MXPA99010998A - SUBSTITUTED 2-(2,6-DIOXOPIPERIDIN-3-YL)-PHTHALIMIDES AND 1-OXOISOINDOLINES AND METHOD OF REDUCING TNF&agr;LEVELS - Google Patents

Abstract

Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and 1-oxo-2-(2, 6-dioxopiperidin-3-yl)isoindolines reduce the levels of TNF&agr;in a mammal. A typical embodiment is 1-oxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4,5,6,7-tetrafluoroisoindoline.

Description

2- (2,6-DIOXOPIPERIDIN-3-IL) FT-_L - MIDAS AND 1-OXOISOINDOLINES SUBSTITUTES AND METHOD FOR REDUCING TNFa LEVELS DESCRIPTION OF THE INVENTION The present invention relates to substituted 2- (2,6-dioxopiperidin-3-yl) phthalimides and 2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindolines. substituted, the method of reducing levels of tumor necrosis factor a and the treatment of inflammatory and autoimmune diseases in a mammal through the administration thereof, and to the pharmaceutical compositions of such derivatives. The tumor necrosis factor a, or TNFa is a cytokine which is released mainly by mononuclear phagocytes in response to a number of immunostimulators. When administered to animals or humans, it causes inflammation, fever, cardiovascular effects, haemorrhage, coagulation, and acute phase in response similar to that seen during acute infections and shock states. The production of excessive or unregulated TNFα as well, has been implicated in a number of disease conditions. This includes entodotoxemia and / or toxic shock syndrome. { Tracey et al. , Na ture 330, 662-664 (1987) and Hinshaw et al, Cir Shock 30, 279-292 (1990)}; cachexia { Dezube et al. , Lancet, 335 (8690), 662 (1990)} , and Respiratory Acute Pain Syndrome in Adults where the concentration of TNFa in excess of 12,000 pg / ml has been detected in pulmonary aspirations of ARDS patients. { Millar et al. , Lancet 2 (8665), 712-714 (1989)} . Systemic infusion of recombinant TNFα also results in changes normally seen in ARDS. { Ferrai-Baliviera et al. , Arch. Surg. 124 (12), 1400-1405 (1989)} . TNFα appears to be involved in bone resorption diseases, including arthritis. When activated, leukocytes will produce bone resorption, an activity to which the data suggest providing TNFa. . { Bertolini et al. , Na ture 319, 516-518 (1986) and Johnson et al. , Endocrinology. 124 (3), 1424-1427 (1989) ..}. . TNFa has also been shown to stimulate bone resorption and inhibit bone formation in vi tro and in vivo through the stimulation of osteoclast formation and activation combined with the inhibition of osteoblast function. Although TNFa may be involved in many bone resorptive diseases, including arthritis, the strongest compelling link with the disease is the association between the production of a TNFa by tumor or host tissues and associated malignant hypercalcemia. { Calci. Tissue Int. (US) 46 (Suppl). S3-10 (1990)} . In Graft versus Host Reaction, increased serum levels of TNFα have been associated with greater complication following acute allogeneic bone marrow transplants. { Holler et al., Blood, 75 (4), 1011-1016 (1990)} .

Cerebral malaria is a lethal hyperacute neurological syndrome associated with high blood levels of TNFα and major severe complication that occurs in malaria patients. Serum levels of TNFa correlate directly with the severity of the disease and the prognosis in patients with acute malaria attacks. { Grau et al. , N. Engl. J. med. 320 (24), 1586-1591 (1989)} . Macrophage-induced angiogenesis is known to be mediated by TNFa. Leibovich et al. . { Na ture, 329, 630-632 (1987)} has shown that TNFa induces the formation of blood vessels in capillarity in vivo in the rat cornea and the development of chick chorioallantoic membranes at very low doses and suggests that TNFa is a candidate for inducing angiogenesis in inflammation, wound repair, and tumor growth. TNFa production has also been associated with cancerous conditions, which particularly induce tumors (Ching et al., Bri T J. Cancer, (1955) 72, 339-343, and Koch, Progress, Medicinal Chemistry, 22, 166 -242 (1985).}. TNFa also plays a role in the area of chronic pulmonary inflammatory diseases The deposition of silica particles follows silicosis, a progressive respiratory failure disorder caused by a fibrotic reaction. blocks silica-induced lung fibrosis in mice. {Pignet et al., Na ture, 344: 245-247 (1990)} . High levels of TNFa production (in serum and in isolated macrophages) have been demonstrated in animal models of silica and asbestos-induced fibrosis. { Bissonnette, et al. , Inflammation 13 (3), 329-339 (1989)} . Alveolar macrophages of patients with pulmonary sarcoidosis have also been found in massive amounts spontaneously released from TNFα when compared to macrophages from normal donors. { Baughman et al. , J. Lab. Clin. Med. 115 (1), 36-42 (1990)} . TNFa is also involved in the inflammatory response which follows reperfusion, called reperfusion injury, and is a major cause of damaged tissue after loss of blood flow. { Vedder et al. , PNAS 87, 2643-2646 (1990)} . TNFα also alters the properties of endothelial cells and has several pro-coagulant activities, such as producing an increase in the activity of the procoagulant tissue factor and suppression of the directed anticoagulant protein C as well as the down-regulation of thrombomodulin expression. { Sherry et al. , J. Cell Biol. 107, 1269-1277 (1988)} . TNFa has pro-inflammatory activities which together with its early production (during the initial stage of an inflammatory event) makes a likely mediator of tissue damage in several major disorders, including, but not limited to, myocardial infarction, stroke and circulatory shock. Of specific importance may be the induced expression of TNFa of adhesion molecules, such as intercellular molecule adhesion (ICAM) or molecular adhesion of endothelial leukocyte (ELAM) or endothelial cells. { Munro et al., Am. J. Path. 135 (1), 121-132 (1989)} . Blockade of TNFa with anti-TNFa monoclonal antibodies has been shown to be beneficial in rheumatoid arthritis. { Elliot et al., Int. J. Pharmac. 1995 17 (2), 141- 145.}. and Crohn's disease. { von Dullemen et al., Gastroenterology, 1995 109 (1), 129-135} . In addition, it is now known that TNFa is a potent activator of retrovirus replication including activation of HIV-1. . { Duh et al., Proc. Nat. Acad. Sci. 86, 5974-5978 (1989); Poli et al., Proc. Nat. Acad. Sci. 87, 782-785 (1990); Monto et al., Blood 79, 2670 (1990); Clouse et al., J. Immunol, 142, 431-438 (1989); Poli et al., AIDS Res. Hum.

