CN101531653B - Salts of 3-(4-amino-1-oxo-1,3-dihydro-iso-indol-2-yl)piperdine-2,6-dione and derivatives thereof, polymorph of the salts, preparation and application thereof - Google Patents

Salts of 3-(4-amino-1-oxo-1,3-dihydro-iso-indol-2-yl)piperdine-2,6-dione and derivatives thereof, polymorph of the salts, preparation and application thereof Download PDF

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CN101531653B
CN101531653B CN200910118977.2A CN200910118977A CN101531653B CN 101531653 B CN101531653 B CN 101531653B CN 200910118977 A CN200910118977 A CN 200910118977A CN 101531653 B CN101531653 B CN 101531653B
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张和胜
马丽鹃
李幸稳
曾广怀
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Xiajiang Hemei Pharmaceutical Co ltd
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TIANJIN HEMEI BIOTECHNOLOGY CO Ltd
XIAJIANG HEMEI PHARMACEUTICAL Co Ltd
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Abstract

The invention provides 3-(4-amino-1-oxo-1, 3-dihydro-iso-indol-2-yl)piperdine-2, 6-dione and salts of derivatives or polycrystals of the salts as well as preparation and application, and discloses pharmaceutical acceptable strong acid salts of 3-(4-amino-1-oxo-1, 3-dihydro-iso-indol-2-yl)piperdine-2, 6-dione and solvolyte thereof, preparation and application thereof for preparing medicament for treating diseases or physiological abnormity which can be cured by inhibiting inflammation inflammatory or generation of neovascularization. The water solubility of the pharmaceutical acceptable strong acid salt of 3-(4-amino-1-oxo-1, 3-dihydro-iso-indol-2-yl)piperdine-2, 6-dione provided by the present invention is greatly larger than that of 3-(4-amino-1-oxo-1, 3-dihydro-iso-indol-2-yl)piperdine-2, 6-dione free alkali. The invention also discloses the plolycrystals of pharmaceutical acceptable strong acid salt of 3-(4-amino-1-oxo-1, 3-dihydro-iso-indol-2-yl)piperdine-2, 6-dione and solvolyte thereof.

