WO1998003502A1 - Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and method of reducing tnf-alpha levels - Google Patents
Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and method of reducing tnf-alpha levels Download PDFInfo
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- WO1998003502A1 WO1998003502A1 PCT/US1997/013375 US9713375W WO9803502A1 WO 1998003502 A1 WO1998003502 A1 WO 1998003502A1 US 9713375 W US9713375 W US 9713375W WO 9803502 A1 WO9803502 A1 WO 9803502A1
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Definitions
- the present invention relates to substituted 2-(2,6-dioxopiperidin-3-yl)phthal- imides and substituted 2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolines, the method of reducing levels of tumor necrosis factor ⁇ in a mammal through the administration thereof, and pharmaceutical compositions of such derivatives.
- Tumor necrosis factor ⁇ is a cytokine which is released primarily by mononuclear phagocytes in response to a number immunostimulators. When administered to animals or humans, it causes inflammation, fever, cardiovascular effects, hemorrhage, coagulation, and acute phase responses similar to those seen during acute infections and shock states. Excessive or unregulated TNF ⁇ production thus has been implicated in a number of disease conditions. These include endo- toxemia and/or toxic shock syndrome ⁇ Tracey et al, Nature 330, 662-664 (1987) and Hinshaw et al, Circ.
- TNF ⁇ appears to be involved in bone resorption diseases, including arthritis. When activated, leukocytes will produce bone-resorption, an activity to which the data suggest TNF ⁇ contributes. ⁇ Bertolini et al, Nature 319, 516-518 (1986) and Johnson et al, Endocrinology 124(3), 1424-1427 (1989). ⁇ TNF ⁇ also has been shown to stimulate bone resorption and inhibit bone formation in vitro and in vivo through stimulation of osteoclast formation and activation combined with inhibition of osteoblast function. Although TNF ⁇ may be involved in many bone resorption diseases, including arthritis, the most compelling link with disease is the association between production of TNF ⁇ by tumor or host tissues and malignancy associated hypercalcemia ⁇ Calci. Tissue Int.
- Cerebral malaria is a lethal hyperacute neurological syndrome associated with high blood levels of TNF ⁇ and the most severe complication occurring in malaria patients. Levels of serum TNF ⁇ correlated directly with the severity of disease and the prognosis in patients with acute malaria attacks ⁇ Grau et al, N. Engl J. Med. 320(24), 1586-1591 (1989) ⁇ .
- TNF ⁇ Macrophage-induced angiogenesis TNF ⁇ is known to be mediated by TNF ⁇ .
- TNF ⁇ induces in vivo capillary blood vessel formation in the rat cornea and the developing chick chorioallantoic membranes at very low doses and suggest TNF ⁇ is a candidate for inducing angiogenesis in inflammation, wound repair, and tumor growth. TNF ⁇ production also has been associated with cancerous conditions, particularly induced tumors ⁇ Ching et al, Brit. J. Cancer, (1955) 72, 339-343, and Koch, Progress in Medicinal Chemistry, 22, 166-242 (1985) ⁇ .
- TNF ⁇ also plays a role in the area of chronic pulmonary inflammatory diseases.
- silica particles leads to silicosis, a disease of progressive respiratory failure caused by a fibrotic reaction.
- Antibody to TNF ⁇ completely blocked the silica-induced lung fibrosis in mice ⁇ Pignet et al, Nature, 344:245-247 (1990) ⁇ .
- TNF ⁇ is also implicated in the inflammatory response which follows reperfusion, called reperfusion injury, and is a major cause of tissue damage after loss of blood flow ⁇ Vedder et al. , PNAS 87, 2643-2646 (1990) ⁇ .
- TNF ⁇ also alters the properties of endothelial cells and has various pro-coagulant activities, such as producing an increase in tissue factor pro-coagulant activity and suppression of the anticoagulant protein C pathway as well as down-regulating the expression of thrombomodulin ⁇ Sherry et al, J. Cell Biol. 107, 1269-1277 (1988) ⁇ .
- TNF ⁇ has pro-inflammatory activities which together with its early production (during the initial stage of an inflammatory event) make it a likely mediator of tissue injury in several important disorders including but not limited to, myocardial infarction, stroke and circulatory shock.
- adhesion molecules such as intercellular adhesion molecule (ICAM) or endothelial leukocyte adhesion molecule (ELAM) on endothelial cells ⁇ Munro et al. Am. J. Path. 135(1), 121-132 (1989) ⁇ .
- TNF ⁇ blockage with monoclonal anti-TNF ⁇ 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 ⁇
- TNF ⁇ is a potent activator of retrovirus replication including activation of HIV-1.
- HIV Human Immunodeficiency Virus
- HIV-1 HIV-1
- HIV-2 HIV-2
- HIV-3 HIV-3
- T-cell mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms.
