55-98-1

Usage

Originator

Myleran,Burroughs- Wellcome,US,1954

Indications

Busulfan (Myleran) is a bifunctional methanesulfonic ester that forms intrastrand cross-linkages with DNA. The drug is well absorbed after oral administration and has a plasma half-life of less than 5 minutes. Metabolites and degradation products are excreted primarily in the urine. Busulfan is used in the palliative treatment of chronic granulocytic leukemia. Daily oral therapy results in decreased peripheral white blood cells and improved symptoms in almost all patients during the chronic phase of the disease. Excessive uric acid production from rapid tumor cell lysis should be prevented by coadministration of allopurinol. At usual therapeutic dosages, busulfan is selectively toxic to granulocyte precursors rather than lymphocytes. Thrombocytopenia and anemia and less commonly, nausea, alopecia, mucositis, and sterility also may occur. Unusual side effects of busulfan include gynecomastia, a general increase in skin pigmentation, and interstitial pulmonary fibrosis.

Manufacturing Process

3.6 grams of redistilled 1,4-butanediol were dissolved in 10 ml of pyridine and the solution was cooled in ice and water. 9.6 grams of redistilled methanesulfonyl- chloride were added dropwise at such a rate that the temperature did not rise above 20°C. The solution was then allowed to stand at room temperature to; 30 minutes, during which time the temperature rose to 60°C. A thick precipitate of pyridine hydrochloride was formed. The mass was cooled in ice water and was treated with 30 ml of ice cold water. On agitation, a white crystalline precipitate was formed. This was filtered off and washed well with ice cold water and allowed to drain on the pump. It weighed 7.8 grams and had a melting point of 100°C. 3.5 grams of the material were recrystallized from acetone and ether to give small white needles, having a melting point of 106°-107°C, unchanged by further recrystallization.

Therapeutic Function

Antineoplastic

Air & Water Reactions

Busulfan is an alkylating agent which hydrolyzes in water. .

Reactivity Profile

Busulfan is an alkylating agent which hydrolyzes in water. . Strong reducers may yield hydrogen sulfide.

Hazard

Extremely toxic, carcinogen, clastogenic, teratogenic, immunosuppressive, delayed bone marrow aplasia, cataracts, pigmentation, pulmonary thrombosis, cardiotoxic effects, thrombocytopenia.

Fire Hazard

Flash point data for Busulfan are not available. Busulfan is probably combustible.

Clinical Use

Busulfan is used in the treatment of chronic myelogenous leukemia and can be administered either orally or by IV infusion.

Side effects

Serious bone marrow hypoplasia and myelosuppression are possible with this agent, and recovery from busulfaninduced pancytopenia can take up to 2 years.

Safety Profile

Confirmed carcinogen producing leukemia, kidney, and uterine tumors. Experimental neoplastigenic and tumorigenic data. Poison by ingestion, subcutaneous, intraperitoneal, intravenous, and possibly other routes. Ingestion by pregnant women can cause cancer of the reproductive system of the fetus includtng the uterus. Human teratogenic effects by ingestion and possibly other routes include developmental abnormaltties of the eye, ear, craniofacial area including the nose and tongue, gastrointestinal system, endocrine system, urogenital system, and other unspecified areas. Other human reproductive effects by ingestion and possibly other routes include: impotence, changes in the uterus, cervix, and vagina, and menstrual-cycle dtsorders. Experimental reproductive effects. Human systemic effects by ingestion: general arteriolar or venous ddation of the eye, changes in structure or function of salivary glands. When heated to decomposition it emits toxic fumes of SOx. See also SULFONATES.

Synthesis

Busulfan, 1,4-butandioldimethansulfonate (30.2.3.1), is made by reacting butandiol with methanesulfonyl chloride.

Veterinary Drugs and Treatments

Busulfan may be useful in the adjunctive therapy of chronic granulocytic leukemias or polycythemia vera in small animals. Not commonly used in veterinary medicine.

