- Antigen-Drug Conjugates as a Novel Therapeutic Class for the Treatment of Antigen-Specific Autoimmune Disorders
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Multiple sclerosis represents the world's most common cause of neurological disability in young people and is attributed to a loss of immune tolerance toward proteins of the myelin sheath. Typical treatment options for MS patients involve immunomodulatory drugs, which act nonspecifically, resulting in global immunosuppression. The study discussed herein aims to demonstrate the efficacy of antigen-specific immunotherapies involving the conjugation of disease causing autoantigen, PLP139-151, and a potent immunosuppressant, dexamethasone. Antigen-drug conjugates (AgDCs) were formed using copper-catalyzed azide-alkyne cycloaddition chemistry with the inclusion of a hydrolyzable linker to maintain the activity of released dexamethasone. Subcutaneous administration of this antigen-drug conjugates to SJL mice induced with experimental autoimmune encephalomyelitis, protected the mice from a symptom onset throughout the 25 day study, demonstrating enhanced efficacy in comparison to dexamethasone treatment. These results highlight the benefits of co-delivery of autoantigens with immunosuppressant drugs as AgDCs for the treatment of autoimmune diseases.
- Pickens, Chad J.,Christopher, Matthew A.,Leon, Martin A.,Pressnall, Melissa M.,Johnson, Stephanie N.,Thati, Sharadvi,Sullivan, Bradley P.,Berkland, Cory
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- Method for recycling betamethasone or dexamethasone synthetic mother liquor materials
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The invention relates to a method for recycling betamethasone or dexamethasone synthetic mother liquor materials. The method comprises the following steps: extracting a compound shown as formula 1 from a mother liquor material; carrying out protection reaction of the 20th site hydroxyl group on the compound shown as formula 1 to obtain a compound shown as formula 2; carrying out a reduction reaction of the 21th site aldehyde group on the compound shown as formula 2 to obtain a compound shown as formula 3, and continuously carrying out oxidation reaction and hydrolysis reaction to obtain a compound shown as 4 which is betamethasone or dexamethasone. The above recycling method can convert the betamethasone or dexamethasone mother liquor material into betamethasone or dexamethasone with highmedicinal value and economic benefit, and huge economic benefit is achieved.
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Paragraph 0064; 0065
(2020/03/12)
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- Synthesis method and application of 9-fluorosteroid compound
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The invention provides a synthesis method and application of a 9-fluorosteroid compound, and relates to the technical field of chemical synthesis. The synthesis method of the 9-fluorosteroid compoundcomprises the following step: reacting a compound II in an ionic liquid containing hydrogen fluoride salt to obtain a 9-fluorosteroid compound III. According to the synthesis method of the 9-fluorosteroid compound, the ionic liquid containing the hydrogen fluoride salt is used as a fluorinating agent to replace a traditional hydrogen fluoride aqueous solution, volatilization of hydrogen fluoride gas is avoided, corrosivity is small, toxicity is greatly reduced, reaction conditions are mild, reaction can be completed at the room temperature, operability is high, the safety coefficient is high,and production applicability is improved. The synthesis method of the 9-fluorosteroid compound is used for preparing corticosteroid drugs, highly toxic chemical reagents are not used in the synthesisroute, the operability is high, the safety coefficient is high, and the production applicability is improved.
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Paragraph 0089-0096; 0134-0136
(2021/01/15)
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- A 17, 21 - double-hydroxy steroid derivatives of synthetic method
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The invention relates to a method of preparing 17, 21-double-hydroxyl steroid derivatives by using 6, 9-substituted silyl steroid enol ether compound I as an initiator.