- HIV entry into the T lymphocyte requires T lymphocyte activation.
- 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.
- the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication.
- Cytokines are implicated in activated T-cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by prevention or inhibition of cytokine production, notably TNF ⁇ , in an HIV-infected individual assists in limiting the maintenance of T lymphocyte caused by HIV infection.
- Monocytes, macrophages, and related cells, such as kupffer and glial cells also have been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells.
- TNF ⁇ cytokine production or activity aids in limiting HIV progression for T cells.
- Additional studies have identified TNF ⁇ as a common factor in the activation of HIV in vitro and has provided 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 TNF ⁇ synthesis may have an antiviral effect in HIV infections, by reducing the transcription and thus virus production.
- AIDS viral replication of latent HIV in T cell and macrophage lines can be induced by TNF ⁇ ⁇ Folks et al, PNAS 86, 2365-2368 (1989) ⁇ .
- a molecular mechanism for the virus inducing activity is suggested by TNF ⁇ 's ability to activate a gene regulatory protein (NFKB) found in the cytoplasm of cells, which promotes HIV replication through binding to a viral regulatory gene sequence (LTR) ⁇ Osborn et al, PNAS 86, 2336-2340 (1989) ⁇ .
- TNF ⁇ in AIDS associated cachexia is suggested by elevated serum TNF ⁇ and high levels of spontaneous TNF ⁇ production in peripheral blood monocytes from patients ⁇ Wright et al, J. Immunol.
- TNF ⁇ has been implicated in various roles with other viral infections, such as the cytomega- lia virus (CMV), influenza virus, adenovirus, and the herpes family of viruses for similar reasons as those noted.
- CMV cytomega- lia virus
- influenza virus influenza virus
- adenovirus adenovirus
- herpes family of viruses for similar reasons as those noted.
- NFKB nuclear factor KB
- the nuclear factor KB 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 disease and inflammatory states and is thought to regulate cytokine levels including but not limited to TNF ⁇ and also to be an activator of HIV transcription (Dbaibo, et al, J. Biol. Chem. 1993, 17762-66; Duh et al, Proc. Natl. Acad. Sci. ⁇ 1989, 86, 5974-78; Bachelerie et al, Nature 1991 , 350, 709-12; Boswas et al, J.
- TNF ⁇ and NFKB levels are influenced by a reciprocal feedback loop. As noted above, the compounds of the present invention affect the levels of both TNF ⁇ and NFKB.
- cAMP adenosine 3',5'-cyclic monophos- phate
- TNF ⁇ levels and/or increasing cAMP levels thus constitutes a valuable therapeutic strategy for the treatment of many inflammatory, infectious, immunologi- cal, and malignant diseases.
- diseases include but are not restricted 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, graft rejection, oncogenic or cancerous conditions, asthma, autoimmune disease, opportunistic infections in AIDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, other arthritic conditions, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythrematosis, ENL in leprosy, radiation damage, oncogenic conditions, and hyperoxic alveolar injury.
- the present invention is based on the discovery that certain classes of non- polypeptide compounds more fully described herein decrease the levels of TNF ⁇ .
- each of R 1 , R 2 , R 3 , and R 4 is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R 1 , R 2 , R , and
- R 4 is -NHR 5 and the remaining of R 1 , R 2 , R , and R 4 are hydrogen;
- R is hydrogen or alkyl of 1 to 8 carbon atoms
- a preferred group of compounds are those of Formula I in which each of R , R , R 3 , and R 4 , independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, and R is hydrogen, methyl, ethyl, or propyl.
- a second preferred group of compounds are those of Formula I in which one of R , R , R , and R 4 is -NH 2 , the remaining of R 1 , R , R , and R 4 are hydrogen, and R is hydrogen, methyl, ethyl, or propyl.
- alkyl denotes a univalent saturated branched or straight hydrocarbon chain containing from 1 to 8 carbon atoms.
- alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, and tert-butyl.
- Alkoxy refers to an alkyl group bound to the remainder of the molecule through an ethereal oxygen atom.
- Representative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.
- R , R , R , and R are chloro, fluoro, methyl or methoxy.
- the compounds of Formula I are used, under the supervision of qualified professionals, to inhibit the undesirable effects of TNF ⁇ .
- the compounds can be adminis- tered 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 also can be used topically in the treatment or prophylaxis of topical disease states mediated or exacerbated by excessive TNF ⁇ production, respectively, such as viral infections, such as those caused by the herpes viruses, or viral conjunctivitis, psoriasis, atopic dermatitis, etc.
- TNF ⁇ mediated diseases for treatment, therapeutical ly or prophylactically, in animals include disease states such as those noted above, but in particular viral infections. Examples include feline immunodeficiency virus, equine infectious anaemia virus, caprine arthritis virus, visna virus, and maedi virus, as well as other lentiviruses.