Description

3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2, the salt of 6-diketone and derivative thereof or the polymorphic form of salt and preparation and application
Technical field
The present invention relates to 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2, the polymorphic form of the solvate of the salt that 6-diketone and various acid generate or solvate, salt or the salt of these salt, and preparation method thereof and application in the medicine that is generated those diseases that can reach curative effect for the preparation for the treatment of by the inflammation-inhibiting factor or new vessel.
Background technology
3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone (II, wherein Y represents H) has multiple pharmacological action.Compound (II) can suppress the release of inflammatory factor in body, also can suppress the generation of new vessel, thereby can be widely used in treatment various diseases, include but not limited to inflammation, autoimmunization exception class disease, cancer and immunological rejection syndromes (seeing United States Patent (USP) 5635517,6281230, Chinese patent 200510013292.3).
Tumor necrosis factor alpha (TNF α) is the main cell element being discharged in the time replying immunostimulation by monokaryon phagocyte.To animal and human use that TNF α can cause inflammation, heating, cardiovascular function are abnormal, hemorrhage, blood coagulation and a series of and acute infection and the similar acute reaction of shock state.In animal body or in human body, produce the excessive or normal prompting of uncontrolled TNF α and suffer from following disease:
1, endotoxemia and/or poisoning shock syndromes [Tracey et al., Nature 330,662-4 1987; Hinshawet al., Circ Shock 30,279-92 (1990)];
2, emaciation [Dezube et al., Laucet, 335 (8690), 662 (1990))];
3, adult breathes catatonic syndrome (ARDS) [Millar et al., Laucet 2 (8665), 712-714 (1989)].
TNF α also play an important role in the bone resorption class disease disease including sacroiliitis [Betolinni et al., Nature319,516-8 (1986)].In vitro and in vivo test all proves that TNF α can stimulate bone resorption by stimulating the generation of osteoclast (Osteoclast) and activating, and suppresses the generation of bone.
So far be that tumour and host tissue discharge the hypercalcemia [Calci.Tissue Int. (US) 46 (Suppl.), S3-10 (1990)] that TNF α is relevant with malignant tumour to the most obvious disease of TNF α relation.With it bone marrow transplant patient, immune response and the increase of patients serum TNF α concentration be closely related [Holler et al., Blood, 75 (4), 1011-1016 (1990)].
The super acute nervosa syndromes brainstem type malaria of lethality is also relevant with TNF alpha levels height in blood, and this disease is the most dangerous one in malaria class disease.When sick sending out, serum TNF alpha levels is directly related with the state of an illness, and often can be in the acute malaria patient generation [Grau et al., N.Engl.J.Med.320 (24), 1586-91 (1989)] that shows effect.
TNF α also plays an important role in chronic pneumonia.Storage containing silicon particle in lung can cause silicosis.Silicosis is the carrying out property respiratory insufficiency disease being caused by the fiberization of lung tissue.In animal pathological model, the antibody of TNF α can be blocked the mouse pulmonary fibrosis process [Pignet et al., Nature, 344:245-7 (1990)] that silica dust causes completely.Experimentation on animals also proves TNF α extremely high [Bissonnette et al., Inflammation 13 (3), 329-339 (1989)] in the animal serum of the pulmonary fibrosis causing at silica dust or asbestos plaster.Pathological study discloses also people much higher [Baughman et al., J.Lab.Clin.Med.115 (1), 36-42 (1990)] than usual of TNF alpha levels in sarcoidosis of lung human lung tissue.Prompting TNF alpha inhibitor is of great importance in the treatment of chronic lung disease and injury of lung.
The reason causing inflammation in reperfusion injury patient (Reperfusion Injury) also may be due to patient body in TNF alpha levels abnormal, and TNF α is considered to cause arch-criminal [the Uadder et al. of the tissue injury that ischemic causes, PNAS87,2643-6 (1990)].
In addition, experimental results show that TNF α can start retroviral the copying [Duh et al., Proc.Nat.Acad.Sci., 86,5974-8 (1989)] including HIV-1.HIV needs to activate T-cell before entering T-cell, once and the T-cell being activated by HIV virus infection, these T-cells must continue to remain on state of activation just can be made HIV virogene express smoothly and/or allow HIV virus copy smoothly.And cytokine, particularly TNF α, in the HIV of T-cell regulate and control protein expression process or play an important role in virus replication.Therefore the generation that, suppresses TNF α just may suppress HIV virus copying in T-cell.[Poll et al.，Proc.Nat.Acad.Sci.，87，782-5(1990)；Monto et al.，Blood79，2670(1990)；Poll et al.，AIDS Res.Human Retrovirus，191-197(1992)]。
The adjustable a lot of class cell functions of cAMP, such as inflammatory reaction, comprise asthma, inflammation [Lome and Cheng, Drugsof the futune, 17 (9), 799-807,1992].When inflammation, the rising of leukocytic cAMP concentration has suppressed leukocytic activation, discharges subsequently inflammation regulatory factor, comprises TNF α, and inflammation in aggravation patient body.Therefore, the release of inhibition TNF α can be alleviated the inflammation class disease including asthma.
Recently, the discovery TNF α such as Yu Yanyan play an important role [Yu Yanyan etc., CHINESE JOURNAL OF INTERNAL MEDICINE 1996,35:28-31] in the hepatic necrosis process of viral hepatitis, and prompting TNF alpha inhibitor is of great importance in the treatment of chronic hepatopathy and liver injury.
The discovery patients with chronic liver peripheral blood lymphocytes such as Li Yingxu level synthetic and secreting tumor necrosis factor obviously increases, and induce other cytokine (such as Il-1 β, Il-6 and Il-8) secretion, and jointly participate in hepatocellular damage process [Qiqihar Medical College's journal, 22 (10): 1119-1120,2001].The research conclusion of their result and Yoshioka etc. [Hepatology, 1989,10:769-777] and Wang Xin etc. [Chinese transmissible disease magazine, 1997,15 (2): 85-88] meets.They and then the reaction of discovery small molecules TNF alpha inhibitor stop to suppress significantly hepatitis patient peripheral blood lymphocytes TNF secretion α, thereby have established molecular pathology basis for TNF alpha inhibitor is used for the treatment of hepatitis, liver cirrhosis and liver cancer.
TNF α is by impelling the synthetic of struvite cytokine and discharging [Abboud H.E.Kidney Int.1993; 43:252-267], impel expression [Egido J.et al, the Kidney Int.1993 of cell adhesion molecule; 43 (suppl39): 59-64], and stimulate PGG 2(PGE 2) and platelet activation factor (PAF) synthetic and discharge [Cammusi G.etal., Kidney Int., 43 (suppl 39): 32-36], make inflammatory cell assemble and adhere to, Marjoram Extract and permeability strengthen, bring out heating, circulation neutrophil leucocyte increases and the Inflammatory response such as hemodynamic change, thereby causes the damage of nephrocyte.A lot of research points out TNF α to play an important role in the morbidity of ephritis and in worsening.
TNF α is by activating macrophage, and immunity stimulates T lymphocytosis, regulates the differentiation of bone-marrow-derived lymphocyte and the cytotoxic effect of enhancing natural killer cell (NK), thereby has participated in the adjusting of immunologic function.
Thereby reducing the interior TNF alpha levels of patient body and/or increasing its cAMP level is that an effective strategy is treated much struvite, infectious, immunity or malignant tumour class disease, include but not limited to septic shock (Sepsis Shock), endotoxin shock, hemodynamics shock (Hemodynamic Shock), Sepsis (Sepsis Syndrom), rear ischemia reperfusion damage (Post Ischemic Reperfusion Injury), malaria (Malaria), mycobacterium infects (MycobacterialInfection), meningitis (Meningitis), psoriatic (Psoriasis), congestive heart failure (Congestive HeartFailure), fibrotic disease (Fibrotic disease), emaciation (Cachexia), transplantation immunity is repelled, cancer, autoimmune disease (Autoimmune disease), the opportunistic diseases of AIDS infects (Opportunistic Infection in AIDS), rheumatoid arthritis (RA), hepatitis, ephritis, rheumatoid spondylitis (Rheumatoid Spondylitis) etc.There is bibliographical information Parkinson's disease diseased region inflammatory factor, especially TNF content is extremely high, on Parkinson's disease pathological model, suppress TNF and discharge reversible course advancement, point out anti-TNF therapy likely to cure Parkinson's disease (McCoy, M.TheJournal of Neuroscience, Sept.13,2006; Vol 26).
Enbrel, the TNF acceptor of solubility, has good therapeutic effect to sacroiliitis, psoriasis, and prompting tnf inhibitor can treatment of arthritis, psoriasis.
Reaction is parked in clinically has good drug effect to children's's meningitis, and prompting tnf inhibitor can be treated meningitis.
To observe hepatitis diseased region TNF horizontal abnormality high for China doctor, and further disclose TNF play central role in hepatic fibrosis and liver cirrhosis process, and prompting tnf inhibitor can be used for treating hepatitis and liver cirrhosis.
In waiting, to observe in nephritis victim's blood TNF level higher, points out the anti-TNF therapy may be effective to nephritis treatment.
