CN102702070A - Solid form containing (+)-2-[1-(3-oxethyl-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, composition and application thereof - Google Patents

Abstract

The invention discloses a solid form containing (+)-2-[1-(3-oxethyl-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, a composition containing the solid form, a method for preparing the solid form and an application method thereof. The method comprises a treatment and/or prevention method capable of improving disease symptoms by lowering TNF-alpha level or inhibiting PDE4.

Description

Comprise (+)-2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1, the solid form of 3-diketone, its composition and use thereof

1. invention field

The present invention is to provide and comprise (+)-2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1, the solid form of 3-diketone, comprise the compsn of this solid form, the method for preparing the method for this solid form and use their treatment various diseases and/or illness.

2. background of invention

Tumor necrosis factor alpha (TNF-α) is a kind of cytokine that the immunostimulation deposits yields is replied and mainly discharged by MNP that is directed against.TNF-α can strengthen most of cell physiological process, for example breaks up, raises, propagation and proteolytic degradation.When low-level, TNF-α creates antagonism and infects the provide protection of reagent, tumour and tissue injury.But TNF-α also plays a role in numerous disease.When the patient is used, TNF-α can cause or aggravates inflammation, heating, cardiovascular effect, hemorrhage, blood coagulation and with acute infection and shock state during being seen similar acute phase reaction.Numerous disease and medical conditions all relate to enhanced or uncontrolled TNF-α produces, for example, and cancer, for example solid tumor and haematogenous tumour; Heart trouble, for example congestive heart failure; And viral, heredity, inflammatory, supersensitivity and autoimmune disease.

Adenosine 3', 5'-encircle single phosphoric acid (cAMP) and also in numerous disease and illness, play a role, such as but not limited to asthma and inflammation, and other illness (Lowe and Cheng, Drugs of the Future, 17 (9), 799-807,1992).Show that cAMP rising in inflammatory leukocytes can suppress the release subsequently that their activation and inflammatory mediator comprise TNF-α and NF-κ B.The cAMP level raises and also can cause airway smooth muscle lax.

The main cell mechanism of believing the cAMP inactivation is that cAMP is decomposed (Beavo and Reitsnyder, Trends in Pharm., 11,150-155,1990) by one type of isozyme that is called cyclic nucleotide phosphodiesterase (PDE).Existing 11 known PDE families.For example have realized that, suppress PDE IV type and discharge and airway smooth muscle lax among both all effective (Verghese etc., JPharm.Exper.Therapeut., 272 (3), 1313-1320,1995) especially suppressing inflammatory mediator.Therefore, the compound that suppresses PDE4 (PDEIV) is inflammation-inhibiting and help airway smooth muscle lax specifically, makes unwanted spinoff simultaneously, and for example cardiovascular or antiplatelet effect minimizes.The PDE4 suppressor factor that uses at present lacks selective action under acceptable therapeutic dose.

Cancer is a kind ofly to have destructive disease especially, and the ill risk of cancer and diffusion relate to the increase of TNF-α blood level.Usually, in the individuality of health, cancer cells can not be survived in the recycle system, and one of them reason is that blood vessel has played the effect that tumour cell exosmoses that hinders.But, shown the external adhesion that has increased cancer cells and endothelium significantly of being increased in of cytokine levels.A kind of explanation be cytokine for example TNF-α stimulated the biosynthesizing and the expression of the cell surface receptor that is called ELAM-1 (endothelial leukocyte adhesion molecule).ELAM-1 is the member of the Ca-dependent cell adhesion receptor family of the known LEC-CAM of being called, and this family comprises LECAM-1 and GMP-140.During Inflammatory response, the ELAM-1 on the endotheliocyte plays a role as leukocytic " homing receptor ".Recently, show the adherent increase (Rice etc., 1989, Science 246:1303-1306) of ELAM-1 mediation colon cancer cell and the endothelium of handling with cytokine on the endotheliocyte.

Inflammatory diseases for example sacroiliitis, relevant arhritis conditions (for example osteo-arthritis and rheumatoid arthritis), inflammatory bowel (for example segmental enteritis and ulcerative colitis), septicemia, psoriatic, atopic dermatitis, contact dermatitis, chronic obstructive pulmonary disease and chronic inflammation tuberculosis also is a popular difficult and complicated illness widely.TNF-α brings into play main effect in Inflammatory response, and in the animal model of inflammatory diseases, uses its antagonist and hindered chronic and acute reaction.

Viral, heredity, struvite, supersensitivity and autoimmune disease relates to enhanced or uncontrolled TNF-α produces.The instance of such disease includes but not limited to: HIV; Hepatitis; Adult respiratory distress syndrome; Bone resorption disease; Chronic obstructive pulmonary disease; Chronic pulmonary inflammation disease; Asthma; Dermatitis; Cystic fibrosis; Septic shock; Septicemia; Endotoxin shock; The haemodynamics shock; Septicemia syndrome; Postischemic reperfusion damage; Meningitis; Psoriatic; Fibrotic disease; Emaciation; Transplant rejection; Autoimmune disease; Rheumatoid spondylitis; Arhritis conditions, for example rheumatoid arthritis and osteo-arthritis; Osteoporosis; Segmental enteritis; Ulcerative colitis; Inflammatory bowel; Multiple sclerosis; Systemic lupus erythematosus; ENL in the leprosy; Radiation injury; Asthma; And hyperoxic alveolar injury.Tracey etc., 1987, Nature 330:662-664 and Hinshaw etc., 1990, Circ.Shock30:279-292 (endotoxin shock); Dezube etc., 1990, Lancet, 335:662 (emaciation); Millar etc., 1989, Lancet 2:712-714 and Ferrai-Baliviera etc., 1989, Arch.Surg.124:1400-1405 (adult respiratory distress syndrome); Bertolini etc., 1986, Nature 319:516-518, Johnson etc.; 1989, Endocrinology 124:1424-1427, Holler etc., 1990; Blood75:1011-1016 and Grau etc., 1989, N.Engl.J.Med.320:1586-1591 (bone resorption disease); Pignet etc., 1990, Nature, 344:245-247, Bissonnette etc., 1989, Inflammation13:329-339 and Baughman etc., 1990, J.Lab.Clin.Med.115:36-42 (chronic pulmonary inflammation disease); Elliot etc., 1995, Int.J.Pharmac.17:141-145 (rheumatoid arthritis); Von Dullemen etc., 1995, Gastroenterology, 109:129-135 (segmental enteritis); Duh etc., 1989, Proc.Nat.Acad.Sci.86:5974-5978, Poll etc., 1990, Proc.Nat.Acad.Sci.87:782-785; Monto etc., 1990, Blood 79:2670, Clouse etc., 1989, J.Immunol.142; 431-438, Poll etc., 1992, AIDS Res.Hum.Retrovirus, 191-197; PoIi etc. 1990, Proc.Natl.Acad.Sci.87:782-784, Folks etc., 1989, PNAS 86:2365-2368 (opportunistic infection that HIV and HIV cause).

The medical compounds that some cytokine comprises the active of TNF-α or suppress its generation can be blocked and favourable therapeutical agent can be become.Shown that many micromolecular inhibitors have the ability of treatment or the prevention inflammatory diseases relevant with TNF-α (summary referring to Lowe, 1998Exp.Opin.Ther.Patents 8:1309-1332).One type of such molecule is at U.S. Patent number 6,020, the substituted styroyl sulfone of describing in 358.

The variation of considering solid form possibly influence various physics and chemical property; And these character may produce benefit or drawback to processing, preparation, stability and bioavailability and other important medicinal property, so the preparation of the solid form of medical compounds and selection are complicated.The potential medical solid comprises crystalline solid and unformed solid.Unformed solid characteristic is the structural order that lacks long distance, and the characteristic of crystalline solid is a structural cycle property.The required classification of medical solid depends on concrete application; Sometimes based on the for example unformed solid of enhanced dissulution feature selection; And crystalline solid possibly be fit to because of character such as physics or chemicalstability needs (referring to, for example, S.R.Vippagunta etc.; Adv.Drug.Deliv.Rev., (2001) 48:3-26; L.Yu, Adv.Drug.Deliv.Rev., (2001) 48:27-42).

No matter be crystallization or unformed, the potential solid form of medical compounds comprises single component and multicomponent solid.The single component solid is made up of medical compounds basically, does not contain other compound.Mutation can appear potentially in the single component crystalline material, polymorphism for example, in polymorphism the certain drugs compound exist multiple three-dimensional arrangement (referring to, for example, S.R.Byrn etc., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette).Ritonavir, a kind of hiv protease suppressor factor that is configured to soft gelatin capsule, example stressed the importance of research polymorphic form.After this product was gone into operation about 2 years; In preparation a kind of unanticipated of new polymorphic form than indissoluble to deposition force product to be recalled from market; Up to developing a kind of preparation with consistency (referring to S.R.Chemburkar etc.; Org.Process Res.Dev., (2000) 4:413-417).

The variety that can occur other in the potential solid form of medical compounds, for example, multicomponent solid possibility.The crystalline solid that comprises two or more ionic speciess can be known as salt (referring to for example, Handbook of Pharmaceutical Salts:Properties, Selection and Use, P.H.Stahl and C.G.Wermuth edit, and (2002), Wiley, Weinheim).For example can comprise for the multicomponent solid additional type that medical compounds or its salt provide other character to improve potentially hydrate, solvolyte, eutectic and inclusion compound etc. (referring to for example, S.R.Byrn etc., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette).In addition, the multicomponent crystal formation can be easy to become polymorphic potentially, and wherein specified multicomponent compsn can multiple three-dimensional crystals be arranged existence.Solid form be prepared in exploitation safety, effectively, be extremely important in the stable and salable medical compounds.

The present invention is to provide that to meet chemical name be (+)-2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1; The embodiment of the demand of the solid form of the compound of 3-diketone (" compd A "); This compound is disclosed in the U. S. application submitted on March 19th, 2003 number 10/392; The U.S. Provisional Application series number 60/366 that 195 (as U.S. Patent number 6,962,940 are authorized to) and on March 20th, 2002 submit to; Submitted on January 7th, 515 and 2003 60/438,450 in.

3. summary of the invention

The present invention relates to utilize the enantiomorph of substituted styroyl sulphones and the method for pharmaceutically acceptable solvolyte, hydrate, eutectic, inclusion compound, prodrug and polymorphic form treatment disease and illness thereof, and the method that in Mammals, reduces cytokine and precursor level thereof.The present invention also relates to pharmaceutical composition, it contains 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1, (+) enantiomorph of 3-diketone and pharmaceutically acceptable carrier.The invention further relates to 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl the ethyl]-4-acetylamino isoindoline-1 that does not contain its (-) enantiomorph basically, (+) enantiomorph of 3-diketone.

The present invention relates to 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1, (+) enantiomorph of 3-diketone particularly.Believe this compound and its racemoid 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1, the 3-diketone is compared the effectiveness and other benefit with increase.

The present invention includes 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1, (+) enantiomorph of 3-diketone is used for can producing the disease improved or the purposes of illness through suppressing TNF-α in Mammals treatment or prevention.In certain embodiments, this treatment comprises minimizing or avoids undesirable action.This illness includes but not limited to cancer, includes but not limited to: the cancer of head, Tiroidina, neck, eye, skin, mouth, larynx, esophagus, chest, bone, blood, marrow, lung, colon, sigmoid colon, rectum, stomach, prostate gland, breast, ovary, kidney, liver, pancreas, brain, intestines, heart, suprarenal gland, subcutis, lymphoglandula, heart and combination thereof.Treatable by this method concrete cancer has multiple myeloma, malignant melanoma, glioblastoma, white blood disease and solid tumor.

The present invention also comprises 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1; (+) enantiomorph of 3-diketone includes but not limited to: the purposes in the septic shock of congestive heart failure, myocardosis, wet lung, endotaxin mediate, acute viral myocarditis, heart heteroplastic transplantation repulsion and the myocardial infarction at treatment or preventing heart disease.

The present invention also comprises use 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1, and (+) enantiomorph of 3-diketone is treated can be through suppressing disease or the illness that PDE4 improves.For example, compound of the present invention and compsn can be used for treatment or prevent viral, heredity, struvite, supersensitivity and autoimmune disease.The instance of such disease includes but not limited to: HIV; Hepatitis; Adult respiratory distress syndrome; Bone resorption disease; Chronic obstructive pulmonary disease; Chronic pulmonary inflammation disease; Dermatitis; Inflammatory skin diseases, atopic dermatitis, cystic fibrosis; Septic shock; Septicemia; Endotoxin shock; The haemodynamics shock; Septicemia syndrome; Postischemic reperfusion damage; Meningitis; Psoriatic; Fibrotic disease; Emaciation; Transplant rejection comprises graft versus host disease; Autoimmune disease; Rheumatoid spondylitis; Arhritis conditions, for example rheumatoid arthritis and osteo-arthritis; Osteoporosis; Segmental enteritis; Ulcerative colitis; Inflammatory bowel; Multiple sclerosis; Systemic lupus erythematosus; ENL in the leprosy (ENL); Radiation injury; Asthma; And hyperoxic alveolar injury.

In yet another embodiment; 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1; Pure (+) enantiomorph of the stereoisomerism of 3-diketone also is useful in the symptom of treatment or prophylaxis of microbial infection or infected by microbes, includes but not limited to the opportunistic infection that infectation of bacteria, fungi infestation, malaria, mycobacterial infections and HIV cause.

The present invention further comprises pharmaceutical composition and single unit dosage; It comprises 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1, (+) enantiomorph of 3-diketone and pharmaceutically acceptable polymorphic form, prodrug, hydrate, inclusion compound and solvolyte.

In a separate embodiments, the present invention includes 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1, (+) enantiomorph of 3-diketone.

In a further embodiment; The present invention includes preparation 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1; The method of (+) enantiomorph that the stereoisomerism of 3-diketone is pure, it comprises makes 1-(3-oxyethyl group-4-methoxyl group-phenyl)-2-methane sulfonyl-ethamine contact with chiral amino acid, and makes the product and the N-(1 of the first step; 3-dioxy-1,3-dihydro-isobenzofuran-4-yl)-the ethanamide contact.In the embodiment that is correlated with, the present invention includes the chirality salt of 1-(3-oxyethyl group-4-methoxyl group-phenyl)-2-methane sulfonyl-ethamine.

Embodiment of the present invention provide solid form, and it comprises chemical name is (+)-2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1, the compound of 3-diketone (" compd A ").Compd A can according to any method that it will be apparent to those skilled in the art, be included in the synthetic or acquisition of the method for describing among the following embodiment based on the instruction of this paper.Compd A also may be in accordance with the method for describing in the U.S. Patent number 6,962,940 of authorizing on November 8th, 2005 and prepares, and its its full text is incorporated this paper by reference into.

In certain embodiments, solid form is the single component crystal formation of compd A.In certain embodiments, solid form is the multicomponent crystal formation, includes but not limited to eutectic and/or the solvolyte (comprising hydrate) of inclusion compound A.In other embodiments, solid form is the single component amorphous forms of compd A.In other embodiments, solid form is the multicomponent amorphous forms.Do not hope to be subject to any particular theory; Some novel solid form provided by the invention has specific favourable physics and/or chemical property; Make it to for example preparing, process, prepare and/or storing useful; Simultaneously also has particularly advantageous biological property, for example like bioavailability and/or biological activity.

In specific embodiments, solid form provided by the invention comprises the solid form of inclusion compound A, includes but not limited to single component and the multicomponent solid form of inclusion compound A.In certain embodiments, solid form provided by the invention comprises polymorphic form, solvolyte (comprising hydrate) and the eutectic of inclusion compound A.Certain embodiments of the present invention provide preparation, separation and/or have characterized the method for solid form provided by the invention.

Solid form provided by the invention can be used as active pharmaceutical ingredient and is used for being prepared in the preparation that the patient uses.Therefore, embodiment of the present invention comprise the purposes of these solid forms as final medicament prodn.Some embodiment provides useful and character that have improvement in the final formulation of preparation, for example preparations such as the compatible character of flow of powder character, compacting character, compressing tablet character, stable character and vehicle, processes, prepares and/or store the solid form of the needed character of final medicament prodn.Certain embodiments of the present invention provide pharmaceutical composition; It contains single component crystal formation, multicomponent crystal formation, single component amorphous forms and/or the multicomponent amorphous forms of inclusion compound A, and pharmaceutically acceptable thinner, vehicle or carrier.Solid form provided by the invention can be used for for example treating, prevents or controls disease provided by the present invention and illness with final medicament prodn.

Certain embodiments of the present invention provide uses solid form provided by the present invention in Mammals, to treat, prevent or control and can produce the disease improved or the method for illness through suppressing TNF-α, for example: HIV; Hepatitis; Adult respiratory distress syndrome; Bone resorption disease; Chronic obstructive pulmonary disease; Chronic pulmonary inflammation disease; Asthma; Dermatitis; Cystic fibrosis; Septic shock; Septicemia; Endotoxin shock; The haemodynamics shock; Septicemia syndrome; Postischemic reperfusion damage; Meningitis; Psoriatic; Fibrotic disease; Emaciation; Transplant rejection; Autoimmune disease; Rheumatoid spondylitis; Arhritis conditions, for example psoriatic arthritis, rheumatoid arthritis and osteo-arthritis; Osteoporosis; Segmental enteritis; Ulcerative colitis; Inflammatory bowel; Multiple sclerosis; Systemic lupus erythematosus; Lupus erythematosus,cutaneous; Sarcoidosis of lung; ENL in the leprosy; Radiation injury; Asthma; And hyperoxic alveolar injury.This illness further includes but not limited to cancer, includes but not limited to: the cancer of head, Tiroidina, neck, eye, skin, mouth, larynx, esophagus, chest, bone, blood, marrow, lung, colon, sigmoid colon, rectum, stomach, prostate gland, breast, ovary, kidney, liver, pancreas, brain, intestines, heart, suprarenal gland, subcutis, lymphoglandula, heart and combination thereof.Treatable by this method concrete cancer has multiple myeloma, malignant melanoma, glioblastoma, white blood disease and solid tumor.In certain embodiments, use the method for solid form provided by the present invention to comprise minimizing or avoid some undesirable action.

Certain embodiments of the present invention provide the method for in cardiopathic treatment or prevention, using solid form provided by the present invention, include but not limited to: the septic shock of congestive heart failure, myocardosis, wet lung, endotaxin mediate, acute viral myocarditis, heart heteroplastic transplantation repulsion and myocardial infarction.

Certain embodiments of the present invention provide use solid form provided by the present invention to treat can be through suppressing the disease that PDE4 improves or the method for illness.For example, solid form provided by the present invention can be used for treatment or prevents viral, heredity, struvite, supersensitivity and autoimmune disease.The instance of this disease includes but not limited to: HIV; Hepatitis; Adult respiratory distress syndrome; Bone resorption disease; Chronic obstructive pulmonary disease; Chronic pulmonary inflammation disease; Dermatitis; Inflammatory skin diseases; Atopic dermatitis; Cystic fibrosis; Septic shock; Septicemia; Endotoxin shock; The haemodynamics shock; Septicemia syndrome; Postischemic reperfusion damage; Meningitis; Psoriatic; Fibrotic disease; Emaciation; Transplant rejection comprises graft versus host disease; Autoimmune disease; Rheumatoid spondylitis; Arhritis conditions, for example rheumatoid arthritis and osteo-arthritis; Osteoporosis; Segmental enteritis; Ulcerative colitis; Inflammatory bowel; Multiple sclerosis; Systemic lupus erythematosus; ENL in the leprosy (ENL); Radiation injury; Asthma; And hyperoxic alveolar injury.

Certain embodiments of the present invention provide the method for in the symptom of treatment or prophylaxis of microbial infection or infected by microbes, using solid form provided by the present invention, include but not limited to the opportunistic infection that infectation of bacteria, fungi infestation, malaria, mycobacterial infections and HIV cause.

Specific embodiments of the present invention provides the method for in treatment of diseases or prevention, using solid form provided by the present invention, and these diseases comprise: psoriatic, psoriatic arthritis, rheumatoid arthritis, chronic skin sarcoid, giant cell arteritis, parkinsonism, prurigo nodularis, lichen planus, complicacy aphthosis, Behcet's disease, lupus, hepatitis, uveitis, sjogren syndrome, depression (comprising major depression), interstitial cystitis, vulvodynia, prostatitis, osteo-arthritis, diffuse large B cell lymphoma, polymyositis, dermatomyositis, inclusion body myositis, EOA, interstitial cystitis, hepatitis, endometriosis, radiculopathy and pyoderma gangraenosum.

Certain embodiments of the present invention provide pharmaceutical composition and the single unit dosage that comprises one or more solid forms provided by the present invention.

3.1 brief description of the drawings

Fig. 1 provides exemplary x-ray powdery diffractometry (" the XRPD ") figure of the form A of compd A.

Fig. 2 provides typical dsc (" the DSC ") figure of the form A of compd A.

Fig. 3 provides typical thermogravimetic analysis (TGA) (" the TGA ") figure of the form A of compd A.

Fig. 4 provides exemplary dynamic Gas Phase Adsorption (" the DVS ") figure of the form A of compd A.

Fig. 5 provides the typical XRPD figure of the form B of compd A.

Fig. 6 provides the typical DSC figure of the form B of compd A.

Fig. 7 provides the typical TGA figure of the form B of compd A.

Fig. 8 provides the typical DVS figure of the form B of compd A.

Fig. 9 provides the typical XRPD figure of the form A of compd A.

Figure 10 provides the typical DSC figure of the form A of compd A.

Figure 11 provides the typical TGA figure of the form A of compd A.

Figure 12 provides the typical DVS figure of the form A of compd A.

Figure 13 provides the typical XRPD figure of the form D of compd A.

Figure 14 provides the typical DSC figure of the form D of compd A.

Figure 15 provides the typical TGA figure of the form D of compd A.

Figure 16 provides the typical DVS figure of the form D of compd A.

Figure 17 provides the typical XRPD figure of the form E of compd A.

Figure 18 provides the typical DSC figure of the form E of compd A.

