154-93-8

Basic information

• Product Name: Carmustine
• Synonyms: bis(2-chloroethyl)nitrosourea;BICNU;BECENUN;BCNU;CARMUSTIN;CARMUSTINE;BCUN;BCNU, N,NBis(2-chloroethyl)-N-nitrosourea, NSC-409962, Becenun, Bicnu,
• CAS NO: 154-93-8
• Molecular Formula: C₅H₉Cl₂N₃O₂
• Molecular Weight: 214.05
• EINECS: 205-838-2
• Product Categories: Active Pharmaceutical Ingredients;Pharmaceutical Chemicals;Mutagenesis Research Chemicals;SURMONTIL;Pharmaceutical Chemicals
• Mol File: 154-93-8.mol

Chemical Properties

• Melting Point: 30 °C(lit.)
• Boiling Point: 404oC
• Appearance: /(Oily liquid to amorphous solid)
• Density: 1.6948 (rough estimate)
• Refractive Index: 1.6100 (estimate)
• Storage Temp.: −20°C
• Solubility: insoluble in H2O; ≥21.51 mg/mL in DMSO; ≥27.15 mg/mL in EtOH
• PKA: 10.19±0.46(Predicted)
• Water Solubility: <0.1 g/100 mL at 18℃
• Merck: 14,1845
• CAS DataBase Reference: Carmustine(CAS DataBase Reference)
• NIST Chemistry Reference: Carmustine(154-93-8)
• EPA Substance Registry System: Carmustine(154-93-8)

Safety Data

• Hazard Codes: T+
• Statements: 45-46-60-61-28
• Safety Statements: 53-22-36/37/39-45
• RIDADR: 3249
• WGK Germany: 3
• RTECS: YS2625000
• HazardClass: 6.1(a)
• PackingGroup: II
• Hazardous Substances Data: 154-93-8(Hazardous Substances Data)

Usage

Uses

Used in Anticancer Applications:
Carmustine is used as an anticancer drug for the treatment of various types of cancer, including acute leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, primary or metastatic brain tumors, malignant melanoma, breast cancer, lung cancer, gastrointestinal cancer, Ewing's sarcoma, and Burkitt's lymphoma. It is also used topically to treat mycosis fungoides. Carmustine may be used alone or in combination with other antineoplastic agents to enhance chemo-sensitivity and efficacy in resistant cases.
Used in Drug Delivery Systems:
Carmustine is used in the development of novel drug delivery systems to overcome its limitations and enhance its applications and efficacy against cancer cells. Various organic and metallic nanoparticles have been employed as carriers for Carmustine delivery, aiming to improve its delivery, bioavailability, and therapeutic outcomes.
Used in Surgical Adjuncts:
Carmustine is used as an intracavity surgical adjunct for recurrent glioblastoma multiforme and high-grade malignant glioma, in the form of a BCNU-impregnated polymer wafer. These wafers were approved by the US Food and Drug Administration (FDA) in 1996 and reapproved in 2003.
Used as an Alkylating Agent:
Carmustine is used as an alkylating agent that interacts with DNA, RNA, and proteins, causing DNA interstrand cross-linking, which is cytotoxic and leads to apoptotic cell death. It is also reported to inhibit glutathione reductase, thioredoxin reductase, and lipoamide dehydrogenase.
Used in Clinical Trials:
Carmustine has been tested in clinical trials as a cytostatic agent for Hodgkin's and non-Hodgkin's lymphoma, myeloma, malignant melanoma, glioblastoma, and other brain tumors.
Used in IV Administration:
Carmustine is available in a 100-mg vial for intravenous (IV) administration in the treatment of several types of brain tumors, Hodgkin's and non-Hodgkin's disease, and multiple myeloma. The agent is very lipid-soluble and easily crosses the blood-brain barrier, achieving concentrations greater than 50% of those seen in plasma.
Used in Implantable Wafers:
Carmustine is also available as an implantable wafer containing 7.7 mg of the drug for intracavity implantation in the treatment of glioblastoma multiforme.