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- Ring opening and fluoridation method and device of steroidal epoxy compound
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The invention discloses a method of preparing a compound II, which is as shown as the following reaction formula as shown in the specification. A 9 alpha-fluorine-11 beta -hydroxyl steroidal compound II is prepared via epoxy compound ring opening and fluoridation of a steroidal epoxy compound I by taking hydrogen fluoride as a fluorination reagent in a solvent consisting of arene and water. In the formula, R is CH3, CH2OH or CH2OAc; R1 is OH; R2 is alpha-CH3 or beta-CH3; and R3 is F or H. A continuous reaction device as shown in Figure 1 can be used in the method.
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Paragraph 0038; 0039; 0041
(2017/07/22)
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- Preparation method for dexamethasone sodium phosphate
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The invention relates to a preparation method for dexamethasone sodium phosphate. The preparation method comprises the following steps: a ring-opening reaction is carried out, namely, dexamethasone acetate epoxide is employed as an initial raw material, HF and DMF are added, a reaction is performed for 3h, a ring-opening reaction is carried out and a dexamethasone acetate solution is prepared; recrystallization is carried out, namely, methanol is added in the dexamethasone acetate solution, recrystallization is carried out, and dexamethasone acetate is prepared; base catalysis hydrolysis is carried out, namely, dexamethasone acetate is added in Na2CO3 and methanol, a reaction is carried out for 10min, dexamethasone is prepared; pyrophosphoryl chlorine esterification is carried out, namely, dexamethasone prepared in the third step is reacted with pyrophosphoryl chlorine and THF, and dexamethasone phosphate ester is prepared; a neutralization salt forming reaction is carried out, namely, the dexamethasone phosphate ester obtainedin the fourth step is reacted with NaOH and methanol at a reaction temperature of 20 DEG C-30 DEG C for 1h, and dexamethasone sodium phosphate is prepared. The steps are simple, raw materials are easily available, the reaction conditions are mild, the method is suitable for industrial production, and the cost is low.
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Paragraph 0014
(2016/11/09)
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- Discovery of Pyrophosphate Diesters as Tunable, Soluble, and Bioorthogonal Linkers for Site-Specific Antibody-Drug Conjugates
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As part of an effort to examine the utility of antibody-drug conjugates (ADCs) beyond oncology indications, a novel pyrophosphate ester linker was discovered to enable the targeted delivery of glucocorticoids. As small molecules, these highly soluble phosphate ester drug linkers were found to have ideal orthogonal properties: robust plasma stability coupled with rapid release of payload in a lysosomal environment. Building upon these findings, site-specific ADCs were made between this drug linker combination and an antibody against human CD70, a receptor specifically expressed in immune cells but also found aberrantly expressed in multiple human carcinomas. Full characterization of these ADCs enabled procession to in vitro proof of concept, wherein ADCs 1-22 and 1-37 were demonstrated to afford potent, targeted delivery of glucocorticoids to a representative cell line, as measured by changes in glucocorticoid receptor-mediated gene mRNA levels. These activities were found to be antibody-, linker-, and payload-dependent. Preliminary mechanistic studies support the notion that lysosomal trafficking and enzymatic linker cleavage are required for activity and that the utility for the pyrophosphate linker may be general for internalizing ADCs as well as other targeted delivery platforms.
- Kern, Jeffrey C.,Cancilla, Mark,Dooney, Deborah,Kwasnjuk, Kristen,Zhang, Rena,Beaumont, Maribel,Figueroa, Isabel,Hsieh, SuChun,Liang, Linda,Tomazela, Daniela,Zhang, Jeffrey,Brandish, Philip E.,Palmieri, Anthony,Stivers, Peter,Cheng, Mangeng,Feng, Guo,Geda, Prasanthi,Shah, Sanjiv,Beck, Andrew,Bresson, Damien,Firdos, Juhi,Gately, Dennis,Knudsen, Nick,Manibusan, Anthony,Schultz, Peter G.,Sun, Ying,Garbaccio, Robert M.