Figure 19 provides the typical TGA figure of the form E of compd A.

Figure 20 provides the typical DVS figure of the form E of compd A.

Figure 21 provides the typical XRPD figure of the form D of compd A.

Figure 22 provides the typical DSC figure of the form D of compd A.

Figure 23 provides the typical TGA figure of the form D of compd A.

Figure 24 provides the typical DVS figure of the form D of compd A.

Figure 25 provides the typical XRPD of the form G of compd A.

Figure 26 provides the typical DSC figure of the form G of compd A.

Figure 27 provides the typical TGA figure of the form G of compd A.

Figure 28 provides the typical DVS figure of the form G of compd A.

Figure 29 has shown 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1, the preparation of (+) enantiomorph of 3-diketone.

Figure 30 has shown that compd A is to the effect of LPS inductive neutrophilia in the lung of clear-headed ferret.

Figure 31 has shown in the clinical study of assessment compd A in the patient who suffers from the severe psoriasis in plaques, in the percentage change of the 29th day whole 15 individual mesocuticle thickness.

Figure 32 has shown in the clinical study of assessment compd A in the patient who suffers from the severe psoriasis in plaques, the variation of average iNOS (standardized hARP) in the biopsy specimen of the 29th day infringement skin.

Figure 33 shown in the patient who suffers from the severe psoriasis in plaques in the clinical study of assessment compd A, and mark from the percentage change of baseline with severity index (PASI) in total psoriatic zone in the 29th day valuable patient.

3.2 Definition

The term " compd A " that the present invention uses refers to (+)-2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl the ethyl]-4-acetylamino isoindoline-1 of enantiomer-pure; The 3-diketone; When post is 150mm * 4.6mm Ultron chirality ES-OVS chirality HPLC post (Agilent Technology), elutriant is the 15:85 ethanol of pH 3.5: 20mM KH ₂PO ₄, and the observation wavelength is when being 240nm, it separated from this HPLC post at about 25.4 minutes.Compd A ¹H NMR spectrum is following basically: 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).Compd A ¹³C NMR spectrum is following basically: 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.Be dissolved in compd A in the methyl alcohol to (+) direction Plane of rotation polarized light.

Not being subject to theory, believing that compd A is S-{2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1, the 3-diketone, it has following structure:

The term " patient " that the present invention uses refers to Mammals, particularly people.

The term " pharmacy acceptable salt " that the present invention uses refers to by pharmaceutically acceptable non-toxic acid or alkali, comprises the salt of inorganic bronsted lowry acids and bases bronsted lowry and organic bronsted lowry acids and bases bronsted lowry preparation.

Only if point out in addition, the term " prodrug " that the present invention uses refers to the verivate of compound, and it can hydrolysis, oxidation or otherwise react so that this compound to be provided down at biotic condition (external or body in).But the instance of prodrug includes but not limited to the part that comprises biological hydrolysis of compd A, but but but but but but the for example verivate and the metabolite of the phosphoric acid salt analogue of the uride of the carbonic ether biological hydrolysis of the carbamate biological hydrolysis of the ester biological hydrolysis of the acid amides biological hydrolysis of biological hydrolysis and biological hydrolysis.Prodrug can use the method preparation of knowing usually, Burger ' s Medicinal Chemistry and Drug Discovery for example, 172-178, those methods of 949-982 (Manfred E.Wolff edit, the 5th edition 1995) description.

Only if point out in addition; Term " but acid amides of biological hydrolysis ", " but ester of biological hydrolysis ", " but carbamate of biological hydrolysis ", " but carbonic ether of biological hydrolysis ", " but uride of biological hydrolysis ", " but phosphoric acid salt of biological hydrolysis " that the present invention uses refers to acid amides, ester, carbamate, carbonic ether, uride or the phosphoric acid salt of compound respectively; It is 1 years old) biological activity of interfering compound not; But can give this compound advantageous feature in vivo, that for example absorbs, acts on continues or effect initial; Or 2) not bioactive, but convert bioactive compounds in vivo to.But the instance of the ester of biological hydrolysis includes but not limited to: lower alkyl esters, alkoxyl group acyloxyate, alkyl acyl aminoalkyl ester and cholinesterase.But the instance of the acid amides of biological hydrolysis includes but not limited to low alkyl group acid amides, alpha-amino acid amides, alkoxyl group acyl group acid amides and alkylamino alkyl-carbonyl acid amides.But the instance of the carbamate of biological hydrolysis includes but not limited to: low-grade alkylamine, substituted quadrol, amino acid, hydroxyalkyl amine, heterocycle and aromatic heterocycle amine and polyetheramine.

Only if point out in addition, the term " stereoisomerism is pure " that the present invention uses refers to a kind of steric isomer of compsn inclusion compound and does not contain other steric isomer of this compound basically.For example, the pure compsn of stereoisomerism that has the compound of a chiral centre is incited somebody to action the opposite enantiomorph that will not contain this compound basically.The pure compsn of stereoisomerism with compound of two chiral centres will not contain other diastereomer of this compound basically.The typical pure compound of stereoisomerism comprises greater than a kind of steric isomer of this compound of about 80% weight with less than other steric isomer of this compound of about 20% weight; More preferably greater than a kind of steric isomer of this compound of about 90% weight with less than other steric isomer of this compound of about 10% weight; Even more preferably greater than a kind of steric isomer of this compound of about 95% weight with less than other steric isomer of this compound of about 5% weight with most preferably greater than a kind of steric isomer of this compound of about 97% weight with less than other steric isomer of this compound of about 3% weight.

Only if point out in addition, the term " enantiomer-pure " that the present invention uses refers to have the pure compsn of stereoisomerism of the compound of a chiral centre.

The term " undesirable action " that the present invention uses includes but not limited to stomach and intestine, kidney and hepatotoxicity, oligoleukocythemia, and the bleeding time that causes owing to for example thrombopenia increases, and gestation prolongs; Feel sick, vomiting, drowsiness; Weakness, dizzy, teratogenesis; Extrapyramidal sign is cathisophobiaed, and cardiac toxic comprises that cardiovascular disorder, inflammation, male sexual disorder and serum liver enzyme level raise.Term " gastrointestinal toxicity " includes but not limited to gastroenteritic ulcer and erosion.Term " Toxicity of Kidney " includes but not limited to situation for example papillary necrosis and chronic interstitial nephritis.

Only if point out in addition, the phrase that the present invention uses " reduce or avoid undesirable action " refers to reduce the severity that one or more the present invention lock the undesirable action of justice.

Should be noted that if exist inconsistently between structure of describing and the title that this structure is provided, then be as the criterion with the structure of describing.In addition, the stereochemistry of if structure or structure division for example thick line of no use or dotted line represent that then this structure or structure division should be understood to include its all steric isomers.

Unless otherwise, the term " solid form " and the relational language of the present invention's use refer to not to be mainly to be in liquid state or gasiform physical form.Unless otherwise, term " solid form " that the present invention uses and relational language refer to not to be the physical form that mainly is in liquid state or gasiform inclusion compound A when being used to refer to compd A in the present invention.Solid form can be crystallization, unformed or its mixture.In specific embodiments, solid form can be a liquid crystals." single component " solid form of inclusion compound A is made up of compd A basically." multicomponent " solid form of inclusion compound A is included in the one or more extra kind of the significant quantity in the solid form, for example ion and/or molecule.For example, in specific embodiments, the crystallization multicomponent solid form of inclusion compound A further comprises one or more kinds of position clocklike that are bonded in non-covalently in lattice.The multicomponent solid form of inclusion compound A comprises eutectic, solvolyte (for example hydrate) and the inclusion compound of compd A.In specific embodiments, term " solid form of inclusion compound A " and relational language comprise single component and the multicomponent solid form of inclusion compound A.In specific embodiments, " solid form of inclusion compound A " and relational language comprise crystal formation, the inclusion compound A of inclusion compound A amorphous forms, and composition thereof.

Unless otherwise; The relational language that the term " crystallization " that the present invention uses and the present invention use; When being used for describing compound, material, modification, material, composition or product; Unless otherwise, refer to that it is crystallization that this compound, material, modification, material, composition or product are measured basic through X-ray diffraction.Referring to, for example, Remington:The Science and Practice of Pharmacy, the 21st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, the 23rd edition, 1843-1844 (1995).

Unless otherwise, the relational language of term " crystal formation ", " crystallized form " and this paper that the present invention uses refers to the crystalline solid form.Crystal formation comprises single component crystal formation and multicomponent crystal formation, and includes but not limited to: polymorphic form, solvolyte, hydrate and/or other molecular complex.In certain embodiments, the crystal formation of material can not contain amorphous forms and/or other crystal formation basically.In certain embodiments, the crystal formation of material can comprise one or more amorphous forms and/or other crystal formation of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% weight.In certain embodiments, the crystal formation of material can be a physics and/or chemical pure.In certain embodiments, the crystal formation of material can be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physics and/or chemical pure.

Unless otherwise, the relational language of term " polymorphic form ", " polymorphic forms " and this paper of the present invention's use refers to basic two or more crystal formations of being made up of same molecular and/or ion.The same with different crystal formations, as molecule and/or ion is arranged in lattice or the result of conformation, different polymorphic forms can have different physical propertiess, for example like temperature of fusion, melting heat, solubleness, dissulution character and/or vibrational spectrum.The difference of physical properties can influence drug parameters, for example package stability, compressibility and density (very important in prescription and product prepn) and dissolution rate (important factor in the bioavailability).The difference of stability can by chemically reactive variation (variable color quickly when for example different oxidation makes formulation ratio comprises another kind of polymorphic form when comprising a kind of polymorphic form) or metataxis (for example; Because the preferred polymorphic form of kinetics changes into the more stable polymorphic form of thermodynamics; Tablet bursts apart in storage) or both (for example, a kind of tablet of polymorphic form is easier to decompose in high humidity) cause.As the result of solubleness/dissulution difference, under extreme case, some solid state transformations possibly cause rendeing a service disappearance, perhaps, are in that another is extreme, cause toxicity.In addition, the work in-process physical properties possibly be important (for example, a kind of polymorphic form possibly form solvolyte more easily, maybe possibly be not easy to filter and wash out impurity, and particle shape and size-grade distribution possibly be different between polymorphic form).

Unless otherwise, the term " solvolyte " that uses of the present invention and " solvation " crystal formation that comprises solvent that refers to material.Term " hydrate " and " hydration " refer to the wherein aqueous solvolyte of solvent package." polymorphic form of solvolyte " refers to that there is multiple crystal formation in specific solvolyte compsn.Similarly, " polymorphic form of hydrate " refers to that there is multiple crystal formation in specific hydrate compositions.The term " desolvated solvolyte " that the present invention uses refers to can be through removing the crystal formation of the material that solvent prepares from solvolyte.

Unless otherwise, the relational language that the term " unformed " that the present invention uses, " amorphous forms " and the present invention use refers to that it is not crystallization basically that material, composition or the product referred to are measured through X-ray diffraction.Particularly, unordered solid form described in term " amorphous forms ", promptly lacks the solid form of the order of crystallization of long distance.In certain embodiments, the amorphous forms of material can not contain other amorphous forms and/or crystal formation basically.In other embodiments, the amorphous forms of material can comprise one or more other amorphous forms and/or crystal formations that are lower than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% weight.In certain embodiments, the amorphous forms of material can be a physics and/or chemical pure.In certain embodiments, the amorphous forms of material is about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physics and/or chemical pure.

The technology that supplies to characterize crystal formation and amorphous forms includes but not limited to: thermogravimetic analysis (TGA) (TGA); Dsc (DSC); X-ray powder diffraction (XRPD); Single crystal method of X-ray diffractometry; Vibrational spectrum for example infrared (IR) and Raman spectrum; Solid-state and solution nucleus magnetic resonance (NMR) spectrum; Opticmicroscope; Hot platform opticmicroscope; Sem (SEM); Electron crystallography and quantitative analysis; Sreen analysis (PSA); Surface-area is analyzed; Solubleness is measured; Dissulution is measured; Ultimate analysis and Karl Fischer analyze.Distinctive unit cell parameters can be used one or more technical measurements, such as but not limited to X-ray diffraction and neutron diffraction, comprises single crystal diffraction and powdery diffractometry.The technology that can be used for the analysed for powder diffraction data comprises the profile refine, for example Rietveld refine, and it can be used for for example comprising above analyzing single relevant diffraction peak in a kind of sample of solid phase.Other method that can be used for the analysed for powder diffraction data comprises the structure cell retrieval, and it allows those skilled in the art to measure unit cell parameters from the sample that comprises crystalline powder.

Unless otherwise; The term " about " that the present invention uses is with " approximately " and numerical value or the value scope that characterizes the particular solid form is provided; For example actual temp or TR; For example as describe DSC or TGA incident heat, for example comprise melt, the actual temp or the TR of dehydration, desolvation or glass transition incident; Quality change is for example as the quality change of the function of temperature or humidity; The content of solvent or water, unit is for example quality or per-cent; Or the peak position, for example the peak position in analyzing through IR or Raman spectrum or XRPD links to each other when using, and refers to that this value or value scope can depart from those of ordinary skills and think reasonable range, but still describes this particular solid form.For example; In specific embodiments; Unless otherwise; The term " about " of in this context, using and " approximately ", refer to this numerical value or value scope can the value of statement or value scope 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5% or 0.25% in variation.

Unless otherwise; The specific crystal formation that comprises " pure basically " (for example not containing other solid form and/or other chemical cpd basically) that the present invention uses or the sample of amorphous forms; In specific embodiments, comprise one or more other solid forms and/or other chemical cpd that weight ratio is lower than about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25% or 0.1% per-cent.

Unless otherwise; " not containing basically " one or more other solid forms that the present invention uses and/or the sample or the compsn of other chemical cpd; Refer to that said composition comprises; In specific embodiments, weight ratio is lower than one or more other solid forms and/or other chemical cpd of about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25% or 0.1% per-cent.

Unless otherwise, the term " treatment " that uses of the present invention refers to eradicate or improves one or more symptoms that disease or illness or this disease or illness are correlated with.In certain embodiments, this term points to the patient who suffers from such disease or illness and uses one or more preventions or therapeutical agent so that the diffusion of this disease or illness or deterioration minimize.In some embodiments, this term refers to behind the paresthesia epilepsy of specified disease, follows or do not follow other extra promoting agent, uses compound provided by the present invention.

Unless otherwise, the term " prevention " of the present invention's use refers to outbreak, recurrence or the diffusion of preventing disease or illness or its one or more symptoms.In certain embodiments, this term refers to before paresthesia epilepsy, particularly to having the patient of disease provided by the present invention or illness risk, follows or do not follow other extra active compound, uses compound provided by the present invention or treats with it.This term comprises the symptom that suppresses or alleviate specified disease.In certain embodiments, the patient who especially has a family history of disease is the candidate of prevention scheme.In addition, the patient who has a symptomatic recurrence history also is the potential candidate of prevention.Just in this point, term " prevention " can exchange with term " prophylactic treatment " and use.

Unless otherwise, the term " control " of the present invention's use refers to prevent or slow down progress, diffusion or the deterioration of disease or illness or its one or more symptoms.In most cases, the patient can not make disease or illness cure from the beneficial effect that prevents and/or treats agent and obtain.Just in this point, term " control " comprises the patient that treatment once suffered from specified disease, to attempt to prevent or minimize the recurrence of disease.

Unless otherwise, " the treatment significant quantity " of the compound that the present invention uses is in disease or treatment of conditions or control, to be enough to provide the treatment benefit, perhaps postpones or minimize the amount of one or more relevant symptoms of disease or illness.The treatment significant quantity of compound refers to the amount of therapeutical agent, and it is united separately or with other treatment, in disease or treatment of conditions or control, the treatment benefit is provided.Term " treatment significant quantity " can comprise improvement totally to be treated, reduces or avoid symptom or the cause of disease or illness, or strengthen the amount of the result of treatment of another kind of therapeutical agent.

Unless otherwise, " the prevention significant quantity " of the compound of the present invention's use is the amount that is enough to preventing disease or illness or prevents its recurrence.The prevention significant quantity of compound refers to the amount of therapeutical agent, and it is united separately or with other medicaments, and the prevention benefit is provided in the prevention of disease.Term " prevention significant quantity " can comprise the amount that improvement totally prevented or strengthened the preventive effect of another kind of preventive.

The term " compsn " that the present invention uses will comprise and contain the product of specifying composition (if point out, containing with specified amount), and any directly or indirectly by the product of specifying composition to produce with the specified amount combination." pharmaceutically acceptable " is meant that thinner, vehicle or carrier must be compatible with other composition of preparation, and harmless to its recipient.

4. detailed description of the Invention

The present invention relates to the pure compd A of stereoisomerism; It is 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1; (+) enantiomorph of 3-diketone; Basically do not contain its (-) enantiomorph, and the novel method and the compsn that comprises it of using the solid form of pure compd A of stereoisomerism and/or inclusion compound A.For example, the present invention includes interior use of external and body of compd A, and compd A is joined in the pharmaceutical composition and single unit dosage useful in various diseases and treatment of conditions and prevention.Can be well known in the art through disease and the illness that reduction TNF-alpha levels or inhibition PDE4 improve, and description is arranged in the present invention.Concrete grammar of the present invention reduces or has avoided as the relevant undesirable action of the compound of TNF-alpha inhibitor.Other concrete grammar of the present invention reduces or has avoided using racemic 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1, the undesirable action that the 3-diketone is relevant.

Concrete grammar of the present invention comprises treatment or preventing disease and illness, includes but not limited to the method for solid tumor, haematogenous tumour and inflammatory diseases.

The medicine of the present invention and the formulation of inclusion compound A or its pharmaceutically acceptable polymorphic form, prodrug, inclusion compound, solvolyte or hydrate (wherein specific embodiments comprises the solid form like inclusion compound A described in the invention) can be used in the method for the invention.

Be not subject to theory, believe compd A, comprise the solid form of inclusion compound A, can suppress TNF-α and produce.Therefore; First embodiment of the present invention relates to and suppresses the method that TNF-α produces, and it comprises makes the cell that shows abnormal T NF-α generation contact with pure compd A or its pharmaceutically acceptable prodrug, metabolite, polymorphic form, solvolyte, hydrate or the inclusion compound (wherein specific embodiments comprises the solid form like inclusion compound A described in the invention) of the stereoisomerism of significant quantity.In a specific embodiments; The present invention relates to suppress the method that TNF-α produces, it comprises makes the mammalian cell that shows abnormal T NF-α generation contact with pure compd A or its pharmaceutically acceptable prodrug, metabolite, polymorphic form, solvolyte, hydrate or the inclusion compound (wherein specific embodiments comprises the solid form like inclusion compound A described in the invention) of the stereoisomerism of significant quantity.

The present invention also relates in the patient treatment, prevention or control can be through reducing the method for the illness that the TNF-alpha levels improves, and it comprises pure compd A or its pharmaceutically acceptable prodrug, metabolite, polymorphic form, solvolyte, hydrate or the inclusion compound (wherein specific embodiments comprises the solid form like inclusion compound A described in the invention) of stereoisomerism to patient's administering therapeutic of this treatment of needs or prevention or prevention significant quantity.In specific embodiments, in Mammals, can produce disease or the illness improved and include but not limited to: HIV through inhibition TNF-α; Hepatitis; Adult respiratory distress syndrome; Bone resorption disease; Chronic obstructive pulmonary disease; Chronic pulmonary inflammation disease; Asthma; Dermatitis; Cystic fibrosis; Septic shock; Septicemia; Endotoxin shock; The haemodynamics shock; Septicemia syndrome; Postischemic reperfusion damage; Meningitis; Psoriatic; Fibrotic disease; Emaciation; Transplant rejection; Autoimmune disease; Rheumatoid spondylitis; Arhritis conditions, for example psoriatic arthritis, rheumatoid arthritis and osteo-arthritis; Osteoporosis; Segmental enteritis; Ulcerative colitis; Inflammatory bowel; Multiple sclerosis; Systemic lupus erythematosus; Lupus erythematosus,cutaneous; Sarcoidosis of lung; ENL in the leprosy (ENL); Radiation injury; Asthma; And hyperoxic alveolar injury.This illness further includes but not limited to cancer, includes but not limited to: the cancer of head, Tiroidina, neck, eye, skin, mouth, larynx, esophagus, chest, bone, blood, marrow, lung, colon, sigmoid colon, rectum, stomach, prostate gland, breast, ovary, kidney, liver, pancreas, brain, intestines, heart, suprarenal gland, subcutis, lymphoglandula, heart and combination thereof.Treatable by this method concrete cancer has multiple myeloma, malignant melanoma, glioblastoma, white blood disease and solid tumor.

Further embodiment of the present invention relates to treatment or preventing cancer in the patient; Include but not limited to solid tumor, haematogenous tumour, white blood disease; The method of multiple myeloma particularly, it comprises compd A or its pharmaceutically acceptable prodrug, metabolite, polymorphic form, solvolyte, hydrate or the inclusion compound (wherein specific embodiments comprise solid form like described in the invention inclusion compound A) pure to the stereoisomerism of patient's administering therapeutic significant quantity of this treatment of needs or prevention; Particularly, wherein patient is a Mammals.

In another embodiment; The present invention relates to suppress the method for PDE4, it comprises that the PDE4 that makes in the cell (for example mammalian cell) contacts with pure compd A or its pharmaceutically acceptable prodrug, metabolite, polymorphic form, solvolyte, hydrate or the inclusion compound (wherein specific embodiments comprises the solid form like inclusion compound A described in the invention) of the stereoisomerism of significant quantity.

Further embodiment of the present invention relates in the patient treatment or prevention can be through suppressing the disease that PDE4 improves or the method for illness, and it comprises pure compd A or its pharmaceutically acceptable prodrug, metabolite, polymorphic form, solvolyte, hydrate or the inclusion compound (wherein specific embodiments comprises the solid form like inclusion compound A described in the invention) of stereoisomerism to patient's administering therapeutic of this treatment of needs or prevention or prevention significant quantity.Can include but not limited to asthma, inflammation (for example by pouring into the inflammation that causes again), chronic or acute occlusion property tuberculosis, chronic or acute pulmonary inflammation disease, inflammatory bowel, segmental enteritis, Behcet's disease or colitis through the illness that inhibition PDE4 improves.