Retrovirus, 191-197 (1992)} . AIDS results from the infection of T lymphocytes with the Human Immunodeficiency Virus (HIV) At least three types or strains of HIV have been identified, namely HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, T cell-mediated immunity damages and infects individuals who manifest severe opportunistic infections and / or unusual neoplasms. HIV enters the T lymphocytes that require the activation of T lymphocyte. Other viruses, such as HIV-1, HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and / or replication is mediated or maintained by such T cell activation. Once activated the T lymphocyte is infected with HIV, the lymphocyte must continue to be maintained in an activated state to allow expression of the HIV gene and / or HIV replication. Cytokines, specifically TNFa, are implicated in activated T cell mediated by HIV protein expression and / or replication virus by playing a role in maintaining T-cell activation. Therefore, interference with the Cytokine activity such as the prevention or inhibition of cytokine production, notably TNFa, in an individual infected with HIV aids in the limitation of T lymphocyte maintenance caused by HIV infection. Monocytes, macrophages and related cells, such as kupffer and gual cells, have also been implicated in the maintenance of HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent on the activation state of the cells. . { Rosenberg et al., The Immunopa thogenesis of HIV Infection. Advances in Immunology, 57 (1989)} . Cytokines, such as TNFa, have been shown to activate HIV replication in monocytes and / or macrophages. { Poli et al. , Proc. Na ti. Acad. Sci, 87, 782-784 (1990)} , therefore, the prevention or inhibition of cytokine production or the activity of AIDS in the progression of HIV limiting for T cells. Additional studies have identified TNFa as a common factor in HIV activation in vitro and proposed a clear mechanism of action via a nuclear regulatory protein found in the cytoplasm of cells (Osborn, et al., PNAS 86 2336-2340). This evidence suggests that a reduction of TNFa synthesis may have an antiviral effect in HIV infections, reducing transcription and thus the production of the virus. Viral AIDS replication of latent HIV in T cells and macrophage lines can be induced by TNFa. { Folks et al. , PNAS 86, 2365-2368 (1989)} . A molecular mechanism for the inducing activity of the virus is suggested by the ability of TNFa to activate a gene regulatory protein (NFKB) found in the cytoplasm of cells, which promotes HIV replication through the binding of a viral regulatory gene sequence (LTR). { Osborn et al. , PNAS 86, 2336-2340 (1989)} . TNFa in AIDS associated with cachexia is suggested by elevated serum TNFα and high levels of spontaneous TNFα production in peripheral blood monocytes from patients. { Wright et al. , J. Immunol. 141 (1), 99-104 (1988)} . TNFa has been implicated in several roles with other viral infections, such as cytomegalovirus (CMV), influenza virus, adenovirus, and herpes virus family, for reasons similar to those observed. Nuclear factor KB (NFKB) is a pleiotropic transcriptional activator (Lenardo, et al., Cell 1989, 58, 227-29). NFKB has been implicated as a transcriptional activator in a variety of inflammatory diseases and states and is thought to level cytokine levels including, but not limited to, TNFα and also to be an activator of HIV transcription (Dbaibo, et al. , J. Biol. Chem. 1993, 17762-66; Duh et al., Proc. Nati Acad. Sci. 1989, 86, 5974-78, Bachelerie et al., Nature 1991, 350, 709-12; Boswas et al., J. Acquired Immune Deficiency Syndrome 1993, 6; 778-786; Suzuki et al., Biochem. And Biophys Res. Comm. 1993, 193, 277-83; Suzuki et al., Biochem, And Biophys, Res Comm. 1992, 189, 1709-15; Suzuki et al., Biochem. Mol. Bio. Int. 1993, 31 (4), 693-700; Shakhov et al., Proc. Nati Acad. Sci, USA 1990, 171, 35-47; and Staal et al., Proc. Nati Acad. Sci. USA 1990, 87, 9943-47). Thus, inhibition of the NFKB linkage can regulate the transcription of cytokine genes and it is thought that modulation and other mechanisms may be useful in inhibiting a multitude of disease states. The compounds described herein can inhibit the action of NFKB in the nucleus and thus are useful in the treatment of a variety of diseases including, but not limited to, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, other arthritic conditions, septic shock, sepsis, endotoxic shock. , graft-versus-host disease, weakening, Crohn's disease, inflammatory bowel disease, ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ENL in leprosy, HIV, AIDS and opportunistic infections in AIDS. TNFa and NFKB levels are influenced by a reciprocal feedback loop. As noted above, the compounds of the present invention affect the levels of both TNFa and NFKB. Many cellular functions are mediated by adenosine levels of 3 ', 5'-cyclic monophosphate (cAMP). Such cellular functions may contribute to inflammatory conditions and diseases including asthma, inflammation and other conditions (Lo e and Cheng, Drugs of the Future, 27 (9), 799-807, 1992). It has been shown that the elevation of cAMP in inflammatory leukocytes inhibits their activation and the subsequent release of inflammatory mediators, including TNFa and NFKB. Increased levels of cAMP also lead to relaxation via the smooth muscle area. Decreased levels of TNFα and / or increased levels of cAMP constitute a valuable therapeutic strategy for the treatment of many inflammatory, infectious, immunological or malignant diseases. These include, but are not limited to septic shock, sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, post-ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, rejection graft, cancer, autoimmune disease, opportunistic infections in AIDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, other arthritic conditions, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythematosus. ENL in leprosy, radiation damage and hyperoxic alveolar damage. Previous efforts aimed at suppressing the effects of TNFα have been averaged from the use of steroids such as dexamethasone and prednisolone in the use of both polyclonal and monoclonal antibodies. { Beutler et al. , Science 234, 470-474 (1985); WO 92/11383} . The present invention is based on the discovery of certain classes of non-polypeptide compounds more fully described herein by decreasing TNFa levels. In particular, the invention pertains to the compounds of the formula: in which: one of X and Y is C = 0 and another of X and Y is C = 0 or CH2; (i) each of R1, R2, R3 and R4, independently of others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3 , and R 4 is -NHR 5 and the rest of R 1, R 2, R 3 and R 4 are hydrogen; R5 is hydrogen or alkyl of 1 to 8 carbon atoms; R6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro; R7 is m-phenylene or p-phenylene or - (CnH2n) - wherein n has a value from 0 to 4; each of R8 and R9 taken independently of each other is hydrogen or alkyl of 1 to 8 carbon atoms, or R8 and R9 taken together are tetramethylene, pentamethylene, hexamethylene or -CH2CH2XCH2CH2- wherein X is -O-, -S- or -NH-; R10 is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl; and (b) the acid addition salts of the compounds which contain a nitrogen atom capable of being