In sum, TNF antagonist can be used for treating the disease that those can obtain medical treatment by controlling TNF level, include but not limited to sacroiliitis, hepatitis, gastritis, digestive tract ulcer, stomatocace, ephritis, rhinitis, bronchitis, COPD (chronic obstructive pulmonary disease), pneumonia, pulmonary tuberculosis, myocarditis, pancreatitis, prostatitis, cervicitis, enteritis, crown syndromes, nerve ending inflammation, myelitis, encephalitis, Parkinson's disease, psoriasis, lupus erythematosus, chronic dermatitis, leprosy, Parkinson's disease, carrying out property encephalatrophy disease, alzheimer's disease, liver cirrhosis.Therefore, low toxicity, the development of small molecules TNF alpha inhibitor efficiently have great social effect and economic worth.
Formula (II) compound also can suppress the generation of new vessel, thereby can be widely used in treatment various diseases, include but not limited to cancer, include but not limited to bone marrow cancer, leukemia, liver cancer, brain tumor, prostate cancer, cancer of the stomach, esophagus cancer, intestinal cancer, laryngocarcinoma, oral carcinoma, rhinocarcinoma, osteocarcinoma, cervical cancer, lung cancer, mammary cancer, kidney, lymphoma, ovarian cancer, carcinoma of the pancreas, adrenal carcinoma, mesothelial cell's cancer, melanoma, myelodysplastic syndrome.
Compound (II) water-soluble poor.Various hydrates and the crystal formation (seeing world patent WO2005/023192) of compound (II) have been studied by Celgene Corp. of the U.S., and coordinate micronization technology, finally successfully research and develop a kind of capsule preparations, by FDA approval listing.
To specific crowd, oral preparations may not reach the drug bioavailability with curative effect meaning, especially resembles the water-soluble so extremely low medicine of formula (II) compound, and injecting drug use can make all patients reach 100% bioavailability.
Can draw the corresponding salt of the difficult and sour effect generation of compound (II) from chemical structure feature and the pKa analysis of compound (II), easy and alkali reaction generates metal-salt on the contrary, such as the conclusion of sodium salt, sylvite or calcium salt.But compound (II) is unstable under alkaline condition, facile hydrolysis.Thereby, there is not yet so far the report of the salt of related compounds (II).
As everyone knows, the drug molecule of free alkali form is prepared to salify, not only can greatly improve the water-soluble and oral administration biaavailability of drug molecule, but also can be through parenteral mode administration, such as intravenously administrable, intramuscular injection, suction, drops provide possibility for medicine is prepared into.The drug molecule of free alkali form is prepared to salify and also provide more more options for preparing controlled release preparation.In addition, become the drug molecule of salt form may possess the superiority on better stability, workability etc. preparation process thereof.
The drug molecule of free alkali form prepare salify also for research and development can be that bulk drug purification process that various countries drug administration institutions accepts provides may.Prepare the medicine of salify can the safety solvent that be representative at Yi Shui, alcohol, ketone easily in recrystallization obtain the bulk drug product of high-quality.Thereby, the drug molecule of free alkali form is prepared to the normally optimal selection of bulk drug material form (drugsubstance) of salify.
In sum, successfully research and develop 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2, the salt of 6-diketone is necessary.
Summary of the invention
In the time of being related to of the water-soluble and pH value of compound shown in Research-type (II), compound shown in contriver's discoverable type (II) under acidic conditions, water-soluble increasing.This disclosed amino in (I) can with XH in hydrogen ion have an effect.Contriver has systematically studied subsequently compound shown in formula (II) and has reacted with various mineral acids and organic acid, and compound shown in pleasantly surprised ground discoverable type (II) can react with strong acid generation salt, but can not with the acid of medium tenacity and weak acid, as the reaction such as phosphoric acid, phenylformic acid, succinic acid, oxalic acid, fumaric acid, toxilic acid, acetic acid salify.
Correspondingly, the compound shown in the open formula (I) of the present invention, and preparation and application:
Wherein, Y represents H, CH 3or F;
XH represents various pharmaceutically acceptable strong acid, includes but not limited to the substituted sulfonic acid shown in hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid or formula (III).
Wherein R represents C 1-6alkyl, aromatic nucleus or heterocycle;
C in the present invention 1-6alkyl is saturated branched hydrocarbyl, unsaturated side chain alkyl, saturated straight chain alkyl, unsaturated straight-chain alkyl, saturated cyclic or unsaturated cyclic hydrocarbon radical, can be optionally by one or more F, Cl, Br, NO 2, OH, COOH, COOR 1, SO 3h, SO 2r 1, SOR 1, CN, CONR 1r 2, aromatic nucleus, aromatic heterocycle, OR 1or NR 1r 2replace.
Aromatic nucleus in the present invention is monocycle aromatic nucleus or condensed ring aromatic nucleus, can be optionally by one or more NO 2, F, Cl, Br, OH, COOH, NHC (O) R 1, NR 1r 2, NHR 1, NH 2, SR 1, OR 1, COOR 1, SO 3h replaces.
Heterocycle in the present invention comprise quaternary, five yuan, hexa-atomic, seven yuan or eight yuan containing one or more heteroatomss as the saturated heterocyclic of nitrogen, oxygen, sulphur atom, unsaturated heterocycle, aromatic heterocycle or fused heterocycle, can be optionally by one or more F, NO 2, Cl, Br, OH, COOH, NHC (O) R 1, NR 1r 2, NHR 1, NH 2, SR 1, OR 1, COOR 1replace;
R in the present invention 1, R 2represent respectively saturated or undersaturated side chain or the straight-chain alkyl that contain 1-4 carbon atom, can optionally be replaced by one or more F, Cl, Br, OH, COOH.
Being applicable to the compound of formula (II) compound salify is that R represents C 1-6cH when alkyl 3, CH 2cH 3, CH 2cH 2cH 3, CH 2cH 2cH 2cH 3, CH (CH 3) 2, CH 2cH (CH 3) 2, C (CH 3) 3, CF 3, CHF 2, CH 2f, CH 2cF 3, CH 2cHF 2, CH 2cH 2f, CH 2cH 2cF 3, CH 2cH 2cHF 2, CH 2cH 2cH 2f, cyclohexyl or cyclopentyl; Relatively being applicable to the compound of formula (II) compound salify is that R represents C 1-6cH when alkyl 3, CH 2cH 3, CH 2cH 2cH 3, CH (CH 3) 2, CH 2cH (CH 3) 2, CF 3, CHF 2, CH 2f, CH 2cF 3, CH 2cHF 2, CH 2cH 2f, CH 2cH 2cF 3; The most applicable and compound formula (II) compound salify is that R represents C 1-6cH when alkyl 3, CH 2cH 3, CH 2cH 2cH 3, CF 3, CHF 2, CH 2f, CH 2cF 3or CH 2cHF 2.
Be applicable to compound shown in the formula (III) of formula (II) compound salify be R while representing aromatic nucleus R represent phenyl, 1-naphthyl, 2-naphthyl, 5-sulfonic acid naphthalene-1-base, p-methylphenyl, o-methyl-phenyl-, between aminomethyl phenyl, p-hydroxybenzene, o-hydroxy-phenyl, between hydroxy phenyl, trifluoromethyl, to carboxyl phenyl, between carboxyl phenyl, adjacent carboxyl phenyl, p-sulfonic acid phenyl, between sulphenyl, ortho-sulfonic acid phenyl, to ethylphenyl, adjacent ethylphenyl, between ethylphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, 2, 3-3,5-dimethylphenyl, 3, 4-3,5-dimethylphenyl, O-Nitrophenylfluorone, m-nitro base or p-nitrophenyl, relatively be applicable to and the formula (III) of formula (II) compound salify shown in compound be R while representing aromatic nucleus be R represent phenyl, 1-naphthyl, 2-naphthyl, 5-sulfonic acid naphthalene-1-base, p-methylphenyl, o-methyl-phenyl-, an aminomethyl phenyl, p-hydroxybenzene, o-hydroxy-phenyl, a hydroxy phenyl, trifluoromethyl, to ethylphenyl, adjacent ethylphenyl, an ethylphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, compound shown in the formula (III) of the most applicable and formula (II) compound salify is that R is that R represents phenyl, 1-naphthyl, 2-naphthyl, 5-sulfonic acid naphthalene-1-base, p-methylphenyl, o-methyl-phenyl-, an aminomethyl phenyl, p-hydroxybenzene, o-hydroxy-phenyl, a hydroxy phenyl, trifluoromethyl, compound to ethylphenyl, adjacent ethylphenyl, an ethylphenyl or p-methoxyphenyl while representing aromatic nucleus.
Be applicable to compound shown in the formula (III) of formula (II) compound salify be R while representing heterocycle R represent the compound of furan nucleus, pyrrole ring, thiphene ring or pyridine ring.
" strong acid " in the present invention, represents that pKa is less than organic acid or the mineral acid of the pKa1 of phosphoric acid.
Compound shown in formula disclosed by the invention (I) water-soluble than chemical combination object height 4-5000 shown in formula (II) doubly.
In compound shown in formula (I), (II) can be 1 with the molar ratio of XH: 0.1-5, proper molar ratio is 1: 0.5-2, optimal molar ratio is 1: 1 or 2: 1.
Compound shown in formula disclosed by the invention (I) can be the form of solvent free while use, can be also the form of the form of solvation, especially hydrate or alcoholate.
Compound shown in formula disclosed by the invention (I) can be single salt while use, can be also the mixture of several salt.
Compound shown in formula disclosed by the invention (I) can be unformed form while use, can be also its various crystal formation forms, or the mixture of these forms.
Compound shown in formula disclosed by the invention (I) can be S type while use, can be also R type, or the mixture of R and S type.
Shown in formula disclosed by the invention (I), compound can be prepared by following method:
Method A, the compound shown in formula (II) is dissolved in to suitable solvent; XH is added; Control temperature of reaction; Place and temperature control.
Method B, XH is dissolved in to suitable solvent; Compound shown in formula (II) is added; Control temperature of reaction; Place and temperature control.
