TWI298724B - Pharmaceutically active isoindoline derivatives - Google Patents

Description

1298724 V. INSTRUCTION DESCRIPTION OF THE INVENTION The present invention relates to a non-polypeptide isointegrator derivative which reduces the level of tumor necrosis factor alpha (TNFa) and treats the disease state modulated thereby. This compound inhibits angiogenesis and can be used to treat cancer, an inflammatory response, i.e., an autoimmune response. For example, a compound that selectively inhibits tumor necrosis factor Alpha is beneficial for treating an inflammatory response and effectively relaxing the airway smooth muscle with minimal unintended side effects, such as cardiovascular or antiplatelet effects. The invention is also related to methods of treatment and the use of pharmaceutical compositions of such compounds. Tumor necrosis factor Alpha, or TNFa, a cytokine that is primarily released by mononuclear swallowing cells to respond to certain immune stimuli. When applied to animals or humans, it causes an inflammatory response, fever, cardiovascular effects, hemorrhage, clotting, and acute phase reactions seen in acute infections and shock conditions. Therefore, certain disease conditions involve excessive or uncontrolled production of tumor necrosis factor alpha. This includes endotoxemia and/or toxic shock symptoms (Cui Xi et al., Nature 33〇, 662-664 (1987) and Zhai Xiao et al., Circulatory Shock 30, 279-292 (1990)): Rheumatoid Arthritis , Crohn's disease, inflammatory bowel disease, cachexia (Dessu et al., Lancet, 335 j8690), 662 (1990)) and adult respiratory distress syndrome. The concentration of tumor necrosis factor alpha is more than 12,000 picograms per house. It has been detected in lung extracts from patients with adult respiratory distress symptoms (Miller et al., Lancet 2 (8665), 712-7 & (1989)). Systemic recombinant tumor necrosis factor alpha injection also causes changes in typical adult respiratory distress symptoms (Fei Rui-Ba Li Fei Rui et al., Surgical Files 124 (12), 1400-1405 (1989)). Tumor necrosis factor Alpha has been shown to be involved in bone resorption diseases, including arthritis, when it is activated, white blood cells will produce bone resorption, a data suggestive of the activity of tumor necrosis factor alpha. (Podolini et al., Nature 319, 516-518 (1986) and Johnson & Johnson, Endocrinology 124 (3), 1424-1427 (1989)). Tumor necrosis factor alpha has also been shown to inhibit bone remodeling and inhibit bone formation in vitro and in vivo by stimulating the formation and activation of osteoblasts and inhibiting osteoblast function. Even though tumor necrosis factor Alpha may be involved in many bone resorption diseases, 1298724 disease 'includes arthritis, but the most striking connection with the disease is the production of tumor necrosis factor alpha and the malignant hypercalcemia for tumor or host tissue. The correlation between (International Organizational Reduction (US) 46 (new), S3-10 (1990)). In the plant-to-host response, increasing the level of serum tumor necrosis factor alpha has been linked to major complications of major subsequent acute allogeneic bone marrow transplantation. (Hu Le et al. 2, Blood, 75 (4), 101M016 (1990)). 〃 Cerebral malaria is a fatal hyperacute neurological symptom associated with the most serious complications of high tumor necrosis due to high levels of tumor necrosis. The level of serum tumor necrosis factor alpha is directly related to the severity of Hercules and the predisposition of patients with New Zealand. (Grow et al., New England Journal of Medicine 32 1586-1591 (1989)). Irregularly controlled angiogenesis is pathological and sustains the development of many neoplastic and non-neoplastic diseases, including solid tumor growth and metastasis, arthritis, certain types of eye diseases, and psoriasis. Please refer, for example, Moses et al., Brain, Biotechnology, 9: 63 (M34, Forkman et al., 1995, New England Journal of Medicine, 333: and Touch, Oba et al., 1985, Journal of Microvascular Research , 29 ·· 4〇1-411; Folkman et al., 1985 'Advances in Cancer Research, Klin and Winhouse Editor, College Press, New York, pp. 175-203; Buzz, 1982, American Journal of Ophthalmology , 94 · · 715 - 743 ; Fokker = human, 1983, science, 221 : 719-725, · and Volkmann and Klegelsbrough, L23i · · 442. In addition, keep the cornea, crystal, and The bloody state of the trabecular meshwork is equally important for vision and ocular physiology. Please refer to, for example, the review of Hua 2 Man et al. 1978, American Journal of Ophthalmology, 85 · 7Q4 - 71Q and Jia Te, etc. 1978, Ophthalmology Survey 22: 291-312. In response to various disease states, tumor metastasis, and abnormal growth tube formation of endothelial cells. Uncontrolled ▲ tube formation caused by pathology 3. Oxygen-dependent Or angiogenesis-related diseases. Controlling the angiogenic process will lead to these conditions. The king has been controlled by the cell, and the part of the sense and invasion has been controlled by the sputum and the peptide peptide growth factor. Exposure to the skin containing the appropriate 1298724 can induce some or all of the angiogenesis, with a living body. Multi-peptides of extracellular endothelial growth factor, including = fibroblast growth factor, alfalfa arsenic θ "二原Ϊί=ί长 factor, granulosa cell community stimulating factor, white blood cell interstitial-8 3ΐ5ήΙ ?ί??^ lis 3 In the case of angiogenesis that occurs under physiological conditions, such as Tian it5, morphological rebirth, embryo development, and female reproductive processes, angiogenesis = unrestricted in time and time Strictly controlled. In the pathology, action, like the characteristics of solid tumor growth, control is a failure. The angiogenesis induced by the cell is regulated by the tumor necrosis factor Alpha. Li Boke et al. , 329, 63G-632 (1987)) showed that tumor necrosis factor alpha induced a very low dose to induce microvascular formation in vivo and the development of chicken chorioallantoic membrane and assumed tumor necrosis Alpha may induce inflammatory response, trauma repair, and angiogenesis of tumor growth. TNF-alpha production has also been independently linked to cancer, especially V-tumor (Qing et al., British Cancer) Journal, (1995) 72, =9:343, and Gao Qi, Advances in Medical Chemistry, 22, 166-242 (1985)). Whether it is involved in the production of tumor necrosis factor Alpha, the role of angiogenesis in solid tumor formation and Significant metastases were found and angiogenic factors were found to be associated with certain solid tumors such as rhabdomyosarcoma, retinoblastoma, Eun's sarcoma, neuroblastoma' and osteosarcoma. Important angiogenesis effects on tumors include solid tumors, and benign tumors such as auditory neuroma, neurofibroma, blisters and suppurative granuloma. Independent of its effect on the production of tumor necrosis factor alpha, avoiding angiogenesis will stop the growth of these tumors and the consequences of harm to animals due to the presence of tumors. Angiogenesis has been linked to tumors that are metastasized by blood, such as leukemia and various acute or chronic bone marrow neoplastic diseases. In such cases, there is no restriction, 1298724 = ball hyperplasia, usually accompanied by anemia, coagulation, and lymph nodes, liver enlargement. Tumor metastasis is also specific to the angiogenic side. Therefore, angiogenesis stimulation occurs when the blood vessels are formed, so that the tumor cells can enter the bloodstream and circulate completely. The tumor cells leave the original position and establish a second location, the metastatic location, which must undergo angiogenesis before new tumor growth and expansion. Various cell types of the body can be transformed into benign or malignant tumor cells. Most. The location of the tumor is the lung, followed by the rectum, breast, prostate, bladder, pancreas, and then (4). Other prevalent cancer types include leukemia, central nervous system cancer, including brain cancer, melanoma, lymphoma, erythroleukemia, uterine cancer, and head and neck cancer. Tumor necrosis factor alpha has also played an important role in areas of chronic lung inflammation. The deposition of Shixi granules causes Shixia soil disease, a progressive respiratory disorder guided by fibrotic reactions. The antibody against swollen lysate completely blocked the lung fibrosis induced by sputum in mice. (Leather and others, Nature, 344: t45^!! 