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration increased by metronidazole. Antipsychotics: avoid with clozapine, increased risk of agranulocytosis. Antifungals: metabolism inhibited by itraconazole, monitor for signs of busulfan toxicity.

Carcinogenicity

1,4-Butanediol dimethanesulfonate is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.

Metabolism

Busulfan is extensively metabolised in the liver, mainly by conjugation with glutathione, either spontaneously or mediated by the enzyme glutathione-S-transferase. About 12 inactive metabolites have been identified, which are excreted in the urine. About 1% of busulfan is excreted unchanged. Elimination in the faeces is considered to be negligible.

references

[1]. probin v, wang y, zhou d. busulfan-induced senescence is dependent on ros production upstream of the mapk pathway. free radic biol med, 2007, 42(12): 1858-1865. [2]. probin v, wang y, bai a, et al. busulfan selectively induces cellular senescence but not apoptosis in wi38 fibroblasts via a p53-independent but extracellular signal-regulated kinase-p38 mitogen-activated protein kinase-dependent mechanism. j pharmacol exp ther, 2006, 319(2): 551-560.[3]. choi yj, ok dw, kwon dn, et al. murine male germ cell apoptosis induced by busulfan treatment correlates with loss of c-kit-expression in a fas/fasl- and p53-independent manner. febs lett, 2004, 575(1-3): 41-51.

InChI:InChI=1/C6H14O6S2/c1-13(7,8)11-5-3-4-6-12-14(2,9)10/h3-6H2,1-2H3

Synthetic route

Butane-1,4-diol (110-63-4) + methanesulfonamide (3144-09-0) → busulfan (55-98-1)

Conditions	Yield
With triethylamine at 5 - 40℃; for 4h; Temperature;	91%

Butane-1,4-diol (110-63-4) + methanesulfonyl chloride (124-63-0) → busulfan (55-98-1)

Conditions	Yield
With triethylamine In dichloromethane at 10 - 20℃; for 24h;	86%
With triethylamine In dichloromethane at 0 - 20℃; for 4h;	73.52%
With pyridine at 25℃; for 2h;	55%

tetrahydrofuran (109-99-9) + methanesulfonyl bromide (41138-92-5) → 1,4-dibromo-butane (110-52-1) + 4,4'-dibromo-di-n-butyl ether (7239-41-0) + busulfan (55-98-1) + 1-bromo-4-methanesulfonyloxy-butane (40671-33-8)

Conditions	Yield
zinc(II) chloride at 75℃; for 5h;

1-bromo-4-methanesulfonyloxy-butane (40671-33-8) + silver methanesulfonate (2386-52-9) → busulfan (55-98-1)

Conditions	Yield
In acetonitrile for 5h; Heating;

Butane-1,4-diol (110-63-4) + Methanesulfonic anhydride (7143-01-3) → busulfan (55-98-1)

bistrimethyl(1,4-butanedioxy)silane (18001-91-7) + methanesulfonyl chloride (124-63-0) → busulfan (55-98-1)

Conditions	Yield
With tin(IV) chloride at 80 - 100℃;

4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran (96042-30-7) + methanesulfonyl chloride (124-63-0) → busulfan (55-98-1)

Conditions	Yield
With triethylamine In water; ethyl acetate

busulfan (55-98-1) + 1,10-N,N'-bis-[cyclomaltoheptaosyl-6A-deoxy-6A-ureido]-4,7,13,16-tetraoxa-1,10-diazacyclooctadecane (1182838-48-7) → C6H14O6S2*C98H164N4O74 (1182838-51-2)

Conditions	Yield
In water; dimethyl sulfoxide at 20℃; for 18h; Inert atmosphere;	100%

busulfan (55-98-1) + 1,10-N,N'-bis-(β-D-ureidocellobiosyl)-4,7,13,16-tetraoxa-1,10-diazacyclooctadecane (1182838-47-6) → C6H14O6S2*C38H68N4O26 (1182838-49-8)