Method C, the compound shown in formula (II) is dissolved in to suitable solvent; After being dissolved in to suitable solvent, XH adds; Control temperature of reaction; Place and temperature control.
Solvent described in above-mentioned preparation method can be any suitable solvent, includes but not limited to one or more the mixed solution in water, alcohol, ester, ketone, ether, acid amides, sulfone or sulfoxide.
Suitable alcohol described in above-mentioned preparation method, ester, ketone, ether, acid amides, sulfone, sulfoxide type solvent, include but not limited to methyl alcohol, ethanol, propyl alcohol, Virahol, acetone, butanone, ether, isopropyl ether, THF (tetrahydrofuran (THF)), 1, 4-dioxane, ethyl formate, ethyl acetate, propyl formate, isopropyl formate, methyl acetate, propyl acetate, isopropyl acetate, butyl formate, DMF (N, dinethylformamide), DMA (N, N-N,N-DIMETHYLACETAMIDE) or DMSO (dimethyl sulfoxide (DMSO)) in one or more mixed solution.
Shown in above-mentioned preparation method's Chinese style (II), the mol ratio of compound and XH can be 1: 0.1-50; More suitable mol ratio is 1: 0.2-10; Most suitable mol ratio is 1: 0.5-2; If XH is volatile acid, the add-on of XH can be more than 10% any amount of formula (II) compound molar weight.
Can be-40-200 ℃ of temperature of reaction in above-mentioned preparation method; More suitable temperature is-20-100 ℃; Most suitable temperature is 0-80 ℃.
To embodiment sample determination mass spectrum and H 1nMR, measurement result proves that compound shown in formula (II), react stable in salification process with XH, does not have side reaction to occur.
The unit using dosage scope of compound shown in formula disclosed by the invention (I) is 0.1 milligram-250 milligrams; The unit using dosage of optimizing is 1 milligram-100 milligrams; Best unit using dosage is: 5 milligrams to 50 milligrams.
The unit using dosage of compound most convenient shown in formula disclosed by the invention (I) is and compound unit's using dosage shown in the formula (I) of compound equivalent shown in the formula (II) of 5 milligrams, 10 milligrams, 25 milligrams, and the unit using dosage wherein the most often using is and the unit using dosage of compound equivalent shown in the formula (II) of 10 milligrams and 25 milligrams.
Unit using dosage described in the present invention refers to the unit that can be applied to patient and easy handling and packing, i.e. single dosage.
The indication of compound shown in formula (I) when the active constituents of medicine is all those diseases that can effectively be alleviated and treat by reducing TNF alpha levels (concentration) in patient body, includes but not limited to struvite, infectious, immunity or malignant tumour class disease.Disease specific kind includes but not limited to septic shock (Sepsis Shock), endotoxin shock, hemodynamics shock (Hemodynamic Shock), Sepsis (Sepsis Syndrom), rear ischemia reperfusion damage (PostIschemic Reperfusion Injury), malaria (Malaria), mycobacterium infects (Mycobacterial Infection), meningitis (Meningitis), psoriatic (Psoriasis), congestive heart failure (Congestive Heart Failure), fibrotic disease (Fibrotic disease), emaciation (Cachexia), transplantation immunity is repelled, cancer, autoimmune disease (Autoimmune disease), the opportunistic diseases of AIDS infects (Opportunistic Infection in AIDS), ENL, lupus erythematosus, intractable lupus erythematosus, Behchet's syndromes, regional ileitis, myelodysplastic syndrome, rheumatoid arthritis (RA), hepatitis, ephritis, rheumatoid spondylitis (Rheumatoid Spondylitis), multiple myeloma, thyroid tumor, kidney, prostate cancer, lymphoma, leukemia and liver cancer.
Compound shown in formula disclosed by the invention (I) can be prepared into the preparation via administering mode application such as oral, injection, suction, eye drip, an ear, transdermal, rectum, vagina administrations such as tablet, capsule, powder pin, pharmaceutical solutions, freeze-dried powder, aerosol, spray, paste, patch, eye drops, ear drop or implant.
An advantage of compound shown in formula disclosed by the invention (I) is can be prepared into injection to use.
Another advantage of compound shown in formula disclosed by the invention (I) is can be prepared into sustained release preparation to use.
Compound shown in formula disclosed by the invention (I) can use with applicable other medicines composition compound, includes but not limited to: oblimersen ( ), remicade, docetaxel, celecoxib, melphalan, dexamethasone, steroid, gemcitabine, cis-platinum, Temozolomide, Etoposide, endoxan, carboplatin, Procarbazine, BCNU, tamoxifen, TPT, Rheumatrex, the interferon alpha of taxol, taxotere, Fluracil, folinic acid, Rinotecan, xeloda, CPT-11, interferon alpha, PEGization, vinealeucoblastine(VLB), Zorubicin, vincristine(VCR), sulindac, prednisone.
Compound shown in formula disclosed by the invention (I) also can use with suitable Chinese medicine extract composition compound.
The present invention includes the application of compound shown in formula (I) or its solvate, wherein XH represents various pharmaceutically acceptable strong acid, it is characterized by described being applied as for the preparation for the treatment of and can reach those diseases of curative effect or physically different medicine by the inflammation-inhibiting factor.
Those diseases or the physically different sacroiliitis that can be that can be reached curative effect by the inflammation-inhibiting factor of the present invention, hepatitis, gastritis, digestive tract ulcer, stomatocace, ephritis, rhinitis, bronchitis, COPD, pneumonia, pulmonary tuberculosis, myocarditis, pancreatitis, prostatitis, cervicitis, enteritis, crown syndromes, nerve ending inflammation, myelitis, encephalitis, Parkinson's disease, psoriasis, lupus erythematosus, chronic dermatitis, leprosy, Parkinson's disease, carrying out property encephalatrophy disease, alzheimer's disease, liver cirrhosis.
The present invention also comprises the application as angiogensis inhibitor of compound shown in formula (I) or its solvate, wherein XH represents various pharmaceutically acceptable strong acid, it is characterized by the described medicine that is generated those diseases that can reach curative effect for the preparation for the treatment of by inhibition new vessel that is applied as.
Of the present invention by suppressing new vessel, to generate those diseases that can reach curative effect be cancer, includes but not limited to bone marrow cancer, leukemia, liver cancer, brain tumor, prostate cancer, cancer of the stomach, esophagus cancer, intestinal cancer, laryngocarcinoma, oral carcinoma, rhinocarcinoma, osteocarcinoma, cervical cancer, lung cancer, mammary cancer, kidney, lymphoma, ovarian cancer, carcinoma of the pancreas, adrenal carcinoma, mesothelial cell's cancer, melanoma, myelodysplastic syndrome, bladder cancer, head and neck cancer, leukemia, neuroblastoma, hemangiopericytoma, the rectum cancer.
The invention also discloses the polymorphic form of the solvate of compound shown in compound shown in formula (I) or formula (I):
The polymorphic form (IA) of the solvate of compound shown in compound or formula (I) shown in formula (I) when XH represents sulfuric acid,
The polymorphic form (IB) of the solvate of compound shown in compound or formula (I) shown in formula (I) when XH represents sulfuric acid,
The polymorphic form (IC) of the solvate of compound shown in compound or formula (I) shown in formula (I) when XH represents sulfuric acid,
The polymorphic form (IIA) of the solvate of compound shown in compound or formula (I) shown in formula (I) when XH represents nitric acid,
The polymorphic form (IIIA) of the solvate of compound shown in compound or formula (I) shown in formula (I) when XH represents Phenylsulfonic acid,
The polymorphic form (IIIB) of the solvate of compound shown in compound or formula (I) shown in formula (I) when XH represents Phenylsulfonic acid,
The polymorphic form (IVA) of the solvate of compound shown in compound or formula (I) shown in formula (I) when XH represents tosic acid,
The polymorphic form (IVB) of the solvate of compound shown in compound or formula (I) shown in formula (I) when XH represents tosic acid,
The polymorphic form (VA) of the solvate of compound shown in compound or formula (I) shown in formula (I) when XH represents Hydrogen bromide,
The polymorphic form (VIA) of the solvate of compound shown in compound or formula (I) shown in formula (I) when XH represents methylsulfonic acid,
The polymorphic form (VIB) of the solvate of compound shown in compound or formula (I) shown in formula (I) when XH represents methylsulfonic acid,
The polymorphic form (VIIA) of the solvate of compound shown in compound or formula (I) shown in formula (I) when XH represents hydrochloric acid,
The measuring condition of X-ray powder diffraction collection of illustrative plates:
Sample size: about 100mg
Target: Cu
Filter disc: monochrome
Voltage/current: 40kV/100mA
1 ° of slit: SS/DS, RS 0.3mm
Sweep velocity: 8 °/point
The test condition of infrared absorption:
Resolving power: 4cm -1
Scanning times: 20
Spectral range: 4000～400cm -1
Heat is analyzed the test condition with differential thermal analysis (TG-DTA):
Sample size: about 6mg
Reference substance: Al 2o 3
Temperature rise rate: 10 ℃/min
Sample introduction: 0.7 second
The upper limit: 250 ℃
Lower limit: room temperature
(1) polymorphic form (IA)
Peak in X-ray powder diffraction collection of illustrative plates
Angle of diffraction (2 θ, °) Intensity (I/I 0) Angle of diffraction (2 θ, °) Intensity (I/I 0)
16.52 74.7 22.321 63.2
17.04 16.4 25.403 14.8
18.763 10.9 26.098 95.7
19.46 100 26.78 37.8
20.422 25.6 29.084 16.5
20.817 16.8 34.715 11.1
21.940 32.4
(2) polymorphic form (IB)
Peak in X-ray powder diffraction collection of illustrative plates