Cyclically non-specific anti-tumor drug

It appears as colorless or yellowish or yellowish green crystal or crystalline powder and is odorless. It is insoluble in water and soluble in methanol or ethanol. Its hydrous solution is stable at pH4 but will be subject to rapid decomposition at solution of pH above 7. Carmustin, together with lomustine, fotemustine and semustine are currently the most widely used cyclically non-specific anti-tumor drugs. It belongs to nitrosourea alkylating agent, although with the role of alkylating agents, has no cross-resistance with general alkylating agent. It is characterized by high lipid solubility, broad anti-tumor spectrum the alkylating agent is generally no cross-resistance with high fat-soluble, broad spectrum anti-tumor, quick onset and easily penetrating through the blood-brain barrier and so on. In the body, it can be decomposed into two active ingredients with one having carbamoyl activity and the other being as alkylating agent that can react with the DNA polymerase to inhibit the synthesis of RNA and DNA. It has effect on the proliferation of cells in each stage while being insensitive to non-proliferating cells. It is easily absorbed orally. It enters the brain at one hour after the intravenous administration. At six hours after administration, the brain drug concentration can reach about 60% to 70% of the plasma concentration with in vivo distribution being the highest in the liver, bile, kidney and spleen. This product has a short half-life being less than 15 minutes. But its metabolites have long half-life, and still have anti-cancer effects with being slowly released after binding to the plasma protein. Therefore, its effect can last long and produce delayed toxicity. This product is rapidly metabolized in the blood after being absorbed with the metabolites excreted slowly and the plasma concentration still remaining high after 48 ??hours. 60% is excreted through urine in the form of metabolites. It is commonly used in the treatment of primary and secondary brain cancer, Hodgkin's disease, meningeal leukemia. It can also be applied for the treatment of multiple myeloma, lymphoma, breast cancer, lymphoma, melanoma, lung cancer; combination with fluorouracil can be adopted for treating colorectal cancer and gastric cancer; it can be used for treating bronchus lung cancer when being used in combination with methotrexate and cyclophosphamide. Carmustin is also effective in treating cancer of head portion as well as testicular cancer.

Toxic reaction

1, bone marrow suppression: it is dose-limiting toxicity, exhibiting as severe neutropenia and thrombocytopenia, usually occurs at 3 to 5 weeks after administration and will last for 1 to 3 weeks with the lowest suppression point occurring in 3 to 5 weeks with the ease being slowly than other alkylating agents. 2, gastrointestinal reactions: severe nausea, vomiting usually begins two hours after administration and will last for 4 to 6 hours. Administration of antiemetic agent before the treatment can prevent this. 3 Other reactions: burning sensation can immediately happen at injection site and limbs. Rare toxicity including liver and kidney dysfunction, usually occur upon large doses administration. It has been reported of the occurrence of painless jaundice and hepatic coma as well as pulmonary fibrosis.

Carmustin

Carmustin belongs to nitrosourea alkylating agents. On the one hand, it binds to DNA through alkylation. On the other hand, it acts on the protein through carbamoylation. It can inhibit DNA polymerase, thus preventing DNA and RNA synthesis with the strongest effect on the G1-s transition period as well as blocking effect on the s-phase, and further enhanced effect on the G2 phase and also certain effect on the G0 phase. It is a cell-cycle non-specific drug. This product high an excellent lipid-solubility, low dissociation and can penetrate through the blood-brain barrier with its metabolites still having anti-cancer effects. It undergoes slow release after binding to protein, thus having a long-lasting efficacy. It has broad anti-tumor spectrum with excellent efficacy in the treatment of meningeal leukemia, brain and spinal cord metastasis of malignant tumors, Hodgkin's disease as well as acute leukemia. It also has certain efficacy on the treatment of breast cancer, lung cancer, bone metastasis, lymphatic sarcoma, melanoma and testicular cancer. It is effective for treating primary and secondary brain tumors. Topical administration has excellent efficacy in treating lymphoma papules. The drug, in combination with fluorouracil, vincristine, dacarbazine, consists FIVB protocol for the treatment of colon; together with fluorouracil and doxorubicin, it form FAB protocol for treating gastric cancer; in combination with vincristine and dacarbazine, it can be used for the treatment of melanoma; in combination with androgen, it can be used for the therapy of breast cancer. The above information is edited by the lookchem of Dai Xiongfeng.

Production method

The product has three synthetic routes: 1. take ethylene imine as raw material, go through phosgene condensation to generate bis-(β-chloroethyl) urea, and then generate carmustin via nitrosation; 2.take urea as raw material, go through condensation, ring-opening, chlorination, nitrosation to obtain it; 3.take ethanolamine as raw materials, and generate carmustin through similar processes as methods2. The first method can generate the finished product with just two steps but with its raw material, phosgene and ethyleneimine, both being extremely toxic chemicals, therefore demanding a high-level labor protection and production equipment. The second method has readily available raw materials as well as convenient operation.

Toxicity grading

Highly toxic

Acute toxicity

Oral-rat LD50: 20 mg/kg; Oral-Mouse LD50: 19 mg/kg.