- R , R , R . R is amino and R and R , as well as the remainder of R , R , R , R , are hydrogen, as for example, l ,3-dioxo-2-(2,6- dioxopiperidin-3-yl)-4-aminoisoindoline or 1 ,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5- aminoisoindoline are known. See, e.g., J ⁇ nsson, Acta Pharma. Succica, 9, 521-542
- the compounds can be prepared using methods which are known in general.
- the compounds can be prepared through the reaction of 2,6- dioxopi ⁇ eridin-3-ammonium chloride, and a lower alkyl ester of 2-bromomethylben- zoic acid in the presence of an acid acceptor such as dimethylaminopyridine or triethylamine.
- substituted benzoate intermediates are known or can be obtained though conventional processes.
- a lower alkyl ester of an or/ ⁇ o-toluic acid is brominated with N-bromosuccinimide under the influence of light to yield the lower alkyl 2-bromomethylbenzoate.
- a dialdehyde is allowed to react with glutamine and the resulting 2-( 1 -oxoisoindolin-2-yl)glutaric acid then cyclized to yield a l-oxo-2-(2,6- dioxopiperidin-3-yl)-isoindoline of Formula I:
- Amino compounds can be prepared through catalytic hydrogenation of the corresponding nitro compound:
- nitro intermediates of Formula IA are known or can be obtained though conventional processes.
- a lower alkyl ester of nitro-or/ ⁇ o-toluic acid is brominated with N-bromosuccinimide under the influence of light to yield a lower alkyl 2- (bromomethyl)nitrobenzoate.
- protecting group can be cleaved to yield the corresponding compound in which one of R,, R 2 , R , and ⁇ , is amino.
- Protecting groups utilized herein denote groups which generally are not found in the final therapeutic compounds but which are intentionally introduced at some stage of the synthesis in order to protect groups which otherwise might be altered in the course of chemical manipulations. Such protecting groups are removed at a later stage of the synthesis and compounds bearing such protecting groups thus are of importance primarily as chemical intermediates (although some derivatives also exhibit biological activity). Accordingly the precise structure of the protecting group is not critical.
- An amino group can be protected as an amide utilizing an acyl group which is selectively removable under mild conditions, espe- aily benzyloxycarbonyl, formyl, or a lower alkanoyl group which is branched in 1- or ⁇ position to the carbonyl group, particularly tertiary alkanoyl such as pivaloyl, a lower alkanoyl group which is substituted in the position ⁇ to the carbonyl group, as for example trifluoroacetyl.
- the compounds of the present invention possess a center of chirality and can exist as optical isomers.
- racemates of these isomers and the individual isomers themselves, as well as diastereomers when there are two chiral centers are within the scope of the present invention.
- the racemates can be used as such or can be separated into their individual isomers mechanically as by chromatography using a chiral adsorbent.
- the individual isomers can be prepared in chiral form or separated chemically from a mixture by forming salts with a chiral acid, such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, ⁇ -bromocam- phoric acid, methoxyacetic acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, and the like, and then freeing one or both of the resolved bases, optionally repeating the process, so as obtain either or both substantially free of the other; i.e., in a form having an optical purity of >95%.
- a chiral acid such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, ⁇ -bromocam- phoric acid, methoxyacetic acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, and the like
- the present invention also pertains to the physiologically acceptable non-toxic acid addition salts of the compounds of Formula I.
- Such salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydro- bromic acid, phosphoric acid, sulfuric acid, methanesulphonic acid, acetic acid, tartaric acid, lactic acid, succi ic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embonic acid, enanthic acid, and the like.
- organic and inorganic acids such as, without limitation, hydrochloric acid, hydro- bromic acid, phosphoric acid, sulfuric acid, methanesulphonic acid, acetic acid, tartaric acid, lactic acid, succi ic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embonic acid, enanthic acid, and
- Oral dosage forms include tablets, capsules, dragees, and similar shaped, com- pressed pharmaceutical forms containing from 1 to 1 0 mg of drug per unit dosage.
- Isotonic saline solutions containing from 20 to 100 mg/mL can be used for parenteral administration which includes intramuscular, intrathecal, intravenous and intra-arterial routes of administration. Rectal administration can be effected through the use of suppositories formulated from conventional carriers such as cocoa butter.
- compositions thus comprise one or more compounds of the present invention associated with at least one pharmaceutically acceptable carrier, diluent or excipient.
- the active ingredients are usually mixed with or diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule or sachet.
- the excipient serves as a diluent, it may be a solid. semi-solid, or liquid material which acts as a vehicle, carrier, or medium for the active ingredient.
- the compositions can 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.
- excipients examples include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidinone, cellulose, water, syrup, and methyl cellulose
- the formulations can additionally include lubricat- ing agents such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxyben- zoates, sweetening agents or flavoring agents.