Angle of diffraction (2 θ, °) Intensity (I/I 0) Angle of diffraction (2 θ, °) Intensity (I/I 0)
5.580 53.6 21.099 37.3
10.437 17.3 21.700 22.5
12.820 50.0 22.759 21.0
16.759 79.6 24.158 14.4
17.139 19.6 25.118 15.8
18.860 100 26.739 67.9
19.241 38.2 27.359 40.1
20.641 54.6 30.020 13.6
Infrared absorption spectrum wavelength (nm) in polymorphic form (IB) Potassium Bromide:
453.2 526.48 653.76 692.33 767.54 806.11 844.68 950.75 1033.71076.1 1286.3 1315.2 1348 1400.1 1436.7 1504.2 1571.7 16181889.9 1951.6 2159.9 2698 3037.4 3172.4 3328.6 3810.7 3938
(3) polymorphic form (IC)
Peak in X-ray powder diffraction collection of illustrative plates
Angle of diffraction (2 θ, °) Intensity (I/I 0) Angle of diffraction (2 θ, °) Intensity (I/I 0)
14.243 46.5 25.645 100
16.392 22.2 26.584 47.4
16.919 99.3 27.339 25.9
17.183 40.6 28.076 45.3
18.780 83.7 28.282 22.6
20.376 22.4 28.833 20.8
21.438 67.2 30.261 32.8
23.380 34.9 32.486 25.7
24.060 25.5
(4) polymorphic form (IIA)
Peak in X-ray powder diffraction collection of illustrative plates
Angle of diffraction (2 θ, °) Intensity (I/I 0) Angle of diffraction (2 θ, °) Intensity (I/I 0)
5.861 51.6 17.701 30.1
7.958 19.5 18.680 28.6
11.720 75.4 20.618 100
13.221 17.0 23.860 69.2
14.418 50.4 25.240 27.5
15.518 18.3 26.600 81.8
16.199 34.5 27.320 96.7
16.701 81.1 29.361 27.3
(5) polymorphic form (IIIA)
Peak in X-ray powder diffraction collection of illustrative plates
Angle of diffraction (2 θ, °) Intensity (I/I 0) Angle of diffraction (2 θ, °) Intensity (I/I 0)
4.799 100 20.799 30.7
9.681 13.6 22.201 23.7
13.818 23.4 24.041 37.2
15.418 36.6 24.559 29.6
17.658 46.3 26.580 16.6
18.602 20.9
(6) polymorphic form (IIIB)
Peak in X-ray powder diffraction collection of illustrative plates
Angle of diffraction (2 θ, °) Intensity (I/I 0) Angle of diffraction (2 θ, °) Intensity (I/I 0)
5.440 46.1 19.119 38.3
10.981 17.2 19.600 34.9
13.080 26.9 20.040 100
14.761 18.6 24.981 74.2
15.800 24.1 26.322 35.1
17.041 85.2 28.782 22.7
17.420 21.6
Infrared absorption spectrum wavelength (nm) in polymorphic form (IIIB) Potassium Bromide:
403.06 445.48 495.62 528.41 582.41 653.76 711.62 777.18 846.61900.61 946.89 1062.6 1157.1 1215 1280.5 1313.3 1346.1 1394.31434.8 1477.2 1506.2 1573.7 1841.7 1878.4 2179.2 2723 3039.33135.7 3301.6 3708.5 3741.3 3799.1 3851.2
(7) polymorphic form (IVA)
Peak in X-ray powder diffraction collection of illustrative plates
Angle of diffraction (2 θ, °) Intensity (I/I 0) Angle of diffraction (2 θ, °) Intensity (I/I 0)
4.640 100 19.339 15.7
13.580 32.3 19.938 18.8
14.360 17.1 20.560 24.3
15.200 21.1 24.181 68.0
17.399 59.5 27.583 15.3
Infrared absorption spectrum wavelength (nm) in polymorphic form (IVA) Potassium Bromide:
441.63 526.48 649.9 721.26 771.4 896.75 948.82 1020.2 1060.71137.8 1218.8 1282.5 1313.3 1394.3 1432.9 1475.3 1508.1 1619.91878.4 1940.1 1994.1 2144.5 2715.3 3012.3 3162.7 3299.7 3812.63939.9
(8) polymorphic form (IVB)
Peak in X-ray powder diffraction collection of illustrative plates
Angle of diffraction (2 θ, °) Intensity (I/I 0) Angle of diffraction (2 θ, °) Intensity (I/I 0)
12.438 20.82 19.799 100
15.522 16.2 21.039 17.7
18.900 83.89 26.662 28.6
(9) polymorphic form (VA)
Peak in X-ray powder diffraction collection of illustrative plates
Angle of diffraction (2 θ, °) Intensity (I/I 0) Angle of diffraction (2 θ, °) Intensity (I/I 0)
10.040 27.2 24.199 52.1
11.963 29.1 24.639 91.5
15.118 17.7 25.920 70.1
16.879 50.9 26.839 42.2
20.479 41.6 28.140 30.5
20.896 18.7 30.040 20.7
21.481 100 31.120 36.6
22.760 23.1 33.539 24.6
23.520 19.8 35.081 19.4
(10) polymorphic form (VIA)
Peak in X-ray powder diffraction collection of illustrative plates
Angle of diffraction (2 θ, °) Intensity (I/I 0) Angle of diffraction (2 θ, °) Intensity (I/I 0)
7.459 10.5 19.179 44.5
11.519 31.1 19.500 39.1
14.798 34.1 21.901 100
14.999 18.3 23.721 29.1
15.719 19.5 26.481 65.7
17.278 38.9 27.721 18.2
(11) polymorphic form (VIB)
Peak in X-ray powder diffraction collection of illustrative plates
Angle of diffraction (2 θ, °) Intensity (I/I 0) Angle of diffraction (2 θ, °) Intensity (I/I 0)
9.941 32.5 21.040 82.8
10.937 47.1 22.080 21.3
15.341 54.0 23.641 36.3
16.501 69.9 24.161 57.5
18.360 33.0 25.539 100
18.919 85.8 28.200 22.2
19.458 63.6 30.500 15.3
20.020 22.8 34.601 15.6
(12) polymorphic form (VIIA)
Peak in X-ray powder diffraction collection of illustrative plates
Angle of diffraction (2 θ, °) Intensity (I/I 0) Angle of diffraction (2 θ, °) Intensity (I/I 0)
10.196 15.9 24.241 52.8
12.018 55.2 24.642 100
13.162 41.9 25.420 32.2
15.279 15.7 26.042 48.0
17.020 40.8 26.581 30.0
19.058 25.4 26.820 36.7
20.460 40.7 28.302 23.2
21.580 49.4 30.359 16.7
22.478 17.6 31.081 25.5
22.980 19.1 35.301 22.4
Infrared absorption spectrum wavelength (nm) in polymorphic form (VIIA) Potassium Bromide:
431.64 497.22 526.16 564.73 651.53 697.82 771.12 884.92948.57 1029.6 1068.2 1218.6 1278.4 1311.2 1349.8 1390.31438.5 1471.3 1500.2 1540.7 1621.7 1849.3 1870.61920.7 2100.1 2119.4 2138.7 2171.5 2221.6 2320 2348.92661.4 3010.5 3029.8 3251.6 3679.8 3710.7 3749.3 38093859.2 3909.3 3930.6 3971.1
The present invention also provides the preparation method of the polymorphic form of the solvate of compound shown in compound shown in formula (I) or formula (I):
Method A, the compound shown in formula (II) is dissolved in to suitable solvent, XH is added, stir, filter.
Method B, XH is dissolved in to suitable solvent; Compound shown in formula (II) is added; Stir, filter.
Method C, the compound shown in formula (II) is dissolved in to suitable solvent; After being dissolved in to suitable solvent, XH joins in the solution that contains compound shown in formula (II); Stir, filter.
Solvent described in above-mentioned preparation method can be any suitable solvent, includes but not limited to one or more the mixed solution in water, alcohol, ester, ketone, ether, acid amides, sulfone or sulfoxide.
Suitable alcohol described in above-mentioned preparation method, ester, ketone, ether, acid amides, sulfone, sulfoxide type solvent, include but not limited to methyl alcohol, ethanol, propyl alcohol, Virahol, acetone, butanone, ether, isopropyl ether, THF (tetrahydrofuran (THF)), 1, 4-dioxane, ethyl formate, ethyl acetate, propyl formate, isopropyl formate, methyl acetate, propyl acetate, isopropyl acetate, butyl formate, DMF (N, dinethylformamide), DMA (N, N-N,N-DIMETHYLACETAMIDE) or DMSO (dimethyl sulfoxide (DMSO)) in one or more mixed solution.
Shown in above-mentioned preparation method's Chinese style (II), the mol ratio of compound and XH can be 1: 0.1-50; More suitable mol ratio is 1: 0.2-10; Most suitable mol ratio is 1: 0.5-2; If XH is volatile acid, the add-on of XH can be more than 10% any amount of formula (II) compound molar weight.
Can be-40-200 ℃ of temperature of reaction in above-mentioned preparation method; More suitable temperature is-20-100 ℃; Most suitable temperature is 0-80 ℃.
The unit using dosage scope of the polymorphic form of the solvate of compound shown in compound shown in formula disclosed by the invention (I) or formula (I) is 0.1 milligram-250 milligrams; The unit using dosage of optimizing is 1 milligram-100 milligrams; Best unit using dosage is: 5 milligrams to 50 milligrams.
The unit using dosage of the polymorphic form most convenient of the solvate of compound shown in compound shown in formula disclosed by the invention (I) or formula (I) is and compound unit's using dosage shown in the formula (I) of compound equivalent shown in the formula (II) of 5 milligrams, 10 milligrams, 25 milligrams, and the unit using dosage wherein the most often using is and the unit using dosage of compound equivalent shown in the formula (II) of 10 milligrams and 25 milligrams.
Unit using dosage described in the present invention refers to the unit that can be applied to patient and easy handling and packing, i.e. single dosage.
The indication of the polymorphic form of the solvate of compound shown in compound shown in formula (I) or formula (I) when the active constituents of medicine is all those diseases that can effectively be alleviated and treat by reducing TNF alpha levels (concentration) in patient body, includes but not limited to struvite, infectious, immunity or malignant tumour class disease.Disease specific kind includes but not limited to septic shock (Sepsis Shock), endotoxin shock, hemodynamics shock (Hemodynamic Shock), Sepsis (SepsisSyndrom), rear ischemia reperfusion damage (Post Ischemic Reperfusion Injury), malaria (Malaria), mycobacterium infects (Mycobacterial Infection), meningitis (Meningitis), psoriatic (Psoriasis), congestive heart failure (Congestive Heart Failure), fibrotic disease (Fibrotic disease), emaciation (Cachexia), transplantation immunity is repelled, cancer, autoimmune disease (Autoimmune disease), the opportunistic diseases of AIDS infects (Opportunistic Infection in AIDS), ENL, lupus erythematosus, intractable lupus erythematosus, Behchet's syndromes, regional ileitis, myelodysplastic syndrome, rheumatoid arthritis (RA), hepatitis, ephritis, rheumatoid spondylitis (Rheumatoid Spondylitis), multiple myeloma, thyroid tumor, kidney, prostate cancer, lymphoma, leukemia and liver cancer.
The polymorphic form of the solvate of compound shown in compound shown in formula disclosed by the invention (I) or formula (I) can be prepared into via oral, injection, suction, eye drip, drip the preparation that the route of administration such as ear, transdermal, rectum or vagina administration are applied, and includes but not limited to injection, injection, powder injection, lyophilized injectable powder, tablet, capsule, dripping pill, sprays, eye drops, ear drop, patch, paste, implant, sustained release preparation or pharmaceutical solutions.