protonated. A first preferred group of compounds are those of Formula I wherein at least one of R1, R21 R3, R4 and R6 is different from hydrogen. Among these, a preferred group are those compounds in which each of R1, R2, R3 and R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms; R6 is hydrogen, methyl, ethyl or propyl; each of R8 and R9 taken independently of the other is hydrogen or methyl; and R10 is hydrogen. Of these compounds, a preferred subgroup are those compounds in which R7 is m-phenylene or p-phenylene, while a second preferred subgroup are those compounds in which R7 ~ (CnH2n) -where n has a value of 0 to 4 A further preferred group of compounds are those of Formula I in which one of R1, R2, R3 and R4 is -NH2 and the remainder of R1, R2, R3 and R4 are hydrogen; R6 is hydrogen, methyl, ethyl or propyl; each of R8 and R9 taken independently of the other is hydrogen, or methyl; R10 is hydrogen. Of these compounds, a preferred first subgroup are those compounds in which R7 is J? -phenylene or p-phenylene while a second preferred subgroup are those compounds in which R7 - (CnH2n) - wherein n has a value of 0 to 4. The term "alkyl" means a univalent, saturated, linear or branched hydrocarbon chain of 1 to 8 carbon atoms. Representative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. "Alkoxy" refers to an alkyl group linked to the rest of the molecule through an ether oxygen atom. Representative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Preferably R1, R2, R3, and R4 are chloro, fluoro, methyl, or methoxy. The compounds of Formula I are used, under the supervision of quality professionals, to inhibit the undesirable effects of TNFa. The compounds may be administered orally, rectally, or parenterally, alone or in combination with other therapeutic agents including antibiotics, steroids, etc., to a mammal in need of treatment. The compounds of the present invention can also be used topically in the treatment or prophylaxis of topical disease mediated or exacerbated by excessive production of TNFa, respectively, such as viral infections, such as those caused by herpes viruses, or viral conjunctivitis, psoriasis. , atopic dermatitis, etc. The compounds can also be used in veterinary treatments of mammals or those humans in need of prevention or inhibition of TNFa production. TNFa mediates diseases for treatment, therapeutically or prophylactically, in animals including disease states such as those observed above, but in particular viral infections. Examples include feline immunodeficiency virus, equine anemia virus infections, caprine arthritis virus, visna virus and maedi virus, as well as other lentiviruses. The compounds can be prepared through an initial formaldehyde reaction with an intermediate of the formula: wherein X and Y are as defined above; each of Ri, R2, R3 and R, independently of others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of Ri, R2, R3 and R4 is nitro or a protective amino acid and the rest of Ri, R2, R3 and R4 are hydrogen; and R6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro. The resulting N-hydroxymethyl intermediate of Formula II is then coupled with a carboxylic acid derivative of Formula IV using methods which are generally known: V. wherein Hal is a reactive halogen such as chlorine, bromine or iodine. The protective groups used here denote groups which are not generally found in the final therapeutic compounds, but which are intentionally introduced to some stage of the synthesis in order to protect groups which might otherwise be altered in the course of manipulations. chemical Such protecting groups are removed in the last stage of the synthesis and the compounds bearing such protective groups are thus of primary importance as chemical intermediates (although some derivatives also exhibit biological activity). Accordingly, the precise structure of the protecting group is not critical. Numerous reactions for the formation and removal of such protecting groups are described in a number of standard works including, for example, "Protective Groups in Organic Chemistry," Plenum Press, London and New York, 1973; Greene, Th. W. "Protective Groups in Organis Synthesis", Wiley, New York, 1981; "The Peptides", Vol. I, Schroder and Lubke, Academic, Press, London and New York, 1965; "Methoden der organischen Chemie", Houben-Weyl, 4th Edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart 1974, the descriptions of which are incorporated herein for reference. An amino group can be protected as an amide using an acyl group which is selectively removable under mild conditions, especially benzyloxycarbonyl, formyl or a lower alkanoyl group which is branched at the 1- position or to the carbonyl group, particularly tertiary alkanoyl such as pivaloyl, a lower alkanoyl group which is substituted at the a-position to the carbonyl group, such as, for example, trifluoroacetyl.

Coupling agents include such reagents as dicyclohexylcarbodiimide and N, N'-carbonyldiimidazole. Following the coupling, the compounds of Formula V can be aminated in a conventional manner, such as for example with an amine in the presence of sodium iodide. Alternatively, a compound of Formula III is allowed to react with a protected aminocarboxylic acid of the Formula IVA: GOES. wherein Z is a protective amino group. Following this coupling, the protective amino group Z is removed. In the above reactions when one of Rlf R2, R3 and R4 is nitro, it can be converted to an amino group by catalytic hydrogenation. Alternatively, if one of Ri, R2, R3 and R is amino-protective, the protecting group may be cleaved to produce the corresponding compound in which one of Ri, R2, R3 and R is amino. In addition to serving as intermediates, certain additional compounds of Formula IIA are likewise biologically active in reducing levels of tumor necrosis factor A in a mammal. These compounds are those of the formula: IIB. in which: one of X and Y is C = 0 and the other of X and Y is C = 0 or CH2; (i) each of R1, R2, R3 and R4, independent of others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3 , and R 4 is -NHR 5 and the rest of R 1, R 2, R 3 and R 4 are hydrogen; R5 is hydrogen, alkyl of 1 to 8 carbon atoms, or CO-R7-CH (R10) NR8R9 wherein each of R7, R8, R9 and R10 is as defined above; and R6 is alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro. Certain of the intermediaries of the Formula IIA, the co-pending applications Nos. of Series 08 / 690,258 and 08 / 701,494 are described, the descriptions of which are incorporated herein by reference. In addition, an alkyl o-bromomethylbenzoate which is suitably substituted with the substituents R1, R2, R3 and R4 is allowed to react with an α-R6-substituted α-aminoglutarimide salt in the presence of a recognized acid such as triethylamine to produce compounds in which one of X and Y is C = 0 and the other is CH2. Compounds of Formula IIA wherein X and Y are both C = 0 can also be prepared by allowing a phthalic anhydride which is appropriately substituted with R1, R2, R3 and R4 to react with a substituted a-aminoglutarimide salt a-R6. in the presence of an acetic acid and sodium acetate. The α-R6-substituted a-aminoglutarimide salt used in the above reactions can be obtained by cyclizing an α-R6-substituted glutamine in