7 (199G)). A high level of production of tumor necrosis factor alpha (in serum 嗟 的 嗟) has also been demonstrated in the animal model of fibrosis induced by Shi Xi and asbestos. (Bissot et al., Inflammatory Response 13 (3), 329-339 (1989)). Since the alveolar macrophages of patients with sarcoidosis have also been found to spontaneously release a large number of tumor necrosis factor alpha from the macrophages of the ruthless donors (Baoman et al., Laboratory Clinical Medicine Journal) 115 (1), 36-42 (1990)). & Tumor necrosis factor Alpha also has an inflammatory response after reperfusion, called reperfusion: bruises, intermediate effects, and the main cause of tissue trauma after blood loss (Vandel et al., National Academy of Sciences, Progress 87, 2643-2646 (1990)). Tumor necrosis Alpha also changes the nature of endothelial cells and has various pre-promoting clotting activities, = promotes the increase of clotting activity before production of tissue factor and inhibits the expression of anticoagulant protein C pathway and down-regulation of thrombin (Shelley et al. , Cell Biology 107: ϋ9^277 (1988)). Tumor necrosis factor alpha has pre-inflammatory reactivity, 1 over/, early production (at the beginning of an inflammatory response) makes it possible: 1298724 Regulators of tissue trauma in certain important diseases, including but not Limited to myocardial infarction, = wind, and circulatory shock. Tumor necrosis factor alpha induces specific important attachment molecules, such as intercellular adhesion molecules (ICAM) or endothelial leukocyte adhesion molecules (ELAM) on endothelial cells (Monroe et al., American Journal of Pathology I% (1) , _ 121-132 (1989) ) 〇; It has been shown that blocking tumor necrosis factor alpha with anti-tumor necrosis factor alpha antibody is beneficial to rheumatoid arthritis (Elliot et al., International Chinese 丨iggg mouth (2), And Crohn's disease (Wandreman et al; bis (1), 129-135). λ In addition, it is currently known that tumor necrosis factor alpha is a viable activation of retrovirus replication including human immunodeficiency The activation of the virus 耵 丨 ( 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得 得Humans, Blood 79, 267〇yi990); Kroz et al., J. Immunol. 142, 431-438 (1989); Bohr et al., Acquired Immunodeficiency Syndrome Study - Human Reversal Virus, 191-197 (1992) . Acquired immunodeficiency syndrome is caused by lymphocytes for human immunodeficiency virus (HIV). At least three types or secret human immunodeficiency viruses have been found; that is, human immunodeficiency virus - 丨, human immunodeficiency virus-2 and human immunity, not complete ^ 毋 -3. Because of the infection of human immunodeficiency virus, tau cell-regulated immunity is disrupted and infected individuals show severe opportunistic infections and/or abnormal growth. Human immunodeficiency virus requires activation of tau lymphocytes into 7 lymphocytes. Other viruses, such as the human immunodeficiency virus-1, human immunodeficiency virus-2, infect T lymphocytes after activation of one cell, and the expression and/or replication of such viral proteins is regulated or transferred by activation of the cells. Once the activated sputum lymphocytes are infected by the human immune system, the T lymphocytes must be maintained in an activated state to allow humans to be free from the presence of silkworms due to performance and/or human-free whole-virus replication. Age, especially v, is a tumor necrosis factor alpha, which plays an important role in maintaining lymphocyte activation. The role of human immunodeficiency virus protein expression and/or viral replication is regulated by activated T cells. Therefore, interfering with cells infected with human immunodeficiency virus 7:1298724 is as effective as avoiding or inhibiting cytokine production, especially tumor necrosis factor Alpha' assisted by tau lymphocytes caused by human immunodeficiency virus infection. Cell maintenance limits. Mononuclear cells, macrophages, and related cells, such as Coffer's cells and neuroglial cells, are also implicated in the maintenance of human immunodeficiency virus infection. These cells, like cells, are targets of viral replication and the level of viral replication depends on the activation of this cell. (Rosenberg et al., Immunopathology of Human Immunodeficiency Virus Infection, Advanced Immunology, 57 (1989)). Cytokines, such as the tumor necrosis factor Alpha, have been shown to activate the replication of human immunodeficiency virus in mononuclear cells and/or macrophages (Bol et al., Proceedings of the National Academy of Sciences 87,782-785 ( 199〇)); Therefore, avoiding or inhibiting cytokine production or activity can help limit the development of human immunodeficiency virus in sputum cells. In addition, studies have identified that tumor necrosis factor alpha is a common factor in the activation of human immunodeficiency virus in vitro and has provided a clear activation mechanism for nuclear regulatory proteins via cytoplasm (Osborne et al., National Science, USA) Dare to make new progress 86 2336-2340). This evidence suggests that reducing the synthesis of tumor necrosis factor alpha may have antiviral activity in human immunodeficiency virus infections by reducing transcription and thus reducing virus production. Human immunodeficiency virus in late T cells and python cells can be induced by tumor necrosis factor alpha (Foks et al., Proceedings of the National Academy of Sciences 86, 2365 - ed. (10) 9). The ability of tumor necrosis to activate a gene-regulated protein NFkB) found in the cytoplasm of cells by T-Alpha has proposed a molecular mechanism that induces the activity of the virus, which promotes the binding of the ☆-type vaccination virus to a virus. Replication of the gene sequence (LTR) and Fu Siben et al, the latest progress of the National Academy of Sciences 86, 2336-2340 I main 9)). The hypothesis of cachexia associated with acquired immunodeficiency syndrome is produced by => tumor necrosis factor A in the midst of the month and the tumor necrosis factor alpha in the peripheral blood of the patient (Like, et al., Immune semester two 99=04 (1988)). Tumor necrosis factor alpha has been linked to other viral infections in a variety of roles, such as cytomegalovirus (cmv), 1298724 influenza virus, adenovirus, and herpes virus families, for reasons similar to those described above. Nuclear factor KB (NFKB) is a multi-dominant transcriptional activator of the gene. (Lena et al., Cell 1989 ' 58, 227-229). Nuclear factor κ Β has been associated with transcriptional activators of various diseases and inflammatory states, and is thought to regulate cytokine levels, but not limited to tumor dysfunction, and is also a sputum, sputum / tongue compound of human immunodeficiency virus ( Dai Baozhen, Journal of Biochemistry, 1992 17762-17766; etc. ☆, the latest progress of the National Academy of Sciences, 1989, 86, 5974 5978; Bacherle et al., Nature, 1991 '350, 709-712; Baus Hua Si et al., Post-Diagnosis I Complete Post-group Journal 1993,6,778-·; Zhang Mu et al., Biochemistry and Biophysics Research Communications, 1993, 193, 277-283, Suzuki et al., Biochemistry and Biophysical Research Newsletter, _, 189, 17G9-1715; Suzuki et al., Biochemistry and Biophysics Research Newsletter, 1993, 31 (4), 693_7〇〇; Chaichof et al., US, National Academy of Sciences , m, 35_47; and Shi Shi et al, f ΪΪΓ end ίί progress _, 87 ' 9943, 47). Therefore, inhibition of cell factor kappa, Ό 5 can regulate the transcription of the cytokine gene and undergo this modulation and other disease states that can inhibit the number of eves. The compounds described herein inhibit the action of cellular f-factor kappa in the nucleus and thus treat various diseases including, but not limited to, rheumatoid arthritis, rheumatoid spondylitis, f arthritis, and his 3; ·f disease if bloody shock 'sepsis' endotoxin shock, graft versus host Ϊ 疾病 , disease, Crohn's disease 'intestinal inflammatory disease, ulcerative sclerosing sclerosis, neonatal red class (four), Hanshen Riding away from knots f, work, human immunodeficiency virus, acquired immunodeficiency syndrome, and post-all syndromes of opportunity. The axis is badly affected by Alpha and the nuclear factor ^ = quasi-received. As mentioned above, the present day has an effect on the levels of tumor necrosis factor alpha and nuclear factor kappa beta. Therefore, the establishment of (four) Lai Zi A's low water treatment strategy 曰 household = more inflammation, infection, immune or malignant diseases. This includes, but is not limited to, blood stasis, septicemia, endotoxin shock, hemodynamic shock and devastation symptoms, reperfusion injury after ischemia, dysentery, mycoplasma infection, meningitis, psoriasis, congestive 1298724 = deficiency, 'fibrous diseases, cachexia f, graft rejection, cancer, autoimmune ϊ ϊ 全 全 机会 机会 机会 机会 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Enteritis, ΐ Ι Ζ Ζ 性 性 性 性 性 性 性 性 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉 汉The invention is about equations! The compound in the middle, the carbon atom represented by the * in the 纟 constitutes the polarizing center:

