to a 3 cubic foot V-shaped tumble blender, microcrystalline cellulose is added, and about 5
Mix for minutes. Add the solid form containing Compound A and mix for an additional 25 minutes. This pre-blend is passed through a roller compressor fitted with a hammer mill at the discharge of the roller compressor and returned to the tumble blender. Add the remaining croscarmellose sodium and magnesium stearate to the tumble blender and mix for about 3 minutes. The final mixture is compressed on a rotary tablet press to 250 mg per tablet (200,000 tablet batch size).

While the invention has been described in terms of specific embodiments, those skilled in the art will recognize that various changes and modifications can be made without departing from the spirit and scope of the invention as defined in the claims. it is obvious. Such modifications are also intended to fall within the scope of the appended claims.

Claims (32)

A solid form comprising the enantiomerically pure compound of formula (I),


A solid form with a powder X-ray diffraction pattern comprising peaks of about 8.1 °, 15.2 °, 17.4 °, 23.6 ° and 25.1 ° at 2θ. Having a differential scanning calorimetry plot including an endothermic event with an onset temperature of about 155 ° C.,
The solid form according to claim 1. The solid form of claim 1 having a thermogravimetric analysis plot comprising a mass loss of less than about 1% when heated from about 25 ° C to about 140 ° C. A solid form comprising the enantiomerically pure compound of formula (I),


Solid form with powder X-ray diffraction pattern comprising peaks at about 10.1 °, 13.5 °, 20.7 ° and 26.9 ° at 2θ. 5. The solid form of claim 4, having a powder X-ray diffraction pattern further comprising peaks at 2θ of about 12.4 °, 15.7 °, 18.1 ° and 24.7 °. Having a differential scanning calorimetry plot including an endothermic event with an onset temperature of about 154 ° C.,
The solid form according to claim 4. 5. The solid form of claim 4, having a thermogravimetric analysis plot comprising a mass loss of less than about 1% when heated from about 25 ° C to about 140 ° C. 5. The solid form of claim 4, wherein the solid form exhibits a mass increase of less than about 1% when subjected to an increase in relative humidity from about 0% to about 95% relative humidity. The solid form of claim 4, which is stable to exposure to about 40 ° C. and about 75% relative humidity for about 4 weeks. A solid form comprising the enantiomerically pure compound of formula (I),


Solid form with powder X-ray diffraction pattern comprising peaks at about 7.5 °, 11.3 °, 16.4 °, 17.8 ° and 26.4 ° at 2θ. Having a differential scanning calorimetry plot including an endothermic event with an onset temperature of about 138 ° C.,
The solid form according to claim 10. The solid form of claim 10, having a thermogravimetric analysis plot comprising a mass loss of less than about 10% when heated from about 25 ° C to about 140 ° C. A solid form comprising the enantiomerically pure compound of formula (I),


Solid form with powder X-ray diffraction pattern comprising peaks at about 7.5 °, 11.3 °, 16.3 °, 25.2 ° and 26.0 ° at 2θ. Having a differential scanning calorimetry plot including an endothermic event with an onset temperature of about 100 ° C.,
14. Solid form according to claim 13. 14. The solid form of claim 13, having a thermogravimetric analysis plot comprising a mass loss of less than about 10% when heated from about 25 ° C to about 110 ° C. A solid form comprising the enantiomerically pure compound of formula (I),


A solid form with a powder X-ray diffraction pattern comprising peaks at about 7.6 °, 9.2 °, 11.4 °, 17.9 ° and 26.6 ° at 2θ. The solid form of claim 16 having a differential scanning calorimetry plot comprising an endothermic event with an onset temperature of about 95 ° C. The solid form of claim 16, having a thermogravimetric analysis plot comprising a mass loss of less than about 8% when heated from about 25 ° C to about 110 ° C. A solid form comprising the enantiomerically pure compound of formula (I),


A solid form with a powder X-ray diffraction pattern comprising peaks of about 8.1 °, 8.6 °, 15.6 °, 17.3 ° and 25.4 ° at 2θ. Having a differential scanning calorimetry plot including an endothermic event with an onset temperature of about 145 ° C.,
20. A solid form according to claim 19. 20. The solid form of claim 19, having a thermogravimetric analysis plot comprising a mass loss of less than about 1% when heated from about 25 ° C to about 180 ° C. A solid form comprising the enantiomerically pure compound of formula (I),


Solid form having a powder X-ray diffraction pattern including peaks at about 7.9 °, 11.7 °, 16.8 °, 18.1 ° and 26.7 ° at 2θ. Having a differential scanning calorimetry plot including an endothermic event with an onset temperature of about 109 ° C.,
The solid form according to claim 22. 23. The solid form of claim 22, having a thermogravimetric analysis plot comprising a mass loss of less than about 8% when heated from about 25 ° C to about 110 ° C. A mixture comprising two or more solid forms selected from the solid forms of claims 1, 4, 10, 13, 16, 19 and 22. A pharmaceutical composition comprising a solid form selected from the solid forms according to claim 1, 4, 10, 13, 16, 19 and 22. 23. A method of treating or preventing a disease or disorder ameliorated by inhibition of TNF- [alpha] production, wherein the solid is selected from solid forms according to claim 1, 4, 10, 13, 16, 19 and 22 Administering a therapeutically effective amount or a prophylactically effective amount of the form. The disease or disorder is psoriasis; psoriatic arthritis; rheumatoid arthritis; chronic cutaneous sarcoidosis;
Giant cell arteritis; Parkinson's disease; Nodular urticaria; Lichen planus; Complex aphthosis; Behcet's disease; Lupus; Hepatitis; Sjogren's disease; Depression; Osteoarthritis; diffuse large B-cell lymphoma; polymyositis; dermatomyositis; inclusion body myositis; erosive osteoarthritis; interstitial cystitis; hepatitis; endometriosis; 28. The method of claim 27, wherein the method is selected from pyoderma gangrenosum. 23. A method of treating or preventing a disease or disorder that ameliorates by inhibition of PDE4, comprising the treatment of a solid form selected from the solid forms of claim 1, 4, 10, 13, 16, 19, and 22. Administering a top effective amount or a prophylactically effective amount. Disease or disorder is HIV; hepatitis; adult respiratory distress syndrome; bone resorption disease; chronic obstructive pulmonary disease; chronic pulmonary inflammatory disease; dermatitis; inflammatory skin disease, atopic dermatitis, cystic fibrosis; septic Shock; Sepsis; Endotoxin shock; Hemodynamic shock; Septic syndrome; Reperfusion injury after ischemia; Meningitis; Psoriasis; Fibrous disease; Cachexia; Graft rejection including graft versus host disease; Rheumatoid spondylitis; arthritic symptoms such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lupus erythematosus; 30. The method of claim 29, selected from erythema; radiation injury; asthma; and hyperoxia alveolar injury. A method of treating or preventing cancer, comprising a therapeutically effective amount or a prophylactically effective amount of a solid form selected from the solid forms according to claim 1, 4, 10, 13, 16, 19, and 22. Administering. 32. The method of claim 31, wherein the cancer is selected from multiple myeloma, malignant melanoma, malignant glioma, leukemia and solid tumor.