which the amine group is protected. The cyclization can be conducted, for example, with N, N '-carbonyldimidazole in the presence of an acceptor acid such as dimethylaminopyridine. Until the reaction is complete, the protecting group can be removed in an appropriate manner. By way of example only, if the protecting group is the N-benzyloxycarbonyl group, it can be removed by catalytic hydrogenation. The a-R6-substituted glutamines in turn can be prepared by treating an a-R6-substituted glutamic anhydride, in which the amino group is protected, with ammonia. Finally, the substituted a-R6 glutamic acid anhydride can be obtained from glutamic acid a-R6 substituted with acetic anhydride. The compounds of Formulas I and IIB possess a center of chirality and can exist as optical isomers. Both of the racemates of these isomers and the individual isomers likewise, as well as the diastereoisomers when they are two chiral centers, are within the scope of the present invention. The racemates can be used as such or they can be separated into their individual isomers mechanically as by chromatography using a chiral absorber. Alternatively, the individual isomers can be prepared in chiral form or chemically separated from a mixture to form salts with a chiral acid, such as individual enantiomers of 10-camphorsulfonic acid, camphoric acid, a-bromocamphoric acid, methoxyacetic acid, tartaric acid, acid diacetyltartaric, malic acid, pyrrolidone-5-carboxylic acid, and the like, and then releasing one or both of the resolved bases, optionally repeating the process, as well as obtaining either or both substantially free of the other; that is, in a form that has an optical purity of > 95% The present invention also pertains to the non-toxic, physiologically acceptable acid addition salts of the compounds of Formulas I and IIB. Such salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, mellic acid, acid maleic, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embonic acid, enanthic acid, and the like. Oral dosage forms include tablets, capsules, lozenges and similar forms, pharmaceutically compressed forms containing from 1 to 100 mg of drug per unit dose. Isotonic saline solutions containing from 20 to 100 mg / ml can be used by parenteral administration which include routes of intramuscular, intrathecal, intravenous and intra-arterial administration. Rectal administration can be effected through the use of suppositories formulated from conventional carriers such as cocoa butter.

The pharmaceutical compositions thus compress one or more compounds of Formulas I IIB associated with at least one pharmaceutically acceptable carrier, diluent or excipient. In the preparation of such compositions, the active ingredients are usually mixed with or diluted by an excipient or enclosed within the carrier which may be in the form of a capsule or sachet. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose, the formulations may additionally be included lubricating agents such as talc , magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl- and propylhydroxybenzoates, sweetening agents or flavoring agents.

The compositions are preferably formulated in dosage unit form, physically meaning suitable discrete units as a unit dose, or a predetermined fraction of a unit dose to be administered in a single or multiple dose regimen to humans and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a pharmaceutically acceptable excipient. The compositions can be formulated either to provide an immediate, sustained or delayed-release active ingredient of the active ingredient after administration to the patient by methods employed well known in the art. Oral dosage forms include tablets, capsules, dragee, and the like, comprising dosage forms containing from 1 to 100 mg of drug per unit dose. Isotonic saline solutions contain from 20 to 100 mg / ml which can be used by parenteral administration including routes of intramuscular, intrathecal, intravenous and intra-arterial administration. Rectal administration can be effected through the use of suppositories formulated from conventional carriers such as cocoa butter. The pharmaceutical compositions thus compress one or more compounds of the Formula I associated with at least one pharmaceutically acceptable carrier, diluent or excipient. In the preparation of such compositions, the active ingredients are usually mixed with, or diluted by, an excipient or enclosed within the carrier which may be in the form of a capsule or sachet. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose, the formulations can be further included by lubricating agents such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl- and propylhydroxybenzoates, sweetening agents or flavoring agents. The compositions are preferably formulated as a dosage unit, meaning physically discrete units suitable as a unit dose, or a predetermined fraction of a unit dose to be administered in a single or multiple dose regimen to humans and other mammals, each unit contains a predetermined amount of active material calculated to produce the effect desired therapeutic in association with a pharmaceutically acceptable excipient. The compositions can be formulated either to provide an immediate, sustained or delayed-release active ingredient of the active ingredient after administration to the patient by methods employed well known in the art. The following examples will serve to further typify the nature of this invention but should not be construed as limiting the scope thereof, the scope of which is defined solely by the appended claims. EXAMPLE 1 N-Benzyloxycarbonyl-α-methyl-glutamic acid To a stirred solution of α-methyl-D, L-glutamic acid (10 g, 62 mmol) in 2 N sodium hydroxide (62 ml) at 0-5 ° C Benzyl chloroformate (12.7 g, 74.4 mmol) is added over 30 minutes. After the addition is complete the reaction mixture is stirred at room temperature for 3 hours. During this time the pH is maintained at 11 by the addition of 2N sodium hydroxide (33 ml). The reaction mixture is then extracted with ether (60 ml). The aqueous layer is cooled in an ice bath and then acidified with 4N hydrochloric acid (34 mL) to pH = 1. The resulting mixture is extracted with ethyl acetate (3 x 100 mL). The combined ethyl acetate extracts were washed with brine (60 ml) and dried (MgSO 4). The solvent was removed in vacuo to give 15.2 g (83%) of N-benzyloxycarbonyl-α-methylglutamic acid as an oil: 1H NMR (CDC13) d 8.73 (m, 5H), 5.77 (b, 1H), 5.09 (s) , 2H), 2.45-2.27 (m, 4H), 2.0 (s, 3H). In a similar form of a-ethyl-D, L-glutamic acid and an α-propyl-D, L-glutamic acid, an N-benzyloxycarbonyl-α-ethylglutamic acid and N-benzyloxycarbonyl-α-propylglutamic acid are obtained, respectively . EXAMPLE 2 N-Benzyloxycarbonyl-α-methyl-glutamic anhydride A stirred mixture of N-benzyloxycarbonyl-α-methyl-glyutamic acid (15 g, 51 mmol) and acetic anhydride (65 ml) is heated to reflux under nitrogen for 30 minutes. The reaction mixture is cooled to room temperature and then concentrated in vacuo to give N-benzylcarbonyl-α-methylglutamic anhydride as an oil (15.7 g) which can be used in the next reaction without further purification: XH NMR (CDC13) d (7.44-7.26 (m, 5H), 5.32-5.30 (m, 2H), 5.11 (s, 1H), 2.69-2.61 (m, 2H), 2.40-2.30 (m, 2H), 1.68 (s, 3H) ).