The polymorphic form of the solvate of compound shown in compound shown in formula disclosed by the invention (I) or formula (I) can use with applicable other medicines composition compound, includes but not limited to: oblimersen ( ), remicade, docetaxel, celecoxib, melphalan, dexamethasone, steroid, gemcitabine, cis-platinum, Temozolomide, Etoposide, endoxan, carboplatin, Procarbazine, BCNU, tamoxifen, TPT, Rheumatrex, one or more in interferon alpha, vinealeucoblastine(VLB), Zorubicin, vincristine(VCR), sulindac or the prednisone of taxol, taxotere, Fluracil, folinic acid, Rinotecan, xeloda, CPT-11, interferon alpha, PEGization.
The polymorphic form of the solvate of compound shown in compound shown in formula disclosed by the invention (I) or formula (I) also can use with suitable Chinese medicine extract composition compound.
The present invention includes the application of the polymorphic form of the solvate of compound shown in compound shown in formula (I) or formula (I), wherein XH represents various pharmaceutically acceptable strong acid, it is characterized by described being applied as for the preparation for the treatment of and can reach those diseases of curative effect or physically different medicine by the inflammation-inhibiting factor.
Those diseases or the physically different sacroiliitis that includes but not limited to that can be reached curative effect by the inflammation-inhibiting factor of the present invention, hepatitis, gastritis, digestive tract ulcer, stomatocace, ephritis, rhinitis, bronchitis, COPD, pneumonia, pulmonary tuberculosis, myocarditis, pancreatitis, prostatitis, cervicitis, enteritis, crown syndromes, nerve ending inflammation, myelitis, encephalitis, Parkinson's disease, psoriasis, lupus erythematosus, chronic dermatitis, leprosy, Parkinson's disease, carrying out property encephalatrophy disease, alzheimer's disease or liver cirrhosis.
The present invention also comprises that the polymorphic form of the solvate of compound shown in compound shown in formula (I) or formula (I) is as the application of angiogensis inhibitor, wherein XH represents various pharmaceutically acceptable strong acid, it is characterized by the described medicine that is generated those diseases that can reach curative effect for the preparation for the treatment of by inhibition new vessel that is applied as.
Of the present invention by suppressing new vessel, to generate those diseases that can reach curative effect be cancer, includes but not limited to bone marrow cancer, leukemia, liver cancer, brain tumor, prostate cancer, cancer of the stomach, esophagus cancer, intestinal cancer, laryngocarcinoma, oral carcinoma, rhinocarcinoma, osteocarcinoma, cervical cancer, lung cancer, mammary cancer, kidney, lymphoma, ovarian cancer, carcinoma of the pancreas, adrenal carcinoma, mesothelial cell's cancer, melanoma, myelodysplastic syndrome, bladder cancer, head and neck cancer, leukemia, neuroblastoma, hemangiopericytoma or the rectum cancer.
Accompanying drawing explanation:
Fig. 1: the X powder diffraction collection of illustrative plates of the polymorphic form (IA) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents sulfuric acid,
Fig. 2: the X powder diffraction collection of illustrative plates of the polymorphic form (IB) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents sulfuric acid,
Fig. 3: the X powder diffraction collection of illustrative plates of the polymorphic form (IC) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents sulfuric acid,
Fig. 4: the X powder diffraction collection of illustrative plates of the polymorphic form (IIA) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents nitric acid,
Fig. 5: the X powder diffraction collection of illustrative plates of the polymorphic form (IIIA) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents Phenylsulfonic acid,
Fig. 6: the X powder diffraction collection of illustrative plates of the polymorphic form (IIIB) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents Phenylsulfonic acid,
Fig. 7: the X powder diffraction collection of illustrative plates of the polymorphic form (IVA) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents tosic acid,
Fig. 8: the X powder diffraction collection of illustrative plates of the polymorphic form (IVB) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents tosic acid,
Fig. 9: the X powder diffraction collection of illustrative plates of the polymorphic form (VA) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents Hydrogen bromide,
Figure 10: the X powder diffraction collection of illustrative plates of the polymorphic form (VIA) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents methylsulfonic acid,
Figure 11: the X powder diffraction collection of illustrative plates of the polymorphic form (VIB) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents methylsulfonic acid,
Figure 12: the X powder diffraction collection of illustrative plates of the polymorphic form (VIIA) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents hydrochloric acid,
Figure 13: the infrared absorption pattern of the polymorphic form (IB) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents sulfuric acid,
Figure 14: the infrared absorption pattern of the polymorphic form (IIIB) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents Phenylsulfonic acid,
Figure 15: the infrared absorption pattern of the polymorphic form (IVA) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents tosic acid,
Figure 16: the infrared absorption pattern of the polymorphic form (VIIA) of the solvate of compound shown in compound or formula (I) shown in the formula (I) when XH represents hydrochloric acid,
Figure 17: solubility test graticule
Specific embodiment
Abbreviation indicates: mg: milligram, and kg: kilogram, mL: milliliter.
The preparation (embodiment 1-6) of the organic acid salt of compound (II)
Get (II, wherein Y represents H) shown in compound (518mg) and equimolar organic acid add in ethanol, heated and stirred, add a small amount of water, continue to stir after 30 minutes, then stirring at room temperature, continues to stir 4 hours after separating out solid, suction filtration, filter cake vacuum-drying 10 hours.In the water of gained salt (1: 1), solubleness is in table one.
Table one: the solubleness of the organic acid salt of (II,, wherein Y represents H) in water
Embodiment organic acid solubleness (mg/mL, 15 ℃)
Embodiment 1 Phenylsulfonic acid 3.76
Embodiment 2 methylsulfonic acids 1.85
Embodiment 3 tosic acid 7.03
Embodiment 4 1-naphthalene sulfonic aicds 5.60
Embodiment 5 2-naphthene sulfonic acid 6.20
Embodiment 61,5-naphthalene disulfonic acid > 500
(II, wherein Y represents H) free alkali .H 2o 0.29
Embodiment 7
Get (II, wherein Y represents H) shown in compound 518mg add and in ethanol and under stirring at room temperature, slowly add 1mL sulfuric acid (98%), the system that is stirred to becomes clarification, stirring is spent the night and is obtained solid, suction filtration, filter cake vacuum-drying 10 hours, obtains the hydrosulfate (II: sulfuric acid=1: 1) containing (II) of 4 crystal water.Ultimate analysis: C 13h 13n 3o 3.H 2sO 4.4H 2o, calculated value C36.36%, H5.36%, N9.79%, measured value C35.79%, H4.59%, N9.68%, fusing point: 277.0-278.8 ℃ decomposition, water-soluble: > 1000mg/ml (15 ℃).
Embodiment 8
Get that (II, wherein Y represents CH 3) shown in compound 546mg add in ethanol and under stirring at room temperature and slowly add 1mL sulfuric acid (98%), the system that is stirred to becomes clarification, stirring spends the night obtains solid, suction filtration, filter cake vacuum-drying 10 hours, obtain containing 1 crystal water (II, wherein Y represents CH 3) hydrosulfate (II: sulfuric acid=1: 1).
Embodiment 9
Get (II, wherein Y represents F) shown in compound 547mg add and in ethanol and under stirring at room temperature, slowly add 1mL sulfuric acid (98%), the system that is stirred to becomes clarification, stirring is spent the night and is obtained solid, suction filtration, filter cake vacuum-drying 10 hours, obtains the hydrosulfate (II: sulfuric acid=1: 1) containing (II, wherein Y represents F) of 1 crystal water.
Embodiment 10
Get the compound (518mg) shown in (II, wherein Y represents H) and add dehydrated alcohol 30mL; Under stirring at room temperature, 1mL concentrated nitric acid (65%) is joined in the ethanol solution of (II), system clarification, stir and separate out solid after 2 hours, suction filtration, filter cake vacuum-drying 10 hours, obtains the nitrate (1: 1) (containing 2 crystal water) of (II).Ultimate analysis: C 13h 13n 3o 3.HNO 3.2H 2o, calculated value C43.58%, H5.03%, N15.64%, measured value C43.83%, H4.87%, N16.98%, fusing point: 225.5 ℃, water-soluble: 3.68mg/ml (15 ℃).
Embodiment 11
Get the compound (518mg) shown in (II, wherein Y represents H) and add dehydrated alcohol 30mL; Add 1mL concentrated hydrochloric acid (38%), heated and stirred, adds a small amount of water to make system become clarification, room temperature continues to stir separates out solid, suction filtration, filter cake vacuum-drying 10 hours, obtains the hydrochloride (1: 1) (containing 1 crystal water) of (II).Ultimate analysis: C 13h 13n 3o 3.HCl.1H 2o, calculated value C43.58%, H5.03%, N15.64%, measured value C43.83%, H4.87%, N16.98%, fusing point: 238.5-238.7 ℃, water-soluble: 1.23mg/ml (15 ℃).
Embodiment 12
Get the compound (518mg) shown in (II, wherein Y represents H) and add dehydrated alcohol 30mL; Add 1mL strong phosphoric acid (85%), putting into oil bath is heated to reflux, add a small amount of water to make system become clarification, reflux 30 minutes, take out stirring at room temperature, separate out after solid and continue to stir 4 hours, suction filtration, filter cake vacuum-drying 10 hours, obtains raw material (II, wherein Y represents H) (containing 1 crystal water).Ultimate analysis: C 13h 13n 3o 3.H 2o, calculated value C53.5%, H5.14%, N14.4%, measured value C54.19%, H4.75%, N14.5%, water-soluble: 0.57mg/ml (15 ℃).