In another embodiment; The present invention relates to control the method for the cAMP level in the cell, it comprises contacts the pure compd A of the cell and the stereoisomerism of significant quantity or its pharmaceutically acceptable prodrug, metabolite, polymorphic form, solvolyte, hydrate or inclusion compound (wherein specific embodiments comprises the solid form like inclusion compound A described in the invention).The term that the present invention uses " control cAMP level " comprises prevention or reduces adenosine 3'; 5'-encircle single phosphoric acid (cAMP) in cell rate of decomposition or increase the adenosine 3' that exists in the cell; 5'-encircles the amount of single phosphoric acid, is preferably mammalian cell, more preferably is the human cell.In concrete grammar, with not with similar cell that compound of the present invention contacts in speed compare, the cAMP rate of decomposition has reduced about 10,25,50,100,200 or 500%.

Further embodiment of the present invention relates in the patient method of treatment or prevention depression, asthma, inflammation (for example contact dermatitis, atopic dermatitis, psoriatic, rheumatoid arthritis, osteo-arthritis, inflammatory skin diseases, the inflammation that caused by perfusion again), chronic or acute occlusion property tuberculosis, chronic or pulmonary inflammation disease, inflammatory bowel, segmental enteritis, Behcet's disease or colitis, and it comprises patient's administering therapeutic of this treatment of needs or prevention or prevents pure compd A or its pharmaceutically acceptable prodrug, metabolite, polymorphic form, solvolyte, hydrate or the inclusion compound (wherein specific embodiments comprises the solid form like inclusion compound A described in the invention) of stereoisomerism of significant quantity; Particularly, wherein the patient is a Mammals.

A separate embodiments of the present invention comprises the method for treatment or prevention myeloproliferative disorder syndrome (MDS), and it comprises pure compd A or its pharmaceutically acceptable solvolyte, hydrate, steric isomer, inclusion compound or the prodrug (wherein specific embodiments comprises the solid form like inclusion compound A described in the invention) of stereoisomerism to patient's administering therapeutic of this treatment of needs or prevention or prevention significant quantity.MDS refers to a different set of hemopoietic stem cell illness.The characteristic of MDS is form and the maturation (abnormal marrow hyperplasia) that cell marrow has infringement, peripheral blood hemocytopenia and proceed to the variable risk of acute leukemia, and it is produced by invalid hemocyte and causes.Referring to The Merck Manual953 (the 17th editions, 1999) and List etc., 1990, J.Clin.Oncol.8:1424.

A separate embodiments of the present invention comprises the method for treatment or prevention myeloproliferative diseases (MPD), and it comprises pure compd A or its pharmaceutically acceptable solvolyte, hydrate, steric isomer, inclusion compound or the prodrug (wherein specific embodiments comprises the solid form like inclusion compound A described in the invention) of stereoisomerism to patient's administering therapeutic of this treatment of needs or prevention or prevention significant quantity.Myeloproliferative diseases (MPD) refers to that a stack features is the unusual illness of hemopoietic stem cell clone.Referring to for example, Current Medical Diagnosis & Treatment, 499 pages (the 37th edition, editors such as Tierney, Appleton & Lange, 1998).

The present invention comprises that also treatment, prevention or pain management include but not limited to the method for complex region property pain syndrome, and it comprises pure compd A or its pharmaceutically acceptable solvolyte, hydrate, steric isomer, inclusion compound or the prodrug (wherein specific embodiments comprises the solid form like inclusion compound A described in the invention) of stereoisomerism to patient's administering therapeutic of this treatment of needs, prevention or control or prevention significant quantity.In one specific embodiment, be applied in be intended to reduce or avoid before the operation or Physiotherapy of symptom of complex region property pain syndrome, during or in the patient, carry out afterwards.

In concrete grammar of the present invention, the compd A that stereoisomerism is pure or its pharmaceutically acceptable polymorphic form, prodrug, solvolyte, hydrate or inclusion compound (wherein specific embodiments comprises the solid form like inclusion compound A described in the invention) are used with at least a additional therapeutic agent is auxiliary.The embodiment of additional therapeutic agent includes but not limited to: anticarcinogen, antiphlogiston, antihistaminic agent and Decongestant.

4.1. The solid form of inclusion compound A

Certain embodiments of the present invention provide solid form, and it comprises the compd A with top chemical structure that shows.Racemic 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1,3-diketone use the method in the U.S. Patent number 6,020,358 to prepare easily, and it incorporates this paper by reference into.Compd A is 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1; (+) enantiomorph of 3-diketone; It can comprise U.S. Patent number 6,962 according to any method preparation that it will be apparent to those skilled in the art; The method of describing in 940, it incorporates this paper by reference into.

The solid form of inclusion compound A comprises single component and multicomponent form, comprises crystal formation and amorphous forms, and includes but not limited to polymorphic form, solvolyte, hydrate, eutectic and inclusion compound.Specific embodiments of the present invention provides the single component of compd A unformed solid form.Specific embodiments of the present invention provides the single component crystalline solid forms of compd A.Specific embodiments of the present invention provides the multicomponent amorphous forms of inclusion compound A.Specific embodiments of the present invention provides the multicomponent crystalline solid forms of inclusion compound A.Multicomponent solid form provided by the invention comprises the solid form that can use term salt, eutectic, hydrate, solvolyte, inclusion compound and/or polymorphic form to describe, also comprises the solid form that can use one or more these term descriptions.

The solid form of inclusion compound A can comprise the method described among the following embodiment or technology preparation known in the art through method described herein, comprise that heating, cooling, lyophilize, freeze-drying, fusing quenching, solvent evaporation fast, slowly solvent evaporation, solvent recrystallization, anti-solvent add, the slurry recrystallization, by melting crystal, desolvation, restricted clearance for example recrystallization in nanoporous or the kapillary, surface or template for example recrystallization on the polymkeric substance, additive for example the eutectic ligand molecule in the presence of recrystallization, desolvation, dehydration, cool off, slowly cool off, be exposed to that solvent and/or water, drying comprise for example vacuum-drying, vapor diffusion, distillation, grinding (comprising for example cold grinding, the grinding of solvent drippage or liquid assisted milling), microwave induced deposition, ultrasonic degradation induced precipitation, induced with laser precipitates and precipitated by supercutical fluid fast.The granularity of the solid form that obtains can change (for example nano level is to the millimeter level); This can through for example change crystallization condition for example crystallization rate and/or recrystallisation solvent system control, or through granularity reduce that technology is for example ground, milled, micronization or ultrasonic degradation control.

Although do not hope to be subject to any particular theory, some solid form is characterised in that the physical properties that is fit to medicine and therapeutic dosage forms is for example stable, solubleness and dissolution rate.In addition; Although do not hope to be subject to any particular theory; Some solid form be characterised in that influence particular procedure (for example output, filtration, washing, drying, mill, mixing, compressing tablet, flowability, dissulution, preparation and freeze-drying) physical properties (for example density, compressibility, hardness, form, dissociate, viscosity, solubleness, moisture absorption, electrical property, thermal behavior, solid state reaction property, physical stability and chemicalstability), this makes some solid form be fit to the preparation solid dosage.Such character can be used like this paper and describe and concrete analysis chemical technology known in the art mensuration, comprises solid-state analytical technology (for example X-ray diffraction, microscope, spectrum and heat are analyzed).

Certain embodiments of the present invention provide the compsn that comprises one or more solid forms.Some embodiment provides the compsn of one or more solid forms and the combination of other activeconstituents.Some embodiment provides in disease and treatment of conditions, prevention or control and has used these method for compositions, includes but not limited to disease provided by the invention and illness.

Except that the solid form of inclusion compound A, the present invention also provides the solid form of the prodrug of inclusion compound A.

Solid form provided by the invention also can comprise non-natural atom isotope part in the one or more atoms place in compd A.For example, compound can come radio-labeled with ri, for example as tritium ( ³H), iodine-125 ( ¹²⁵I), Sulphur-35 ( ³⁵S) or carbon-14 ( ¹⁴C).Radiolabeled compound useful as therapeutics for example cancer therapeutic agent, research reagent for example combines the for example interior developer of body of test reagent and diagnostic reagent.No matter whether all isotropic substance mutation of compd A be radioactive, all is comprised in the scope of embodiment provided by the invention.

4.1.1. The form A of compd A

Certain embodiments of the present invention provide the form A crystal formation of compd A.In certain embodiments, the form A of compd A can be obtained by all kinds of SOLVENTS, includes but not limited to comprise the solvent system of acetone, ethanol and composition thereof.In certain embodiments, form A can use quick crystallisation by cooling process to obtain.

In certain embodiments, the form A of compd A can characterize through the X-ray powder diffraction analysis.The typical XRPD figure of the form A of compd A provides in Fig. 1.In certain embodiments, the characteristic of the form A of compd A is the XRPD peak that is arranged in one, two, three, four, five, six, seven, eight, nine, ten, 11 or 12 position of following apparent position: 8.1,14.4,15.2,17.4,18.4,19.2,20.5,22.8,23.2,23.6,24.5,25.1 degree, 2 θ.In certain embodiments, the characteristic of the form A of compd A be with Fig. 1 in the XRPD figure that is complementary of the figure that shows.In certain embodiments, the characteristic of the form A of compd A is to have the XRPD figure that the peak among 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24 or 25 peak and the canonical form A provided by the present invention figure is complementary.

In certain embodiments, the form A of compd A can characterize through the heat analysis.The typical DSC figure of the form A of compd A shows in Fig. 2.In certain embodiments, the characteristic of form A is the DSC figure that comprises the heat absorption incident of the about 145 ° of C of starting temperature.In certain embodiments, the characteristic of form A is the DSC figure that further comprises the heat absorption incident of the about 155 ° of C of starting temperature.The typical TGA figure of the form A of compd A shows in Fig. 3.In certain embodiments, the characteristic of form A is when being heated to about 140 ° of C from about 25 ° of C, comprises to be lower than the about 1% of sample total mass, the TGA figure of for example about 0.05% mass loss.In certain embodiments, the form A of compd A does not comprise a large amount of water or other solvent in lattice.In certain embodiments, form A is a solvation not.In certain embodiments, form A is anhydrous.

In certain embodiments, the form A of compd A can characterize through the water adsorption analysis.Typical water adsorption isothermal chart shows in Fig. 4.In certain embodiments, when relative humidity (" RH ") is increased to about 95%RH from about 0%, form A shows and is lower than the about 1% of sample initial mass, for example about 0.4% quality change.In certain embodiments, when RH rolls back about 0%RH, by the quality disappearance of absorption acquisition.Therefore, in certain embodiments, form A is nonhygroscopic basically.In certain embodiments, the XRPD figure of form A material was constant basically after the adsorption/desorption Fufen was analysed.In certain embodiments, form A is stable for humidity.

In certain embodiments, the form A of compd A can characterize through its stability features.In certain embodiments, form A material is stable, and for example when being exposed to high temperature, when being exposed to high humidity, when being exposed to one or more solvents, and/or under pressure, its XRPD figure keeps constant basically.In certain embodiments, for example, be exposed to about 40 ° of C environment and the about four stars after date of about 75%RH environment, form A is stable.In certain embodiments, be exposed to one or more solvent systems that comprise for example ethanol, water and/or heptane at least about the four stars after date at about 40 ° of C, form A is stable.In certain embodiments, when being exposed to the solvent four stars during phase that includes but not limited to toluene, form A changes into the form A of compd A.In certain embodiments, under the pressure of the about 2000psi of pressure about one minute, form A was stable.

In certain embodiments, the form A of compd A can characterize through grain size analysis.In certain embodiments, the characteristic of form A is a white powder.In certain embodiments, the sample of form A comprises the particle with lamellar morphology.In certain embodiments, the sample of form A comprises D ₉₀Value is lower than the particle of about 18 μ m.(the D that the present invention uses ₉₀Value, representative is 90 through the percentile of the size-grade distribution of linear measure; Promptly 90% particle has the length of this value or shorter).

Certain embodiments of the present invention provide the form A of pure basically compd A.Certain embodiments of the present invention provide the form A of compd A, and the solid form that it does not contain other inclusion compound A basically for example comprises, like form B, C, D, E, F, G and/or the unformed solid form of inclusion compound A provided by the invention.The form A that certain embodiments of the present invention provide is the mixture of the solid form of inclusion compound A, comprises for example comprising following one or more mixture: like form B, C, D, E, F, G and the unformed solid form of inclusion compound A provided by the invention.

4.1.2. The form B of compd A

Certain embodiments of the present invention provide the form B crystal formation of compd A.In certain embodiments; The form B of compd A can be obtained by all kinds of SOLVENTS, the solvent system that includes but not limited to comprise 2-propyl alcohol, acetone, acetonitrile, ethanol, ETHYLE ACETATE, heptane, methyl alcohol, methyl ethyl ketone, methyl tert-butyl ether, methylene dichloride, propyl carbinol, n-butyl acetate, THF, toluene, water and comprise its two or more mixture.For example, in certain embodiments, form B can be through from comprising 1:1 ethanol: crystallization obtains the solvent system of water, and for example through being included in about 25 ° of C evaporation 1:1 ethanol: the solvent system of water, then the process of unpack format B obtains.For example; In certain embodiments; Form B can be through from comprising 1:1 acetone: crystallization obtains the alcoholic acid solvent system, and for example through being included in about 25 ° of C at 1:1 acetone: the solid form of pulp inclusion compound A is about 2 days in the ethanol, and then the process of unpack format B obtains.

In certain embodiments, the form B of compd A can characterize through the X-ray powder diffraction analysis.The typical XRPD figure of the form B of compd A provides in Fig. 5.In certain embodiments, the characteristic of the form B of compd A is the XRPD peak that is arranged in one, two, three, four, five, six, seven, eight, nine, ten, 11 or 12 position of following apparent position: 10.1,12.4,13.5,15.7,16.3,18.1,20.7,22.5,24.7,26.2,26.9,29.1 degree, 2 θ.In certain embodiments, the characteristic of the form B of compd A be with Fig. 5 in the XRPD figure that is complementary of the figure that shows.In certain embodiments, the characteristic of the form B of compd A is to have the XRPD figure that the peak among 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24 or 25 peak and the canonical form B provided by the invention figure is complementary.

In certain embodiments, the form B of compd A can characterize through the heat analysis.The typical DSC figure of the form B of compd A shows in Fig. 6.In certain embodiments, the characteristic of form B is the DSC figure that comprises the heat absorption incident of the about 154 ° of C of starting temperature.The typical TGA figure of the form B of compd A shows in Fig. 7.In certain embodiments, the characteristic of form B is when being heated to about 140 ° of C from about 25 ° of C, comprises to be lower than the about 1% of sample total mass, the TGA figure of for example about 0.25% mass loss.In certain embodiments, the form B of compd A does not comprise a large amount of water or other solvent in lattice.In certain embodiments, form B is anhydrous.In certain embodiments, form B is a solvation not.

In certain embodiments, the form B of compd A can characterize through the water adsorption analysis.Typical water adsorption isothermal chart shows in Fig. 8.In certain embodiments, when RH is increased to about 95%RH from about 0%, form B shows and is lower than the about 1% of sample initial mass, for example about 0.6% quality change.In certain embodiments, when RH rolls back about 0%RH, by the quality disappearance of absorption acquisition.In certain embodiments, form B is nonhygroscopic basically.In certain embodiments, the XRPD figure of form B material was constant basically after the adsorption/desorption Fufen was analysed.In certain embodiments, form B is stable for humidity.

In certain embodiments, the form B of compd A can characterize through its stability features.In certain embodiments, form B material is stable, and for example when being exposed to high temperature, when being exposed to high humidity, when being exposed to one or more solvents, and/or under pressure, its XRPD figure keeps constant basically.In certain embodiments, for example, be exposed to about 40 ° of C environment and the about four stars after date of about 75%RH environment, form B is stable.In certain embodiments, about 40 ° of C be exposed to comprise for example ethanol, water or heptane solvent system at least about the four stars after date, form B is stable.In certain embodiments, be exposed to the about four stars of solvent system during the phase that comprises toluene for example, form B changes into the form A of compd A.In certain embodiments, after under the pressure of the about 2000psi of pressure about one minute, form B is stable.

In certain embodiments, the form B of compd A can characterize through grain size analysis.In certain embodiments, the characteristic of form B is a white powder.In certain embodiments, the sample of form B comprises the particle with sheet-like form.In certain embodiments, the sample of form B comprises the particle that the D90 value is lower than about 12 μ m.

Certain embodiments of the present invention provide the form B of pure basically compd A.Certain embodiments of the present invention provide the form B of compd A, and the solid form that it does not contain other inclusion compound A basically for example comprises, like form A, C, D, E, F, G and/or the unformed solid form of inclusion compound A provided by the invention.The form B that certain embodiments of the present invention provide is the mixture of the solid form of inclusion compound A, comprises for example comprising following one or more mixture: like form A, C, D, E, F, G and the unformed solid form of inclusion compound A provided by the present invention.

4.1.3. The form A of compd A

Certain embodiments of the present invention provide the form A crystal formation of compd A.In certain embodiments; The form A of compd A can be obtained by all kinds of SOLVENTS system, the solvent system that includes but not limited to comprise acetone, acetonitrile, ethanol, heptane, methyl alcohol, methyl ethyl ketone, THF, toluene, water and comprise its two or more mixture.For example, in certain embodiments, form A can obtain through crystallization from the solvent system that comprises toluene, for example uses toluene as anti-solvent through comprising, then the process of unpack format C obtains.

In certain embodiments, the form A of compd A can characterize through the X-ray powder diffraction analysis.The typical XRPD figure of the form A of compd A provides in Fig. 9.In certain embodiments, the characteristic of the form A of compd A is the XRPD peak that is arranged in one, two, three, four, five, six, seven, eight, nine, ten, 11 or 12 position of following apparent position: 7.5,11.3,15.3,16.4,17.8,21.4,22.6,23.5,24.8,25.5,26.4,27.6 degree, 2 θ.In certain embodiments, the characteristic of the form A of compd A be with Fig. 9 in the XRPD figure that is complementary of the figure that shows.In certain embodiments, the characteristic of the form A of compd A is to have the XRPD figure that the peak among 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24 or 25 peak and the canonical form C provided by the present invention figure is complementary.

In certain embodiments, the form A of compd A can characterize through the heat analysis.The typical DSC figure of the form A of compd A shows in Figure 10.In certain embodiments, the characteristic of form A is the DSC figure that comprises the heat absorption incident of the about 138 ° of C of starting temperature.In certain embodiments, distinctive form A DSC figure further comprises one or more additional events, for example like the heat absorption incident of the about 166 ° of C of starting temperature.The typical TGA figure of the form A of compd A shows in Figure 11.In certain embodiments, the characteristic of form A is when being heated to about 140 ° of C from about 25 ° of C, comprises to be lower than the about 10% of sample total mass, the TGA figure of for example about 5.9% mass loss.In certain embodiments, like what show through for example TG-IR analysis, TGA mass loss incident comprises the loss of solvent toluene.In certain embodiments, the form A of compd A is a solvation.In certain embodiments, form A is the toluene solvant thing.In certain embodiments, the every mole compound A of the lattice of form A comprises about three moles of toluene.

In certain embodiments, the form A of compd A can characterize through the water adsorption analysis.Typical water adsorption isothermal chart shows in Figure 12.In certain embodiments, when RH is increased to about 95%RH from about 0%, form A shows and is lower than the about 1% of sample initial mass, for example about 0.5% quality change.In certain embodiments, when RH rolls back about 0%RH, by the quality disappearance of absorption acquisition.In certain embodiments, form A is nonhygroscopic basically.In certain embodiments, the XRPD figure of form A material was constant basically after the adsorption/desorption Fufen was analysed.In certain embodiments, form A is stable for humidity.

In certain embodiments, the form A of compd A can characterize through its stability features.In certain embodiments, the form A material is stable, and for example when being exposed to high temperature, when being exposed to high humidity, when being exposed to one or more solvents, and/or under pressure, its XRPD figure keeps constant basically.In certain embodiments, for example, be exposed to about 40 ° of C environment and the about four stars after date of about 75%RH environment, form A is stable.In certain embodiments, about 40 ° of C be exposed to comprise for example ethanol, water, heptane or toluene solvent system at least about the four stars after date, form A is stable.In certain embodiments, after under the pressure of the about 2000psi of pressure about one minute, form A is stable.

In certain embodiments, the form A of compd A can characterize through grain size analysis.In certain embodiments, the characteristic of form A is a white powder.In certain embodiments, the sample of form A comprises the particle with lamellar morphology.In certain embodiments, the sample of form A comprises D ₉₀Value is lower than the particle of about 12 μ m.

Certain embodiments of the present invention provide the form A of pure basically compd A.Certain embodiments of the present invention provide the form A of compd A, and the solid form that it does not contain other inclusion compound A basically for example comprises, like form A, B, D, E, F, G and/or the unformed solid form of inclusion compound A provided by the present invention.The form A that certain embodiments of the present invention provide is the mixture of the solid form of inclusion compound A, comprises for example comprising following one or more mixture: like form A, B, D, E, F, G and the unformed solid form of inclusion compound A provided by the present invention.

4.1.4. The form D of compd A

Certain embodiments of the present invention provide the form D crystal formation of compd A.In certain embodiments, the form D of compd A can be obtained by all kinds of SOLVENTS, includes but not limited to comprise the solvent system of methylene dichloride.For example, in certain embodiments, form D can obtain through crystallization from the solvent system that comprises methylene dichloride, and for example through comprising the evaporation methylene dichloride, then the process of unpack format D obtains.