In a similar form of N-benzyloxycarbonyl-α-ethylglutamic acid and N-benzyloxycarbonyl-α-propylglutamic acid, N-benzylcarbonyl-α-ethylglutamic anhydride and N-benzylcarbonyl-α-propylglutamic anhydride are obtained, respectively. EXAMPLE 3 N-Benzyloxycarbonyl-1-methylisoglutamine A stirred solution of N-benzylcarbonyl-α-methylglutamic anhydride (14.2 g, 51.5 mmol) in methylene chloride (100 mL) was cooled in an ice bath. The gaseous ammonia was bubbled in a cooled solution for 2 hours. The reaction mixture is stirred at room temperature for 17 hours and then extracted with water (2 x 50 ml). The combined aqueous extracts were cooled in an ice bath and acidified with 4N hydrochloric acid (32 ml) to pH 1. The resulting mixture was extracted with ethyl acetate (3 x 80 ml). The combined ethyl acetate extracts were washed with brine (60 ml) and then dried (MgSO 4). The solvent was removed in vacuo to give 11.5 g of N-benzyloxycarbonyl-a-amino-a-methylisoglutamine: XH NMR (CDC13 / DMS0) d (7.35 (m, 5H), 7.01 (s, IH), 6.87 (s, 1H), 6.29 (s, 1H), 5.04 (s, 2H), 2. 24-1.88 (m, 4H), 1.53 (s, 3H). In a similar form of N-benzylcarbonyl-α-ethylglutamic anhydride and N-benzylcarbonyl-α-propylglutamic anhydride, N-benzyloxycarbonyl-a-amino-a-ethylisoglutamine and N-benzyloxycarbonyl-a-amino-a-propylisoglutamine, respectively, are obtained. EXAMPLE 4 N-Benzyloxycarbonyl-α-amino-α-methylglutarimide A stirred mixture of N-benzyloxycarbonyl-α-methylisoglutamine (4.60 g, 15.6 mmol), 1,1'-carbonyldiimidazole (2.80 g, 17.1 mmol), and 4-dimethylaminopyridine. (0.05 g) in tetrahydrofuran (50 ml) were heated to reflux under nitrogen for 17 hours. The reaction mixture was then concentrated in vacuo in an oil. The oil was mixed in water (50 ml) for 1 hour. The resulting suspension was filtered and the solid was washed with water and dried with air to yield 3.8 g of the crude product as a white solid. The crude product was purified by flash chromatography (methylene chloride: ethyl acetate 8: 2) to yield 2.3 g (50%) of N-benzyloxycarbonyl-α-amino-α-methylglutarimide as a white solid, m.p. 150.5-152.5 ° C. * H NMR (CDC13) d 8.21 (s, 1H), 7.34 (s, 5H), 5.59 (s, 1H), 5.08 (s, 2H), 2.74-2.57 (m, 3H), 2.28-2.25 (, 1H) ), 1.54 (s, 3H); 13 C NMR (CDCl 3) d 174.06, 171.56, 154.68, 135.88, 128.06, 127.69, 127.65, 66.15, 54.79, 29.14, 28.70, 21.98; CLAP: Aguas Nova-Pak column C18, 4 microns, 3.9 x 150 mm, 1 ml / minute, 240 nm, 20/80 CH3CN / 0.1% H3P04 (ac), 7.56 minutes (100%); Analysis Calculated for C14H? 6N204; C, 60 86; H, 5 84; N, 10 14 Found: C, 60 88; H, 5 72; N, 10 07 In a similar form of N-benzyloxycarbonyl-a-amino-a-ethylisoglutamine and N-benzyloxycarbonyl-a-amino-a-propylisoglutamine N-benzyloxycarbonyl-a-amino-a-ethylglutarimide and N-benzyloxycarbonyl-a-amino- α-propylglutarimide, respectively. EXAMPLE 5 α-Amino-α-Methylglutarimide Hydrochloride N-Benzyloxycarbonyl-α-amino-α-methylglutarimide (2.3 g, 8.3 mmol) was dissolved in ethanol (200 mL) with gentle heat and the resulting solution was allowed to cool to room temperature . To this solution was added 4N hydrochloric acid (3 ml) followed by 10% Pd / C (0.4 g). The mixture was hydrogenated in a Parr apparatus under 50 psi of hydrogen for 3 hours. Water (50 ml) was added to the mixture to dissolve the product. This mixture was filtered through a pad of Celite which was washed with water (50 ml). The filtrate was concentrated in vacuo to yield a solid residue. The solid was mixed in ethanol (20 ml) for 30 minutes. The mixture was filtered to yield 1.38 g (93%) of a-amino-a-methylglutarimide hydrochloride as a white solid: XH NMR (DMSO-d6) d 11.25 (s, 1H), 8.92 (s, 3H), 2.84 -2.51 (m, 2H), 2.35-2.09 (m, 2H), 1.53 (s, 3H); CLAP, Aguas Nova-Pak column C? 8, 4 microns, 1 ml / minutes, 240 nm, 20/80 CH3CN / 0.1% H3P04 (ac) 1.03 minutes (94.6%). In a similar form of N-benzyloxycarbonyl-a-amino-a-ethylgutarimide and N-benzyloxycarbonyl-a-amino-a-propylgutarimide are obtained the a-amino-a-ethylgutarimide hydrochloride and the a-amino-a-hydrochloride propylglutarimide, respectively. EXAMPLE 6 3- (3-Nitrophalamido) -3-methylpiperidine-2,6-dione A stirred mixture of a-amino-a-methylglutarimide hydrochloride (1.2 g, 6.7 mmol), 3-nitrophthalic anhydride (1.3 g, 6.7 mmol) ) and sodium acetate (0.6 g, 7.4 mmol) in acetic acid (30 mL) were heated to reflux under nitrogen for 6 hours. The mixture was then cooled and concentrated in vacuo. The resulting solid was stirred in water (30 ml) and methylene chloride (30 ml) for 30 minutes. The suspension was filtered, the solid was washed with methylene chloride, and dried in vacuo (60 ° C, <1 mm) to yield 1.44 g (68%) of 3- (3-nitrophalamido) -3-methylpiperidin-2,6-dione as an off-white solid: m.p. 265-266.5 ° C; XH NMR (DMSO-d6) d 11.05 (s, 1H), 8.31 (dd, J = l .1 and 7.9 Hz, 1H), 8.16-8.03 (m, 2H), 2.67-2.49 (m, 3H), 2.08 -2.02 (m, 1H), 1.88 (s, 3H); 13 C NMR (DMSO-d 6) d 172.20, 171.71, 15.89, 163.30, 144.19, 136.43, 133.04, 128.49, 126.77, 122.25, 59.22, 28.87, 28.49, 21.04; CLAP, Water Nova-Pak / Cis column, 4 microns, 1 ml / minutes, 240 nm, 20/80 CH3CN / 0.1% H3P04 (aq), 7.38 minutes (98%). Analysis calculated for C? 4H ?? N306: C, 53.00; H, 3.49 N, 13.24. Found: C, 52.77; H, 3.29; N, 13.00 In a similar form of a-amino-a-ethylglutarimide