Embodiment 13
Get the compound (518mg) shown in (II, wherein Y represents H) and add anhydrous methanol 100mL; Add anhydrous methanol (100mL) solution of 98% vitriol oil (200mg), stirring at room temperature 30min makes system become clarification, vacuum rotary steam desolventizes to such an extent that add after solid anhydrous THF to continue to stir 1 hour, suction filtration, filter cake vacuum-drying 10 hours, obtain the vitriol (2: 1) of (II, wherein Y represents H).
Embodiment 14
Get the compound (518mg) shown in (II, wherein Y represents H) and add anhydrous methanol 100mL; Add 1, anhydrous methanol (100mL) solution of 5-naphthalene disulfonic acid (288mg), stirring at room temperature 30min makes system become clarification, vacuum rotary steam desolventizes to such an extent that add after solid anhydrous THF to continue to stir 1 hour, suction filtration, filter cake vacuum-drying 10 hours, obtains (II, wherein Y represents H) 1,5-naphthalene disulfonic acid (2: 1).
Embodiment 15
Get the compound (518mg) shown in (II, wherein Y represents H) and add dehydrated alcohol 30mL; Add 0.27mL Hydrogen bromide (40% aqueous solution), stirring at room temperature makes system become clarification, after slowly separating out solid, continuation stirring is spent the night, suction filtration, filter cake vacuum-drying 10 hours, obtains the hydrobromate (1: 1) (containing 1 crystal water) of (II, wherein Y represents H).Ultimate analysis: C 13h 13n 3o 3.HBr.1H 2o, calculated value C43.58%, H4.47%, N11.73%, measured value C43.24%, H4.70%, N11.68%, fusing point: 217 ℃ of decomposition, water-soluble: 5.5mg/ml (15 ℃).
Compound (II, wherein Y represents H) reacts (embodiment 16-26) with organic monoacid
Get (II, wherein Y represents H) shown in compound (518mg) add dehydrated alcohol 30mL to dissolve to obtain (II, wherein Y represents H) ethanol solution, get equimolar organic monoacid and add 10mL dehydrated alcohol wiring solution-forming, organic acid ethanolic soln is joined to (II, wherein Y represents H) ethanol solution in oil bath be heated to reflux, add a small amount of water to make system become clarification, reflux after 30 minutes, take out stirring at room temperature, after separating out solid, continue to stir 4 hours, suction filtration, 10 hours HNMR of filter cake vacuum-drying prove raw material (II, wherein Y represents H) (or containing the raw material (II of 1 crystal water, wherein Y represents H)).
Embodiment organic acid
Embodiment 16 phenylformic acid
Embodiment 17 succinic acid
Embodiment 18 fumaric acid
Embodiment 19 toxilic acids
Embodiment 20 oxalic acid
Embodiment 21 L-glutamic acid
Embodiment 22 Vc acid
Embodiment 23 acetic acid
Embodiment 24 gluconic acids
Embodiment 25 Whitfield's ointments
Embodiment 26 nicotinic acid
Embodiment 27
3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2, the stability of 6-dione bisulphate salt tetrahydrate (embodiment 7) aqueous solution
By 17mg 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-dione bisulphate salt tetrahydrate (is equivalent to 10mg 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone) be dissolved in 10ml deionized water, room temperature is placed 12 hours, and content is higher than 98% of labelled amount.
The preparation of embodiment 28 polymorphic forms (IA)
In 100ml single port bottle, add 550mg 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 30ml dehydrated alcohol, add the 1ml vitriol oil, stirred overnight at room temperature, suction filtration under stirring at room temperature.
The preparation of embodiment 29 polymorphic forms (IB)
In 250ml single port bottle, add 5.181g 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 150ml dehydrated alcohol, add the 2ml vitriol oil, reflux, stirred overnight at room temperature, suction filtration under stirring at room temperature.
The preparation of embodiment 30 polymorphic forms (IC)
In 250ml single port bottle, add 2.59g 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 30ml acetone; The 2.2ml vitriol oil is dissolved in 20ml acetone and is added dropwise in reaction flask under stirring at room temperature, drip and finish after 55 ℃ of stirring 30min, stirred overnight at room temperature, suction filtration.
The preparation of embodiment 31 polymorphic forms (IIA)
In 100ml single port bottle, add 506mg 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 30ml dehydrated alcohol, add 1ml concentrated nitric acid, stirred overnight at room temperature, suction filtration under stirring at room temperature.
The preparation of embodiment 32 polymorphic forms (IIIA)
In 100ml single port bottle, add 518mg 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 30ml dehydrated alcohol, under stirring at room temperature, add Phenylsulfonic acid 378mg and 0.5ml water, reflux 30min, stirred overnight at room temperature, suction filtration.
The preparation of embodiment 33 polymorphic forms (IIIB)
In 500ml single port bottle, add 4.637g Phenylsulfonic acid and 200ml ethanol, add 6.473g 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 9ml water, reflux 30min, stirred overnight at room temperature, suction filtration.
The preparation of embodiment 34 polymorphic forms (IVA)
In 100ml single port bottle, add 519mg 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 40ml dehydrated alcohol, under stirring at room temperature, add 352mg tosic acid and 1ml water, reflux 30min, stirred overnight at room temperature, suction filtration.
The preparation of embodiment 35 polymorphic forms (VA)
In 100ml single port bottle, add 519mg 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 40ml dehydrated alcohol, add 0.27ml Hydrogen bromide, stirred overnight at room temperature, suction filtration under stirring at room temperature.
The preparation of embodiment 36 polymorphic forms (VIA)
In 250ml single port bottle, add 2.593g 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 70ml dehydrated alcohol; 0.78ml methylsulfonic acid is dissolved in to the mixing solutions of 10ml dehydrated alcohol and 1ml water, under stirring at room temperature, is added dropwise in reaction flask, stirred overnight at room temperature, suction filtration.
The preparation of embodiment 37 polymorphic forms (VIB)
In 500ml single port bottle, add 6.472g 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 300ml dehydrated alcohol, under stirring at room temperature, add 1.62ml methylsulfonic acid, reflux 30min, stirred overnight at room temperature, suction filtration.
The preparation of embodiment 38 polymorphic forms (VIIA)
In 250ml single port bottle, add 5.180g 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 150ml dehydrated alcohol, add 1.6ml concentrated hydrochloric acid and 10ml water, stirred overnight at room temperature, suction filtration under stirring at room temperature.
The preparation of embodiment 39 polymorphic forms (VIIA)
In 250ml there-necked flask, add 1.038g 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 35ml tetrahydrofuran (THF), pass into HCl gas 1 hour, stirring at room temperature, suction filtration under stirring at room temperature.
The preparation of embodiment 40 polymorphic forms (VIIA)
In 100ml single port bottle, add 1.038g 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 30ml dehydrated alcohol, be heated to 60 ℃, under stirring, add 6N hydrochloric acid to obtaining settled solution, reaction solution is down to-20 ℃, spend the night, suction filtration.
The preparation of embodiment 41 polymorphic forms (VIIA)
In 100ml single port bottle, add 1.037g 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 30ml dehydrated alcohol, be heated to 60 ℃, adds 6N hydrochloric acid to obtaining settled solution under stirring, and room temperature is placed and spent the night, suction filtration.
The preparation of embodiment 42 polymorphic forms (IVB)
In 250ml single port bottle, add 5.18g 3-(4-amino-1-oxo-1,3-xylylenimine-2-yl) piperidines-2,6-diketone and 80ml dehydrated alcohol and 20ml water, be heated to 80 ℃, obtain settled solution, add 4.18g tosic acid, be down to after room temperature and continue to stir 3.5 hours, suction filtration.
The mensuration of saturation solubility in each embodiment sample water:
The configuration of typical curve:
By qualitative each embodiment sample solution be that 190-900nm does uv scan in wavelength region, maximum absorbance is decided to be 2, there is determinand to there is identical consistent absorption peak in 304nm place, although there are other to absorb honeybee in 205-190nm region, but peak shape is slightly had any different, its maximum absorption band wavelength also has difference, therefore determine that the fixed wave length of concentration-absorbance measurement is 304nm.
In saturated solution process for preparation, find that the solubleness of embodiment 7 is greater than 1g/mL, do concentration-absorbancy typical curve therefore chosen with this compound.
Get embodiment 7 (279.26mg) adding distil water fixed molten in 100 milliliters of volumetric flasks, now strength of solution is 2.793mg/mL; Get respectively above-mentioned solution 1mL,, 2mL, 3mL, 5mL, fixed molten respectively at 50 milliliters of volumetric flasks, now strength of solution is respectively 0.056mg/mL, 0.112mg/mL, 0.167mg/mL, 0.279mg/mL, does typical curve take absorbancy-concentration as coordinate, γ 2relation conefficient is 0.99951 (seeing Figure of description).
Solubility test:
It is the saturated solution of 5 milliliters that sample thief is mixed with volume on a small quantity, be positioned in 25 ℃ of waters bath with thermostatic control constant temperature approximately 1 hour, get supernatant liquor, dilute suitable multiple according to standard curve range, ultraviolet spectrophotometer is measured its concentration, and mensuration reading is multiplied by extension rate obtains determinand solubleness.