In the formula I: when X is -C(〇)- or -CH2-; R1 is an alkyl group of one to eight carbon atoms or -NHR3; R is a hydrogen atom, an alkyl group of one to eight carbon atoms or a halogen And R3 is a hydrogen atom, a burnt group of one to eight carbon atoms or a cycloalkyl group of three to eighteen carbon atoms, which is substituted or substituted by a tooth element, an amino group, or an amino group of one to four carbon atoms. , the 'n-iS element 'amino group, or an amino group of one to four carbon atoms is substituted or substituted, or -C〇R4, wherein R4 is a hydrogen atom, an alkyl group of one to eight carbon atoms, not a halogen element, an amino group , or an amino group of one to four carbon atoms, substituted or substituted, a cycloalkyl group of three to eighteen carbon atoms, a -1298724 generation or a substituted or unhalogenated κ group or an amino group of four carbon atoms Burning substituted or substituted benzene, not halogenated 'amino' or - to four carbon atoms of ammonia lions ^ also « these are protonated acid isotonic derivatives. Tingzhi Lai includes organic and non-mineral hydrochloric acid, desertified hydrogen acid, miscellaneous, sulfuric acid, antimony sulfuric acid, acid, dicarboxylic acid, hydroxamic acid, heptanoic acid and the like.乌一吹扒杨 This = compound, prepared by some methods. For example, the equation can be adapted to ^11^3,5^^ ΐί _ to produce a protected compound of the equation ::

In the foregoing reaction, R1 is as defined above, X is -CHr_, R2, is a hydrogen atom or an alkyl group, and Z and Y are protecting groups such as, for example, benzene oxycarbonyl and a hydrocarbon oxide. When X is -CH2-, an acridine-2,6-dione in the formula 反应 is reacted with a substituted alkyl benzoate in the formula IIIA··1298724

2-HN

Ο—Y Ο—Oalkyl V^c_—

o~ γ IB

Compounds of IIIA are known. R2 in Equation 11 is hydrogenogen: Gas: Monia's methanol treatment produces the equation ΙΙΒ中中^^, 虱土-4_虱oxy~4_carboxyacetone decylamine and then in acetic acid

Z-HN

Ό C-OH 0

〇 0H 0 II | || H2NC — CH—CH2 A 6h - C - 0H NH-Z

IIA

IIB

When it is a base, the lactone in the equation „A can be exemplified as a quinone nitrogen-propyl clock by forming two equivalents of a strong base, for example, to form a dianion, and then burning it as if f. Based on the example. Alternatively, the unrecognized (iv) IIC can be converted to para-propyl ester and then treated with phenylacetic acid to form amylolysin nD. The temple powder is dissolved, and the calcined halide is treated. The q-carbon atom of the compound IIE is alkylated and the subsequent acid treatment cleaves the para-propionaldehyde and the amyl lysin to produce an intermediate product W and is then protected like a benzene oxycarbonyl derivative. _, H2N