Hazardous characteristics of explosive

It may cause deadly harm to the human respiratory system and can cause pulmonary fibrosis, dyspnea and verticillium.

Flammability and hazard characteristics

Combustion can produce toxic nitrogen oxides, chlorides fumes; it can lead to poisoning: nausea, vomiting, leukopenia and thrombocytopenia as well as bone marrow damage.

Storage characteristics

Treasury: ventilation, low-temperature and dry; store it separately from food raw materials.

Extinguishing agent

Dry powder, foam, sand, carbon dioxide, water mist.

Originator

BCNU,Gencorp Aerojet,US

Manufacturing Process

A solution of sodium nitrite (6.9 g, 0.10 mole) in water (60 ml) was added dropwise to a cold (0-5°C), stirred solution of 1,3-bis(2-chloroethyl)urea (8.0 g, 0.044 mole) in formic acid (50 ml). The reaction mixture was stirred further at 0°C until the pale yellow oil that had formed solidified. The nitrosourea was collected and washed quickly with cold water (2 x 10 ml), and dried in vacuum; yield 6.7 g. (71%).

Therapeutic Function

Antitumor

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Carmustin decomposes rapidly in acid and in solutions above pH 7; most stable in petroleum ether or aqueous solution at pH 4.

Hazard

Extremely toxic, central nervous system depression, pulmonary fibrosis, renal and hepatic damage, cytotoxic, immunosuppressive, carcino- gen.

Fire Hazard

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

Biochem/physiol Actions

Carmustine is a DNA alkylating agent causing DNA interstrand crosslinks. Effective against glioma and other solid tumors.

Clinical Use

Alkylating agent: Myeloma, lymphoma and brain tumours

Safety Profile

Confirmed carcinogen withexperimental carcinogenic and tumorigenic data. A humanpoison by parenteral route. An experimental poison byingestion, intravenous, intraperitoneal, parenteral, andsubcutaneous routes. Human systemic effects byparenteral, int

Synthesis

Carmustin, 1,3-bis-(2-chloroethyl)-1-nitrosourea (30.2.4.4), is made by nitrating 1,3-bis(2-chloroethyl)urea with nitrogen trioxide.

Potential Exposure

BCNU has been used since 1971 as an antineoplastic agent in the treatment of Hodgkin’slymphoma; multiple meyloma; and primary or metastatic brain tumors. It also has been reported to have antiviral, antibacterial, and antifungal activity, but no evidence was found that it is used in these ways. BCNU is not known to be naturally occurring. Health professionals who handle this drug (for example, pharmacists, nurses, and physicians) may possibly be exposed to BCNU during drug preparation, administration, or cleanup; however, the risks can be avoided through use of containment equipment and proper work practices

Drug interactions

Potentially hazardous interactions with other drugs Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).

Carcinogenicity

Bis(chloroethyl) nitrosourea (BCNU) is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.

Environmental Fate

It is generally assumed that BCNU exerts its cytotoxicity through the liberation of alkylating and carbamoylating moieties. An alkylating entity, particularly chloroethyl carbonium ion, is strongly electrophilic and can alkylate a variety of biomolecules, including the purine and pyrimidine bases of DNA. BCNU causes DNA interstrand cross-linking, which is associated with cytotoxicity. The carbamoylation of lysine residues of protein can inactivate certain enzymes, thus interfering with DNA and RNA synthesis and repair processes. The inhibition of glutathione reductase by this carbamoylation further contributes to cytotoxicity.

Metabolism

Intravenous carmustine is rapidly metabolised, and no intact drug is detectable after 15 minutes. It is partially metabolised to active metabolites by liver microsomal enzymes, which have a long half-life. It is thought that the antineoplastic activity may be due to metabolites. Approximately 30% of a dose is excreted in the urine after 24 hours, and 60-70% of the total dose after 96 hours. About 10% is excreted as respiratory CO2 . Terminal halflife of the metabolites is about 1 hour.

Shipping

UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials. UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1- Poisonous materials, Technical Name Required.

Toxicity evaluation

There is no information available on the environmental fate of BCNU. However, it is predicted that BCNU spontaneously decomposes due to its high reactivity. Estimates indicate that the half-life of BCNU particulates and vapor in air is 4.4 days. Though expected to be highly mobile when adsorbed to soil and suspended solids, it is likely that this adsorption may be precluded by hydrolysis. Volatilization from soil or water is not expected, and the potential for bioaccumulation is low. BCNU degrades into 2-chloroethylamine, which is not considered hazardous to the environment.

Incompatibilities

Acids and acid solutions above pH 7 cause rapid decomposition. Most stable at pH 4 in aqueous solution or petroleum ether.