hydrochloride and a-amino-a-propylgutarimide hydrochloride, 3- (3-nitrophthalimido) -3-ethylpiperidin-2,6-dione and 3- (3-nitrophthalimide) are obtained. ) -3-propylpiperidin-2, -6-dione, respectively. EXAMPLE 7 3- (3-aminophthalimido) -3-methyl-piperidin-2,6-dione 3- (3-Nitrophthalimido) -3-methylpiperidine-2,6-dione (0.5 g, 1.57 mmol.) Was dissolved in acetone (250 ml) with mild heat and then cooled to room temperature, 10% Pd / C (0.1 g) was added under nitrogen, and the mixture was hydrogenated in a Parr apparatus at 50 psi hydrogen for 4 hours. The mixture was then filtered through Celite and the pad washed with acetone (50 ml) The filtrate was concentrated in vacuo to yield a yellow solid The solid was mixed in ethyl acetate (10 ml) for 30 minutes The mixture was then filtered and dried (60 ° C, <1 mm) to yield 0.37 g (82%) of 3- (3-aminophthalimido) -3-methylpiperidin-2,6-dione as a yellow solid: mp 268-269 ° C; XH NMR (DMSO-d6) d (10.98 (s, 1H), 7.44 (dd, 1 = 7.1 and 7.3 Hz, 1H), 6.99 (d,] = 8.4 Hz, 1H), 6.94 (d,] = 6.9 Hz, 1H), 6.52 (s, 2H), 2.71-2.47 (m, 3H), 2.08-1.99 (m, 1H), 1.87 (s, 3H), 13C NMR (DMSO-d6) d (172.48, 172.18, 169.51, 168.06, 146.55, 135.38, 131.80, 121.51, 110.56, 108.30, 58.29, 29.25, 28.63, 21.00; CLAP, Water Nova-Pak / column Cie, 4 microns, 1 ml / minutes, 240 nm, 20/80 CH3CN / 0.1% H3PO4 (ac), 5.62 minutes (99.18%). Analysis calculated for C? 4H? 3N304: C, 58.53; H, 4.56; N, 14.63. Found: C, 58.60; H, 4.41; N, 14.36.- In a similar form of 3- (3-nitrophthalimido) -3-ethylpiperidin-2,6-dione and 3- (3-nitrophthalimido) -3-propylpiperidin-2,6-dione, 3- ( 3-amino-phthalimido) -3-ethylpiperidin-2,6-dione and 3- (3-aminophthalimido) -3-propyl-piperidin-2,6-dione, respectively. EXAMPLE 8 Methyl 2-bromomethyl-3-nitrobenzoate A stirred mixture of methyl 2-methyl-3-nitrobenzoate (17.6 g, 87.1 mmol) and N-bromosuccinimide (18.9 g 105 mmol) in carbon tetrachloride (243 ml) was heated under gentle reflux with a light bulb of 100 W, located 2 cm out of reflux in the reaction mixture overnight. After 18 hours, the reaction mixture was cooled to room temperature and filtered. The filtrate was washed with water (2 x 120 mL), brine (120 mL) and dried (MgSO). The solvent was removed in vacuo to give a yellow solid. The product was purified by flash chromatography (hexane: ethyl acetate 8: 2) to give 22 g (93%) of methyl 2-bromomethyl-3-nitrobenzoate as a yellow solid: m.p. 69-72 ° C; XH NMR (CDC13) d (8.13-8.09 (dd, J = 1.36 and 7.86 Hz, 1H), 7.98-7.93 (dd, J = 1.32 and 8.13 Hz, 1H), 7.57-7.51 (t, J = 7.97Hz, 1H), 5.16 (s, 2H), 4.0 (s, 3H), 13C NMR (CDC13) d (65.84, 150.56, 134.68, 132.64, 132.36, 129.09, 53.05, 22.70, CLAP: Water Nova-Pak column C? 8 , 4 microns, 1 ml / minute, 240 nm, 40/60 CH3CN / 0.1% H3P04 (ac), 8.2 minutes 99% Analysis calculated for C9H8N04Br: C, 39.44; H, 2.94; N, 5.11, Br. 29.15 Found: C, 39.51; H, 2.79; N, 5.02; Br. 29.32.Example 9 3- (l-oxo-4-nitroisoindolin-l-yl) -3-methylpiperidin-2,6-dione To a stirred mixture of a-amino-a-methylglutarimide hydrochloride (2.5 g, 14.0 mmol) and methyl 2-bromoethyl-3-nitrobenzoate (3.87 g, 14.0 mmol in dimethylformamide (40 mL) were added triethylamine (3.14 g, 30.8 mmol). The resulting mixture is heated to reflux under nitrogen for 6 hours.The mixture is cooled and then concentrated in vacuo.The resulting solid is stirred in water (50 ml) and CH2C12 for 30 minutes. , the solid was washed with methylene chloride, and dried in vacuo (60 ° C, <1 mm) to give 2.68 g (63%) of 3- (1-oxo-4-nitroisoindolin-1-yl) -3-methylpiperidin-2,6-dione as an off-white solid: m.p. 233-235 ° C: H NMR (DMSO-d6) d (10.95 (s, IH), 8.49-8.46 (d, J = 8.15 Hz, 1H), 8.13-8.09 (d, J = 7.43 Hz, 1H), 7.86-7.79 (t, J = 7.83 Hz, 1H), 5.22-5.0 (dd, J = 19.35 and 34.6 Hz, 2H), 2.77-2.49 (m, 3H), 2.0-1.94 (m, 1H), 1.74 ( S, 3H); 13C NMR (DMSO-d6) d (173.07, 172.27, 164.95, 143.15, 137.36, 135.19, 130.11, 129.32, 126.93, 57.57, 48.69, 28.9, 27.66, 20.6, HPLC, Water Nova-Pak column C ß, 4 microns, 1 ml / min, 240 nm, 20/80 CH3CN / 0.1% H3P04 (aq), 4.54 min 99.6%, Anal., Calculated for C14H13 3O5: C, 55.45; H, 4.32; N, 13.86. Found: C, 52.16; H, 4.59; N, 12.47 Substituting equivalent amounts of a-amino-a-ethylglutarimide hydrochloride and a-amino-a-propylglutarimide hydrochloride for a-amino-a-methylglutarimide hydrochloride are respectively obtained 3- (1-oxo-4-nitro-satolin-1-yl) -3-ethyl-piperidin-2,6-dione and 3- (1-oxo-4-nitroisoindolin-1-yl) -3-propyl-piperidin-2, 6- dione EXAMPLE 10 3- (l-Oxo-4-aminoisoindolin-l-yl) -3-methylpiperidin-2,6-dione 3- (l-Oxo-4-nitroinsoindolin-l-yl) -3-methylpiperidin-2,6-dione (1.0 g, 3.3 mmol) was dissolved in methanol (500 ml) under mild heat and allowed to cool to room teature . To this solution was added 10% Pd / C (0.3 g) under nitrogen. The mixture was hydrogenated in a Parr apparatus at 50 psi of hydrogen for 4 hours. The mixture was filtered through celite and the celite was washed with methanol (50 ml). The filtrate was concentrated in vacuo to an off-white solid. The solid was stirred in methylene chloride (20 mL) for 30 minutes. The mixture was then filtered and the solid was dried (60 ° C <1 mm) to yield 0.54 g (60%) of 3- (l-oxo-4-aminoisondinolin-1-yl) -3-methylpiperidin-2, 6-dione as a white solid: mp 