IIC 0

々C-OH

0 II Ό,: C—OCC(CH3)3 0 12 .1298724

Or

CH-N 0

O p-occ(ch3)2

CH^:fsj CH[

IID

O

Or C-〇CC(CH3)3

H2N

!IF

HE

IA

The hydrolysis of a hydrocarbyl group is achieved by p-toluene; for example,

As noted above, it is generally advantageous to have a finely divided base, but it is intended to be functionally convertible to the desired functional group. The protecting groups utilized herein provide functional groups that are not normally found in the final therapeutic compound but are intentionally added to the synthetic reaction on certain axes to protect functional groups that may be circulated. The compound of the protecting group will be removed or converted to the desired functional group at a later stage of the synthesis reaction. The compound with 13 1298724 protecting group will therefore become an important chemical intermediate at the beginning, even if These derivatives also exhibit biological activity). Therefore the correct structure of the protecting group is not important. Several reactions to form and remove these protecting groups are described in some standard practices, for example, , Protective Organic Chemistry, Enrichment Press, Lun and New York, 1973; Green, Th. W ·, Protected-Based Organic Synthesis, Power, New York, 19gl, ,, Peptide/', Volume 1, Shi Guode and Lu Booke, College Press, Lunmei and New York, 1965;,, Organic Chemistry Method ', Holborn-Weir, Fourth Brush', Volume 15/1, Zuo Gesem Wirger, published in 1974, all of which are attached to this article for reference. Thus, an amino group can be protected by a selective removal of the f-amine form under mild conditions, especially a sulfhydryl group, a lower group which is branched into a fluorenyl group at the 丨- or ^^ position. The alkyl alkane group, especially the tetraalkylidene group, is pival〇yl, or a lower alkoxy group substituted at the alpha position to a carbon fluorenyl group, such as, for example, trifluoroacetone. If a carboxyl group is to be protected, it can be converted to an ester and then selectively removed in a sufficiently mild manner without interfering with the desired structure of the molecule, especially an alkyl ester of one lower order to twelve carbon atoms. The analogy is methyl or ethyl and especially in Bu or "a positional branch such as para-propyl; and such lower-grade siu vines are substituted at the 1- or 2-position to (I) Lower alkoxy groups, for example, mercaptomethoxy, ethylidene, and methylethoxy, (ii) lower order alkyl sulfides such as methylthiomethyl and 1- Ethylthioethyl; (ii)i, such as 2, 2, 2-trichloroethane, 2-bromoethane, and 2-iodoethoxycarbonyl; (iv) one or two Each of the phenolic groups is unsubstituted or one or two or three are substituted, for example, the lower order alkane is like a fourth stage propane, and the lower order alkoxy group of the formula is methoxy, decyloxy, _ The prime image is chlorine, and a nitro group, such as, for example, benzene, 4-nitrobenzene, diphenol methyl, bis-(4-methoxyphenol) methyl; or (v) an aromatic group, such as a fluorenyl group. Phenol. A carboxyl group can also be protected in the form of an organic sulfhydryl group. For example, dimethyl sulphur or sulphur or sulphur, for example, trimethyl sulphate. When R1 is an amino group, the reaction described herein can be an intermediate of nitro. However, 14 1298724, the catalytic reduction of nitro group (with argon) is carried out as an amine. Similarly, when R is a gas-based derivative, such as N-mercapto-amine or N-alkyl-based ammonia, the relative The unsubstituted amino compound is formed. ▲ The compound includes a dipolarizing center (indicated by the * in the equation )) and thus may exist as a mirror image structure and a binary homo isomer. The compound can substantially purify the polarizing isomer ( S, S), -(S,R), -(R,R), or -(R,s)- or a mixture of two or more thereof is included in the scope of the present invention The mixture may be used as such or may have been automatically separated into its individual isomers by chromatographic analysis using a polarizing sorbent. Alternatively, the isomer may be prepared in a polarized isomeric form or via a mixture. Polarized acid or with individual mirror structures like the following, 10y camphor Camphoric acid, brominated camphoric acid, methoxyacetic acid, tartaric acid, diethylene brewing, acid, malic acid kisses, fine--5-rebel, etc., forming a chemical separation, then removing one or both in the dissolution test Repeat this step as appropriate, and one or two of them do not contain another species; have a form of optical purity higher than 95%: The best subgroup is the equation: hydrogen, methyl , or fluorine, especially a compound of chlorine. The first sub-group is the compound of the formula ^, ^ is an amino group. The sub-group is the compound of the equation 丨 where ^ is methyl. The fourth good sub-group is the equation 丨The compound with the meaning of -c (0) - the fifth good subgroup is the compound of the formula I where X is -CH2-.

ΙαΪ Progressive Λ is a group of the formula IM2 is nitrogen, methyl, or fluorine, especially methyl, cyano, alkylamine or decylamine' and x is _c(8)- or I < compound. ^ ^ Α ^ ",, ♦ methods, for example, enzyme immunoassay, radioactive H ίίί ΐ 'affinity', etc., of which the following are typical. A 4- (rat-amine) different, full -1, 3-dioxin; 2-(2,6-dioxo-310A-5-fluorinated hexafluorene) +(nitrogen-benzene^15 J298724-dioxy-3-hydrocarbyl-5-fluorinated Hexapurin-5-alk)-4-acetamide isoindane-1,3-dione; 2-(2,6-dioxo-3-alkyl-5-fluorinated hexapyridine-5- Alkyl)-4-acetamidamine iso-p-tolerant 1-ketone; 2-(2,6-dioxo-3-hydrocarbyl-5-fluorinated hexahydropyran than bite-5-burn)-4- Aminoisoindan-1-one; (2,6-dioxo-3-alkyl-5-fluorinated hexafluoropyridin-5-, alkane)-4-aminoisoindan-1,3-dione ; 2-(2,6-dioxo-3-alkyl-5-fluorenylhexafluoropyridin-5-alkane)-4-methylaminoisoindan-1-one; 2-(2,6- Dioxo-3- "hydrocarbyl-5-fluorinated hexahydropyridin-5-alkane)-4-methylaminoisoindan-1,3-dione; 2-(2,6-dioxo-3 -hydrocarbyl-5-fluorinated hexahydropyridine-5-alkyl)-4-mercaptoisoindan-1-one; 2-(2,6-dioxo-3-alkyl-5-methylhexahydropyridine -5-alkane-4-(nitro-aniline) isoindane-1,3-dione 2-(2,6-Dioxy-3-hydrocarbyl-5-methylhexahydropyridin-5-calcined)-4-(nitro-aniline)iso, '3 full-1-one; 2-(2 ,6-dioxo-3-ylidene-5-methylhexafluoropyridin-5-alkane)-4-ethenylaminoisoindan-1,3-dione; 2-(2,6-dioxo -3-hydrocarbyl-5-methylhexanium ratio biting-5-calcin)-4-ethylamino-, iso-one-one; 2-(2,6-dioxo-3-hydrocarbyl-5 -methylhexahydroindole-5-calcinyl-4-aminoisoindan-1-one; 2-(2,6-dioxo-3-alkyl-5-methylhexapyridine-5- Alkyl)-4-aminoisoindan-1,3-dione; 2-(2,6-dioxo-3-alkyl-5-fluorenylpyridinium-5-alkane)-4-methylamino Isoindane-1,3-dione; 2-(2,6-dioxo-3-alkyl-5-mercaptohexahydropyridin-5-alkane)-4-decylaminoisoindole-1 -ketone; 2-(2,6-dioxo-3-alkyl-5-methylhexahydropyridine-5-alkyl)-4-mercaptoisoindan-1,3-dihedral; 2-( 2,6-Dioxy-3-ylamino-hexa-nitrogen-pyridyl-5-pyro)-4-indolylisodone-1-one; 2-(2,6-dioxo-3-indole Oxygen hexamethylene. Bis-5-burning)-4-(nitro-benzoguanamine)isoindane-1,3-dione; 2-(2,6-dioxo-3-oxo-oxyhexahydropyridine -5-burning)-4-(nitrogen-phenylenamine)iso-sigma-11 Full-1-ketone; 2-(2,6-dioxo-3-indolizine hexahydrobenzidine-5-burn)-4-ethylamine amine iso-sigma-bungo-1-one; 2- (2 , 6-dioxo-3-indolizine hexahydro σ ratio σ ding -5-burning) -4- ethoxylated amine ° 弓 朵 朵 - - 1,3-dione; 2- (2, 6-diox -3-氲 氲吼 氲吼 -5 -5 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -4-aminoisoπ 丨 丨 丨 朵 - - 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- °Noisy full-1-ketone; 2-(2,6-dioxy-3-hydrohexahydropyridin-5-alkane)-4-methylaminoisoindan-1,3-dione; 16 1298724 2-(2,6-Dioxy-3-hydrogen hexahydropyridin-5-alkane)-4-methylisoindan-1-one; 2-(2,6-dioxy-3-hydrogen Oxyhexahydropyridin-5-alkane)-4-methylisoindan-1,3-dioxime.