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p. 1430 - 1445
(2016/02/18)
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- METHOD FOR PRODUCING PULVERIZED ORGANIC COMPOUND PARTICLE
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Disclosed is a method for producing pulverized particles of a crystalline organic compound which is poorly water-soluble. Also disclosed is a pulverized organic compound particle produced by such a method. Specifically disclosed is a method for producing a poorly water-soluble organic compound particle for medical use, which is characterized in that a poorly water-soluble organic compound for medical use is mixed with a physiologically acceptable salt and a physiologically acceptable polyol, and subjected to wet milling. Also specifically disclosed is a poorly water-soluble organic compound particle for medical use, which is produced by such a production method.
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- INDUCED HEPATOCYTES
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An object of the present invention is to produce hepatic cells from non-hepatic cells that can be obtained less invasively and at low cost. The gene of HNF3α, HNF3β, or HNF3γ and the gene of HNF4α are transduced into non-hepatic cells. The present invention enables the production of induced hepatocytes from somatic cells that are non-hepatic cells, such as skin cells. The use of the induced hepatocytes obtained by the present invention can establish and develop, as general medical treatment, cell transplantation into the liver, artificial livers, and drug response tests, which are the areas that have not been generalized because of the difficulty of procuring hepatocytes.
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- THERAPEUTIC FOR HEPATIC CANCER
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A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
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- Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
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Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
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- COMPOSITION FOR TREATING SULFUR MUSTARD TOXICITY AND METHODS OF USING SAME
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One embodiment of the present invention provides a composition, comprising, in amounts effective to treat sulfur mustard or half sulfur mustard induced toxicity or skin damage: an agent that inhibits alkylation of —SH and >NH protein groups; an agent that reduces —SS— to SH; a scavenger of reactive oxygen species; a substrate that maintains tissue reduction-oxidation status; an agent that protects against invading inflammatory cells and associated oxidative stress; an antagonist of prostaglandin synthesis; and an agent that induces tissue regeneration. Methods of using the composition are also provided.
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- FLUOROQUINOLONE DERIVATIVES FOR OPHTHALMIC APPLICATIONS
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The present invention relates to fluoroquinolone derivatives having enhanced ocular penetration characteristics and/or antimicrobial activity, and to compositions comprising such derivatives. The derivatives and compositions are particularly well suited for treating ophthalmic bacterial infections. The present invention more particularly relates to the discovery that a 2-methyl substitution on a diazabicyclo group attached to a fluoroquinolone ring system produces improved permeability characteristics, and that a 5-amino substitution on a fluoroquinolone ring system results in improved anti-microbial activity.
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- Medicines for treating tumoral pathologies containing the ro5-4864 compound and an apoptosis-inducing agent
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The invention concerns the use of Ro5-4864, and compounds derived therefrom, for preparing medicines for treating tumoral pathologies. The invention also concerns said compounds combined with an apoptosis-inducing agent, as combination products for simultaneous, separate or prolonged use, in cancer therapy.
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- Method for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor
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Methods for reducing or preventing transplant rejection in the eye of an individual are described, comprising: a) performing an ocular transplant procedure; and b) implanting in the eye a bioerodible drug delivery system comprising an immunosuppressive agent and a bioerodible polymer.
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- 21-Substituted steroid compound
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A glycoside represented by formula (I), wherein dexamethasone or betamethasone is the aglycon and the 21-position is substituted by a simple sugar or an acylated sugar selected from the group consisting of glucose, galactose, mannose, rhamnose, fucose, N-acetylglucosamine, N-acetylgalactosamine, galacturonic acid, glucuronic acid and sialic acid. STR1
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- Mucosal adhesive device for long-acting delivery of pharmaceutical combinations in oral cavity
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Mucosal adhesive devices are provided for use in the oral cavity for therapy against infections. The devices are dosage units which comprise a combination of antimicrobial agents such as antifungal agents and anti-inflammatory agents, optionally also a local anesthetic. The dosage units yield a gradual and relatively constant release of the pharmaceuticals over at least a 12-hour period.