268-270 ° C; XH NMR (DMSO-d6) d (10.85 (s, 1H), 7.19-7.13 (t, J = 7.63 Hz, 1H), 6.83-6.76 (m, ~ H), 5.44 (s, 2H), 4.41 (s) , 2H), 2.71-2.49 (m, 3H), 1.9-1.8 (m, 1H), 1.67 (s, 3H); 13C NMR (DMSO-d6) -d (173.7, 172.49, 168.0, 143.5, 132.88, 128.78 , 125.62, 116.12, 109.92, 56.98, 46.22, 99.04, 27.77, 20.82; CLAP, Nova-Pak Waters / C18 column 4 microns, 1 ml / min, 240 nm, 20/80 CH3CN / 0.1% H3P04 (ac), 1.5 min (99.6%): Anal Calculated for C? 4H? 5N303: C, 61.53; H, 5.53; N, 15.38. Found: C, 58.99; H, 5.48; N, 14.29. oxo-4-nitroisoindolin-l-yl) -3-ethylpiperidin-2,6-dione and 3- (l-oxo-4-nitroisoindolin-l-yl) -3-propylpiperidin-2,6-dione were similarly obtained. - (l-oxo-4-aminoisoindolin-l-yl) -3-ethylpiperidin-2,6-dione and 3- (l-oxo-4-aminoisoindolin-l-yl) -3-propylpiperidin-2,6-dione EXAMPLE 11 The tablets, each containing 50 mg of 1-oxo-2- (2,6-dioxo-3-methylpiperidin-3-yl) -4,5,6,7-tetrafluoroiso-indoline, can Prepare as follows: Co nstitutents (for 1000 tablets) l-oxo-2- (2,6-dioxo-3-methyl piperidin-3-yl) -4,5,6,7- tetrafluoroisoindoline 50.0 g lactose 50.7 g wheat starch 7.5 g glycol polyethylene 5.0 g talcum 5.0 g magnesium stearate 1.8 g demineralised water c. s. The solid ingredients are first forced through a 0.6 mm wide mesh screen. The active ingredient, lactose, talcum, magnesium stearate and half the starch are then mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water. The resulting paste is added to the pulverulent substances and the mixture is granulated, if necessary with the addition of water. The granulate is dried overnight at 35 ° C, forced through a 1.2 mm wide mesh screen and compressed to form tablets of approximately 6 mm in diameter which are concave on both sides. EXAMPLE 12 The tablets, each containing 100 mg of 1-oxo-2- (2,6-dioxopiperidin-3-yl) -4-aminoisoindoline, can be prepared as follows: Constituents (for 1000 tablets) l-oxo -2- (2,6-dioxo-piperidin-3-yl) -4-amino isoindoline 100.0 g lactose 100.0 g wheat starch 47.0 g magnesium stearate 3.0 g All solid ingredients are first forced through a 0.6 sieve mm wide mesh. The active ingredient, lactose, magnesium stearate and half of the starch are then mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to 100 ml of the boiling water. The resulting paste is added to the pulverulent substances and the mixture is granulated, if necessary with the addition of water. The granulate is dried overnight at 35 ° C, forced through a 1.2 mm wide mesh screen and compressed to form tablets of approximately 6 mm in diameter which are concave on both sides. EXAMPLE 13 The chewable tablets, each containing 75 mg of 2- (2,6-dioxo-3-methylpiperidin-3-yl) -4-aminophthalimide, can be prepared as follows: Composition (for 1000 tablets) 2 - (2,6-dioxo-3-methylpiperidin-3-yl) -4-aminophthalamide 75.0 g mannitol 230.0 g lactose 150.0 g talcum 21.0 g glycine 10.0 g saccharin 1.5 g 5% gelatin solution cs All solid ingredients are first forced through a 0.25 mm wide mesh screen. Mannitol and lactose are mixed, they are granulated with the addition of gelatin solution, forced through a 2 mm wide mesh screen, dried at 50 ° C and again forced through a 1.7 mm wide mesh screen. 2- (2,6-dioxo-3-methylpiperidin-3-yl) -4-aminophthalimide, glycine and saccharin are carefully mixed, mannitol, granulated lactose, stearic acid and touch are added and the mixture is mixed. Completely complete and compress to form tablets of approximately 10 mm in diameter, which are concave on both sides and have a rupture groove on the upper side. EXAMPLE 14 The tablets, each containing 10 mg of 2- (2,6-dioxoethyl-piperidin-3-yl) -4-aminophthalimide, can be prepared as follows: Composition (for 1000 tablets) 2- (2,6-dioxoethylpiperidine) -3-yl) - 4-aminophthalamide 10.0 g lactose 328.5 g corn starch 17.5 g polyethylene glycol 6000 5.0 g talcum 25.0 g magnesium stearate 4.0 g demineralised water c. s. The solid ingredients are first forced through a 0.6 mm wide mesh screen. Then the ingredient of active imide, lactose, talcum, magnesium stearate and half of the starch are intimately mixed. The other half of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 260 ml of water. The resulting paste is added to the pulverulent substances, and everything is mixed and granulated, if necessary with the addition of water. The granulate is dried overnight at 35 ° C, forced through a 1.2 mm wide mesh screen and compressed to form tablets of approximately 10 mm in diameter which are concave on both sides and have a notch in the middle. rupture on the upper side. EXAMPLE 15 Dry filled gelatin capsules, each containing 100 mg of l-oxo-2- (2,6-dioxo-3-methyl-piperidin-3-yl) -4,5,6,7-tetrafluoroisoindoline, can be prepared as follows: Composition (for 1000 capsules) l-oxo-2- (2,6-dioxo-3-methylpiperidin-3-yl) -4,5,6,7-tetrafluoroisoindoline 100.0 g microcrystalline cellulose 30.0 g lauryl sulfate of sodium 2.0 g magnesium stearate 8.0 g Sodium lauryl sulfate was sieved in l-oxo-2- (2,6-dioxo-3-methylpiperidin-3-yl) -4,5,6,7-tetrafluoro-isondinoline a through a wide mesh screen of 0.2 mm and the two components are intimately mixed for 10 minutes. The microcrystalline cellulose is then added through a 0.9 mm wide mesh screen and the whole is again intimately mixed for 10 minutes.