Human peripheral blood mononuclear cells from normal deductors were obtained by Fic〇ll-Hypaque concentration gradient centrifugation. The cells were cultured by adding 10% AB+ serum, 2 mM L-faceamine, 100 units of penicillin per ml, and 1 mg of streptomycin per ml of RPMI medium. The test compound was dissolved in diterpene (Sigma) and further diluted by the addition of RPMi. The concentration of the most dimethyl phosogen in the human peripheral blood mononuclear cell suspension was 〇·25 weight percent with or without addition. The test compound was tested by a half log dilution starting from 50 mg of mother milliliters. The test compound was added to human peripheral blood mononuclear cells (1 〇 6 cells per ml) in a 96-well plate one hour before the addition of the lipopolysaccharide. > Hearts around the blood mononuclear cells (1 〇 6 cells per ml) with or without adding = test substance and per ml! The milligrams were stimulated by lipopolysaccharide treatment from Salmonella Minnesota (Liszt Biolab, Conbell, Canada). The iron cells were cultured at 37 degrees Celsius for 18 hours. Collect the supernatant and immediately detect ^ "Sub-Alpha level or freeze at minus 70 degrees Celsius before testing (can not exceed Al Falcons Alfa concentration to human _ tumor necrosis factor === epidemic test kit (10) coffee 'Boston, Masai Zhu _ the system of desire, "inhibition of non-included antibiotics, steroids, etc. Oral will contain eight, 縻 縻 ,, clothing, and similar shapes, ink shrinking materials, human agents, capsules, sugar count Zhang 趟 趟 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , The physiological condition, and the desired response, are quantified, but the usual dose is from about 1 to about 1000 mg administered once or more daily. In general, the initial therapeutic domination can be based on the compound of the present invention. It is known that other disease states regulated by tumor necrosis factor alpha are effective in interfering with tumor necrosis factor alpha activity. The number of T cells and T4/T8 ratios and/or viremias that are regularly detected by the subject will be measured. Is the level of retrovirus or viral protein, and / or the process of disease-related problems regulated by cytokines is like cachexia or muscle degeneration. If no effect is observed under normal treatment, the cytokine activity interfering agent The dosage is increased, for example, 50% per week. The compounds of the present invention can also be used for the typical treatment or prevention of disease states regulated or stimulated by the production of tumor necrosis factor Alpha excess. Treatment of mammals or other non-humans to prevent the need for permanent necrosis factor Alpha production. Treatment or == II: Primary "viral infection. Examples include feline immunodeficiency virus, Ma ί: = disease: 'mountain arthritis ♦, demyelination Sphingomic white matter "Adenoma virus, and other lentiviruses. t and 4 flat lung methods, methods for treating inflammatory blood group formation" methods for treating cancer, methods for treating Crohn's disease, and methods for treating diseases , = 1298724 ^ of the graft-versus-host reaction method U, by applying an effective amount of the equation to the mammal - the purity of the compound is right-handed - Or the mixture of levo-I-structures and isomers. These methods are superimposed, and can be administered in different ways, one or more doses of fascination, and therapeutic agents that are administered at the same time. a pharmaceutical composition, wherein (1) - the compound of formula 1 is substantially chiral, and the dextro- or levo-isomer of the oxime or a mixture of such isomers is effective in the administration of a single g-dosing, binding ( Ii) pharmaceutically acceptable pharmaceutical syrups can be classified into oral dosage forms, including mash, capsules, icing 5 and compressed pharmaceutical forms containing 1 to 1 gram per unit dose. A mixture of 20 to 1 GG mg may be formulated as an injection drug. The pharmaceutical composition will include - or a plurality of compounds of the invention together with a minimum of one acceptable side's diluent or diluent. The composition is prepared and the active ingredient is encapsulated or encapsulated in a carrier to form a capsule or sachet. When assigned to the component carrier, carrier or matrix. Thus, the composition may be a tablet, the tablet being a float, a latex, a solution, (d), a soft or hard gelatin capsule, a sputum, a halogen-free injection solution, and a sterile packaged powder. Examples of suitable shaping include lactose d-glucose, sucrose, sorbitol, mannitol, starch, labrador gum, acid, gelatin, microcrystalline cellulose, polyethylene, tetramethyleneimine, dinitrogen Ketones, cellulose, water, syrup, and methylcellulose. In addition, the formulation may include lubricants such as talc, hard-tested towns, and mineral oils, humectants, emulsifying and suspending agents. Base and propyl via benzoic acid, sweetener or flavoring agent. Wfit unilateral volume form is better, that is, suitable for doping dose or established early agent 1 segment to physiologically discontinuous unit single- or multi-dose dosing to the human body or other mammals, each unit contains one calculated A suitable pharmaceutical excipient is used to produce the desired therapeutic effect. This group = formulation = | 1298724 provides immediate, sustained delayed release of the active ingredient after administration to a patient via a recommended procedure well known in the art. The following examples will further represent the nature of the invention but should not be construed as limiting the scope of the invention, which is defined by the scope of the appended claims. ... Example 1 Hexahydrogen port ratio ^ 28. 2 Catalyst (·, 0.9 g) in acetic acid (1998) 7_12) and shaken in the support for three hours. Mix, transfer, Α, (liter) and add hydrogen (50-60 psi) to the 3-methyl-isopropanite sheet and rinse with acetic acid. It was heated to reflux for 18 hours. "Qi (true ^^, 2亳莫耳) and this mixture is isoindolin-2-alkyl)~2, ^^ is separated by gas to give 3-(4-methyl-1,3- Dioxin analysis column purification, - Oxy-5-acetamidine hexahydropyridine can be further colored (1 g, 3.5 mM), alkane-2,6-dioxyethyl , >~(4-Methyl-1,3-dioxaisoindole 2:1·8 mmol) in methanol H匕: 虱pyridine solution and p-toluene citrate (〇·33 g, 2~ liters under vacuum to heat and reflux for 5 hours. The solvent is suffixed to ~1,3~2 g 6-dioxane. The ratio is σ定—3—烧)—4— Methyl ^" Yang Yun can be further purified by chromatography column. Methyl isoindole-1.3 - 1,3--3-alkane