- compositions preferably are formulated in unit dosage form, meaning physically discrete units suitable as a unitary dosage, or a predetermined fraction of a unitary dose to be administered in a single or multiple dosage regimen to human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.
- the compositions can be formulated so as to provide an immediate, sustained or delayed release of active ingredient after administration to the patient by employing procedures well known in the art.
- Oral dosage forms include tablets, capsules, dragees, and similar shaped, compressed pharmaceutical forms containing from 1 to 100 mg of drug per unit dosage.
- Isotonic saline solutions containing from 20 to 100 mg/mL can be used for parenteral administration which includes intramuscular, intrathecal, intravenous and intra-arterial routes of administration. Rectal administration can be effected through the use of suppositories formulated from conventional carriers such as cocoa butter.
- compositions thus comprise one or more compounds of the present invention associated with at least one pharmaceutically acceptable carrier, diluent or excipient.
- the active ingredients are usually mixed with or diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule or sachet.
- the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, carrier, or medium for the active ingredient.
- the compositions can 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.
- excipients examples include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidinone, cellulose. water, syrup, and methyl cellulose, the formulations can additionally include lubricating agents such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxyben- zoates, sweetening agents or flavoring agents.
- lubricating agents such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxyben- zoates, sweetening agents or flavoring agents.
- compositions preferably are formulated in unit dosage form, meaning physically discrete units suitable as a unitary dosage, or a predetermined fraction of a unitary dose to be administered in a single or multiple dosage regimen to human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.
- compositions can be formulated so as to provide an immediate, sustained or delayed release of active ingredient after administration to the patient by employing procedures well known in the art.
- 1 -Oxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline, 1 -oxo-2-(2,6-dioxopip- eridin-3-yl)-4-nitroisoindoline, l-oxo-2-(2,6-dioxopiperidin-3-yl)-6-nitroisoindoline, and l-oxo-2-(2,6-dioxopiperidin-3-yl)-7-nitroisoindoline can be obtained by allowing 2,6-dioxopiperidin-3-ammonium chloride to react with methyl 2-bromomethyl-5- nitrobenzoate, methyl 2-bromomethyl-4-nitrobenzoate, methyl 2-bromomethyl-6- nitrobenzoate, and methyl 2-bromomethyl-7-nitrobenzoate, respectively, in dimethylformamide in the presence of triethylamine.
- methyl 2-(bromomethyl)nitro- benzoates in turn are obtained from the corresponding methyl esters of r ⁇ t ⁇ o-ortho- toluic acids by conventional bromination with N-bromosuccinimide under the influ- ence of light.
- N-benzyloxycarbonyl- ⁇ -methyl-glutamic acid 15 g, 51 mmol
- acetic anhydride 65 mL
- the reaction mixture was cooled to room temperature and then concentrated in vacuo to afford N-benzylcarbonyl- ⁇ -methylglutamic anhydride as an oil (15.7 g) which can be used in next reaction without further purification:
- H NMR (CDC1 3 ) ⁇ 7.44-7.26 (m, 5H), 5.32-5.30 (m, 2H), 5.1 1 (s, IH), 2.69-2.61 (m, 2H), 2.40-2.30 (m, 2H), 1.68 (s, 3H).
- N-benzylcarbonyl- ⁇ -ethylglutamic anhydride N-benzylcarbonyl- ⁇ -propylglutamic anhydride there is obtained N-benzyloxycarbonyl- ⁇ -amino- ⁇ -ethylisoglutamine and N-benzyloxycarbonyl- ⁇ -amino- ⁇ -propylisogluta- mine, respectively.
- EXAMPLE 7 N-benzylcarbonyl- ⁇ -ethylglutamic anhydride and N- benzylcarbonyl- ⁇ -propylglutamic anhydride there is obtained N-benzyloxycarbonyl- ⁇ -amino- ⁇ -ethylisoglutamine and N-benzyloxycarbonyl- ⁇ -amino- ⁇ -propylisogluta- mine, respectively.
- N-Benzyloxycarbonyl- ⁇ -amino- ⁇ -methylglutarimide (2.3 g, 8.3 mmol) was dissolved in ethanol (200 mL) with gentle heat and the resulting solution allowed to cool to room temperature.
- 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 filtered through a Celite pad which was washed with water (50 mL). The filtrate was concentrated in vacuo to afford a solid residue.
- the solid was slurried in ethanol (20 mL) for 30 min.
- 3-(3-Nitrophthalimido)-3-methylpiperidine-2,6-dione (0.5 g, 1.57 mmol) was dissolved in acetone (250 mL) with gentle heat and then cooled to room temperature. To this solution was added 10% Pd/C (0.1 g) under nitrogen. The mixture was hydrogenated in a Parr apparatus at 50 psi of hydrogen for 4 hours. The mixture then was 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 slurried in ethyl acetate (10 mL) for 30 minutes.