Claims (12)

1. the polymorphic form of compound shown in formula (I), is characterized by XH and represents Phenylsulfonic acid, and Y represents that the X-ray powder diffraction collection of illustrative plates of the polymorphic form (IIIA) of compound shown in the formula (I) of H has following peak:
Angle of diffraction (2 θ, °) Intensity (I/I 0) Angle of diffraction (2 θ, °) Intensity (I/I 0) 4.799 100 20.799 30.7 9.681 13.6 22.201 23.7 13.818 23.4 24.041 37.2 15.418 36.6 24.559 29.6 17.658 46.3 26.580 16.6 18.602 20.9
2. the polymorphic form of compound shown in formula (I), is characterized by XH and represents Phenylsulfonic acid, and Y represents that the X-ray powder diffraction collection of illustrative plates of the polymorphic form (IIIB) of compound shown in the formula (I) of H has following peak:
Angle of diffraction (2 θ, °) Intensity (I/I 0) Angle of diffraction (2 θ, °) Intensity (I/I 0) 5.440 46.1 19.119 38.3 10.981 17.2 19.600 34.9 13.080 26.9 20.040 100 14.761 18.6 24.981 74.2 15.800 24.1 26.322 35.1 17.041 85.2 28.782 22.7 17.420 21.6
3. the method for the polymorphic form of compound shown in preparation claim 1-2 any one Chinese style (I), it is characterized by compound shown in formula (II) reacts and makes in suitable solvent system with Phenylsulfonic acid, described suitable solvent system be selected from methyl alcohol, ethanol, propyl alcohol, Virahol,, wherein, in formula II, Y represents H.
4. the application of the polymorphic form of compound shown in claim 1-2 any one Chinese style (I) in those diseases or the physically different medicine that can be reached curative effect for the preparation for the treatment of by the inflammation-inhibiting factor.
5. the application of the polymorphic form of compound shown in claim 4 Chinese style (I), it is characterized by described disease is sacroiliitis.
6. the application of the polymorphic form of compound shown in claim 4 Chinese style (I), it is characterized by described disease is hepatitis, gastritis, digestive tract ulcer, stomatocace, ephritis, rhinitis, bronchitis, COPD, pneumonia, pulmonary tuberculosis, myocarditis, pancreatitis, prostatitis, cervicitis, enteritis, crown syndromes, nerve ending inflammation, myelitis, encephalitis, peritonitis, Parkinson's disease, psoriasis, lupus erythematosus, chronic dermatitis or leprosy.
7. the application of the polymorphic form of compound shown in claim 4 Chinese style (I), it is characterized by described disease is stomach ulcer.
8. the application of the polymorphic form of compound shown in claim 1-2 any one Chinese style (I) in the medicine that is generated those diseases that can reach curative effect for the preparation for the treatment of by inhibition new vessel.
9. the application of the polymorphic form of compound shown in claim 7 Chinese style (I), it is characterized by described disease is cancer.
10. the application of the polymorphic form of compound shown in claim 7 Chinese style (I), it is characterized by described disease is bone marrow cancer, leukemia, liver cancer, brain tumor, prostate cancer, cancer of the stomach, esophagus cancer, intestinal cancer, laryngocarcinoma, oral carcinoma, rhinocarcinoma, osteocarcinoma, cervical cancer, lung cancer, mammary cancer, kidney, lymphoma, ovarian cancer, carcinoma of the pancreas, adrenal carcinoma, mesothelial cell's cancer, melanoma or myelodysplastic syndrome.
11. preparations that contain the polymorphic form of compound shown at least one claim 1-2 any one Chinese style (I), it is characterized by described preparation is tablet, capsule, powder pin, paste, patch or implant, uses via oral, rectum or vagina administration mode.
Preparation in 12. claims 11, it is characterized by described preparation is freeze-dried powder.
CN200910118977.2A 2008-03-13 2009-03-11 Salts of 3-(4-amino-1-oxo-1,3-dihydro-iso-indol-2-yl)piperdine-2,6-dione and derivatives thereof, polymorph of the salts, preparation and application thereof Active CN101531653B (en)

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Patentee before: XIAJIANG HEMEI PHARMACEUTICAL Co.,Ltd.

Country or region before: China

Patentee before: TIANJIN HEMAY BIO-TECH Co.,Ltd.

PE01 Entry into force of the registration of the contract for pledge of patent right

Denomination of invention: Polycrystalline forms of salts or salts of 3- (4-amino-1-oxo-1,3-dihydroisoindole-2-yl) piperidine-2,6-dione and its derivatives, and their preparation and application

Granted publication date: 20140709

Pledgee: Xiajiang Yucai Financing Guarantee Co.,Ltd.

Pledgor: XIAJIANG HEMEI PHARMACEUTICAL Co.,Ltd.

Registration number: Y2024980018271