Finally, the magnesium stearate is added through a sieve of 9 mesh wide 8 mm and, after mixing for 3 additional minutes, the mixture is introduced in portions of 140 mg each in a size 0 (elongated) capsules of gelatine filled dry. EXAMPLE 16 A 0.2% injection or infusion solution can be prepared, for example, in the following manner: l-oxo-2- (2,6-dioxo-3-methyl piperidin-3-yl) -4.5, 6, 7-tetrafluoro isoindoline 5.0 g sodium chloride 22.5 g phosphate buffer pH 7.4 .. 300.0 g demineralized water at 2500 ml l-oxo-2- (2,6-dioxo-3-methylpiperidin-3-yl) was dissolved -4, 5, 6, 7-tetrafluoroisoindoline in 1000 ml of water and filtered through a microfilter. The pH regulator solution was added and the total was made at 2500 ml with water. To prepare dosage unit forms, the 1.0 or 2.5 ml portions each were introduced into glass ampules (each containing respectively 2.0 or 5.0 mg of imide).

Claims (12)

1. CLAIMS 1. A 2,6-dioxopiperidine selected from the group consisting of (a) a compound of the formula: in which: one of X and Y is C = 0 and another of X and Y is C = 0 or CH2; (i) each of R1, R2, R3 and R4, independently of others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3 , and R 4 is -NHR 5 and the rest of R 1, R 2, R 3 and R 4 are hydrogen; R5 is hydrogen or alkyl of 1 to 8 carbon atoms, or C0-R7-CH (R10) NR8R9; R6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro; R7 is m-phenylene or p-phenylene or - (CnH2n) - wherein n has a value from 0 to 4; each of R8 and R9 taken independently of each other is hydrogen or alkyl of 1 to 8 carbon atoms, or R8 and R9 taken together are tetramethylene, pentamethylene, hexamethylene or -CH2CH2XCH2CH2- wherein X is -0-, -S- or -NH-; R10 is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl; and (b) the acid addition salts of the compounds which contain a nitrogen atom capable of being protonated.
2. 2. The compound according to claim 1, characterized in that each of R1, R2, R3 and R4, independent of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms; R6 is hydrogen, methyl, ethyl or propyl; R7 is / n-phenylene or p-phenylene; each of R8 and R9 taken independently of the other is hydrogen or methyl; and R10 is hydrogen.
3. The compound according to claim 1, characterized in that each of R1, R2, R3, and R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms; R6 is hydrogen, methyl, ethyl or propyl; R7 is - (CnH2n) _ in which n has a value from 0 to 4; each of R8 and R9 taken independently of the others is hydrogen or methyl; and R10 is hydrogen.
4. 4. The compound according to claim 1, characterized in that each of R1, R2, R3 and R4 is -NH2 and the rest of R1, R2, R3 and R4 are hydrogen; R6 is hydrogen, methyl, ethyl or propyl; R7 is m-phenylene or p-phenylene; each of R8 and R9 taken independently of the other is hydrogen or methyl; and R10 is hydrogen.
5. The compound according to claim 1, characterized in that each of R1, R2, R3 and R4 is -NH2 and the rest of R1, R2, R3 and R4 are hydrogen, R6 is hydrogen, methyl, ethyl or propyl; R7 is or - (CnH2n) - wherein n has a value from 0 to 4; each of R8 and R9 taken independently of the other is hydrogen or methyl; and R10 is hydrogen.
6. 6. A 2,6-dioxopiperidine selected from the group consisting of (a) a compound of the formula: in which: one of X and Y is C = 0 and another of X and Y is C = 0 or CH2; (i) each of R1, R2, R3 and R4, independently of others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3 , Y R is -NHR5 and the rest of R1, R2, R3 and R4 are hydrogen; R is hydrogen or alkyl of 1 to 8 carbon atoms, or CO-R-CH (R10) NR8R9; R6 is alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro; R7 is m-phenylene or p-phenylene or - (CnH2n) - wherein n has a value from 0 to 4; each of R8 and R9 taken independently of each other is hydrogen or alkyl of 1 to 8 carbon atoms, or R8 and R9 taken together are tetramethylene, pentamethylene, hexamethylene or -CH2CH2XCH2CH2- wherein X is -O-, -S- or -NH-; R10 is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl; and (b) the acid addition salts of the compounds which contain a nitrogen atom capable of being protonated.
7. The compound according to claim 6, characterized in that each of R1, R2, R3 and R4 independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms and R6 is methyl, ethyl or propyl.
8. The compound according to claim 6, characterized in that each of R1, R2, R3 and R4 is -NH2 and the rest of R1, R2, R3 and R4 are hydrogen and R6 is methyl, ethyl or propyl.
9. 9. The method of reducing undesirable levels of TNFa in mammals, characterized in that it comprises administering to it an effective amount of a compound according to claim 1.
10. 10. The method of reducing undesirable levels of TNFα in mammals, characterized in that it comprises administering thereto an effective amount of a compound according to claim 6.
11. 11. A pharmaceutical composition, characterized in that it comprises an amount of a compound according to claim 1, sufficient for administration in a single or multiple dose regimen to reduce TNFa levels in mammals in combination with a carrier.
12. 12. A pharmaceutical composition, characterized in that it comprises an amount of a compound according to claim 6, sufficient for administration in a single or multiple dose regimen to reduce levels of TNFa in a mammal in combination with a carrier.