In certain embodiments, the form D of compd A can characterize through the X-ray powder diffraction analysis.The typical XRPD figure of the form D of compd A provides in Figure 13.In certain embodiments, the characteristic of the form D of compd A is the XRPD peak that is arranged in one, two, three, four, five, six, seven, eight, nine, ten, 11 or 12 position of following apparent position: 7.5,9.6,11.3,13.9,16.3,17.7,20.5,23.2,24.6,25.2,26.0,28.8 degree, 2 θ.In certain embodiments, the characteristic of the form D of compd A be with Figure 13 in the XRPD figure that is complementary of the figure that shows.In certain embodiments, the characteristic of the form D of compd A is to have the XRPD figure that the peak among 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24 or 25 peak and the canonical form D provided by the present invention figure is complementary.

In certain embodiments, the form D of compd A can characterize through the heat analysis.The typical DSC figure of the form D of compd A shows in Figure 14.In certain embodiments, the characteristic of form D is the DSC figure that comprises the heat absorption incident of the about 100 ° of C of starting temperature.The typical TGA figure of the form D of compd A shows in Figure 15.In certain embodiments, the characteristic of form D is when being heated to about 110 ° of C from about 25 ° of C, comprises to be lower than the about 10% of sample total mass, the TGA figure of for example about 6.5% mass loss.In certain embodiments, like what show through for example TG-IR analysis, TGA mass loss incident comprises the loss of methylene chloride (being methylene chloride).In certain embodiments, the form D of compd A is a solvation.In certain embodiments, form D is the dichloromethane solvent thing.In certain embodiments, the every mole compound A of the lattice of form D comprises about 2.5 moles of methylene dichloride.

In certain embodiments, the form D of compd A can characterize through the water adsorption analysis.Typical water adsorption isothermal chart shows in Figure 16.In certain embodiments, when RH is increased to about 95%RH from about 0%, form D shows and is lower than the about 3% of sample initial mass, for example about 1.5% quality change.In certain embodiments, when RH rolls back about 0%RH, by the quality disappearance of absorption acquisition.Therefore, in certain embodiments, form D is slight moisture absorption.In certain embodiments, the XRPD figure of form D material was constant basically after the adsorption/desorption Fufen was analysed.In certain embodiments, form D is stable for humidity.

In certain embodiments, the form D of compd A can characterize through its stability features.In certain embodiments, form D material is stable, and for example its XRPD figure keeps constant basically under pressure.For example, in certain embodiments, after under the pressure of the about 2000psi of pressure about one minute, form D is stable.In certain embodiments, be exposed to about 40 ° of C environment and the about four stars after date of about 75%RH environment, form D is stable, although in certain embodiments, the peak intensity that the XRPD of form D figure obtains descends.In certain embodiments, this decline of XRPD peak intensity is because formed the amorphous material of inclusion compound A.In certain embodiments, be exposed to the about four stars of solvent system during the phase that comprises for example heptane, ethanol and/or water at about 40 ° of C, form D changes into the form B of compd A.In certain embodiments, be exposed to the about four stars of solvent system during the phase that comprises toluene at about 40 ° of C, form D changes into the form A of compd A.

In certain embodiments, the form D of compd A can characterize through grain size analysis.In certain embodiments, the characteristic of form D is a white powder.In certain embodiments, the sample of form D comprises the particle with sheet-like form.In certain embodiments, the sample of form D comprises D ₉₀Value is lower than the particle of about 18 μ m.

Certain embodiments of the present invention provide the form D of pure basically compd A.Certain embodiments of the present invention provide the form D of compd A, and the solid form that it does not contain other inclusion compound A basically for example comprises as form A, B, C, E, F, G and/or the unformed solid form of inclusion compound A provided by the present invention.The form D that certain embodiments of the present invention provide is the mixture of the solid form of inclusion compound A, comprises for example comprising following one or more mixture: like form A, B, C, E, F, G and the unformed solid form of inclusion compound A provided by the present invention.

4.1.5. The form E of compd A

Certain embodiments of the present invention provide the form E crystal formation of compd A.In certain embodiments, the form E of compd A can be obtained by all kinds of SOLVENTS, the solvent system that includes but not limited to comprise acetone, acetonitrile, heptane, methylene dichloride and comprise its two or more mixture.For example, in certain embodiments, form E can obtain through crystallization from the solvent system that comprises acetonitrile, and for example through comprising the evaporation acetonitrile, then the process of unpack format E obtains.

In certain embodiments, the form E of compd A can characterize through the X-ray powder diffraction analysis.The typical XRPD figure of the form E of compd A provides in Figure 17.In certain embodiments, the characteristic of the form E of compd A is the XRPD peak that is arranged in one, two, three, four, five, six, seven, eight, nine, ten, 11 or 12 position of following apparent position: 7.6,9.2,11.4,15.5,16.5,17.9,19.6,20.5,21.6,22.8,23.8,26.6 degree, 2 θ.In certain embodiments, the characteristic of the form E of compd A be with Figure 17 in the XRPD figure that is complementary of the figure that shows.In certain embodiments, the characteristic of the form E of compd A is to have the XRPD figure that the peak among 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24 or 25 peak and the canonical form E provided by the present invention figure is complementary.

In certain embodiments, the form E of compd A can characterize through the heat analysis.The typical DSC figure of the form E of compd A shows in Figure 18.In certain embodiments, the characteristic of form E is the DSC figure that comprises the heat absorption incident of the about 95 ° of C of starting temperature.The typical TGA figure of the form E of compd A shows in Figure 19.In certain embodiments, the characteristic of form E is when being heated to about 110 ° of C from about 25 ° of C, comprises to be lower than the about 8% of sample total mass, the TGA figure of for example about 4.0% mass loss.In certain embodiments, like what show through for example TG-IR analysis, TGA mass loss incident comprises the loss of solvent acetonitrile.In certain embodiments, the form E of compd A is a solvation.In certain embodiments, form E is an acetonitrile solvate.In certain embodiments, the every mole compound A of the lattice of form E comprises about 2.5 moles of acetonitriles.

In certain embodiments, the form E of compd A can characterize through the water adsorption analysis.Typical water adsorption isothermal chart shows in Figure 20.In certain embodiments, when RH is increased to about 95%RH from about 0%, form E shows and is lower than the about 10% of sample initial mass, for example about 5.1% quality change.In certain embodiments, when RH rolls back about 0%RH, by the quality disappearance of absorption acquisition.In certain embodiments, form E is moisture absorption.In certain embodiments, the XRPD figure of form E material was constant basically after the adsorption/desorption Fufen was analysed.In certain embodiments, form E is stable for humidity.

In certain embodiments, the form E of compd A can characterize through its stability features.In certain embodiments, form E material is stable, and for example its XRPD figure keeps constant basically under pressure.For example, in certain embodiments, after under the pressure of the about 2000psi of pressure about one minute, form E is stable.

In certain embodiments, the form E of compd A can characterize through grain size analysis.In certain embodiments, the characteristic of form E is a white powder.In certain embodiments, the sample of form E comprises the particle with sheet-like form.In certain embodiments, the sample of form E comprises D ₉₀Value is lower than the particle of about 18 μ m.

Certain embodiments of the present invention provide the form E of pure basically compd A.Certain embodiments of the present invention provide the form E of compd A, and the solid form that it does not contain other inclusion compound A basically for example comprises as form A, B, C, D, F, G and/or the unformed solid form of inclusion compound A provided by the present invention.The form E that certain embodiments of the present invention provide is the mixture of the solid form of inclusion compound A, comprises for example comprising following one or more mixture: like form A, B, C, D, F, G and the unformed solid form of inclusion compound A provided by the present invention.

4.1.6. The form D of compd A

Certain embodiments of the present invention provide the form D crystal formation of compd A.In certain embodiments, the form D of compd A can be obtained by all kinds of SOLVENTS, the solvent system that includes but not limited to comprise acetone, ethanol, water and comprise its two or more mixture.For example; In certain embodiments; Form D can obtain through crystallization from the solvent system that comprises ethanol and/or water, and for example through comprising that the solid form that makes inclusion compound A contacts with the solvent system that comprises ethanol and/or water, then the process of unpack format F obtains.

In certain embodiments, the form D of compd A can characterize through the X-ray powder diffraction analysis.The typical XRPD figure of the form D of compd A provides in Figure 21.In certain embodiments, the characteristic of the form D of compd A is the XRPD peak that is arranged in one, two, three, four, five, six, seven, eight, nine, ten, 11 or 12 position of following apparent position: 8.1,8.6,15.6,17.3,19.3,21.4,22.8,24.6,25.4,25.9,26.6,27.7 degree, 2 θ.In certain embodiments, the characteristic of the form D of compd A be with Figure 21 in the XRPD figure that is complementary of the figure that shows.In certain embodiments, the characteristic of the form D of compd A is to have the XRPD figure that the peak among 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24 or 25 peak and the canonical form F provided by the present invention figure is complementary.

In certain embodiments, the form D of compd A can characterize through the heat analysis.The typical DSC figure of the form D of compd A shows in Figure 22.In certain embodiments, the characteristic of form D is the DSC figure that comprises the heat absorption incident of the about 145 ° of C of starting temperature.The typical TGA figure of the form D of compd A shows in Figure 23.In certain embodiments, the characteristic of form D is when being heated to about 180 ° of C from about 25 ° of C, comprises to be lower than the about 1% of sample total mass, the TGA figure of for example about 0.1% mass loss.In certain embodiments, the form D of compd A does not comprise a large amount of water or other solvent in lattice.In certain embodiments, form D is a solvation not.In certain embodiments, form D is anhydrous.

In certain embodiments, the form D of compd A can characterize through the water adsorption analysis.Typical water adsorption isothermal chart shows in Figure 24.In certain embodiments, when RH is increased to about 95%RH from about 0%, form D shows and is lower than the about 1% of sample initial mass, for example about 0.2% quality change.In certain embodiments, when RH rolls back about 0%RH, by the quality disappearance of absorption acquisition.In certain embodiments, form D is nonhygroscopic basically.In certain embodiments, the XRPD figure of form D material was constant basically after the adsorption/desorption Fufen was analysed.In certain embodiments, form D is stable for humidity.

In certain embodiments, the form D of compd A can characterize through its stability features.In certain embodiments, the form D material is stable, and for example its XRPD figure keeps constant basically under pressure.For example, in certain embodiments, after under the pressure of the about 2000psi of pressure about one minute, form D is stable.In certain embodiments, about 25 ° of C be exposed to comprise for example ethanol, acetone or its mixture solvent system approximately two days later, form D is stable.

In certain embodiments, the form D of compd A can characterize through grain size analysis.In certain embodiments, the characteristic of form D is a white powder.In certain embodiments, the sample of form D comprises the particle with sheet-like form.In certain embodiments, the sample of form D comprises D ₉₀Value is lower than the particle of about 18 μ m.

Certain embodiments of the present invention provide the form D of pure basically compd A.Certain embodiments of the present invention provide the form D of compd A, and the solid form that it does not contain other inclusion compound A basically for example comprises as form A, B, C, D, E, G and/or the unformed solid form of inclusion compound A provided by the present invention.The form D that certain embodiments of the present invention provide is the mixture of the solid form of inclusion compound A, comprises for example comprising following one or more mixture: like form A, B, C, D, E, G and the unformed solid form of inclusion compound A provided by the present invention.

4.1.7. The form G of compd A

Certain embodiments of the present invention provide the form G crystal formation of compd A.In certain embodiments, the form G of compd A can be obtained by all kinds of SOLVENTS, includes but not limited to comprise the solvent system of ETHYLE ACETATE.For example; In certain embodiments; Form G can obtain through crystallization from the solvent system that comprises ETHYLE ACETATE, and for example through comprising that the solid form with inclusion compound A contacts with the solvent system that comprises ETHYLE ACETATE, then the process of unpack format G obtains.

In certain embodiments, the form G of compd A can characterize through the X-ray powder diffraction analysis.The typical XRPD figure of the form G of compd A provides in Figure 25.In certain embodiments, the characteristic of the form G of compd A is the XRPD peak that is arranged in one, two, three, four, five, six, seven, eight, nine, ten, 11 or 12 position of following apparent position: 7.9,9.5,11.7,15.7,16.8,18.1,19.7,21.8,22.8,25.1,25.8,26.7 degree, 2 θ.In certain embodiments, the characteristic of the form G of compd A be with Figure 25 in the XRPD figure that is complementary of the figure that shows.In certain embodiments, the characteristic of the form G of compd A is to have the XRPD figure that the peak among 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24 or 25 peak and the canonical form G provided by the present invention figure is complementary.

In certain embodiments, the form G of compd A can characterize through the heat analysis.The typical DSC figure of the form G of compd A shows in Figure 26.In certain embodiments, the characteristic of form G is the DSC figure that comprises the heat absorption incident of the about 109 ° of C of starting temperature.The typical TGA figure of the form G of compd A shows in Figure 27.In certain embodiments, the characteristic of form G is when being heated to about 110 ° of C from about 25 ° of C, comprises to be lower than the about 8% of sample total mass, the TGA figure of for example about 3.8% mass loss.In certain embodiments, like what show through for example TG-IR analysis, TGA mass loss incident comprises the loss of solvent ethyl acetate.In certain embodiments, the form G of compd A is a solvation.In certain embodiments, form G is the ethyl acetate solvent thing.In certain embodiments, the every mole compound A of the lattice of form G comprises about three mole of acetic acid ethyl esters.

In certain embodiments, the form G of compd A can characterize through the water adsorption analysis.Typical water adsorption isothermal chart shows in Figure 28.In certain embodiments, when RH is increased to about 95%RH from about 0%, form G shows and is lower than the about 1% of sample initial mass, for example about 0.4% quality change.In certain embodiments, when RH rolls back about 0%RH, by the quality disappearance of absorption acquisition.In certain embodiments, form G is nonhygroscopic basically.In certain embodiments, the XRPD figure of form G material was constant basically after the adsorption/desorption Fufen was analysed.In certain embodiments, form G is stable for humidity.

In certain embodiments, the form G of compd A can characterize through its stability features.In certain embodiments, form G material is stable, and for example its XRPD figure keeps constant basically under pressure.For example, in certain embodiments, after under the pressure of the about 2000psi of pressure about one minute, form D is stable.In certain embodiments, be exposed to the solvent system in the time of about two days that comprises for example ethanol, acetone or its mixture at about 25 ° of C, form G changes into form B.

In certain embodiments, the form G of compd A can characterize through grain size analysis.In certain embodiments, the characteristic of form G is a white powder.In certain embodiments, the sample of form G comprises the particle with sheet-like form.In certain embodiments, the sample of form G comprises D ₉₀Value is lower than the particle of about 18 μ m.

Certain embodiments of the present invention provide the form G of pure basically compd A.Certain embodiments of the present invention provide the form G of compd A, and the solid form that it does not contain other inclusion compound A basically for example comprises as form A, B, C, D, E, F and/or the unformed solid form of inclusion compound A provided by the present invention.The form G that certain embodiments of the present invention provide is the mixture of the solid form of inclusion compound A, comprises for example comprising following one or more mixture: like form A, B, C, D, E, F and the unformed solid form of inclusion compound A provided by the present invention.

4.2. Treat-ment

Present invention resides among the patient treatment, prevention and control can be through reducing the disease that the TNF-alpha levels improves or the method for illness; It comprises the solid form to one or more inclusion compounds A of patient's administering therapeutic of this treatment of needs, prevention or control or prevention significant quantity; For example as, like the form A of compd A provided by the present invention, the form B of compd A, the form A of compd A, the form D of compd A, the form E of compd A, the form D of compd A, the form G of compd A or the amorphous forms of compd A.

Can include but not limited to through the illness that inhibition TNF-α improves: heart trouble, the septic shock of for example congestive heart failure, myocardosis, wet lung, endotaxin mediate, acute viral myocarditis, heart heteroplastic transplantation are repelled and myocardial infarction; Solid tumor includes but not limited to sarcoma, cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, Ewing's tumour, leiomyosarcoma, rhabdosarcoma, colorectal carcinoma, carcinoma of the pancreas, mammary cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, rodent cancer, gland cancer, syringocarcinoma, sebaceous carcinoma, papillary carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, spermocytoma, embryonal carcinoma, the nephroblastoma, cervical cancer, tumor of testis, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, Kaposi's sarcoma, pinealoma, hemangioblastoma, acoustic tumor, oligodendroglioma, meningioma, melanoma, neuroblastoma and retinoblastoma; And haematogenous tumour; Include but not limited to acute lymphoblastic leukemia " ALL ", acute lymphocytoblast property B cell leukemia, acute lymphocytoblast property T HTLV, acute myeloblastic leukemia " AML ", acute promyelocytic leukemia " APL ", acute monoblastic leukemia, Di Guglielmo syndrome property white blood disease, acute megakaryoblast property white blood disease, acute grain monocytic leukemia, acute nonlymphocytic leukemia, acute nondifferentiated leukemia, chronic myelocytic leukemia " CML ", lymphocytic leukemia " CLL ", hairy cell leukemia, multiple myeloma and acute and chronic leukemia, for example lymphocytoblast property, marrow property, lymphatic and myelocytic leukemia.

Concrete grammar of the present invention further comprises uses extra therapeutical agent (being the therapeutical agent outside the compd A).The embodiment of additional therapeutic agent includes but not limited to anticarcinogen, such as but not limited to: alkylating agent, mustargen, ethyleneimine, methyl melamine, AS, nitrosourea, triazene, folacin, pyrimidine analogue, purine analogue, vinca alkaloids, epipodophyllotoxin, microbiotic, topoisomerase enzyme inhibitor and anti-cancer vaccine.