Conditions	Yield
In water; dimethyl sulfoxide at 20℃; for 18h; Inert atmosphere;	100%

busulfan (55-98-1) + 2-(benzhydrylideneamino)-1-(10,10-dimethyl-3,3-dioxo-3λ6-thia-4-aza-tricyclo[5.2.1.01.5]dec-4-yl)ethanone (138566-17-3) → C16H26N2O3S

Conditions	Yield
Stage #1: 2-(benzhydrylideneamino)-1-(10,10-dimethyl-3,3-dioxo-3λ6-thia-4-aza-tricyclo[5.2.1.01.5]dec-4-yl)ethanone With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.333333h; Inert atmosphere; Stage #2: busulfan In tetrahydrofuran at -78℃; for 3.16667h;	83%

busulfan (55-98-1) + potassium thioacetate (10387-40-3) → 1,4-bis-acetylsulfanyl-butane (6633-90-5)

Conditions	Yield
In acetone for 70h; Ambient temperature;	82%

busulfan (55-98-1) + 4-methoxy-aniline (104-94-9) → N-(4-methoxyphenyl)pyrrolidine (54660-04-7)

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	81.3%

busulfan (55-98-1) + C116H146O24 + 3-phenyl-3H-diazirine (42270-91-7) → C120H152O24*C7H6N2

Conditions	Yield
With caesium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide at 20℃; for 84h;	80.6%

busulfan (55-98-1) + C116H130(2)H16O24 + 3-phenyl-3H-diazirine (42270-91-7) → C120H136(2)H16O24*C7H6N2

Conditions	Yield
With caesium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide at 20℃; for 84h;	80%

busulfan (55-98-1) + aniline (62-53-3) → N-phenylpyrrolidine (4096-21-3)

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	78.6%

ethanol (64-17-5) + busulfan (55-98-1) + carbon monoxide (201230-82-2) → diethyl adipate (141-28-6)

Conditions	Yield
With sodium iodide; dicobalt octacarbonyl In various solvent(s) at 100℃; under 38000 Torr; for 24h;	78%

busulfan (55-98-1) + C18H27N3O5 (193282-97-2) → C23H37N3O8S (1610616-07-3)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 7h;	77%

busulfan (55-98-1) + benzo[1,3]dioxolo-5-ylamine (14268-66-7) → 1-(3,4-methylenedioxyphenyl)pyrrolidine

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	76.3%

busulfan (55-98-1) + p-toluidine (106-49-0) → 1-p-tolylpyrrolidine (54104-82-4)

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	75.1%

busulfan (55-98-1) + 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (582-52-5) → Methanesulfonic acid 4-[(3aR,5R,6S,6aR)-5-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-yloxy]-butyl ester + 1,4-bis<3-O-(1,2:5,6-di-O-isopropylidene-α-D-glucofuranos-3-yl)>butane (167535-48-0)

Conditions	Yield
With potassium hydroxide In dimethyl sulfoxide; toluene at 50℃; for 8h;	A 3.2% B 75%

busulfan (55-98-1) + 4-chloro-aniline (106-47-8) → 1-(4-chlorophenyl)pyrrolidine (4280-30-2)

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	72.4%

busulfan (55-98-1) + 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose (4064-06-6) → Methanesulfonic acid 4-((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyl-tetrahydro-bis[1,3]dioxolo[4,5-b;4',5'-d]pyran-5-ylmethoxy)-butyl ester + 1,4-bis<6-O-(1,2:3,4-di-O-isopropylidene-α-D-galactopyranos-6-yl)>butane (167535-76-4)

Conditions	Yield
With potassium hydroxide In dimethyl sulfoxide; toluene at 50℃; for 8h;	A 3.2 g B 72%

busulfan (55-98-1) + 3-chloro-aniline (108-42-9) → N-(3-chlorophenyl)tetrahydropyrrole

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	70.2%

busulfan (55-98-1) + 4-Aminoacetophenone (99-92-3) → N-(4-acetylphenyl)pyrrolidine (21557-09-5)

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	65.5%

busulfan (55-98-1) + 2-Chloroaniline (95-51-2) → N-(2-chlorophenyl)tetrahydropyrrole (105516-46-9)