20 1298724 One of the nitrogen-isoindole-1,3~dione (10· gram, p-dioxopyridin-3-ane)-4-mine (3 ml, in acetic acid (200 ml)) 59 millimoles). The mixture and the mixture were cooled to room temperature at room temperature and the resulting yellow was returned to the apparatus for 2 days. The reaction mixture (1: 1,500 ml) was mixed for 30 minutes, and the solid was filtered in _ with /hexane-2,6-dihydrohexahydropyridine-3-ene)- Obtained 2-(5-bromination (6.8 g, 54% yield). It will be mixed with "哚-1,3~2" as an off-white solid evolution-2,6-dioxohexine _3_ 2-(5-16 mM) and sodium acetate (2. gram, ϋ丨, -1,3-dione (6. gram, solvent removed by vacuum) A solid was obtained. The room temperature was secreted for 2 days. The _ (3.7 g, 65% yield), 6-milk hexahydropyridin-3-alkylacetate pyridine-3-alcohol hydrazine -2-alkylene) ?』一—The acetic acid 5-(4-amino-1,3-dioxo-;[,3-dihydro-iso-two-six^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The mixture of the vibrating edge is made up of 4°, and the mixture of the mixture is under the hydrogen (Parr) (xf〇^). The Lai float is passed through the bribe and the methanol is used to threaten the solid. The solid is treated with methanol (3 liters), and the solid is washed with methanol to obtain yellow cis-5_(4_aminoguanidine-dioxyxin)-iso-_2_illusion_2,6_ Dioxane shouting _3_ mineralate solids 0 , 64% yield): melting point is 22 〇 -223 ° C. Oxypyridin-3-alkane) isoindole (tetra) - η - acetic acid in sterol (50 ml) 5_ (4_ 教基一u_二氧-u-dichloro_ 21 1298724 isodecane-2-alk)-2,6-dihydrohexahydropyridin-3-alkyl ester (1.5 g, 4.5 mmol) and p-toluenesulfonic acid (0.46克, 2·4 mmol), heated and refluxed for 22 hours. The suspension was filtered and washed with methanol (2*30 mL) to give yellow 4-amino-2-(5~~~~~~~~~~~~ Dioxane 吼 -3- 烧 )) isoindane-1,3-dione solid (1·〇克 '79% yield): melting point is 285-287 degrees Celsius. Example 3

IS Stone Schottky-2-(5-lactaloxy-2,6-digas six years old / than 唆-3-burning) different 1^丨 receiving edge 1 - ancient 2,6-monooxy-3-benzene Oxycarbamide-5-acetamidine hexahydroquinone alpha (9 g '28·2, ear) and his carrier catalyst (10%, 〇·9 g) in acetic acid solution (9 ml) ^ (50-60 psi) shake for three hours. The suspension was filtered through a pad of diatomaceous earth and rinsed, then the solvent was removed in vacuo. The residue, triethylamine (2.9 g, 28 mf) and methyl 2-bromomethyl-3-nitrobenzoate (7·7 g, 28·8 mmol in dimethyl Heating in carbamide (100 ml) at 80 ° C for 18 hours. This was removed in vacuo to give 3-(4-nitro-1-oxidic isoindol-2-al)-2,6- Dioxime B. Oxidation of six gas ° bit can be further purified by chromatographic analysis column. Dioxo right, 氲pyrvin) isoindole abalone) ^ 1 in 1 alcohol (10 ml) 3_ ( 4_Zhaoji+Oxidized oxidized oligo-full-2 A laughing into a lack of S oxygen ~5~ acetylated hexahydropyridine (0·96 g, 3.5 mM) and 3, 容 · 33 g, L8 The solution of millimolar) was heated and refluxed for 5 hours. Example 4, full ~ 1 - ketone and further purified by chromatography column. 1298724 -2,6-^^-5- The liquid is used as a residual piece for a small hour. Indole - 2 ~ alkane) ~ 2 First and then 3-(4-amino-1 - oxidative deionization column for purification., one ruthenium hexahydropyridine and further chromatographic separation) - Oxidized hexahydropyridine (〇: 9: g, wood full ~ 2 ~ alkane) - 2, 6-dioxo-5-ethyl oxime removed to give 4-amino I (5-) hydroquinone ° "_ 5 hours The solvent is subjected to vacuum and the color layer is analyzed by dichrohydrogen shunt + burning.

[5-Hydrogen: 5-acetamidine oxidation will be induced in tetrahydrofuran tetramethane (15 ml of noise-containing 2-burning)-2,6-dioxo-5-ethenyloxy-1,3-dioxaiso-11 When benzylguanidinium chloride (0.5 g, = 疋 (1 g, 3.5 mmol), the solvent is removed by vacuum and the solution is heated and refluxed to a small appearance) -2,6-dioxo-5 - 醯 醯 丄 丄 & ', - gas ~ 4-amine 异 弓 弓 朵 -2- -2- 将 将 将 将 将 将 将 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇 甲醇醯 Oxidation ^ - 2 2 - 4 benzene, different ah full - 2 _ toluene two (0 · 33 grams, U mA, f. 5 millimoles) and Xingdou 彡, the mixture is heated and refluxed for 5 hours. The solution 23 1298724 -2, 6' tm, 3-(ι, 3 · ": Oxygen _4-aniline (tetra) is filled with ^ methoxyl, gas pyridine and further chromatographic column purification Six pieces of decylamine)-L--- 丽τ~5-wind-oxygen screen six-by-mouth mouth~~~~^~~^Α_喃魏醯脸)-1, 卩2-2)-2,6 - Dioxo_5-acetamidine hexahydropyridinium ( ΖΖίίίΤ '3·5^^ '2D f, 3 - (4 ~ (2 'bite amine) -1,3 - dioxo';屯化.元,--Oxygen+Ethyl ruthenium hexahydro hydrazine bite and advance-step color analysis column-- '丨丨·| Τ—^ ·丨