Concrete additional therapeutic agent includes but not limited to: U 42126; Aclarubicin; The hydrochloric acid acodazole; Acronine; U 73975; RIL-2; Altretamine; Duazomycin C; The acetic acid ametantrone; Aminoglutethimide; Amsacrine; Anastrozole; Antramycin; Asparaginase; Asperline; Azacitidine; Azatepa; Azotomycin; BB-94; Benzodepa; Bicalutamide; Bisantrene hydrochloride; Two methylsulfonic acid Bisnafides; U 77779; BLEOMYCIN SULPHATE; Brequinar sodium; U-54461; Busulfan; Sanarnycin; Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; NSC-180024; U 80244; SPC 101210; TV; U 12241; Cis-platinum; CldAdo; The methylsulfonic acid crisnatol; Endoxan; Cytosine arabinoside; Dicarbazine; Dactinomycin; Daunorubicin hydrochloride; NSC 127716; U 78938; Dezaguanine; The methylsulfonic acid Dezaguanine; NSC-182986; Docetaxel; Dx; Doxorubicin hydrochloride; Droloxifene; K-21060E; NSC-12198; Duazomycin; Edatrexate; Vaniqa; Elsamitrucin; Enloplatin; Enpromate; NSC 56308; Epirubicin hydrochloride; R 55104; IMI 58; Estramustine; Estramustine phosphate sodium; SR-2508; VP; The phosphoric acid VP; Etoprine; CGS-16949A; NSC 281272; HPR; Floxuridine; NSC-328002; Fluracil; Flurocitabine; GR 63178X; Phosphotrienin sodium; Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Thio ALP; Interleukin-II (the interleukin-II or the rIL2 that comprise reorganization); Intederon Alpha-2a; Interferon Alpha-2b; Interferon alfa-n1; Alferon N; Interferon beta-Ia; Interferon-gamma-Ib; NSC 256927; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; TAP-144; Liarozole hydrochloride; Lometrexol sodium; Lomustine; Losoxantrone hydrochloride; Masoprocol; Maytenin; Mustine hydrochlcride; Magace; Melengestrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; U-197; Meturedepa; NSC 284356; Rice holder jinx; NSC 77471; Mitogillin; NSC-B 2992; MTC; Mitosper; Mitotane; NSC-301739; Mycophenolic Acid; R 17934; Nogalamycin; Ormaplatin; Oxisuran; Taxol; Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan; The hydrochloric acid piroxantrone; Plicamycin; Plomestane; Porfimer sodium; Porfiromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazofurin; SQ 22558; Rogletimide; SPC 100270; The hydrochloric acid SPC 100270; Semustine; Simtrazene; Sparfosate sodium; Sparsomycin; NSC-192965; Spiromustine; Spiral shell platinum; Streptonigrin; Streptozocin; Sulofenur; Talisomycin; Tecogalan sodium; Tegafur; Teloxandrone hydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone; ITG; Tioguanine; Plug is for group; Tiazofurine; Win-59075; FC-1157a; Trestolone acetate; The phosphoric acid triciribine; Trimetrexate; The trimetrexate glucuronate; Triptorelin; Tubulozole hydrochloride; Uramustine; Uredepa; Vapreotide; Visudyne; Vinblastine sulphate; Vincristine sulphate; Vindesine; LY-099094; The sulfuric acid vinepidine; The sulfuric acid vinglycinate; The sulfuric acid vinleurosine; Vinorelbine tartrate; The sulfuric acid vinrosidine; The sulfuric acid vinzolidine; Vorozole; Zeniplatin; Zinostatin; NSC-164011.Other anticarcinogen includes but not limited to: 20-shows-1,25 dihydroxy vitamin d3s; 5-ethinyluracil; Abiraterone; Aclarubicin; The acyl group fulvene; The gland cyclopentanol; U 73975; RIL-2; Full TK antagonist; Altretamine; Ambamustine; 2,4 dichlorphenoxyacetic acids; Amifostine; Amino-laevulic acid; Amrubicin; Amsacrine; Anagrelide; Anastrozole; Rographolide; Angiogenesis inhibitor; Antagonist D; Antagonist G; Antarelix; Anti-dorsalization morphogenetic proteins-1; Androgen antagonist, prostate cancer; Estrogen antagonist; Antineoplaston; Antisense oligonucleotide; The glycocoll NSC-234714; The apoptogene regulator; Apoptosis regulator; Apurinic acid; Ara-CDP-DL-PTBA; The l-arginine desaminase; 9-[2-methoxyl group-4-(methyl sulphonyl is amino) phenyl amino]-N, 5-dimethyl--4-acridine methane amide; SH 489; Atrimustine; Axinastatin 1; Axinastatin2; Axinastatin 3; Azasetron; Azalomycin; Azatyrosine; Baccatin III derivative; Barlan alcohol (balanol); BB-94; The BCR/ABL antagonist; The benzo chlorins; Benzoyl-star spore rhzomorph; The beta-lactam verivate; β-alethine; Beta clarithromycin (betaclamycin) B; Betulinic acid; The bFGF suppressor factor; Bicalutamide; Bisantrene; Two '-aziridino spermine; Bisnafide; Two cetiedil citrate A; U 77779; Bu Fulei (breflate); U-54461; Budotitane; BSA; Calcipotriol; Calphostin C; Camptothecin derivative; Canary pox IL-2; Capecitabine; Methane amide-amino-triazole; NSC 609974; CaRest M3; CARN 700; Be derived from the suppressor factor of cartilage; U 80244; Casein SU11752 (ICOS); Castanospermine; Cecropin B; Cetrorelix; Chlorins; The nefrosulfin quinoxaline; ZK 96480; The cis porphyrin; CldAdo; The Clomiphene analogue; Clotrimazole; Kao Lisi mycin (collismycin) A; Kao Lisi mycin B; Combretastatin A4; The combretastatin analogue; Conagenin; Crambescidin 816; Crisnatol; From beads algal rim peptide 8; From beads algal rim peptide A verivate; Curacin A; Encircle penta anthraquinone; Ring platinum (cycloplatam); But match mycin (cypemycin); Cytosine arabinoside octadecyl sodium phosphate; The lysis factor; Hexestryl diphosphate; Dacliximab; NSC 127716; The cyclodepsipeptide of dehydrogenation (dehydrodidemnin) B; Deslorelin; DEXAMETHASONE BP98; Right ifosfamide; Dexrazoxane; Dexverapamil; NSC-182986; Cyclodepsipeptide (didemnin) B; 3,4-dihydroxyl benzo hydroxamic acid (didox); Diethylammonium removes the first spermine; Dihydro-5-azacytidine; Dihydro is safe plain, 9-; Two oxamycins; The xenyl spiromustine; Docetaxel; V-1326; Dolasetron; Doxifluridine; Droloxifene; Dronabinol; Many Ka-7038s (duocarmycin) SA; Ebselen; NSC 609224; Ro 14-5243; Edrecolomab; Eflornithine; Elemenum Emulsion; Emitefur; Epirubicin; SKF-105657; The estramustine analogue; Estrogen agonist; Estrogen antagonist; SR-2508; The phosphoric acid VP; FCE-24304; Fadrozole; NSC 281272; HPR; Filgrastim; Finasteride; Husband's degree of evening up; Flezelastine; The fluoranthene sterone; Fludarabine; Hydrochloric acid fluorine daunomycin; Forfenimex; Formestane; Phosphotrienin; Fotemustine; De Kesafei quinoline gadolinium; Gallium nitrate; Ro 09-1390; RS 26306; The gelatinase suppressor factor; Gemcitabine; The gsh suppressor factor; Thionamic acid 1,7 heptane two basic esters; Heregulin; HMBA; Hypericin; Ibandronic acid; Idarubicin; CB-7432; Idramantone; Thio ALP; Ilomastat; The imidazo dihydroketoacridine; S-26308; The immunostimulant polypeptide; The IGF-1R suppressor factor; The Interferon, rabbit agonist; Interferon, rabbit; Interleukin-; M-iodobenzylguanidine; The iodine Dx; Sweet potato alcohol, 4-; Iroplact; Irsogladine; Foreign country's lattice azoles (isobengazole); Isohomohalicondrin B; U 98079A; Jasplakinolide; Kahalalide F; Nitrilotriacetic sheet spiral shell element-N; Lanreotide; That mycin of thunder (leinamycin); Lenograstim; The sulfuric acid lentinan; Leptolstatin; Letrozole; LIF; The white corpuscle IFN-; Leuprorelin+oestrogenic hormon+progesterone; Leuprorelin; LEVAMISOLE HCL; Liarozole; Linear polyamine analogue; Lipophilic two glycopeptides; Lipophilic platinic compound; Lissoclinamide 7; Lip river platinum; The earthworm propylhomoserin; Lometrexol; Lonidamine; Losoxantrone; Lovastatin; RWJ 21757; OSI 211; De Kesafei quinoline lutetium; 1-((R)-5-hydroxyl hexyl) Theobromine; The cracking polypeptide; Maitansine; Mannostatin A; Marimastat; Masoprocol; Maspin; The stromlysin suppressor factor; NMPI; Menogaril; Mei Balong; Meterelin; Methioninase; Metoclopramide; The MIF suppressor factor; Mifepristone; Miltefosine; Mirimostim; The double-stranded RNA of mispairing; Mitoguazone; Mitolactol; Mitomycin analogs; NSC 300288; Mitotoxin fibroblast growth factor-saporin; Mitoxantrone; Ro 40-8757; Sch-39300; Monoclonal antibody, pregnancy urine extract; Monophosphoryl lipid A+mycobacterium cell walls sk; Mopidamol; The agent of multi-medicine resistance gene inhibition; Treatment based on many tumor inhibitors 1; The Mannomustine carcinostatic agent; Indian Ocean sponge B; The mycobacterium cell wall extracts; Myriaporone; N-ethanoyl Goe 1734; The N-substituted benzamide; Nafarelin; Nagrestip; Nx+pentazocine; Napavin; The naphthalene terpinum; Neu-up 100; S 254; Nemorubicin; Neridronic acid; Proteinase, kidney brush border neutral; RU-23908; Silt mycin (nisamycin); The nitrogen protoxide regulator; The nitroxide inhibitor; Nitrullyn; O6-benzyl guanine; Sostatin; Okicenone; Oligonucleotide; Onapristone; Ondansetron; Ondansetron; Diclofenamide; Oral cytokine induction agent; Ormaplatin; Osaterone; Oxaliplatin; Ao Kesa mycin (oxaunomycin); Taxol; Paclitaxel analogs; D51-7059; Palau amine; The palmityl nitragin; Pamidronic acid; Panoxatriol; Panomifene; The secondary bacterium iron of hexa-coordinate catechu amine iron chelating agent is plain; SR 95225; Pegaspargase; Peldesine; Piperylene gathers sodium sulfate; Pentostatin; Pan arrest azoles (pentrozole); PFOB; Perfosfamide; Sinapyl alcohol; Azophenlyene mycin (phenazinomycin); Toluylic acid; Inhibitors of phosphatases; Dissolve the chain bacterium; The hydrochloric acid pilocarpine; Pirarubicin; Piritrexim; Placetin A; Placetin B; The suppressor factor of plasminogen activator; Platinum complexes; Platinic compound; Platinum-three amine compound; Porfimer sodium; Porfiromycin; Prednisone; Propyl group two-dihydroketoacridine; Prostaglandin(PG) J2; Proteasome inhibitor; Immunomodulator based on albumin A; Inhibitors of protein kinase C; Inhibitors of protein kinase C, little algae; Inhibitors of protein tyrosine phosphatase; Purine nucleoside phosphorylase inhibitor; Purpurin; Pyrazoloacridine; Oxyphorase myocoril T 46155 conjugate; The raf antagonist; ZD-1694; Ranimustine; The ras farnesyl protein transferase inhibitor; The ras suppressor factor; The ras-GAP suppressor factor; The demethyl retelliptine; Etidronic acid rhenium Re 186; Nitragin; Ribozyme; RII dimension A amine; Rogletimide; Rohitukine; Romurtide; Roquinimex; Rubiginone B1; Ruboxyl; SPC 100270; Saintopin; SarCNU; Sa Ke phytol (sarcophytol) A; Sargramostim; The Sdi1 dummy; Semustine; Be derived from old and feeble suppressor factor 1; Positive MODN; Signal transduction inhibitor; Signal transduction modulators; Single chain antigen binding protein; Sizofiran; Sobuzoxane; Sodium borocaptate; Sodium phenylacetate; Solverol; SM-binding protein; Sonermin; Sparfosic acid; But this visits mycin (spicamycin) D; Spiromustine; The spleen pentapeptide; CD-spiro ketal precursor delta-lactone 1; Shark amine; Stem cell inhibitors; The stem cell division suppressor factor; Stipiamide; Stromlysin suppressor factor sulfinosine; Strong vasoactive peptide antagonists of imitating; Suradista; Suramin; Sphaerophysine; The synthetic TGSS C3; Tallimustine; The tamoxifen methiodide; TCNU; Tazarotene; Tecogalan sodium; Tegafur; Tellurapyrylium; Telomerase inhibitor; Temoporfin; TM; Teniposide; Ten oxidation tetrachloros; Four nitrogen amine (tetrazomine); Thalictrine; Thiocoraline; TSF; Thrombopoietin is imitated thing; Thymosin-Alpha1; The thymopoietin receptor stimulant; Thymotrinan; TTH; Ethyl tin is C.I. Natural Red 8 just; Win-59075; Dichloro titanium alkene; Marine alkaloids topsentin; Toremifene; All-round STEMCELLFACTOR; TI; Tretinoin; Triacetyl uridine; Triciribine; Trimetrexate; Triptorelin; Tropisetron; Turosteride; Tyrosine kinase inhibitor; Tyrphostin tyrphostins; The UBC suppressor factor; Ubenimex; Be derived from the GIF of urogenital sinus; The urokinase receptor antagonist; Vapreotide; Variolin B; Carrier system, the red corpuscle gene therapy; Velaresol; Veratramin(e); Verdins; Visudyne; Vinorelbine; Vinfosiltine; Wei Taxin (vitaxin); Vorozole; Zanoterone; Zeniplatin; Zilascorb; And Zinostatin stimalamer.

The embodiment of this paper further is included among the patient treatment or prevention can be through suppressing the disease that PDE4 improves or the method for illness, and it comprises that the patient to this treatment of needs or prevention uses the solid form of one or more inclusion compounds A.Can include but not limited to asthma, inflammation, chronic or acute occlusion property tuberculosis, chronic or acute pulmonary inflammation disease, inflammatory bowel, segmental enteritis, Behcet's disease, colitis, ulcerative colitis and sacroiliitis or the inflammation that causes by perfusion again through suppressing illness that PDE4 improves.In a preferred embodiment, wait to treat or the disease or the illness of preventing are chronic obstructive pulmonary diseases.

Concrete grammar of the present invention can comprise uses extra therapeutical agent, such as but not limited to antiphlogiston, antihistaminic agent and Decongestant.The instance of such additional therapeutic agent includes but not limited to: antihistaminic agent includes but not limited to thanomin, quadrol, piperazine and thiodiphenylamine; Antiphlogiston; Nonsteroid anti-inflammatory drugs (NSAIDS), include but not limited to Frosst), salicylate, PARACETAMOL BP98, indomethacin, sulindac, R-ETODOLAC, fragrant that ester, tolmetin, ketorolac, diclofenac, Ibuprofen BP/EP, Naproxen Base, fenoprofen, KP, FLURBIPROFEN USP24, Taisho), piroxicam, meloxicam, pyrazolone derivative; And steroid, include but not limited to reflunomide and adrenocortical steroid.

Concrete grammar of the present invention is avoided or has been reduced the relevant drug drug interaction of the medicament (comprising racemic substituted phenylethyl sulfone) that in such treatment of conditions, uses and other undesirable action.Be not subject to any theory; The solid form of some inclusion compound A can be with respect to racemic 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1; The 3-diketone comprises that its solid form further provides the result of treatment or the therapeutic index of overall improvement.

As stated, the solid form of some inclusion compound A can be used for treatment or prevention various diseases and illness.In the acute or chronic control of disease or illness, the prevention of given activity composition of the present invention or the amount of therapeutic dose can change with the character of disease or illness and the route of administration of severity and activeconstituents.Perhaps, dosage also has administration frequency, also will change according to age, body weight and the reaction of individual patient.Suitable dosage regimen can be considered these factors and selection easily by those skilled in the art.In general, to the described illness of this present invention, dosage every day of recommendation be every day about 1mg to about 1,000mg gave as single dosage once-a-day in one day, gave preferably as the dosage that separates.More specifically, every day, dosage was to give for twice separate doses every day of equal portions.Especially, every day dosage range can for every day about 5mg to about 500mg, more especially at every day about 10mg and about 200mg.Especially, every day, dosage can be used with the formulation of 5mg, 10mg, 15mg, 20mg, 25mg, 50mg or 100mg.In control during the patient, treatment should be from beginning than low dosage, maybe for about 1mg to about 25mg, and depend on patient's W-response, if be necessary, be increased to every day about 200mg and arrive approximately 1,000mg is as single dose or the dosage that separates.Perhaps, every day, dosage was from 0.01mg/kg to 100mg/kg.

In some cases, it possibly be necessary outside the disclosed dosage range of the present invention, using activeconstituents, and this will be obvious to those of ordinary skills.It should be noted that in addition clinicist or treatment doctor combine the reaction of individual patient, will how and when understand interrupt, adjustment or stopped treatment.

The phrase " treatment significant quantity " that the present invention uses, " prevention significant quantity " and " treatment or prevention significant quantity " comprise above-mentioned dosage and administration frequency timetable.Different treatment significant quantities can be applied to various disease and illness, and this is that those of ordinary skills will understand easily.Similarly; Be enough to treat or prevent such illness; But be not enough to cause or be enough to and reduce and racemic 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1; The amount of the undesirable action that the 3-diketone is relevant is also included within above-mentioned dosage and the administration frequency timetable.

4.3. Pharmaceutical composition

This paper provides the pharmaceutical composition and the single unit dosage of the solid form that comprises one or more inclusion compounds A.The present invention also provides the pharmaceutical composition of the solid form that comprises one or more inclusion compounds A and the preparation method of single unit dosage.For example; In certain embodiments, comprise solid form provided by the present invention or use the separately formulation of solid form provided by the present invention preparation can be suitable for oral, mucous membrane (comprising rectum, nose or vagina), parenteral (comprise subcutaneous, intramuscular, inject, intra-arterial or intravenously), hypogloeeis, transdermal, oral cavity or topical application.

In certain embodiments, pharmaceutical composition provided by the present invention and formulation contain the solid form of one or more inclusion compounds A.Certain embodiments of the present invention provide the solid form that contains inclusion compound A; For example as; Like the pharmaceutical composition and the formulation of form A, B, C, D, E, F, G or the unformed solid form of inclusion compound A provided by the present invention, wherein the solid form of inclusion compound A is pure basically.Certain embodiments of the present invention provide the solid form that contains inclusion compound A; For example; Pharmaceutical composition and formulation like form A, B, C, D, E, F, G or the unformed solid form of inclusion compound A provided by the present invention; Other solid form that it does not contain inclusion compound A basically for example comprises, like form A, B, C, D, E, F, G and/or the unformed solid form of inclusion compound A provided by the present invention.Certain embodiments of the present invention provide the pharmaceutical composition and the formulation of the mixture of the solid form that contains inclusion compound A, comprise for example comprising following one or more mixture: like form A, B, C, D, E, F and the unformed solid form of inclusion compound A provided by the present invention.Pharmaceutical composition provided by the present invention and formulation also comprise one or more pharmaceutically acceptable vehicle, diluent or carrier usually.

The concrete pharmaceutical composition that is comprised by this embodiment contains solid form and at least a additional therapeutic agent of one or more inclusion compounds A.The instance of additional therapeutic agent includes but not limited to anticarcinogen and anti-inflammatory therapy agent, include but not limited to provided by the present invention those.

That single unit dosage of the present invention is suitable for is oral, mucous membrane (for example nose, hypogloeeis, vagina, oral cavity or rectum), parenteral (for example subcutaneous, intravenously, inject, intramuscular or intra-arterial) or transdermal administration patient.The instance of formulation includes but not limited to: tablet; The capsule sheet; Capsule is soft elastic gelatin capsule for example; Cachet; Lozenge; Lozenge; Dispersion agent; Suppository; Ointment; Paste (poultice); Paste; Powder; Dressing; Emulsifiable paste; Plaster; Solution; Paster; Aerosol (for example nasal spray or inhalation); Gel; Be fit to liquid dosage form oral to the patient or that mucous membrane is used, comprise suspension-s (the for example suspension-s of water or on-aqueous liquid, O/w emulsion or water-in-oil liquid emulsion), solution and elixir; Be fit to liquid dosage form to patient's parenteral administration; And sterile solid (for example crystallization or amorphous solid), it can be by reprovision to provide the liquid dosage form that is fit to patient's parenteral administration.

The compsn of formulation of the present invention, shape and type will depend on its purposes usually and change.For example, compare with the formulation of the chronic treatment that is used for same disease, the formulation that is used for the emergency treatment of inflammation or associated conditions can comprise more substantial one or more activeconstituentss.Similarly, compare with the oral dosage form that is used to treat same disease or illness, parenteral dosage forms can comprise one or more activeconstituentss of less amount.The variation each other of these of the concrete formulation that the present invention is included and other modes will be conspicuous to those skilled in the art.Referring to, for example Remington's Pharmaceutical Sciences, the 18th edition, Mack Publishing, Easton PA (1990).

Typical pharmaceutical composition and formulation comprise one or more vehicle.Suitable vehicle is that the pharmacy field technician knows, and the limiting examples of suitable vehicle provides in the present invention.Concrete vehicle whether is fit to join pharmaceutical composition or formulation depends on multiple factor well known in the art, includes but not limited to formulation is applied to patient's mode.For example, oral dosage form for example tablet can comprise the vehicle that is not suitable in parenteral dosage forms, using.The suitability of concrete vehicle also can depend on the concrete activeconstituents in the formulation.

Lactose-free compsn of the present invention can comprise vehicle well known in the art and that in for example USP (USP) SP (XXI)/NF (XVI), list.In general, lactose-free compsn comprises activeconstituents, tackiness agent/weighting agent and the lubricant of pharmaceutically compatible and pharmaceutically acceptable amount.Preferred lactose-free formulation comprises activeconstituents, Microcrystalline Cellulose, pregelatinized Starch and Magnesium Stearate.

Because water can promote the degraded of some compounds, so the present invention further comprises anhydrous pharmaceutical composition and the formulation that comprises activeconstituents.For example, in order to confirm for example quality guaranteed period or preparation characteristics such as stability in time, add water (for example 5%) and be the means of the simulation long storage that pharmaceutical field accepts extensively.Referring to, for example, Jens T.Carstensen, Drug Stability:Principles & Practice, the 2nd edition, Marcel Dekker, NY, NY, 1995,379-80 page or leaf.In fact, water and heat can quicken the decomposition of some compounds.Therefore, water can be significant to the effect of preparation, because in preparation, processing, packing, storage, the transportation of preparation with run into moisture and/or moisture through regular meeting between the usage period.

Anhydrous pharmaceutical composition of the present invention and formulation can be used the composition of anhydrous or low moisture content, under low moisture or low, prepare.Can substantive the contact be arranged with moisture and/or moisture if be expected at preparation, packing and/or lay up period, then comprising lactose and at least a, to contain the pharmaceutical composition and the formulation of activeconstituents of primary amine or secondary amine preferably anhydrous.

Anhydrous pharmaceutical composition should be produced and store to such an extent that its no aqueous nature is held.Therefore, anhydrous compsn preferably uses the known material packing that prevents to be exposed to water, makes them can be contained in the suitable prescription test kit.The instance of suitable packing includes but not limited to seal aluminium foil, plastics, unit-dose container (for example bottle), Blister Package and band packing.

The present invention further comprises pharmaceutical composition and formulation, and it comprises one or more compounds that reduces the activeconstituents rate of decomposition.Such compound is known as " stablizer " in this article, and it includes but not limited to inhibitor for example xitix, pH buffer reagent or salt buffer agent.

The same with the amount and the type of vehicle, the amount of the activeconstituents in the formulation can depend on various factors with particular type and be different, such as but not limited to the approach of using to the patient.But, exemplary dosage form provided by the present invention every day about 1mg to about 1, in the 000mg scope, give in the morning as single dosage once-a-day, but in one day, give preferably as the dosage that separates.More especially, dosage every day every day is with the separate doses administered twice of equal portions.Especially, every day dosage range can for every day about 5mg to about 500mg, more especially for every day about 10mg arrive about 200mg.In control during the patient, treatment can be from beginning than low dosage, maybe for about 1mg to about 25mg, and depend on patient's W-response, if be necessary, be increased to every day about 200mg and arrive approximately 1,000mg is single dose or the dosage that separates.

4.3.1. Oral dosage form

Be suitable for Orally administered pharmaceutical composition of the present invention and can be used as discrete formulation existence, such as but not limited to tablet (for example masticable tablet), capsule sheet, capsule and liquid (for example seasoning syrup).Such formulation comprises the activeconstituents of predetermined amount, and the preparation of the pharmaceutical methods that can know by one of skill in the art.Generally referring to Remington's Pharmaceutical Sciences, the 18th edition, Mack Publishing, Easton PA (1990).

Through activeconstituents and at least a vehicle are prepared exemplary oral dosage form of the present invention according to conventional pharmaceutical hybrid technology thorough mixing.According to using required dosage form, vehicle can have various broad form.For example, the vehicle that is applicable to liquid oral or aerosol dosage forms includes but not limited to water, terepthaloyl moietie, oil, alcohol, seasonings, sanitas and tinting material.The instance that is applicable to the vehicle of solid oral dosage form (for example powder, tablet, capsule and capsule sheet) includes but not limited to starch, sugar, Microcrystalline Cellulose, thinner, granulating agent, lubricant, tackiness agent and disintegrating agent.

Because use conveniently, use the tablet and the capsule of solid excipient to represent best oral dosage unit form.If desired, tablet can be through the water-based or the non-aqueous technology coatings of standard.Such formulation can be through any pharmaceutical methods preparation.In general, through activeconstituents and liquid vehicle, fine solid carrier or both are evenly mixed to come pharmaceutical compositions and formulation fully,, process required shape to product if be necessary then.

For example, can be through compacting or the molded tablet for preparing.Can randomly prepare the tablet of compacting through compacting in suitable machine with the activeconstituents that is in free-flowing form (for example powder or particle) of mixed with excipients.Can prepare molded tablet through molded mixture in suitable machine by the wetting powder compounds of inert liquid diluent.