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- Biotransformation of corticosteroids by Penicillium decumbens ATCC 10436
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The biotransformation of a series of corticosteroids by the fungus Penicillium decumbens ATCC 10436 has been investigated. Conversion to the corresponding 5α-dihydroxteroid was observed for all the Δ4-3-ketosteroids studied with the exception of deoxycorticosterone, which was converted to a Δ14-diene. Deoxycorticosterone acetate was, however, converted to a 5α- dihydro product concomitant with ester hydrolysis. Other substrates carrying a C-21 acetoxy group were also hydrolyzed to the alcohol. In two cases (resulting from deoxycorticosterone acetate and 11-deoxycortisone) the 5α- 3-keto-product was further reduced to the 3β-alcohol. No reduction of δ14-dienes was observed.
- Holland, Herbert L.
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p. 646 - 649
(2007/10/02)
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- Gastric preparation with sustained release
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A gastric preparation developed in order to solve the technical problems of conventional preparations, which is prepared by the bilayer packing technique and comprises 5 to 60%, desirably 10 to 40% of a rapid release portion which can establish the therapeutic level of a drug shortly after the administration and 95 to 40%, desirably 90 to 60% of a sustained release portion which has a specific gravity or 1 or less and can maintain a satisfactory release rate.
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- GABA ESTERS AND GABA ANALOG ESTERS
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Ester derivatives of gamma-aminobutyric acid (GABA) and GABA analogues which cross the blood-brain barrier are disclosed, as well as methods of synthesizing and using the compounds.The ester derivatives have the formula: STR1 where A is a radical compound having at least one esterifiable OH group; n varies from one to the total number of esterifiable OH group contained in A; and R 1, R. sub.2, R. sub.3 and R 4 are hydrogen or a substituent.
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- High molecular weight prodrug derivatives of antiinflammatory drugs
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Compounds of the formula 1, PS - O - A - (CH2)n- B - D (1), wherein PS-O represents an alkoxide residue of any of the free hydroxy groups of a polysaccharide (PS-OH) compound with molecular weight (Mw) of from 40,000 to 5,000,000 selected from dextran, carboxymethyl dextran, diethylaminoethyl dextran, starch, hydroxyet-hyl starch, alginates, glycogen, pullullan, agarose, cellulose, chitosan, chitin and carrageenan,A is a carbonyl group or absent,n is zero or a positive integer from 1 to 14,B is oxygen, a carbonyl group, NR wherein R is hydrogen or lower alkyl, or B is absent, and, D is (i) a group of the formula:, R1 - CO - (11), wherein R1-CO- represents the acyl residue of a carboxylic acid drug (R1-COOH) used in the treatment of inflammatory disorders; or (ii) a group of the formula:, R2 - O - (12), wherein R2-O- refers to the C-21 alkoxide residue of a known antiinflammatory steroid (R2-OH) or an alkoxide residue of any other drug or medicament containing a hydroxy functional group used in the treatment of inflammatory disorders; with the proviso that when A is absent, n is 0, and B is absent, then R1-CO- is different from the acyl residue of acetylsalicylic acid;, and non-toxic pharmaceutically acceptable acid addition salts thereof;, and non-toxic pharmaceutically acceptable cation salts thereof. Such compounds are biolabile prodrugs providing controlled release and prolonged duration of action of the parent active antiinflamma-tory agents locally at the administration site after intra-articular, intra-muscular, subcutaneous or extra-dural application while at the same time being highly stable in aqueous solution in the pH range 3--5. After oral administration of such prodrugs the parent drug is liberated selectively in the terminal ileum and the colon over an extended period of time.
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- Process and intermediates for the preparation of 17 alphahydroxyprogesterones and corticoids from an enol steroid
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This invention discloses an improved process for the production of corticoids from 17α-hydroxy steroids utilizing peroxymonosulfate.