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	64.7%

Upstream product

• 110-63-4 Butane-1,4-diol 
• 124-63-0 methanesulfonyl chloride 
• 109-99-9 tetrahydrofuran 
• 41138-92-5 methanesulfonyl bromide 
• 40671-33-8 1-bromo-4-methanesulfonyloxy-butane 
• 2386-52-9 silver methanesulfonate 
• 7143-01-3 Methanesulfonic anhydride 
• 18001-91-7 bistrimethyl(1,4-butanedioxy)silane 
• 96042-30-7 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran 
• 3144-09-0 methanesulfonamide 

Downstream Products

• 15394-33-9 methyl 4-(methylsulfanyl)butyl sulfide 
• 141-28-6 diethyl adipate 
• 628-21-7 1,4-Diiodobutane 
• 203571-17-9 4-iodo-1-butanol metanesulfonate 
• 161264-20-6 8,9,10,11,39,40,41,42-octahydro-1,18,26,28,53,55,63,74-octaphenethyl-34,47-(epoxybutanoxy)-20,24:57,61-dimethano-2,52:3,51:16,30;17,29-tetrametheno-1H,18H,26H,28H,53H,55H-bis[1,3]benzodioxocino[9,8-d:9',8'-d']bis[1,3]benzodioxocino... 
• 219636-75-6 4-Methoxy-3-pyrrolidin-1-yl-benzoic acid methyl ester 
• 6633-90-5 1,4-bis-acetylsulfanyl-butane 
• 77354-98-4 1,4-bis-(2-formylphenoxy)butane 
• 1174496-22-0 C₇H₅FN₂*C₁₂₀H₁₅₂O₂₄ 
• 54104-82-4 1-p-tolylpyrrolidine 
• 4280-30-2 1-(4-chlorophenyl)pyrrolidine 
• 21557-09-5 N-(4-acetylphenyl)pyrrolidine 
• 54660-04-7 N-(4-methoxyphenyl)pyrrolidine 
• 10220-22-1 1-(4-nitro-phenyl)-pyrrolidine 

Relevant academic research and scientific papers

Busulfan drug intermediate 1,4 bis-methyl sulfonate butyl diester synthetic method

A busulfan drug intermediate 1,4-bis-methyl sulfonate butyl diester synthetic method comprises the following steps: 0.15mol of 1,4-butanediol and 150-170ml of triethylamine are added into a reaction vessel, solution temperature is reduced to 3-5 DEG C, stirring speed is controlled at 130-160rpm, 0.36-0.38mol of methanesulfonic acid amine is slowly dropwise added, after the completion of the dropwise addition, the solution temperature is raised to 35-40 DEG C, the solution is stirred for 3-4h, solution temperature is reduced to 15-20 DEG C, a solid is precipitated, and the solid is filtered, washed with a saline solution, dehydrated with a dehydrating agent, and recrystallized in cyclohexane to obtain a white solid of 1,4-bis-methyl sulfonate butyl diester; and the saline solution in the step is any one of sodium nitrate and potassium sulphate.

BIVALENT BROMODOMAIN LIGANDS, AND METHODS OF USING SAME

Described herein are compounds capable of modulating one or more biomolecules substantially simultaneously, e.g., modulating two or more binding domains (e.g., bromodomains) on a protein or on different proteins. For example, in one aspect, a bivalent compound or a pharmaceutically acceptable salt, stereoisomer, metabolite, or hydrate thereof is provided. In another aspect, a method of treating a disease associated with a protein having tandem bromodomains in a patient in need thereof is provided. The method comprises administering to the patient the bivalent compound as described.

DITHIOAMINE REDUCING AGENTS

Dithioamine reducing agents useful for the reduction of disulfide bonds. The reducing agents of this invention are useful, for example, to reduce disulfide bonds, particularly in proteins, or to prevent the formation of disulfide bonds, particularly in proteins and other biological molecules. Reducing agents of this invention are useful and suitable for application in a variety of biological applications, particularly as research and synthetic reagents. The invention provides S-acylated dithioamines which can be selectively activated reducing agents by removal of the S-acyl groups enzymatically or chemically. The invention further provides dithiane precursors of thioamino reducing agents. The invention provides dithioamine reducing agents, S-acylated dithioamines and dithianes which are immobilized on surfaces, including among others, glass, quartz, microparticles, nanoparticles and resins.