The instance of the vehicle that can in oral dosage form of the present invention, use includes but not limited to tackiness agent, weighting agent, disintegrating agent and lubricant.The tackiness agent that is adapted at using in pharmaceutical composition and the formulation includes but not limited to: W-Gum; Potato starch; Or other starch; Gelatin; Natural and synthetic glue is Sudan Gum-arabic for example; Sodiun alginate; Lalgine; Other alginate; The powder tragacanth gum; Guar gum; Mierocrystalline cellulose and verivate thereof (TKK 021 for example; FM; ECG-505; Xylo-Mucine); Vinylpyrrolidone polymer; Methylcellulose gum; Pregelatinized Starch; HPMC (for example 2208; 2906; No. 2910); Microcrystalline Cellulose; And composition thereof.

The instance of the weighting agent that is adapted at using in disclosed pharmaceutical composition of the present invention and the formulation includes but not limited to: talcum, lime carbonate (for example particle or powder), Microcrystalline Cellulose, cellulose powder, VISOSE, kaolin, N.F,USP MANNITOL, silicic acid, Sorbitol Powder, starch, pregelatinized Starch, and composition thereof.Tackiness agent in the pharmaceutical composition of the present invention or weighting agent exist to about 99% weight with about 50 of pharmaceutical composition or formulation usually.

The suitable form of Microcrystalline Cellulose includes but not limited to as AVICEL-PH-101 ^TM, AVICEL-PH-103 ^TM, AVICEL RC-581 ^TM, AVICEL-PH-105 ^TMThe material that (can be from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA obtains) sells, and composition thereof.Concrete tackiness agent is as AVICEL RC-581 ^TMThe Microcrystalline Cellulose of selling and the mixture of Xylo-Mucine.Suitable anhydrous or low-moisture vehicle or additive comprise AVICEL-PH-103 ^TMWith starch 1500LM ^TM

The tablet of disintegration when in compsn of the present invention, using disintegrating agent to be exposed to aqueous environments to be provided at.The tablet that comprises too much disintegrating agent maybe disintegration in storage, may not be and comprise the tablet of very few disintegrating agent with required speed disintegration, or can not disintegration under required condition.Therefore, should use the disintegrating agent of capacity to form solid oral dosage form of the present invention, this amount is exceeded few only, can not change the release of activeconstituents nocuously.The amount of the disintegrating agent that uses changes based on the type of preparation, and is those of ordinary skills' identifications easily.Typical pharmaceutical composition comprises about 0.5 disintegrating agent to about 15% weight, particularly about 1 disintegrating agent to about 5% weight.

The disintegrating agent that can in pharmaceutical composition of the present invention and formulation, use includes but not limited to: agar, Lalgine, lime carbonate, Microcrystalline Cellulose, cross-linked carboxymethyl cellulose sodium, PVPP, Polacrilin potassium, sodium starch glycollate, potato or tapioca(flour), pregelatinized Starch, other starch, clay, other algins, other Mierocrystalline celluloses, glue, and composition thereof.

The lubricant that can in pharmaceutical composition of the present invention and formulation, use includes but not limited to: calcium stearate, Magnesium Stearate, MO, light mineral oil, glycerine, Sorbitol Powder, N.F,USP MANNITOL, polyoxyethylene glycol, other terepthaloyl moietie, Triple Pressed Stearic Acid, sodium lauryl sulphate, talcum, Wecobee M (for example peanut oil, Oleum Gossypii semen, sunflower seed oil, til, sweet oil, Semen Maydis oil and soya-bean oil), Zinic stearas, OE, Laurate ethyl, agar, and composition thereof.Extra lubricant comprises for example syloid silica gel (AEROSIL200 ^TM, W.R.Grace company, Baltimore, MD preparation), the solidified gas colloidal sol (TX sells for Degussa company, Piano) of synthetic silica, CAB-O-SIL ^TM(Cabot company, Boston, the silica product that the high heat that MA sells is processed), and composition thereof.If use fully, lubricant uses to account for the pharmaceutical composition that comprises it or the amount that is less than about 1% weight of formulation usually.

4.3.2. The time-delay release dosage form

Can use the solid form of inclusion compound A provided by the present invention through the delivery apparatus that controlled-release device or those of ordinary skills know.Instance includes but not limited at U.S. Patent number 3,845 770,3,916,899,3,536,809,3,598; 123, and 4,008,719,5,674,533,5,059; 595,5,591,767,5,120,548,5,073,543,5; Those that describe in 639,476,5,354,556 and 5,733,566, it incorporates this paper separately by reference into.Can use such formulation to come one or more activeconstituentss are provided slowly or sustained release, it uses for example Vltra tears, other polymeric matrixs, gel, permeable film, osmosis system, multiple coatings, particulate, liposome, microsphere or its of different ratios to make up the release characteristic that provides required.Can easily select the known suitable controlled release preparation of those of ordinary skills (comprise described in the invention those), use with activeconstituents of the present invention being used for.Therefore, the present invention includes and be suitable for Orally administered single unit dosage, such as but not limited to the tablet, capsule, soft capsule and the capsule sheet that are fit to controlled release.

The medicament prodn of all controlled releases all has common objective, promptly improves the pharmacological agent that can reach with respect to its non-controlled release equivalent.Ideally, in therapeutic treatment, use the controlled release preparation of optimum design to be characterised in that the medicine that uses minimum cures or control illness in the shortest time.The advantage of controlled release preparation comprises the pharmaceutical activity of prolongation, the administration frequency of reduction and the patient's compliance that increases.In addition, controlled release preparation can be used to time or other characteristics of influence onset, the blood concentration of medicine for example, and therefore can influence the generation of spinoff (for example undesirable action).

Most of controlled release preparations are designed to discharge a certain amount of medicine (activeconstituents) at first, and it promptly produces required result of treatment, and progressively and continuously discharges the medicine of other amounts, in the time period that prolongs, to keep the treatment or the preventive effect of this level.In order to keep this constant level of medicine in vivo, medicine must discharge with given pace from formulation, and this speed will be replaced the medication amount of discharging by metabolism with in the body.The controlled release of activeconstituents can include but not limited to pH, temperature, enzyme, water or other physiological conditions or compound through various conditioned stimulus.

4.3.3. Parenteral dosage forms

Parenteral dosage forms can be used to the patient by all means, includes but not limited to subcutaneous, intravenously (comprise and injecting), intramuscular and intra-arterial.Because using of parenteral dosage forms got around the natural defence of patient to pollutent usually, so they are preferably aseptic or can before the patient uses, sterilized.The instance of parenteral dosage forms includes but not limited to injection solution, is suitable in pharmaceutically acceptable vector, dissolving or suspending for power-product, injection suspension-s and the emulsion of injection.

The suitable vector that can be used to provide parenteral dosage forms of the present invention is well known to those skilled in the art.Instance includes but not limited to: USP water for injection; The water-based vector is such as but not limited to sodium chloride injection, ringer's injection, Vadex injection liquid, Vadex and sodium chloride injection and lactic acid salt ringer's injection; Be prone to water blended vector such as but not limited to ethanol, polyoxyethylene glycol and W 166; And non-aqueous vector is such as but not limited to Semen Maydis oil, Oleum Gossypii semen, peanut oil, til, OE, Isopropyl myristate and phenylamino benzoic acid methyl esters.

The compound that also can in parenteral dosage forms of the present invention, add the solubleness that improves disclosed one or more activeconstituentss of the present invention.

4.3.4. Transdermal, part and mucous membrane formulation

Transdermal of the present invention, part and mucous membrane formulation include but not limited to ophthalmic solution, sprays, aerosol, emulsifiable paste, washing lotion, ointment, gel, solution, emulsion, suspension-s or other form well known by persons skilled in the art.Referring to, for example Remington's Pharmaceutical Sciences, the 16th and 18 edition, Mack Publishing, Easton PA (1980&1990); With Introduction to Pharmaceutical Dosage Forms, the 4th edition, Lea & Febiger, Philadelphia (1985).The formulation that is fit to the intraoral mucous membrane tissue of treatment can be configured to mouth wash shua or oral gel.In addition, the transdermal formulation comprises " storage type " or " matrix type " paster, and they can be applied to skin, and adheres to one section specified time, to allow the activeconstituents infiltration of aequum.

The material that suitable vehicle (for example carrier and thinner) and other can be used to provide transdermal, part and mucous membrane formulation that the present invention comprises is that the pharmacy field technician knows, and depends on the concrete tissue that given pharmaceutical composition or formulation will be applied to.Consider this fact; Typical vehicle includes but not limited to water, acetone, ethanol, terepthaloyl moietie, Ucar 35,1; 3-butyleneglycol, Isopropyl myristate, Wickenol 111, MO, and composition thereof, to form nontoxic and pharmaceutically acceptable washing lotion, tincture, emulsifiable paste, emulsion, gel or ointment.If desired.Can also in pharmaceutical composition and formulation, add wetting Agent for Printing Inks or wetting agent.The instance of such supplementary component is well known in the art.Referring to, for example Remington's Pharmaceutical Sciences, the 16th and 18 edition, Mack Publishing, Easton PA (1980&1990).

Depend on concrete tissue to be treated, can be before, simultaneously or use extra composition afterwards with activeconstituents of the present invention treatment.For example, penetration enhancers can be used for auxiliary to organizing delivering active ingredients.Suitable penetration enhancers includes but not limited to: acetone; Various alcohol are ethanol, oleyl alcohol and tetrahydrofurfuryl carbinol for example; Alkyl sulfoxide is DMSO 99.8MIN. for example; N,N-DIMETHYLACETAMIDE; N; Polyoxyethylene glycol; Pyrrolidone is Vinylpyrrolidone polymer for example; The Kollidon of different grades (Vinylpyrrolidone polymer, polyvidone); Urea; With various water solubles or insoluble sugar ester, for example Tween 80 ^TM(polysorbate80) and Span 60 ^TM(sorbitan monostearate).

Also can regulate the pH value of pharmaceutical composition or formulation, the perhaps pH value of pharmaceutical composition or the applied tissue of formulation is to improve sending of one or more activeconstituentss.Similarly, polarity, its ionic strength or the tension force that can regulate solvent carrier are sent with improvement.Compound for example stearate also be introduced in pharmaceutical composition or the formulation, with wetting ability or the lipotropy that advantageously changes one or more activeconstituentss, sends thereby improve.In this, stearate can serve as lipid vector, emulsifying agent or the tensio-active agent of preparation and send and improve or penetration enhancers.The different solid forms that comprise activeconstituents can be used to further regulate the character of the compsn that obtains.

4.3.5. Test kit

The present invention comprises test kit, and it can simplify an amount of activeconstituents using the patient when being used by the medical practitioner.

Typical agents box of the present invention comprises the compd A of unit dosage or second activeconstituents of its pharmaceutically acceptable solid form or prodrug and unit dosage.The instance of second activeconstituents includes but not limited to those that the present invention is listed.

Test kit of the present invention can further comprise the device that is used for using activeconstituents.The instance of such device includes but not limited to syringe, dropping liquid bag, paster and sucker.

Test kit of the present invention can further comprise the pharmaceutically acceptable vector that can be used for using one or more activeconstituentss.For example; If activeconstituents provides with the solid form that must prepare again for parenteral administration; Test kit can comprise the suitable vector of a sealed vessel so, and activeconstituents can dissolve to form the sterile solution of the no particulate that is fit to parenteral administration therein.The embodiment of pharmaceutically acceptable vector includes but not limited to: USP water for injection; The water-based vector is such as but not limited to sodium chloride injection, ringer's injection, Vadex injection liquid, Vadex and sodium chloride injection and lactic acid salt ringer's injection; Be prone to water blended vector such as but not limited to ethanol, polyoxyethylene glycol and W 166; And non-aqueous vector is such as but not limited to Semen Maydis oil, Oleum Gossypii semen, peanut oil, til, OE, Isopropyl myristate and phenylamino benzoic acid methyl esters.

5. Embodiment

The application is with U.S. Patent number 6,962, and the full text of 940 (mandates on November 8th, 2005) is incorporated this paper by reference into, comprises the embodiment that wherein provides.

5.1. Embodiment 1:2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1,3-diketone synthetic

(1.0g is 3.7mmol) with 3-kharophen Tetra hydro Phthalic anhydride (751mg, 3.66mmol) the heating 15h under refluxing of the stirred solution in acetic acid (20mL) with 1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethamine.Remove solvent in a vacuum, output oil.The oil that obtains is yellow solid (1.0g, productive rate 59%): mp, 144 ° of C through chromatogram output product; ¹H NMR (CDCl ₃) δ: 1.47 (t, J=7.0Hz, 3H, CH ₃), 2.26 (s, 3H, CH ₃), 2.88 (s, 3H, CH ₃), 3.75 (dd, J=4.4,14.3Hz, 1H, CH), 3.85 (s, 3H, CH3), 4.11 (q, J=7Hz, 2H, CH ₂), 5.87 (dd, J=4.3,10.5Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J=7Hz, 1H, Ar), 7.64 (t, J=8Hz, 1H, Ar), 8.74 (d, J=8Hz, 1H, Ar), 9.49 (br s, 1H, NH); ¹³C 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; C ₂₂H ₂₄NO ₇The analytical calculation value of S: C, 57.38; H, 5.25; N, 6.08.Observed value: C, 57.31; H, 5.34; N, 5.83.

5.2. Embodiment 2: (+) 2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-acetylamino isoindoline-1,3-diketone synthetic

The preparation of 3-aminophthalic acid

With 10%Pd/C (2.5g), 3-nitrophthalic acid (75.0g, 355mmol) and ethanol (1.5L) under nitrogen atmosphere, install in the 2.5L Parr hydrogenator.Filling hydrogen reaches 55psi in reaction vessel.Mixture vibration 13 hours, keep simultaneously hydrogen pressure 50 and 55psi between.Release hydrogen is with purging with nitrogen gas mixture 3 times.Suspension-s filters through bed of diatomaceous earth, and uses washed with methanol.Filtrating concentrates in a vacuum.The solid that obtains is pulp again in ether, and passes through isolated by vacuum filtration.The solid dried in vacuum provides 54g (productive rate 84%) the 3-aminophthalic acid to constant weight, is yellow product. ¹H-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)； ¹³C-NMR(DMSO-d6)δ：112.00，115.32，118.20，131.28，135.86，148.82，169.15，170.09。

The preparation of 3-kharophen Tetra hydro Phthalic anhydride

In the 1L 3-neck round-bottomed flask that has been equipped with mechanical stirrer, TM and condensing surface, pack into the 3-aminophthalic acid (108g, 596mmol) and diacetyl oxide (550mL).Reaction mixture reflux 3 hours is cooled to about 25 ° of C, and further is cooled to 0-5 ° of C, keeps other 1 hour.Collect crystalline solid through vacuum filtration, and wash with ether.Solid product at room temperature dried in vacuum obtains 75g (productive rate 61%) 3-kharophen Tetra hydro Phthalic anhydride to constant weight, is white product. ¹H-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-(the heavily dissolving of 3-oxyethyl group-4-p-methoxy-phenyl-1-(methyl sulphonyl)-second-2-base amine

2-(3-oxyethyl group-4-p-methoxy-phenyl)-1-(methyl sulphonyl)-second-2-base amine (137.0g packs in the 3L 3-neck round-bottomed flask that has been equipped with mechanical stirrer, TM and condensing surface; 500mmol), N-ethanoyl-L-leucine (52g, 300mmol) and methyl alcohol (1.0L).The slurry reflux that stirs 1 hour.Let stirred mixture be cooled to room temperature, and at room temperature continue to stir other 3 hours.Cross filter pulp, and wash with methyl alcohol (250L).Air-dry solid, at room temperature dried in vacuum obtains 109.5g (productive rate 98%) crude product (85.8%ee) to constant weight then.Rough solid (55.0g) and methyl alcohol (440mL) were refluxed 1 hour, be cooled to room temperature, and at room temperature stirred other 3 hours.Cross filter pulp, with methyl alcohol (200mL) washing leaching cake.Air-dry solid, then 30 ° of C dried in vacuum to constant weight, output 49.6g (recovery 90%) (S)-2-(3-oxyethyl group-4-p-methoxy-phenyl)-1-(methyl sulphonyl)-second-2-base amine-N-ethanoyl-L-leucine salt (98.4%ee).Chirality HPLC (1/99EtOH/20mM KH ₂PO ₄PH 7.0, Ultron chirality ES-OVS, and from Agilent Technologies, 150mm * 4.6mm, the 0.5mL/ branch, 240nm): 18.4 minutes (S-isomer, 99.2%), 25.5 minutes (R-isomer, 0.8%).

The preparation of compd A

500mL 3-neck round-bottomed flask is equipped with mechanical stirrer, TM and condensing surface.(S)-2-(3-oxyethyl group-4-p-methoxy-phenyl)-1-(methyl sulphonyl)-second-2-base amine N-ethanoyl-L-leucine salt (25g packs in reaction vessel; 56mmol; 98%ee), 3-kharophen Tetra hydro Phthalic anhydride (12.1g, 58.8mmol) and Glacial acetic acid min. 99.5 (250mL).Mixture refluxes and spends the night, and is cooled to < 50 ° of C then.Remove solvent in a vacuum, resistates dissolves in ETHYLE ACETATE.The solution with water that obtains (250mL * 2), saturated NaHCO ₃The aqueous solution (250mL * 2) and salt solution (250mL * 2) washing, and use dried over sodium sulfate.Evaporating solvent in a vacuum, resistates is with the dual solvent recrystallization that contains ethanol (150mL) and acetone (75mL).Solid passes through isolated by vacuum filtration, and washs with ethanol (100mL * 2).Product to constant weight, provides 19.4g (productive rate 75%) S-{2-[1-(3-oxyethyl group-4-p-methoxy-phenyl)-2-methyl sulphonyl ethyl]-4-kharophen isoindoline-1, the 3-diketone 60 ° of C dried in vacuum }, 98%ee.Chirality HPLC (15/85EtOH/20mM KH ₂PO ₄PH 5, Ultron chirality ES-OVS, and from Agilent Technology, 150mm * 4.6mm, the 0.4mL/ branch, 240nm): 25.4 minutes (S-isomer, 98.7%), 29.5 minutes (R-isomer, 1.2%). ¹H-NMR(CDCl ₃)δ：1.47(t，3H)，2.26(s，3H)，2.87(s，3H)，3.68-3.75(dd，1H)，3.85(s，3H)，4.07-4.15(q，2H)，4.51-4.61(dd，1H)，5.84-5.90(dd，1H)，6.82-8.77(m，6H)，9.46(s，1H)； ¹³C-NMR(DMSO-d6)δ：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。

Figure 29 provides the reaction scheme of the preparation of (+) enantiomorph that shows compd A.

5.3. Embodiment 3:TNF-α suppresses

LPS inductive TNF-α test in people's whole blood

Except the whole blood that uses fresh extraction substitutes the PBMC, adopt the LPS inductive TNF-α test among the human PBMC as mentioned below equally to measure the ability that compound suppresses people's whole blood LPS inductive TNF-α generation basically.(Muller etc., 1999, Bioorg.&Med.Chem.Lett., 9:1625-1630.) to compd A, people's whole blood LPS inductive TNF-α IC ₅₀=294nM.

LPS inductive serum TNF in the mouse-α suppresses

Compound according to the previous method of describing (Corral etc., 1996, MoI.Med. 2:506-515), tests in this animal model.To compd A, LPS inductive serum TNF-α suppresses (ED in the mouse ₅₀, mg/kg, oral)=0.05.

LPS inductive TNF-α produces

LPS (LPS) is that it has induced many pro-inflammatory cytokines to comprise the generation of TNF-α by the Gram-negative bacteria intracellular toxin produced of intestinal bacteria (E.coli) for example.In PMBC (PBMC), be derived from monocyte as the TNF-α that replying of LPS produced, it has formed about 5-20% of total PBMC.The ability that test compounds inhibition human PBMC's LPS inductive TNF-α produces as previous description (Muller etc., 1996, J.Med.Chem., 39:3238).PBMC from normal donor passes through Ficoll Hypaque (Pharmacia, Piscataway, NJ, USA) Density Gradient Centrifugation acquisition.Cell is replenishing 10%AB ± human serum (Gemini Bio-products; Woodland; CA, USA), RPMI (Life Technologies, the Grand Island of 2mM L-glutaminate, 100U/ml penicillium mould and 100 μ g/ml Streptomycin sulphates (Life Technologies); NY, USA) the middle cultivation.

With PBMC (2 * 10 ⁵Individual cell) be inoculated into 96 holes flat Costar tissue culturing plate (Corning, NY, USA) in, three parts of every formulas.Cell compound lack or in the presence of with 100ng/ml LPS (Sigma, St.Louis, MO, USA) stimulation.(NJ USA) is dissolved among the DMSO (Sigma) for Celgene Corp., Warren, and further dilution in substratum immediately before use with compound.Whole DMSO concentration in all samples is 0.25%.Stimulated last hour at LPS, compound is added in the cell.Cell at 37 ° of C at 5%CO ₂Under cultivated 18-20 hour, collect supernatant then, with substratum dilution, and through ELISA (Endogen, Boston, MA, USA) test TNF-alpha levels.To compd A, LPS inductive TNF-α IC ₅₀=77nM.

The beta induced TNF-α of IL-1 produces

During the process of inflammatory diseases, TNF-α often produces to be stimulated by cytokine IL-1 β, and is not stimulated by the LPS of bacterial origin.The ability that test compounds inhibition human PBMC's the beta induced TNF-α of IL-1 produces as above-mentioned LPS inductive TNF-α produces, difference is that PBMC is white corpuscle unit (Sera-Tec Biologicals, North Brunswick from the source; NJ; USA) pass through with Ficoll-Paque Plus (Amersham Pharmacia, Piscataway, NJ; USA) centrifugal and isolating, and with 3 * 10 ⁵Individual cells/well is inoculated into the RPMI-1640 substratum (BioWhittaker that comprises 10% heat-inactivated foetal calf serum (Hyclone), 2mM L-glutaminate, 100U/ml penicillium mould and 100mg/ml Streptomycin sulphate (perfect medium) in the 96 hole tissue culturing plates; Walkersville, Maryland, USA) in; With 10,2,0.4,0.08,0.016,0.0032,0.00064 and 0 μ M compound; Two parts of every formulas, whole DMSO concentration is 0.1%, in the incubator of 37 ° of C in humidity at 5%CO ₂Following pre-treatment one hour, the people IL-1 β (Endogen) with the 50ng/ml reorganization stimulated 18 hours then.To compd A, the TNF-α IC that IL-is beta induced ₅₀=83nM.