Mi-5-hydroxy hexamine s 3 - (4 - (2 - °), 3- dioxo", 2-alkane - 2, in methanol (2 liters) 6-Dioxyi-acetonitrile hexahydropyridine (1.33 g 3 2 5 Torr) and p-toluenesulfonic acid (0.33 g, i 8 mmol), Rongluo column pure ί., —— ' 'Wei Ji six hydrogen shouting money - step by color layer sample seven Κ 4-methoxy acetamamine - oxygen 口 弓 卜 朵 朵 一 一 一 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ A A A A A乙乙庐庐2_1,^^氧异吲哚-2-alkane)-?--------------------------------------------------------- 4-(4-amino-丨3-two mouths in tetrahydrofuran (20 ml) -2-burn)-2,6-dioxo-5-acetinated hexahydro* (1 g, 3 5 m/ear) and methoxyethyl chloroform (0·38 g '3·5亳莫The solution in the ear is heated to reflux for one hour. 24 1298724 The agent is removed by vacuum to obtain 3_(4-methoxyacetamide-! 3-----), 2, 6-: Oxygen_5_acetamidine oxidation Hexahydrogen is required to proceed—(4)2; = _2> oxyethyl.u-diox (tetra)mole) and p-benzoic acid (〇. 33 g, I 8 mmol), ^^克' and 3 5 love to remove the solvent by vacuum to get 3_ (4_methoxyethyl hydrazine = °二=5小日^一2-烧)~2 6-一盏5 gas preparation basin, 1'3 one oxygen outlet mouth full. 2,6 n job base six (four) go forward - step by step Chromatography column pure sample eight burns) t (4-amino-1,3-dioxyiso, full of one 2-puffed C-based eight wind 吼? -2,6-dione (〇·82 g , 3 · 0 millimoles) and 2-bite" · 34 grams of ' 3 · 5 millimoles of the towel solution plus fine hours. Mix the mixture for 18 hours. The mixture acts as 3-(4-m-t-t-amine--------------------------------------------------------------- Example 9-acid jlG ml) 3 - (4 - amino + oxidized iso-t-full - 2-burn) - 5 - oxalate hexahydropyridin 1 ^ 2, 6-dione (〇 · 82 g, 3 · The solution in 〇 莫 ) and 2-furan aldehyde oxime 34 g '3.5 mM was heated and refluxed for four hours. Add the mixture to the temperature to add sodium (130 mg, 3.5 mmol) and place the mixture on 18 25 1298724. Purification Example Twelve, 6-dioxopyran P-bite-3-Hyun 4 -Nitro-2 - 1,3-dioxa-propoxy group to stand 1 〇 工 - - 匕 ' 匕 匕 匕 匕 匕 匕 匕 匕 匕 匕 匕 匕 匕 匕 匕 匕~2,6-dioxo-j oxime oxidized 1 b-di-, 3-dioxoiso- ah--2- sulphonate)-propyl-dicarbonate a86^=ii2 ears 5^7.75 millimoles) and two- Between: dioxo-5-acetamidine oxidized six gas • set in parallel with 1 in position - propionic acid tetra 2 (10) thorn in the cake 1-between oxidized hexahydro-hydrogen * milk. gram, 4. 3 ^ ΐ °) 5 = dazzle ) - 2 Guang Dioxo-5-acid sodium sodium (4.3 ml, 4 · 3 mmoles f〇1 solution added to two (trimethyl stone Xi Xi), Dunhua stupid animine a 1 g 4.3 mM)) After the addition, the temperature was warmed to room temperature and the mixture was removed in vacuo. The mixed house is raised and hydrochloric acid (1G ml, iN) - and two f" „ with ethyl acetate (1 〇 the solvent is removed by vacuum to obtain 3_H, when the machine layer will burn) ~ 2, 6-Dioxo-5-acetamidine servant·^ Homo-dioxyisoindole-2-(3-fluoro-5-straight crystal purification. Ethylene oxide/hydrogen hydrazine into the color layer Analytical column or 3^(L)--------------------- ―5—E-brewed hexa-nitrogen pyridine (1 g, and 2.9 mmol) The solvent was heated to reflux for 5 hours with a solution of ί = (G·28 g, 丨·5 mmol). 3, more than two more than 4 琐 一 一 2 一 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Full ~2^?/fR(1()〇"ml) t3_Fluorine-3_(4-amino), 3-dioxyisophene and singularly oxidized one 5_E liquefied hexa Π ° ° ° (1. 〇 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' And rinsing with decyl alcohol to obtain 3_ and 'into; cattle full-m 6_ dioxo-5-ethyl hexahydropyranol 疋 疋 step by color chromatography column purification. Hydrogen ox 2, 6-diox 6 急 ^ methanol (1 〇 ml) of 3_ (4_amino_u_diox (tetra) _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _毫摩尔) gram, 丨.5 millimoles) mixed with fine correction, time. Beer, 3 ten-based (3 are 5_hydroxyoxy~2,6-dioxane oxime example ten-isolation It, 3 —dione and further purified by chromatography column. 境)m tablets gas has 5G mg of 2_ (2,6_dioxo I oxyhydrogen hexazone bite + 4 wind-based different bows Bumuman -1,3 - Diketone, which can be prepared in the following manner. · Ingredients (per 1000 tablets) 27.1298724 2-(2,6-Dioxy-3-hydrogen hexahydroindole π ding -5-burning) -4-aminoiso , 满满-1,3-dione 50·0g lactose 50. 7g wheat house powder 7. 5g polyethylene glycol 6000 5. 0g talc 5. Og magnesium stearate 1.8g deionized water sufficient amount of the active ingredient, Lactose, talc, magnesium stearate and half a starch are mixed. The remaining half of the starch is suspended in 40 ml of water and the suspension is added In a 100 ml boiling water solution of polyethylene glycol, the formed paste was added to the powder and the mixture was granulated, and if necessary, water was added. The granules were dried at 35 ° C overnight and forced through A screen having a width of 1 mm 2 is compressed and formed into a suitable 6 mm diameter double concave lozenge. Example Thirteen Bonding Agent 'Master Tablet Contains 100 mg of 2-(2,6-dioxo-3-hydrogen hexahydropyridinium-5-alkane)-4-methylaminoisoindan-1-one It can be prepared in the following manner: Ingredients (per 1000 tablets) 2-(2,6-Dioxy-3-hydrogen hexahydropyridine-5-alkyl)-4-methylaminoisoindan-1 ketone 100· 0g Lactose 100. 〇g Wheat house powder 47 〇g Stearic acid town 3 First, the solid component is forced through a sieve of 6 宽 wide aperture. The active ingredient, lactose, magnesium stearate and a half amount of starch are then mixed. The remaining half of the starch was suspended in 40 ml of water and the suspension was added to 1 ml of boiling water. The resulting paste is added to the powder and the mixture forms granules, and if necessary, water is added. The granules were dried overnight at 35 degrees Celsius and forced through a screen having a width of 12 cm holes 28 1298724 and compressed to form a suitable 6 mm diameter double concave bond. Example fourteen tablets, each containing 75 mg of 2-(2,6-dioxo-3-hydroxyoxy-5-methylhexahydroacridine-5-alkyl)-4-methylisoindole Man--, 3-dione can be injurious in the following manner: Ingredients (per 1000 bonds) 2-(2,6-Dioxy-3-hydroxyoxy-5-methylhexahydropyridin-5-alkane 5g saccharin 1. 5g saccharin 1. 5g stearic acid 10. 5g stearic acid 1. 5g stearic acid 1. 5g saccharin 1. 5g mannitol 1. 5g A sufficient amount of 5% gelatin solution was first forced through a 0.25 mm wide aperture screen. The mannitol and lactose are then mixed and added to a gelatin solution to form granules which are forced to pass through a grid of 2 mm pore width, dried at 50 degrees Celsius, and forced through a sieve having a diameter of 1 mm. Carefully mix 3-(3-ethoxy-4-methoxyphenol nitro-hydroxyl-3-phthalimidodiethyl ketoxime, glycine, saccharin, and then Mannitol, lactose granules, stearic acid and talc are added and all are thoroughly mixed and compressed to form a suitable 10 mm diameter double concave surface with a groove on top. Example fifteen key agent, each containing 10 Mg 2-(2,6-dioxo-3-hydroxyhydrohexahydropyridin-5-amino)-4-aminoisoindan-1-one can be prepared in the following manner: Ingredients (per 1000 tablets) 2-(2,6-Dioxy-3-argonoxyhexahydroacridine_5-Hyun)~Aminoisoindole- 1 酉同同 10. 0g lactose corn starch 328. 5g 17. 5g 29 -1298724 5 0g 25. 0g 4. 0g A sufficient amount of polyethylene glycol 6000 talc magnesium stearate deionized water is first forced through a sieve of 6 Å wide pore size. Then the active imine component, lactose , talc, magnesium stearate and half amount of starch are closely mixed. The remaining half of the starch is suspended in 65 ml of water, and the suspension is added to a boiling water of 260 ml containing polyethylene glycol. Aqueous solution. The formed paste is added to the powder mixture in which the particles are formed, water is added if necessary. The granules in degrees Celsius%