- Hydrogen chloride gas was bubbled into a stirred 5°C solution of t-butyl N-(4- nitrophthaloyl)-L-glutamine (5.7 g, 15.1 mmol) in methylene chloride (100 mL) for 25 min. The mixture was then stirred at room temperature for 16 hours. Ether (50 mL) was added and the resulting mixture was stirred for 30 min.
- N-(4-Nitrophthaloyl)-D-glutamine Hydrogen chloride gas was bubbled into a stirred 5°C solution of t-butyl N-(4- nitrophthaloyl)-D-glutamine (5.9 g, 15.6 mmol) in methylene chloride (100 mL) for 1 hour then stirred at room temperature for another hour. Ether (100 mL) was added and stirred for another 30 minutes.
- Hydrogen chloride gas was bubbled into a stirred 5°C solution of /-butyl N-(l - oxo-4-nitro-isoindolin-2-yI)-L-glutamine (3.6 g, 9.9 mmol) in methylene chloride (60 mL) for 1 hour. The mixture was then stirred at room temperature for another hour. Ether (40 mL) was added and the resulting mixture was stirred for 30 minutes.
- the mixture was poured into ice water (200 mL) and the aqueous layer was extracted with methylene chloride (40 mL). The methylene chloride solution was washed with water (2 x 60 mL), brine (60 mL) and dried.
- Tablets each containing 50 mg of l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5- aminoisoindoline, can be prepared in the following manner: Constituents (for 1000 tablets)
- the solid ingredients are first forced through a sieve of 0.6 mm mesh width.
- the active ingredient, lactose, talc, magnesium stearate and half of the starch then are 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 sieve of 1.2 mm mesh width and compressed to form tablets of approximately 6 mm diameter which are concave on both sides.
- Tablets each containing 100 mg of l ,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5- aminoisoindoline, can be prepared in the following manner:
- All the solid ingredients are first forced through a sieve of 0.6 mm mesh width.
- the active ingredient, lactose, magnesium stearate and half of the starch then are mixed.
- the other half of the starch is suspended in 40 mL of water and this suspension is added to 100 mL of 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 sieve of 1.2 mm mesh width and compressed to form tablets of approximately 6 mm diameter which are concave on both sides.
- Tablets for chewing each containing 75 mg of l-oxo-2-(2,6-dioxopiperidin-3- yl)-4-aminoisoindoline, can be prepared in the following manner:
- composition for 1000 tablets
- All the solid ingredients are first forced through a sieve of 0.25 mm mesh width.
- the mannitol and the lactose are mixed, granulated with the addition of gelatin solution, forced through a sieve of 2 mm mesh width, dried at 50°C and again forced through a sieve of 1.7 mm mesh width.
- Tablets each containing 10 mg of l-oxo-2-(2,6-dioxopiperidin-3-yl)-5-amino- isoindoline, can be prepared in the following manner: Composition (for 1000 tablets)
- the solid ingredients are first forced through a sieve of 0.6 mm mesh width. Then the active imide ingredient, lactose, talc, 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 the whole is mixed and granulated, if necessary with the addition of water. The granulate is dried overnight at 35°C, forced through a sieve of 1.2 mm mesh width and com- pressed to form tablets of approximately 10 mm diameter which are concave on both sides and have a breaking notch on the upper side.
- Gelatin dry-filled capsules each containing 100 mg of l-oxo-2-(2.6-dioxopip- eridin-3-yl)-6-aminoisoindoline, can be prepared in the following manner:
- Composition for 1000 capsules
- the sodium lauryl sulfate is sieved into the l -oxo-2-(2,6-dioxopiperidin-3-yl)- 6-aminoisoindoline through a sieve of 0.2 mm mesh width and the two components are intimately mixed for 10 minutes.
- the microcrystalline cellulose is then added through a sieve of 0.9 mm mesh width and the whole is again intimately mixed for 10 minutes.
- the magnesium stearate is added through a sieve of 0.8 mm width and, after mixing for a further 3 minutes, the mixture is introduced in portions of 140 mg each into size 0 (elongated) gelatin dry-fill capsules.
- a 0.2% injection or infusion solution can be prepared, for example, in the following manner:
- l-Oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline is dissolved in 1000 mL of water and filtered through a microfilter.
- the buffer solution is added and the whole is made up to 2500 mL with water.
- Tablets each containing 50 mg of l-oxo-2-(2.6-dioxopiperidin-3-yl)-4, 5,6,7- tetrafluoroisoindoline, can be prepared in the following manner:
- the solid ingredients are first forced through a sieve of 0.6 mm mesh width.
- the active ingredient, lactose, talc, magnesium stearate and half of the starch then are mixed.