5.4. Embodiment 4:PDE selectivity

PDE1,2,3,5 and 6 enzyme tests

Compound to the specificity of PDE4 through in single concentration (10 μ M) down to ox PDE1, people PDE2, PDE3 with from PDE5 (Hidaka and Asano, 1976, the Biochem.Biophys.Acta of human blood platelets; 429:485, and Nicholsen etc., 1991; Trends Pharmaco.Sci. is 12:19) and from PDE6 (Baehr etc., 1979 of the outer section of bovine retina columnar cell; J.Biol.Chem., 254:11669 and Gillespie etc.; 1989, MoI.Pharm., 36:773) test is assessed.The result enumerates in table 1.

The PDE7 enzyme test

PDE7 is cAMP selectivity PDE, mainly in T cell and Skelettmuskel, expresses.The cytokine of T cell source for example IL-2 and IFN-γ can suppress to regulate potentially through PDE7.As PDE7 such as the previous description through anion-exchange chromatography from Hut78 human T-cell purifying (Bloom and Beavo, 1996, Proc.Natl.Acad.Sci.USA, 93:14188-14192).As in the table 1 PDE4 being described, compound tests to the PDE7 that in the presence of 10nM cAMP, prepares.

5.5. Embodiment 5:PDE4 suppresses

PDE4 (being derived from the U937 cell) enzyme test

PDE4 enzyme such as previous description through gel filtration chromatography from U937 person monocytic cell purifying (Muller etc., 1998, Bioorg.&Med.Chem.Lett.8:2669-2674).At 30 ° of C at 50mM Tris HClpH 7.5,5mM MgCl ₂, 1 μ M cAMP, 10nM [ ³H]-carried out the phosphodiester enzyme reaction 30 minutes among the CAMP, through boiling termination, handle with the 1mg/ml snake venom, use AG-IXS ion exchange resin (BioRad) to separate like (Muller etc., 1998, Bioorg.& Med.Chem.Lett.8:2669-2674) as describing.Reaction consumes less than 15% available substrates.The result enumerates in table 1.

Table 1.PDE specificity

* compd B is compd A (-) enantiomorph.

5.6. Embodiment 6: human T-cell's test

SEB inductive IL-2 and IFN-γ produce

SEB (SEB) is the superantigen that is derived from gram-positive microorganism streptococcus aureus (Staphylococcus aureus).The physiological stimulation that the SEB specificity facilitates to the T cell of expressing specific T cells acceptor V β chain.White corpuscle unit separates human PBMC's (the T cell by about 50% is formed) as stated from the source, and with 3 * 10 ⁵Individual cells/well is inoculated in the perfect medium in the 96 hole tissue culturing plates, with 10,2,0.4,0.08,0.016,0.0032,0.00064 and 0 μ M compound, two parts of every formulas, whole DMSO concentration is 0.1%, in the incubator of 37 ° of C in humidity at 5%CO ₂Following pre-treatment 1 hour, (MO USA) stimulated 18 hours for Sigma Chemical Co., St.Louis to use 100ng/ml SEB then.(MN USA) measures IL-2 and IFN-γ level for R&D Systems, Minneapolis through ELISA.To compd A, IL-2IC ₅₀=291nM.To compd A, IFN-γ IC ₅₀=46nM.

5.7. Embodiment 7:cAMP lifting test

PGE ₂Inductive cAMP promotes

PGE ₂(PGE ₂) with monocyte, T cell and other white corpuscle on the prostanoid receptors bind, and therefore promoted intracellular cAMP level, thereby caused the inhibition of cell response.PGE ₂With the collaborative cAMP of the lifting level in these cell types that is combined in of PDE4 suppressor factor, and at PGE ₂Exist down, the lifting of the cAMP that the PDE4 suppressor factor causes in PBMC is directly proportional with the inhibition activity of this PDE4 suppressor factor.In the human PBMC, intracellular cAMP measures as follows: PBMC separates as stated, and with 1 * 10 ⁶The every hole of individual cell is inoculated among the RPMI-1640 in 96 orifice plates.Cell in the DMSO of final concentration 2%, with 100,10,1,0.1,0.01 and 0 μ M compound, two parts of every formulas, in the incubator of 37 ° of C in humidity at 5%CO ₂Following pre-treatment one hour.Cell is used PGE then ₂(10 μ M) (Sigma) stimulated 1 hour.Cell is used the HCl cracking, final concentration 0.1N, and with the inhibition phosphodiesterase activity, and plate is freezing at-20 ° of C.The cAMP that produces uses cAMP (low pH) immunoassay kit (R&D Systems) to measure.For racemoid, PBMC cAMP EC ₅₀Be 3.09 μ M.To compd A, PBMC cAMP EC ₅₀Be 1.58 μ M.

CAMP in people's neutrophilic granulocyte promotes following the measurement.Through centrifugal, from source white corpuscle (Sera-Tec Biologicals), remove PBMC with Ficoll-Paque Plus (Amersham Pharmacia).Red corpuscle/the polymorphonuclear cell that obtains (PMN) group is resuspended in Hank's balanced salt solution (BioWhittaker), and mixes with 3%DextranT-500 (Amersham Pharmacia) in isopyknic 0.9% salt solution.Make erythroprecipitin 20 minutes, and removed PMN, and 4 ° of C at 120rpm centrifugal 8 minutes.The cracking 30 seconds in 0.2% cold salt solution of remaining red corpuscle adds equal-volume 1.6% salt solution, lets cellular-restoring etc. ooze.PMN was 4 ° of C at 1200rpm centrifugal 8 minutes, and is resuspended in RPMI-1640 then, and as above to the lifting of the said test of PBMC cAMP.Through (CA USA) goes up the execution flow cytometry, finds that PMN is about 74%CD18/CD11b for Becton Dickinson, San Jose at FACSCalibur ⁺, 71%CD16 ⁺CD9 ⁺Neutrophilic granulocyte.The result shows in table 2.

FMLF inductive LTB4 produces

N-formyl radical-methionine(Met)-Ile-Phe (fMLF) is the polypeptide of bacterial origin; Its activate neutrophilic granulocyte quick degranulationization, move, adhere on the endotheliocyte and discharge leukotrienes LTB4, it is arachidonic acid metabolite and self is the neutrophilic granulocyte chemoattractant.As discussed previously (Hatzelmann and Schudt, 2001, J.Pharm.Exp.Ther 297:267-279) and below doing changes, and test compounds hinders the ability that fMLF inductive neutrophilic granulocyte LTB4 produces.Neutrophilic granulocyte such as above-mentioned separation, resuspended in the phosphate buffered saline buffer of calcic or magnesium (Bio Whittaker) not, this damping fluid comprises 10mM HEPES, and pH is 7.2, and with concentration 1.7 * 10 ⁶Individual cells/well is inoculated in the 96 hole tissue culturing plates.Cell is at 37 ° of C 5%CO ₂With 50 μ M Thiomersalate (Sigma)/1mM CaCl ₂/ 1mM MgCl ₂Handled 15 minutes, and used 1000,200,40,8,1.6,0.32,0.064 and the 0nM compound then, whole DMSO concentration is 0.01%, and two parts of every formulas were handled 10 minutes.Neutrophilic granulocyte stimulated 30 minutes with 1 μ M fMLF, then through adding methyl alcohol (final concentration 20%) cracking, and in dry ice/isopropanol is bathed freezing 10 minutes.Split product is stored at-70 ° of C, up to measuring LTB4 content through competitive LTB4ELISA (R&D Systems).The result shows in table 2.

Zymosan inductive IL-8 produces

The yeast saccharomyces cerevisiae of zymosan A or heat killed (Saccharomyces cerevisiae) combines with the lip-deep adhesion molecule Mac-1 of neutrophilic granulocyte and causes phagolysis, cell activation and IL-8 to produce.That zymosan inductive IL-8 produces is as discussed previously (Au etc., 1998, Brit.J.Pharm. 123:1260-1266) measures and does following change.People's neutrophilic granulocyte is purifying as stated, with 3 * 10 ⁵Individual cells/well is inoculated in the perfect medium in the 96 hole tissue culturing plates, with 10,2,0.4,0.08,0.016,0.0032,0.00064 and 0 μ M compound, and two parts of every formulas, whole DMSO concentration is 0.1%, at 37 ° of C 5%CO ₂Handled 1 hour.Neutrophilic granulocyte uses the zymosan A (Sigma) that boiled without opsonification with 2.5 * 10 then ⁵Individual particulate/hole stimulated 18 hours.The results supernatant, and through ELISA (R&D Systems) test I L-8.The result shows in table 2.

FMLF inductive CD18/CD11b expresses

The CD18/CD11b of neutrophilic granulocyte (Mac-1) expresses (Derian etc., 1995, J.Immunol., 154:308-317) measurement, and change below doing as discussed previously.Neutrophilic granulocyte separates as stated, then in perfect medium with 1 * 10 ⁶Individual cell/ml is resuspended, with 10,1,0.1,0.01 and 0 μ M compound, and two parts of every formulas, whole DMSO concentration is 0.1%, at 37 ° of C 5%CO ₂Pre-treatment 10 minutes.Cell stimulated 30 minutes with 30nM fMLF then, was cooled to 4 ° of C then.Cell is with rabbit igg (Jackson ImmunoResearch Labs, West Grove, PA, USA) (10 μ g/1x10 ⁶Individual cell) handles,,, and on FACSCalibur, pass through flow cytometry with CD18-FITC and CD11b-PE (Becton Dickinson) dyeing with blocking-up Fc acceptor.CD18/CD11b when from all samples, deducting stimulation and not existing expresses (mean fluorecence), suppresses curve and calculates IC obtaining ₅₀Value.The result shows in table 2.

The fMLF inductive is to the adhesion of HUVEC

Human umbilical vein endothelial cells (HUVEC) as discussed previously (Derian etc., 1995, J.Immunol. 154:308-317) as the adherent substrate of neutrophilic granulocyte, and changes below doing.(Cedar Knolls, NJ USA) obtain the HUVEC cell, and neutrophilic granulocyte cytochalasin B of no use is handled by Anthrogenesis.Cell was with 10,1,0.1,0.01,0.001 and 0 μ M compound treatment 10 minutes, and whole DMSO concentration is 0.1%, two parts of every formulas; Stimulated 30 minutes with 500nM fMLF, and with after the PBS washed twice, (VT USA) goes up measurement fluorescence for Bio-Tek Instruments, Winooski to read the plate device at FLX800.The result shows in table 2.

Table 2. test-results

People's neutrophilic granulocyte test (all values is in nM)	Racemic compound	Compd A
			PGE 2Inductive cAMP EC 50	12589	?4570
FMLF inductive LTB4IC 50	20.1	?2.48

[0283]

Zymosan inductive IL-8IC 50	ND	94
			FMLF inductive CD18 expresses IC 50	ND	390
FMLF inductive CD11b expresses IC 50	ND	74
			The fMLF inductive is to the adhesion IC of HUVEC 50	ND	150

5.8. Embodiment 8: water solubility

Equilibrium solubility is measured in the buffered soln of pH 7.4.The damping fluid of pH 7.4 passes through with 10NNaOH 0.07M NaH ₂PO ₄The pH regulator to 7.4 of solution prepares.The ionic strength of solution is 0.15.Will be at least the 1mg powder combine with the 1ml damping fluid, to prepare>mixture of 1mg/ml.The vibration of these samples>2 hours, and be allowed to condition at hold over night under the room temperature.Then through filtering sample with 0.45 saturated μ m nylon syringe strainer of sample earlier.Twice of filtrating serial sampling.Preparation standard in 50% methyl alcohol is through the HPLC filtrates tested.The water solubility of compd A is bigger 3.5 times than racemic mixture.The solubleness of measuring: compd A=0.012mg/mL; Racemic mixture=0.0034mg/mL.

5.9. Embodiment 9:LPS inductive lung neutrophilia ferret model

Use clear-headed ferret model to investigate the anti-inflammatory of administered through oral (p.o.) PDE4 suppressor factor when approach is used, emetic and behavior effect.Through these experiments, can measure the therapeutic index (TI) of various PDE4 suppressor factor.TI calculates divided by anti-inflammatory dosage (causing the dosage that 50% of LPS inductive neutrophilia suppresses) through the threshold dose that causes emetic outbreak and behavior change.

Animal rearing

Male ferret (Mustela Pulorius Euro, heavy 1-2kg).Ferret is by Bury Green Farm or Misay Consultancy supply.After transportation, let animal in storing chamber, adapt to one period that is no less than 7 days.Food comprises that the SDS diet C ball shape food and the per week that infinitely give give three times Whiskers ^TMThe cat food.Water is the animal level tap water through pasteurization, and change every day.

Give PDE4 suppressor factor

Oral (p.o.) uses the PDE4 suppressor factor, and predose is 1-10g/kg, but for whether definite TI is 10 or higher, rises to 30mg/kg subsequently, and/or to use than low dosage, with the minimum dose of confirming to cause that 50% of neutrophilia suppresses.The ferret overnight fasting, but let it freely drink water.Use is insinuated into the 15cm administration pin the esophagus from the larynx rear portion, to animal orally give vector or PDE4 suppressor factor.After the administration, animal turns back in the storage cages that organic glass door has been installed so that observe, and lets it freely drink water.After the administration, constantly observe animal and write down any vomiting or behavior change.Behind the oral administration 60 to 90 minutes, let animal diet followed.

Be exposed to LPS

Behind orally give compound or the contrast vector 30 minutes, ferret is placed in the organic Glass Containers of sealing, and be exposed to LPS aerosol (100 μ g/ml) 10 minutes.(DeVilbiss USA) generates the LPS aerosol, and imports in the synthetic glass exposure chamber through atomizer.After 10 minutes exposure period, animal returns storage cages, lets it freely drink water, and lets its free diet in later period.Behind the oral administration, observation continues at least 2.5 hours time, and writes down emetic outbreak and behavior change.

Bronchoalveolar lavage

LPS exposes back six hours, through the excessive vetanarcol kill animals of using of intraperitoneal.In tracheae, insert PA tube then, with (twice in phosphate buffered saline buffer (PBS) the lavation lungs of 10 units/ml) of 20ml heparinization.

Blood sampling/tissue displacement

Through through the chest cardiac puncture, remove terminal blood sample this (10ml).Blood is 2, and 500rpm rotation 15 minutes is removed blood plasma and stored at-20 ° of C.Remove brain and freezing equally, supply the compounds content analysis at-20 ° of C.

Cell counting

Bronchoalveolar lavage (BAL) sample is 1, centrifugal 5 minutes of 500rpm.Remove supernatant, the cell mass that obtains is resuspended in 1ml PBS.The cell smear for preparing resuspended liquid, and with the dyeing of Leishmans staining, to allow the cell divide counting.Use remaining resuspended sample to make total cell count.Measure the neutrophilic granulocyte total amount among the BAL thus.

The parameter of measuring

1.LPS the inhibition per-cent of inductive lung neutrophilia.

2. vomiting of emetic Fa Zuo – counting and the amount of retching.

3. the following behavior effect of behavior change-attention: hydrostomia, shortness of breath, oral cavity scratching, calm posture, ataxia, arched back and the walking that falls back.Any behavior change all uses severity grading (slightly, moderate or severe) to come half to quantize.

4. calculate TI, for the maximum dose level that does not cause emetic outbreak found divided by find 50% or suppress the lowest dose level of lung neutrophilia more.

In the lung of clear-headed ferret, compd A is explained in Figure 30 the effect of LPS inductive neutrophilia.

Vomiting and behavior change

Behind the PDE4 oral administration, observe ferret at least two hours, and write down emetic outbreak (vomiting and retch) and behavior change.

In the relevant pretreated ferret of vector (acetone/cremophor/ zero(ppm) water) of oral administration, do not observe emetic outbreak (retching or vomiting).In the animal (7/22) of sub-fraction control treatment, see slight behavior change (lick lip and fall back walking).

Compd A (0.1-3mg/kg, oral) does not cause emetic outbreak (retching and vomiting).Observe some behavior changes (calm posture, lick lip and fall back walking), and classify as slight.At 10mg/g, in 2/6 ferret, observe some retch but not obviously vomiting, follow hydrostomia and behavior change (being assessed as slight or moderate).At the maximum dose level (30mg/kg) of test, in 3/4 animal, observe moderate to significant emesis, follow tangible behavior change.These data are summarized in table 3.

Table 3. ferret that regains consciousness: emetic outbreak and behavior change behind the Orally administered compd A

Observe animal after administration three hours.The animal number that numeral in the parenthesis responds.Animal number range from 4 to 22 in every group.

Therapeutic index is calculated

By these experiments, through using the threshold dose of inducing emetic outbreak divided by the ED that suppresses lung neutrophilia ₅₀Value is every kind of compound determination therapeutic index (TI).TI calculates general introduction in table 4.The TI that compd A has is 12, does not cause emetic outbreak at the anti-inflammatory dosage of 1mg/kg.

Inhibition (the ED of table 4. pair LPS inductive lung neutrophilia ₅₀) and the therapeutic index general introduction of inducing the effective dose of vomiting and being derived from these values

5.10. embodiment 10: the biological activity of compd A in suffering from severe psoriasis in plaques patient

Compd A is the new oral medicament of the generation of downward modulation pro-inflammatory cytokine in people's cell model.Compd A has shown the generation that reduces TNF-α, IL-12 and IFN-γ, and promotes the generation of IL-10.Psoriatic is strong relevant with the dysregulation of cytokine and chemokine, and this permission is carried out potential treatment with immunomodulatory compounds.This 2 phase, open-label, the single armed pilot study is designed the biological activity of coming assessment compd A in severe psoriasis in plaques patient.Carry out the extra assessment of clinical effectiveness, with the potential curative effect of assessment compd A in treatment severe psoriasis in plaques.

Orally administered compd A, every day, 20mg totally 29 days, followed the tracks of the phase with extra 28 days to the observation of patient safety.In baseline, the 15th day with obtained the skin penetrating biopsy specimen (6mm) of target patch on the 29th day.Get harmless skin biopsy at baseline equally.The main pharmacodynamics terminal point is the 29th day epidermal thickness percentage change from baseline.Carry out the epidermis skin thickness by blind examiner and measure and immunohistochemical analysis, with assessment CD11c, CD83, K16, ICAM-1, HLA-DR and fillagrin.Analyze biopsy specimen through RT-PCR, analytic target is: TNF-α, p40-IL12/IL23, IL-10, IFN-γ, IP10, IL-2, IL-8, iNOS, p19-IL23, K16, CD83 and hARP.During 29 days treatment phases of research, carry out PASI, PGA and BSA measurement and study clinical efficacy.Adverse events report, clinical labororatory's assessment, health check-up, ECG and life sign measurement assessment security.Amounting to 19 patients participates in: 15 patients have a complete set of biopsy estimated, and 17 patients have complete curative effect assessment.

This research mesocuticle variation in thickness assessment is main terminal point.19 patients participate in the research, and wherein 15 at baseline with had a complete set of biopsy estimated on the 29th day.In 19 individualities 17 are at baseline and measured the clinical efficacy parameter on the 29th day.At baseline with had in the 29th day among 15 patients that can estimate biopsy, there are eight (53.3%) to show that the epidermis skin thickness has descended 20%.Baseline and the 29th day, have in whole 15 individualities that can estimate biopsy, the average decline of epidermal thickness is 20.5% (p=0.015).Figure 31 has shown the variation that has in the individuality that can estimate biopsy from 29 days epidermal thicknesses of baseline to the.

The crucial struvite mark of assessment comprises epidermis and corium T cell, CD83+ and CD11c cell in biopsy specimen.8 patients' that respond result shows 42.56% and 28.79% (decline of >=20% epidermal thickness) that descended respectively of respondent's mesocuticle and corium T cell.Respondent's mesocuticle and corium CD83+ cell are respectively 32.50% and 25.86% from the average decline of baseline.In respondent's epidermis and corium, the CD11c cell has descended 40.16% and 18.50%.Table 5 has been enumerated the decline of the struvite mark of crucial skin biopsy among respondent and the nonresponder.In addition, a patient who has unusual K16 at baseline had normal K16 at the 29th day.Three patients that have unusual ICAM-1 at baseline had normal ICAM-1 at the 29th day.Two patients with unusual HLA-DR had normal HLA-DR at the 29th day, and three patients that have unusual fillagrin at baseline had normal fillagrin at the 29th day.

The decline per-cent of the 29th day crucial struvite mark of table 5.

Cell	?	Epidermis	Corium
				The T cell	The respondent	-42.56%	-28.79%
?	The nonresponder	+8.74%	-17.34%
				?CD83+	The respondent	-32.50%	-25.86%
?	The nonresponder	-16.31%	+0.46%
				?CD11c	The respondent	-40.16%	-18.50%
?	The nonresponder	-2.54%	-21.19%

Biopsy specimen comprises through the mRNA genetic expression that RT-PCR assesses crucial struvite mark: TNF α, p40-IL12/IL23, IL-10, IFN γ, IP10, IL-2, IL-8, iNOS, p19-IL23, K16 and CD83.After 29 days, the mRNA of iNOS expresses and has reduced by 66.5% (p=0.025) in the infringement skin with the compd A treatment.Reduction and increase that the mRNA of other struvite mark expresses have shown overall improvement tendency.Figure 32 illustrates iNOS change of Expression during the research.