PROCESS FOR PRODUCTION OF BIS-QUATERNARY AMMONIUM SALT, AND NOVEL INTERMEDIATE

Object To provide a method for producing a bis-quaternary ammonium salt efficiently and a novel synthetic intermediate thereof. Solution The present invention relates to a method for producing a bis-quaternary ammonium salt represented by a general formula [3] which comprises reacting a disulfonic acid ester represented by a general formula [1] (in the formula, definitions of two R1's and T are as described in claim 1) with a tertiary amine represented by a general formula [2] (in the formula, definitions of R3 to R5 are as described in claim 1), and a disulfonic acid ester represented by a general formula [1′] (in the formula, two R16's represent independently a halogen atom or a C1-C3 fluoroalkyl group, and two m's represent independently an integer of 1 to 5).

THERAPEUTIC FOR HEPATIC CANCER

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.

Synthesis of C3- and C2-symmetric tris- and bis-sulfoxide ligands by asymmetric oxidation

A series of tris- and bis-sulfoxides were synthesized by multiple asymmetric oxidation of the corresponding sulfides. High enantioselectivities were obtained based on Horeau-type amplification of selectivity. Naphthyl-substituted sulfoxides allowed for higher selectivity and greater ease of purification. These sulfoxides were tested as ligands in rhodium-catalyzed olefin hydroacylation and 1,4-addition of phenyl boronic acid to 2-cyclohexen-1-one. While no enantioinduction was observed in hydroacylation, up to 80% ee was obtained for a tris-sulfoxide and a bis-sulfoxide ligand in the 1,4-addition. Bis-sulfoxides with flexible backbones gave lower and inversed enantioselectivity, suggesting backbone rigidity plays a key role in enantioinduction.

POLYMERS PREPARED FROM MIXTURES OF MULTIFUNCTIONAL N-VINYLFORMAMIDE AND HYBRID REACTIVE N-VINYLFORMAMIDE CROSSLINKING MONOMER MOIETIES AND USES THEREOF

The present invention provides polymers resulting from polymerization of at least one reactive vinyl monomer moiety and a multifunctional N-vinylformamide crosslinking moiety; polymers resulting from polymerization of at least one reactive vinyl monomer moiety and a hybrid N-vinylformamide crosslinking moiety having at least one N-vinylformamide functionality and at least one other reactive vinyl functionality; polymers resulting from polymerization of at least one hybrid reactive N-vinylformamide monomer moiety having one N-vinylformamide functionality and at least one other reactive non-vinyl functionality and a multifunctional N-vinylformamide crosslinking moiety; and polymers resulting from polymerization of at least one hybrid reactive N-vinylformamide monomer moiety having one N-vinylformamide functionality and at least one other reactive non-vinyl functionality and a hybrid N-vinylformamide crosslinking moiety having at least one N-vinylformamide functionality and at least one other reactive vinyl functionality. The invention further provides a wide variety of compositions comprising the novel crosslinked polymers.

Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same

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.

Substituted Sulfonamide Compounds

Substituted sulfonamide compounds corresponding to the formula I wherein m, n, p, Q, R1, R2, R3, R4, X, Y and Z have the respective meanings defined herein, pharmaceutical compositions containing such compounds, a process for their preparation, and the use of such compounds for the treatment and/or inhibition of pain and other conditions mediated by bradykinin receptor 1 (B1R) and/or bradykinin receptor 2 (B2R).

SUBSTITUTED SULFONAMIDE DERIVATIVES

The invention relates to substituted sulfonamide derivatives of the general formula (I'); processes for their preparation, medicaments containing these compounds, and the use of substituted sulfonamide derivatives for the preparation of medicaments