- the other half of the starch is suspended in 40 mL of water and this suspen- sion 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 sieve of 1.2 mm mesh width and compressed to form tablets of approximately 6 mm diameter which are concave on both sides.
- Tablets each containing 100 mg of l-oxo-2-(2,6-dioxopiperidin-3-yl)-4, 5,6,7- tetrachloroisoindoline, can be prepared in the following manner:
- All the solid ingredients are first forced through a sieve of 0.6 mm mesh width.
- the active ingredient, lactose, magnesium stearate and half of the starch then are mixed.
- the other half of the starch is suspended in 40 mL of water and this suspension is added to 100 mL of 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 sieve of 1.2 mm mesh width and compressed to form tablets of approximately 6 mm diameter which are concave on both sides.
- Tablets for chewing each containing 75 mg of l-oxo-2-(2,6-dioxopiperidin-3- yl)-4,5,6,7-tetrafluoroisoindoline, can be prepared in the following manner: Composition (for 1000 tablets)
- All the solid ingredients are first forced through a sieve of 0.25 mm mesh width.
- the mannitol and the lactose are mixed, granulated with the addition of gelatin solution, forced through a sieve of 2 mm mesh width, dried at 50°C and again forced through a sieve of 1.7 mm mesh width.
- Tablets each containing 10 mg of l-oxo-2-(2,6-dioxopiperidin-3-yl)-4, 5,6,7- tetramethylisoindoline, can be prepared in the following manner:
- composition for 1000 tablets
- the solid ingredients are first forced through a sieve of 0.6 mm mesh width.
- the active imide ingredient, lactose, talc, 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 the whole is mixed and granulated, if necessary with the addition of water.
- the granulate is dried overnight at 35°C, forced through a sieve of 1.2 mm mesh width and compressed to form tablets of approximately 10 mm diameter which are concave on both sides and have a breaking notch on the upper side.
- Gelatin dry-filled capsules each containing 100 mg of l-oxo-2-(2,6-dioxo- piperidin-3-yl)-4,5,6,7-tetramethoxyisoindoline, can be prepared in the following manner:
- Composition for 1000 capsules
- the sodium lauryl sulfate is sieved into the l-oxo-2-(2.6-dioxopiperidin-3-yl)- 4,5,6,7-tetramethoxyisoindoline through a sieve of 0.2 mm mesh width and the two components are intimately mixed for 10 minutes.
- the microcrystalline cellulose is then added through a sieve of 0.9 mm mesh width and the whole is again intimately mixed for 10 minutes.
- the magnesium stearate is added through a sieve of 0.8 mm width and, after mixing for a further 3 minutes, the mixture is introduced in portions of 140 mg each into size 0 (elongated) gelatin dry-fill capsules.
- a 0.2% injection or infusion solution can be prepared, for example, in the following manner: l-oxo-2-(2,6-dioxopiperidin-3-yl)-
- 1 -Oxo-2-(2,6-dioxopiperidin-3-yl)-4,5,6,7-tetrafluoroisoindoline is dissolved in 1000 mL of water and filtered through a microfilter.
- the buffer solution is added and the whole is made up to 2500 mL with water.
- portions of 1.0 or 2.5 mL each are introduced into glass ampoules (each containing respectively 2.0 or 5.0 mg of imide).
- Tablets each containing 50 mg of l-oxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)- 4,5,6, 7-tetrafluoroisoindoline, can be prepared in the following manner:
- the solid ingredients are first forced through a sieve of 0.6 mm mesh width.
- the active ingredient, lactose, talc, magnesium stearate and half of the starch then are mixed.
- the other half of the starch is suspended in 40 mL of water and this suspen- sion 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 sieve of 1.2 mm mesh width and compressed to form tablets of approximately 6 mm diameter which are concave on both sides.
- Tablets each containing 100 mg of l-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoiso- indoline, can be prepared in the following manner:
- All the solid ingredients are first forced through a sieve of 0.6 mm mesh width.
- the active ingredient, lactose, magnesium stearate and half of the starch then are mixed.
- the other half of the starch is suspended in 40 mL of water and this suspension is added to 100 mL of 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 sieve of 1.2 mm mesh width and compressed to form tablets of approximately 6 mm diameter which are concave on both sides.
- Tablets for chewing each containing 75 mg of 2-(2,6-dioxo-3-methylpiperidin-3- yl)-4-aminophthalimide, can be prepared in the following manner:
- composition for 1000 tablets
- All the solid ingredients are first forced through a sieve of 0.25 mm mesh width.
- the mannitol and the lactose are mixed, granulated with the addition of gelatin solu- tion, forced through a sieve of 2 mm mesh width, dried at 50°C and again forced through a sieve of 1.7 mm mesh width.