In the individuality of 19 participation, accomplished 29 days treatment phases and had the assessment of complete clinical curative effect for 17 altogether.In the individuality of 19 participation, at the 29th day, have 14 (73.7%) to show that its PASI improves, 3 (15.8%) among these patients have shown that its total psoriatic zone marks from baseline with severity index (PASI)>50% decline.Figure 33 shows that the PASI scoring is from the percentage change of baseline among the 29th day valuable patient.In addition; After compd A treatment 29 days; Among 17 valuable patients, there are 9 (52.9%) to show the improvement of static doctor's total evaluation (sPGA), and have 10 (58.8%) to show that its psoriatic body surface area (BSA) descends from baseline among 17 valuable patients.During treatment and tracking phase, assess security through monitoring adverse events, ECGs, lab investigation, health check-up and vital sign.Report is not dead, has no the patient to withdraw from too early because of adverse events yet.Modally comprise headache (26.3%) and nauseating (15.8%) with the relevant adverse events of treatment.

In this clinical study, once a day oral administration of compound A 20mg totally 29 days in the individuality of suffering from the severe psoriasis in plaques, be safe.Descend along with there being 8 (53.3%) to reach 20% of epidermal thickness at the 29th day in 15 individualities, reach main terminal point.In skin biopsy, notice the decline of crucial struvite mark, comprise T cell, CD83+ and the CD11c cell of corium and epidermis.RT-PCR analyzes demonstration, and iNOS mRNA has significantly descended 66.5% in the 29th day skin biopsy on statistics.After 29 days, notice male clinical efficacy signal with the compd A treatment.At the 29th day, the patient's of participation 73.7% showed the improvement of its psoriatic symptom, and these patients' 15.8% show that its PASI scoring is from baseline>50% decline.At the 29th day, the patient's of participation 47.4% showed the improvement of its sPGA, and 52.6% its psoriatic body surface area (BSA) of demonstration of the patient who participates in descends from baseline.

5.11. embodiment 11: prove the curative effect of compd A in suffering from the psoriatic individuality of moderate to severe and the 2 phases research of security

This 2 phase, polycentric, at random, double blinding, placebo, parallel-group, dosage comparative studies assessed curative effect and the security of compd A in the individuality of suffering from moderate to severe psoriasis in plaques, these individualities are candidates of whole body therapeutic.

This research comprises the treatment phase in 12 week, then is that the phase is followed the tracks of in the observation in 4 weeks.Amount to 260 individualities and accept compd A 20mg secondary every day, compd A 20mg at random once a day or placebo, totally 12 weeks.The main terminal point of this research is, with the individuality of compd A treatment the 12nd the week/treat its psoriatic zone and severity index scoring reach 75% decline (" PASI-75 ") based on baseline visit per-cent for the last time.Last treatment is defined in the last PASI assessment of accomplishing during the treatment phase in 12 week.

The 12nd the week/last treatment, with placebo (10%; P=0.023) relatively, significantly the individuality (24%) with the treatment of 20mg secondary every day of higher proportion has reached PASI-75.To accepting the individuality of 20mg secondary every day or placebo, the 12nd the week/last treatment, the ratio that reaches PASI-50 is respectively 57% and 23%; And the ratio that reaches PASI-90 is respectively 14% and 6%.The 12nd the week/last treatment, the PASI of the individuality of 20mg secondary every day and placebo has reached 52% and 17% average decline respectively from baseline.The individuality of accepting compd A continues to improve in time, descends at the highest average percent that shows the PASI scoring the 12nd week.Generally speaking, in all three treatment groups, the adverse events characteristic is similar.Most adverse events of report are slight.In this research, not report and the relevant serious adverse events of research medicine.In 20mg secondary every day group, during observing the tracking phase, there is not the aggravation of individual experience psoriatic.

In this clinical study, compd A is presented in the individuality of suffering from moderate to severe psoriasis in plaques and is tolerated well, and is safe.After 12 weeks treatment, PASI reaches the clinical activity that 50%, the 75% and 90% individual ratio improved has been explained compd A.

5.12. Embodiment 12: the solid form screening study

5.12.1. Experimental technique

solubility studies.Compd A sample (about 100mg) through weighing is handled with about 2mL test solvent.The solvent that uses is SILVER REAGENT or HPLC level.The mixture that obtains stirred 24 hours at about 25 ° of C at least.When through being observed visually all solids when dissolving, calculate the solubleness of estimating.Estimate solubleness through these experiments based on the solvent TV that is used for obtaining solution.Owing to use the speed of a large amount of solvents or stripping slow, so actual solubility maybe be greater than those calculated values.If there is not stripping in experimental session, then solubleness is measured through gravimetry.The filtrating of known volume is evaporated to drying, and measures the weight of resistates.

The research of solution evaporation.Solubleness to compd A is wherein carried out solution evaporation, for example acetone, acetonitrile, methylene dichloride and THF greater than the solvent of about 50mg/mL.Through about 25 ° of C or about 50 ° of C in nitrogen in the opening bottle slow evaporating solvent, obtain solid sample.

balance studies.Balance test is carried out through in about 2mL test solvent, adding excessive compd A.The mixture that obtains stirred 24 hours at about 25 ° of C or about 50 ° of C at least.When reaching balance, remove saturated solution, and let it respectively in about 25 ° of C or about 50 ° of C slowly evaporation in the opening bottle in nitrogen.The slurry that is obtained by balance is filtered, and at air drying.

The research of crystallisation by cooling.Carry out crystallisation by cooling research.Solid is dissolved in solvent at the about 65 ° of C of temperature that raise, and let it be cooled to about 25 ° of C.To there be the crystalline sample to be placed in the refrigerator (about 0-5 ° C) at about 25 ° of C.Solid separates through decant, and is allowed to condition at air drying.

The research of solvent/anti-solvent deposition.Deposition is carried out through the solvent/anti-solvent combination.Solid compd A therein has in the solvent of relative high-dissolvability and dissolves, and the solvent (being anti-solvent) that then compd A of selecting is had relative low solubility therein adds in the solution.In some solvent/anti-solvent systems, deposition forms immediately.If deposition does not occur immediately, the mixture that obtains is cooled off in refrigerator (about 0-5 ° C), up to forming deposition.Deposition is separated through decant then, and is allowed to condition at air drying.

change research.The change experiment is carried out through the slurry of preparation solid form in saturated solvent.Slurry stirred 2 days at about 25 ° of C at least.Through filtering, remove saturated solution, and at the air drying solid.

pressure investigation.Pressure test was carried out through pressing down sample with Carver Mini C press in the power of 2000psi at least one minute.Then through the XRPD analyzing samples.

Study on Hygroscopicity.The water absorbability of various solid forms uses the surface measurement DVS of system instrument to study.Usually the sample size between will about 10-50mg is loaded in the DVS instrument sample disk, and sample is analyzed on DVS robotization adsorption analysis appearance at about 25 ° of C.Relative humidity is increased to about 95%RH by about 0%, interval about 10%.Relative humidity descends in a similar manner then, attaches circulation to accomplish complete adsorption/desorption.Experimental session is with the fixed time interval recording quality.

5.12.2. Characterizing method

Usually through X-ray powder diffraction (XRPD) analysis as at the sample that generates described in the solid form screening.XRPD is at Thermo ARL X ' TRA ^TMImplement on the X-ray powder diffraction meter, use Cu K α radiation,

Apparatus preparation thin burnt X-ray tube.The voltage of x ray generator and amperes are separately positioned on 45kV and 40mA.Disperse sheet and be arranged on 4mm and 2mm, and measured sheet is arranged on 0.5mm and 0.2mm.The radioactive rays of diffraction detect through peltier refrigerative Si (Li) solid-state detector.Usually carry out θ-2 θ continuous sweep with 2.40 °/minute (0.5 second/0.02 ° per steps) from 1.5 ° of 2 θ to 40 ° of 2 θ.Use agglomerating aluminum oxide standard to check the peak position.In general, the measuring basis through about ± 0.2 ° of 2 θ is measured expection XRPD peak position independent variation.In general, understand like this area, if the characteristic peak of the characteristic peak of first figure and second figure is positioned at roughly the same position, these two XRPD scheme to match each other so.Understand like this area; Confirm whether two XRPD figure matees or two XRPD figure in independent peak whether mate, possibly need to consider independent variable and variation, the variation of XRPD data collection parameters and/or the variation of XRPD data processing etc. of parameter such as but not limited to preferred direction, impurity, percent crystallinity, granularity, the setting of diffractometer instrument mutually.Confirm whether two figure mate and can carry out through naked eyes and/or Computer Analysis.Use the instance of the XRPD figure of these methods and parameter collection and analysis to provide in the present invention, for example like Fig. 1, Fig. 5, Fig. 9, Figure 13, Figure 17, Figure 21 and Figure 25.

Dsc (DSC) is analyzed at TA instrument Q 1000 ^TMLast execution.About 5mg sample is placed in the DSC dish of taring, and accurately writes down sample weight.Usually, sample is heated to the about 200 ° of C of final temperature with about 10 ° of C/ branch speed from about 25 ° of C in nitrogen.Usually, incident heat is registered as the starting temperature of reckoning.Use these methods and parameter collection and the thermographic instance of analysis DSC to provide in the present invention, for example like Fig. 2, Fig. 6, Figure 10, Figure 14, Figure 18, Figure 22 and Figure 26.

Thermogravimetric analysis (TGA) is at TA instrument Q500 ^TMLast execution.The calibration of use caoxalate.About 10mg sample is placed on the dish, accurately weighs, and in the TGA stove of packing into.Sample is heated to the about 200 ° of C of final temperature with about 10 ° of C/ branch speed from about 25 ° of C in nitrogen.Use these methods and parameter collection and the thermographic instance of analysis TGA to provide in the present invention, for example like Fig. 3, Fig. 7, Figure 11, Figure 15, Figure 19, Figure 23 and Figure 27.

Solvation solvent through the TG-IR experimental identification with quantitatively, use to have connected the spectrophotometric TA instrument of Thermo Nicolet AEM Fourier conversion IR Q500 ^TMTGA.Usually, the about 20-50mg of sample size is weighed in the aluminium dish, and is heated to about 200 ° of C.The TGA run duration, steam flows to cell through hot delivery conduit.The temperature of delivery conduit and cell all is arranged on about 225 ° of C.The 10 second time of every repetition, collect IR spectrum.Volatile matter is through the storehouse identification of search Aldrich gas-phase spectrum, and the steam that exists storehouse matching result demonstration to be discerned.

The form of sample and sreen analysis use the Olympus microscope to carry out.Instrument is used the USP standard calibration.Use Image Plus-Material Plus software to measure the D90 value.The representative of D90 value is 90 through the percentile of the size-grade distribution of linear measure; Promptly 90% particle has the length of this value or shorter.

5.12.3. Solid form screening study result

The solid form of the inclusion compound A that during the solid form screening study, prepares comprises form A, B, C, D, E, F, G and amorphous forms.Form A, B, C, D, E, F and G typical XRPD figure, DSC figure, TGA figure and DVS figure separately is provided as Fig. 1-Figure 28 in the present invention.

solubility studies.The form B that measures compd A is in the approximate solubility of about 25 ° of C in all kinds of SOLVENTS.The result shows in table 6.Discovery form B the most solvable in acetone, acetonitrile, methylene dichloride, methyl ethyl ketone and THF (greater than about 50mg/mL) then is in ETHYLE ACETATE (about 30.15mg/mL).Find that also form B has low solubility in several solvents, comprise propyl carbinol, heptane, 2-propyl alcohol, toluene and water (being lower than about 1mg/mL).

Solution evaporation researchThe result of the solution evaporation research of carrying out at about 25 ° of C and about 50 ° of C summarizes in table 7.

Balance studiesThe result of the balance studies that carries out at about 25 ° of C and about 50 ° of C summarizes in table 8.

The research of crystallisation by cooling.The result of crystallisation by cooling research summarizes in table 9.Crystallisation by cooling research output crystalline material from many solvents comprises acetone, acetonitrile, n-butyl acetate, ETHYLE ACETATE, methyl alcohol, methylene dichloride, methyl ethyl ketone (MEK) and THF (THF).The crystalline material that obtains characterizes through XRPD, DSC and TGA usually.

The research of solvent/anti-solvent deposition.The result of solvent/anti-solvent deposition research summarizes in table 10.When with heptane, water and toluene when about 40 ° of C add in the solution of form B in THF, form deposition immediately.When with heptane, methyl tert-butyl ether (MTBE), toluene and water respectively when about 25 ° of C add in the solution of form B in acetonitrile, form settled solution or mixture.After the stirred overnight, obtain crystalline material from MTBE/ acetonitrile, water/acetonitrile and toluene/acetonitrile.But, there is not crystallization to occur to heptane/acetonitrile mixture.When with water when about 50 ° of C add in the solution of form B in methyl alcohol, form deposition immediately, and when with heptane and toluene respectively when about 50 ° of C add in the solution of form B in methyl alcohol, formation settled solution or mixture.After the stirred overnight, from toluene and methanol and heptane/methyl alcohol, obtain crystalline material.When with toluene when about 25 ° of C add in the solution of form B in methylene dichloride, form deposition immediately, and when with MTBE when about 25 ° of C add in the solution of form B in methylene dichloride, the acquisition settled solution.After the stirred overnight, from the MTBE/ methylene dichloride, obtain crystalline material.But, in the time of in heptane being added to the solution of form B in methylene dichloride, do not have crystallization to occur.When with heptane when about 50 ° of C add in the solution of form B in MEK, form deposition immediately, and when with MTBE and toluene respectively when about 50 ° of C add in the solution of form B in MEK, the acquisition settled solution.After the stirred overnight, from MTBE/MEK and toluene/MEK, obtain crystalline material.When with heptane when about 50 ° of C add in the solution of form B in n-butyl acetate, form deposition immediately, and when with MTBE and toluene respectively when about 50 ° of C add in the solution of form B in MEK, the acquisition settled solution.After the stirred overnight, from MTBE/ n-butyl acetate and toluene/n-butyl acetate, obtain crystalline material.When with water and toluene respectively when about 40 ° of C add in the solution of form B in acetone, form deposition immediately, and when with ethanol and 2-propyl alcohol respectively when about 40 ° of C add in the solution of form B in acetone, the acquisition settled solution.After the stirred overnight, from ethanol/acetone and 2-propyl alcohol/acetone, obtain crystalline material.The crystalline material that obtains is identified through XRPD, DSC, TGA.

stability study.The result of stability study summarizes in table 11.Through solid sample being exposed to the four stars phase under 40 ° of C/75%RH stressed conditions, the stability of research form A, B, C and D.In addition, form A, B, C and the D stability in different solvents is through studying in 40 ° of C balance four stars phase in different solvents.Cross filter pulp then, and at air drying.Solid sample by stability experiment obtains is passed through XRPD and dsc analysis.

Change researchThe result of change research summarizes in table 12.

Pressure investigationForm A, B, C, D, E, F and G to compd A carry out pressure test.Like what arrive, find that each form be studied all is basic physically stable through the XRPD analysis and observation.

Study on Hygroscopicity.Form A, B, C, D, E, F and G are carried out water absorbability (water adsorption/desorption) research.After the complete adsorption/desorption of experience attached circulation in the DVS system, each solid sample was analyzed through XRPD.XRPD result points out that as the result that DVS analyzes, none lives through substantial solid-state conversion in the form of analysis.

The solubility studies of table 6. form B

Solvent system	Approximate solubility (mg/ml)
		Acetone	>;50
Acetonitrile	>;50
		Propyl carbinol	>;0.72
N-butyl acetate	9.75
		Absolute ethyl alcohol	1.38
ETHYLE ACETATE	30.15
		Heptane	0.41
Methylene dichloride	>;50
		Methyl ethyl ketone	>;50
Methyl alcohol	4.05
		Methyl tert-butyl ether	1.17
The 2-propyl alcohol	0.81
		THF	>;50
Toluene	0.90
		Water	0.69
Ethanol: water (1:1)	2.86

The research of table 7. solution evaporation

Table 8. balance studies

The research of table 9. crystallisation by cooling

Initial form	Solvent system	XRPD analyzes	The DSC incident heat
				B	Acetone	Form E	?
B	Acetonitrile	Form E	95.42°C
				B	N-butyl acetate	Form B	?
B	ETHYLE ACETATE	Form B	?
				B	Methylene dichloride	Form D	100.90°C
B	Methyl alcohol	Form B	?
				B	Methyl ethyl ketone	Form B	?
B	THF	Form H	?

The research of table 10. solvent/anti-solvent deposition

^*Abbreviation: MEK=methyl ethyl ketone; DCM=methylene dichloride (being methylene chloride); The MtBE=methyl tert-butyl ether

Table 11. stability study

Table 12. change research

5.13. Embodiment 13:200MG dose capsule

Table 13 has been explained the batch prescription and the single dose prescription of the single dose unit of the solid form (promptly about 40% weight ratio) that in the 0# capsule, comprises 200mg inclusion compound A.

The capsular prescription of table 13.200mg

Make pregelatinized W-Gum (SPRESS ^TMB-820) and the compd A composition through 710 μ m sieve, in the diffusion mixer that the band baffle plate of packing into then inserts, mixed 15 minutes.Make Magnesium Stearate pass through 210 μ m sieve, add in the diffusion mixer.Use Dosator type capsule filler mixture to be packed in the 0# capsule into 500mg/ capsule (production lot 8400 capsules) then.

5.14. Embodiment 14:100MG oral dosage form

Table 14 has been explained batch prescription and single dose unit's prescription of the solid form that comprises 100mg inclusion compound A.

The prescription of table 14.100mg tablet

Make Microcrystalline Cellulose, cross-linked carboxymethyl cellulose sodium and compd A composition through #30 mesh sieve (about 430 μ are to about 655 μ).Make Pluronic

(by JRH Biosciences; Lenexa company, KS preparation) tensio-active agent is through #20 mesh sieve (about 457 μ are to about 1041 μ).Rolled in the stirrer in Pluronic

tensio-active agent and 0.5kg cross-linked carboxymethyl cellulose sodium 16 quarts of bivalves of packing into, mixed about 5 minutes.Then mixture is transferred to 3 cubic feet of bivalves and roll in the stirrer, add Microcrystalline Cellulose, mixed about 5 minutes.Add the solid form of inclusion compound A, mixed other 25 minutes.This pre-composition has the roller compaction machine of beater grinder through discharging place, and retracts in the stirrer that rolls.Remaining cross-linked carboxymethyl cellulose sodium and Magnesium Stearate join in the stirrer that rolls, and mix about 3 minutes.Final mixture is compressed to 250mg/ sheet (200,000 of production lots) on Rotarytabletpress.

Although the present invention is described specific embodiments, those skilled in the art will be obviously can not deviate from the claim defined purport of the present invention and scope and carry out various changes and modification.Such modification also drops in the appended claim scope.

Claims (11)

1. the solid form that comprises formula (I) compound of enantiomer-pure:

Its X-ray powder diffraction figure comprises the peak at about 10.1,12.4,13.5,15.7,16.3,18.1,20.7,22.5,24.7,26.2,26.9 and 29.1 degree 2 θ places.

2. solid form as claimed in claim 1, its dsc figure comprises the heat absorption incident of the about 154 ° of C of starting temperature.

3. solid form as claimed in claim 1, when being heated to about 140 ° of C from about 25 ° of C, its thermogravimetic analysis (TGA) figure comprises and is lower than about 1% mass loss.

4. solid form as claimed in claim 1, when being heated to about 140 ° of C from about 25 ° of C, its thermogravimetic analysis (TGA) figure comprises and is lower than about 0.25% mass loss.

5. solid form as claimed in claim 1, when experience when about 0% relative humidity is increased to about 95% relative humidity, its demonstration is lower than about 1% quality to be increased.

6. solid form as claimed in claim 1, when experience when about 0% relative humidity is increased to about 95% relative humidity, its demonstration is lower than about 0.6% quality to be increased.

7. solid form as claimed in claim 4, when being exposed to about 4 weeks of about 40 ° of C and about 75% relative humidity, it is stable.

8. the pharmaceutical composition that comprises each described solid form among the claim 1-7.

Among the claim 1-7 each described solid form be used for treating in preparation can be through suppressing the purposes that TNF-α produces the medicine of the disease improved or illness, wherein said disease or illness are selected from psoriatic, psoriatic arthritis, rheumatoid arthritis, chronic skin sarcoid, giant cell arteritis, Parkinson's disease, prurigo nodularis, lichen planus, complicacy aphthosis, Behcet's disease, lupus, hepatitis, uveitis, sjogren syndrome, depression, interstitial cystitis, vulvodynia, prostatitis, osteo-arthritis, diffuse large B cell lymphoma, polymyositis, dermatomyositis, inclusion body myositis, EOA, interstitial cystitis, hepatitis, endometriosis, radiculopathy and pyoderma gangraenosum.

10. each described solid form is used for treating the purposes of medicine that can be through suppressing disease that PDE4 improves or illness in preparation among the claim 1-7, and wherein said disease or illness are selected from: HIV; Hepatitis; Adult respiratory distress syndrome; Bone resorption disease; Chronic obstructive pulmonary disease; Chronic pulmonary inflammation disease; Dermatitis; Inflammatory skin diseases, atopic dermatitis, cystic fibrosis; Septic shock; Septicemia; Endotoxin shock; The haemodynamics shock; Septicemia syndrome; Postischemic reperfusion damage; Meningitis; Psoriatic; Fibrotic disease; Emaciation; Transplant rejection; Graft versus host disease; Autoimmune disease; Rheumatoid spondylitis; Arhritis conditions; Rheumatoid arthritis; Osteo-arthritis; Osteoporosis; Segmental enteritis; Ulcerative colitis; Inflammatory bowel; Multiple sclerosis; Systemic lupus erythematosus; ENL in the leprosy; Radiation injury; Asthma; And hyperoxic alveolar injury.

11. each described solid form is used for treating the purposes of the medicine of cancer in preparation among the claim 1-7, wherein said cancer is selected from multiple myeloma, malignant melanoma, glioblastoma, white blood disease and solid tumor.

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