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- Amine containing ester prodrugs of corticosteroids
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Novel solution stable ester prodrugs of corticosteroids of the formula STR1
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- Sulfonate containing ester prodrugs of corticosteroids
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Novel solution stable ester prodrugs of corticosteroids of the formula STR1 and their salts.
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- Sulfonate containing ester prodrugs of corticosteroids
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Novel solution stable ester prodrugs of corticosteroids of the formula STR1 and their salts.
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- SYNTHESIS OF MULTI CARBON-13 LABELED DEXAMETHASONE
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A synthesis of dexamethasone multiply labeled with (13)C about the A ring is described. 16-α-Methyl-17α,20-dihydroxypregn-1,4,9(11)-trien-3,20-dione (1) was blocked as the bismethylenedioxy derivative and degraded to the ring C,D-fragment, Des-A,B-9-keto-16α-methyl-17α,20;20,21-bismethylenedioxypregn-8α-propionic acid (9).Conversion to the enol lactone and condensation with 1-diethylphosphono-4-pentanone-(13)C ethylene ketal followed by methylation and A-ring closure afforded the BMD derivative of 16α-methyl-pregn-4,9(11)-diene-3-one(13)C (14).The steroidal intermediate was further transformed to dexamethasone-(13)C.
- Crowe, D. F.,Christie, P. H.,DeGraw, J. I.,Fujiwara, A. N.,Grange, E.,et al.
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p. 3083 - 3090
(2007/10/02)
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- Water-soluble steroid compounds
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Beta-cyclodextrin forms a water-soluble complex or inclusion compound with steroid compounds having a molecular structure smaller than the interior cavity in the doughnut-shaped molecular structure of beta-cyclodextrin. The resulting inclusion compounds can be used for a variety of applications including aqueous topical ophthalmic preparations and topical dermatological ointments.
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- Process of selective solvolysis
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The 17α-monoesters and 17α,21-diesters of corticosteriods are well known and represent nowadays the most efficient group of anti-inflammatory compounds for topical application, having minimal systemic action.
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- Trimethyl siloxane steroid intermediates
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A procedure for converting steroids characterized by presence of an 11βOH group into potent corticoids having one or more substituents, such as 6αF, 16α, 17α-hydroxy or isopropylidene dioxy, 16α or 16β methyl, Δ1,4 ; by reacting the 11β-hydroxy steroid with trichloromethyl siloxane steroid, thereby rendering the normally sensitive 11 substituent inert to the series of reactions which thereafter incorporate one or more of the desired above listed substituents into the steroid molecule. The siloxy group is then hydrolyzed to regenerate the 11β-hydroxy substituent. Many of the trimethyl siloxy steroids are novel compounds. The siloxane may be selectively cleaved by reaction of the finely divided steroid with 40-60% aqueous HF.
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- 16-Alkyl-1,4,9(11)-pregnatrienes and 9,11-epoxides thereof
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The invention disclosed herein relates to processes and intermediates useful in the preparation of certain 16-lower alkyl-1,4-pregnadiene compounds. It is particularly concerned with novel methods of preparing 16-lower alkyl-9α-fluoro-11β,17α,21-trihydroxy-1,4-pregndiene-3,20-dione and esters thereof, and with novel intermediates useful in these novel methods. It is further concerned with 16-lower alkyl-1,4,9(11)-pregnatriene-17α,21-diol-3,20-diones and their 21-lower alkanoates which, in addition to being valuable as intermediates, are valuable diuretic agents useful in the treatment of edema.
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- Novel N-nitroso compounds, compositions containing such compounds, processes for their preparation and methods of treatment therewith, and novel intermediates
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This invention relates to novel N-halogenoalkyl-N-nitroso carbamates and N 4 halogenalkyl-N 4 -nitroso allophanates of steroid compounds, having an anti-tumor activity, and to the preparation thereof. The invention is also concerned with pharmaceutical compositions containing the said compounds, and methods of treatment therewith.
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