- 2-(2,6-Dioxo-3-methylpiperidin-3-yl)-4- aminophthalimide, the glycine and the saccharin are carefully mixed, the mannitol, the lactose granulate, the stearic acid and the talc are added and the whole is mixed thoroughly and compressed to form tablets of approximately 10 mm diameter which are concave on both sides and have a breaking groove on the upper side.
- Tablets each containing 10 mg of 2-(2,6-dioxoethylpiperidin-3-yl)-4-aminophthal- imide, can be prepared in the following manner:
- composition for 1000 tablets
- the solid ingredients are first forced through a sieve of 0.6 mm mesh width. Then the active imide ingredient, lactose, talc, 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 the whole is mixed and granulated, if necessary with the addition of water. The granulate is dried overnight at 35°C, forced through a sieve of 1.2 mm mesh width and compressed to form tablets of approximately 10 mm diameter which are concave on both sides and have a breaking notch on the upper side.
- Gelatin dry-filled capsules each containing 100 mg of l-oxo-2-(2,6-dioxo-3- methylpiperidin-3-yl)-4,5,6,7-tetrafluoroisoindoline. can be prepared in the following manner: Co position (for 1000 capsules)
- the sodium lauryl sulfate is sieved into the l-oxo-2-(2,6-dioxo-3-methylpiperidin-
- a 0.2% injection or infusion solution can be prepared, for example, in the following manner:
- l-Oxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4,5,6,7-tetrafluoroisoindoline is dissolved in 1000 mL of water and filtered through a microfilter.
- the buffer solution is added and the whole is made up to 2500 mL with water.
- portions of 1.0 or 2.5 mL each are introduced into glass ampoules (each containing respectively 2.0 or 5.0 mg of imide).
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Abstract
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Priority Applications (33)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK97936295.1T DK0925294T6 (en) | 1996-07-24 | 1997-07-24 | SUBSTITUTED 2- (2,6-DIOXOPIPERIDIN-3-YL) PHTHALIMIDES AND -1-OXOISOINDOLINES AND METHOD FOR REDUCING TNF-ALPHA LEVELS |
PL97373743A PL195916B1 (en) | 1996-07-24 | 1997-07-24 | 1-oxoisoindoline and 1,3-dioxoisoindoline substituted optic isomers, pharmaceutical compositions containing them and application thereof |
SK91-99A SK9199A3 (en) | 1996-07-24 | 1997-07-24 | 2,6-dioxopiperidines, pharmaceutical composition them containing and their use |
PL332867A PL191566B1 (en) | 1996-07-24 | 1997-07-24 | Substituted 2-(2-2,6-dioxopiperidin-3-yl)phtalamides and 1-oxoisoindolins as well as method of lowering the TNF-Ó level |
ES97936295.1T ES2187805T7 (en) | 1996-07-24 | 1997-07-24 | 2- (2,6-Dioxopiperidin-3-yl) -phthalimides and 1-oxoisoindolines and method to reduce TNF-alpha levels |
JP50725998A JP4065567B2 (en) | 1996-07-24 | 1997-07-24 | Substituted 2- (2,6-dioxopiperidin-3-yl) phthalimides and -1-oxoisoindolines and methods for reducing TNFα levels |
NZ333903A NZ333903A (en) | 1996-07-24 | 1997-07-24 | Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1oxoisoindolines and method of reducing TNF-alpha levels in a mammal |
HU9903929A HU228769B1 (en) | 1996-07-24 | 1997-07-24 | Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and their use for production of pharmaceutical compositions for mammals to reduce the level of tnf-alpha |
EP97936295.1A EP0925294B3 (en) | 1996-07-24 | 1997-07-24 | Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and method of reducing tnf-alpha levels |
KR10-1999-7000565A KR100534498B1 (en) | 1996-07-24 | 1997-07-24 | SUBSTITUTED 2-(2,6-DIOXOPIPERIDIN-3-YL)-PHTHALIMIDES AND -1-OXOISOINDOLINES AND METHOD OF REDUCING TNFa LEVELS |
DE69717831.5T DE69717831T3 (en) | 1996-07-24 | 1997-07-24 | SUBSTITUTED 2- (2,6-DIOXOPIPERIDIN-3-YL) -PHTHALIMIDES AND -1-OXOISOINDOLINES AND METHOD FOR REDUCING THE TNF-ALPHA MIRROR |
DE200712000079 DE122007000079I2 (en) | 1996-07-24 | 1997-07-24 | SUBSTITUTED 2- (2,6-DIOXOPIPERIDIN-3-YL) -PHTHALIMIDES AND -1-OXOISOINDOLINES AND METHOD FOR REDUCING THE TNF-ALPHA MIRROR |
AT97936295T ATE229521T3 (en) | 1996-07-24 | 1997-07-24 | SUBSTITUTED 2-(2,6-DIOXOPIPERIDINE-3-YL)-PHTHALIMIDES AND -1-OXOISOINDOLINES AND METHOD FOR REDUCING TNF-ALPHA LEVELS |