After drying overnight, it was forced through a sieve having a width of 1 mm 2 and compressed to form a tablet having a double concave surface of appropriate diameter = 10 mm and a groove above. Tian sample 16 gelatin is filled into capsules, each containing 100 mg of (2,6-dioxo-3-hydroxyoxy-5-fluorinated hexahydroguanidine-5-burn)-4-aminoisoindole Full, can be prepared in the following manner: Ingredients (per 1000 capsules) Hyun)-4-aminoisoindoles 100. 0g 30· 〇g 2. 0g 2-(2,6-Dioxy-3-hydroxyl -5-fluorinated hexahydropurine-5

Full-1-酉 Same Microcrystalline Cellulose Sodium Laurate Sodium Magnesium Stearate 8. 0g Firstly, sodium lauryl sulfate is passed through a 〇·2 mm wide farmer's eve # _ A>u. Dioxane + argon edge 5 rhyme (10) coffee (2, 6- after the two components are closely mixed for ten minutes. Then the microcrystalline fiber; = two = wide screen sieve people' and then all the intimate mixing is very I 〇 9 narrative example seventeen pass - 〇. 8 public ship diameter _ sieve people into the ten - m ^ magnesium stearate milligram respectively into the zero (extended) gelatin dry (two) capsule and then mixed in the following manner: A 0.2% injection or perfusion solution can, for example, 30 • 1298724 2-(2,6-dioxo-3-hydrogen hexahydropyridin-5-alkane)-4-aminoisoindole-1 -ketone hydrochloride 5. Og sodium chloride 22.5g phosphate buffer ρΗ7· 4 300. Og deionized water is added to 2500 ml to 2-(2,6-dioxo-3-hydrogen hexahydropurine-5_ -4-Aminoiso-indot-1-one hydrochloride is dissolved in 1000 ml of water and filtered through a microfiltration membrane. The buffer solution is added and the total volume is added to 2500 ml with water. The form of each of the 1.0 amps or 2. 5 ml of each of the glass ampoules (each containing 2. 0 or 5.0 mg of imine).

Simple illustration

31

Claims (1)

1298724 VI. Application for patent range f>( ^ 1 1· A compound consisting of (a) having the lower side of the column and filling it with (b) protonated acid addition salt Among the group consisting of: Wherein: the carbon atom marked with * indicates a chiral center; X is -C (〇) or -ch2-; R1 is a methyl or amine group; and R2 is a halogen atom, an alkyl group of one to eight carbon atoms, Or halogen element. 2. The compound according to claim 1, wherein the heterogeneous street bio R is a wind atom or a sulfhydryl group. 3. The compound according to claim 2, wherein R2 is a hydrogen atom. 4. The compound according to item 3 of the patent application, wherein the different, 0 full-difant R1 is an amino group. 5. The compound according to claim 4, wherein the heterogeneous street flavor X is -(C0). 6. The compound according to item 4 of the patent application, wherein the difference is the same. The 嗓 嗓 柯 味 味 X is -CH2-. 7. The compound according to item 3 of the patent application, wherein the odor is full of the R1 is a methyl group. 8. The compound according to claim 2, wherein the heterologous η 朵 朵 彳 彳 。 。 。 。 。 。 。 。 。 。 。 。 。. 9. The compound according to claim 2, wherein the different π 嗓 嗓 full street X is a CH2-. 10. The compound according to claim 1 of the patent application, which is 2-(2,6-dioxo-3-indolylhexahydro-β-r-but-burn)_4-aminoiso-sigma -1,3~dione. 11. The compound according to claim 1 of the patent application, which is 2-(2,β-dioxy 32 1298724-3 argon oxyhydrohexahydropyridin-5-form)-4-aminoisoindole- 1-ketone. 12· / The compound according to the scope of claim patent, which is 2-(2,β-dioxo-3 hydroxyhydrohexahydropyridin-5-alkyl)-4-F-isoindole -1,3-dione. 】 3· ^ According to the compound of the first paragraph of the patent scope, which is 2-(2,6-dioxo 3-hydrogen hexahydroacridine-5-form) _4-methylisoindole 1-ketone. A pharmaceutical composition for reducing or inhibiting an undesired mammalian tumor necrosis factor alpha level, which comprises the compound according to claim 1 of the patent application as an active ingredient. 15. A pharmaceutical composition for treating a mammalian disease, which comprises the compound according to item 1 of the scope of application f as an active ingredient, wherein the disease is caused by a inflammatory disease, an autoimmune disease, an arthritis , rheumatoid arthritis, intestinal disease $ disease, Crohn's disease, aphthous ulcer, cachexia, graft versus host response, gas =, adult respiratory distress syndrome, and acquired immunodeficiency syndrome group I household frill fH . 16. - A pharmaceutical combination for the treatment of breastfeeding _ disease Patent Fan Chen tears De Helin active age.制药化3 A pharmaceutical composition according to the angiogenic effect of the sputum, which is an active ingredient according to the compound of the scope of claim. 33