AU38998/97A AU715779C (en) | 1996-07-24 | 1997-07-24 | Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and method of reducing TNF-alpha levels |
CA 2261762 CA2261762C (en) | 1996-07-24 | 1997-07-24 | Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and method of reducing tnf-alpha levels |
RU99103124/04A RU2595250C1 (en) | 1996-07-24 | 1997-07-24 | SUBSTITUTED 2,6-DIOXOPIPERIDINES, PHARMACEUTICAL COMPOSITION BASED ON THEREOF AND METHODS OF DECREASE OF TUMOR NECROSIS FACTOR-α LEVEL |
UA99010371A UA60308C2 (en) | 1996-07-24 | 1997-07-24 | Substituted 2-(2,6-dioxopiperidin-3-yl)phthalimides and 1-oxoisoindolines and a method for reducing the level of ТNF-a |
FI990101A FI120687B (en) | 1996-07-24 | 1999-01-19 | Substituted 2- (2,6-dioxopiperidin-3-yl) phthalimides and -1-oxoisoindolines and method for lowering TNFalfa levels |
HK99106117A HK1021819A1 (en) | 1996-07-24 | 1999-12-24 | Substituted 2(2,6-dioxopiperidin-3-yl) phthalimides and -1-oxoisoindolines and method of reducing tnf-alpha levels |
US09/543,809 US6281230B1 (en) | 1996-07-24 | 2000-04-06 | Isoindolines, method of use, and pharmaceutical compositions |
US09/633,908 US6476052B1 (en) | 1996-07-24 | 2000-08-07 | Isoindolines, method of use, and pharmaceutical compositions |
US09/634,061 US6316471B1 (en) | 1996-07-24 | 2000-10-17 | Isoindolines, method of use, and pharmaceutical compositions |
US09/716,528 US6335349B1 (en) | 1996-07-24 | 2000-11-20 | Substituted 2(2,6-dioxopiperidin-3-yl)isoindolines |
US09/781,179 US6555554B2 (en) | 1996-07-24 | 2001-02-12 | Isoindolines, method of use, and pharmaceutical compositions |
US10/119,486 US7041680B2 (en) | 1996-07-24 | 2002-04-10 | (R) and (S) isomers of substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and 1-oxoisoindolines and methods of using the same |
US10/337,602 US7119106B2 (en) | 1996-07-24 | 2003-01-06 | Pharmaceutical compositions of 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline |
LU91359C LU91359I2 (en) | 1996-07-24 | 2007-09-06 | 1-Oxo- (2,6-dioxopiperidin-3-yl) -4-aminoisoindoline, optionally in the form of an addition salt, and its pharmaceutically acceptable salts - REVLIMID |
NL300291C NL300291I2 (en) | 1996-07-24 | 2007-09-10 | Substituted 2 (2,6-dioxopiperidin-3-yl) phthalimidel and 1-oxoisoindoles and method for reducing TNF alpha levels |
FR07C0056C FR07C0056I2 (en) | 1996-07-24 | 2007-11-05 | |
US13/622,314 US20130030021A1 (en) | 1996-07-24 | 2012-09-18 | Substituted 2-(2,6-Dioxopiperidin-3-yl)-phthalimides and 1-Oxoisoindolines and Method of Reducing TNFalpha Levels |
HUS1300056C HUS1300056I1 (en) | 1996-07-24 | 2013-10-15 | Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and their use for production of pharmaceutical compositions for mammals to reduce the level of tnf-alpha |
US14/156,325 US20140187584A1 (en) | 1996-07-24 | 2014-01-15 | Substituted 2-(2,6-Dioxopiperidin-3-yl)-phthalimides and -1-Oxoisoindolines and Method of Reducing TNFalpha Levels |
US14/876,710 US20160096818A1 (en) | 1996-07-24 | 2015-10-06 | Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and -1-oxoisoindolines and method of reducing tnfalpha levels |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/690,258 | 1996-07-24 | ||
US08690258 US5635517B1 (en) | 1996-07-24 | 1996-07-24 | Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines |
US08/701,494 US5798368A (en) | 1996-08-22 | 1996-08-22 | Tetrasubstituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines and method of reducing TNFα levels |
US08/701,494 | 1996-08-22 | ||
US4827897P | 1997-05-30 | 1997-05-30 | |
US60/048,278 | 1997-05-30 |
Related Parent Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08690258 Continuation US5635517B1 (en) | 1996-07-24 | 1996-07-24 | Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines |
US08690258 Continuation-In-Part US5635517B1 (en) | 1996-07-24 | 1996-07-24 | Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines |
US08/701,494 Continuation US5798368A (en) | 1996-07-24 | 1996-08-22 | Tetrasubstituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines and method of reducing TNFα levels |
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