Waste Disposal

It is inappropriate and possibly dangerous to the environment to dispose of expired or waste pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

InChI:InChI=1/C5H9Cl2N3O2/c6-1-3-8-5(11)10(9-12)4-2-7/h1-4H2,(H,8,11)

Synthetic route

1,3-bis(2-chloroethyl)urea (2214-72-4) → 1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8)

Conditions	Yield
With tin(IV) chloride; sodium nitrite In dichloromethane at 20℃; for 2h;	100%
With formic acid; sodium nitrite In dichloromethane; water at 0 - 3℃; for 1h;	87%
With formic acid; sodium nitrite

1,2,2,2-Tetrachloroethyl N-(2-chloroethyl) N-nitroso-carbamate (113900-20-2) + chloroethylamine (689-98-5) → 1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8)

Conditions	Yield
With potassium carbonate In tetrahydrofuran for 2h; Ambient temperature; Yield given;

1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8) → ethylene glycol (107-21-1) + acetaldehyde (75-07-0) + 2-chloro-ethanol (107-07-3)

Conditions	Yield
With sodium phosphate buffer at 37℃; for 96h; Product distribution; Mechanism; other nitrosoureas; var. pH, also in the presence of KBr;	A 2% B 19% C 51%

1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8) → 1,3-bis(2-chloroethyl)urea (2214-72-4) + 2-<(2-chloroethyl)amino>-2-oxazoline (71353-16-7) + 1-(2-chloroethyl)imidazolidin-2-one (2387-20-4) + ethanol (64-17-5) + ethylamine (75-04-7)

Conditions	Yield
With potassium hydroxide; aluminum nickel In methanol Product distribution; Mechanism; degradation under various conditions (HBr in glac. CH3CO2H) with preparation of nonmutagenic reaction mixtures of products;

1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8) → ethanol (64-17-5)

Conditions	Yield
With equine liver alcohol dehydrogenase; 1,4-dihydronicotinamide adenine dinucleotide; potassium phoshpate buffer; water at 25℃; for 12h; Mechanism; the other reagent ; other 1H- and 18O-labeled 1-nitrosoureas;

1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8) + trifluoroacetic anhydride (407-25-0) → 1,3-Bis-(2-chloro-ethyl)-1,3-bis-(2,2,2-trifluoro-acetyl)-urea

Conditions	Yield
at 85℃; for 6h;

glutathione (35436-84-1) + 1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8) → S-(2-chloroethyl)glutathione + (S)-4-[(R)-1-(Carboxymethyl-carbamoyl)-2-mercapto-ethylcarbamoyl]-4-(2-chloro-ethylamino)-butyric acid + S-glutathione + N,S-bis-glutathione

Conditions	Yield
With phosphate buffer at 37℃; for 3h; pH 7.4; Further byproducts given. Title compound not separated from byproducts;
With phosphate buffer at 37℃; for 3h; pH 7.4; Further byproducts given;

glutathione (35436-84-1) + 1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8) → S-(2-chloroethyl)glutathione + (S)-4-[(R)-1-(Carboxymethyl-carbamoyl)-2-mercapto-ethylcarbamoyl]-4-(2-chloro-ethylamino)-butyric acid + S-glutathione + (S)-4-Amino-4-[(R)-2-{2-[(R)-2-((S)-2-amino-4-carboxy-butyrylamino)-2-(carboxymethyl-carbamoyl)-ethylsulfanyl]-ethylsulfanyl}-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid

Conditions	Yield
With phosphate buffer at 37℃; for 3h; pH 7.4; Further byproducts given;

1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8) → S-cysteinylglycine + (S)-4-Amino-4-[(R)-1-(carboxymethyl-carbamoyl)-2-((E)-2-chloro-vinylcarbamoylsulfanyl)-ethylcarbamoyl]-butyric acid + S-glutathione + (S)-4-Amino-4-[(R)-1-(carboxymethyl-carbamoyl)-2-(4,5-dihydro-oxazol-2-ylsulfanyl)-ethylcarbamoyl]-butyric acid

Conditions	Yield
for 4h; Product distribution; Mechanism; rat's liver; also in vitro with glutathione at 37 deg C inphosphate buffer;

1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8) + L-ornithine hydrochloride (3184-13-2) → Nδ-nitroso-Nδ-(2-chloroethyl)carbamoyl-L-ornithine; Nδ-(2-chloroethyl)nitrosocarbamoyl-L-ornithine; mixture of

Conditions	Yield
Stage #1: 1,3-bis(2-chloroethyl)-1-nitrosourea; L-ornithine hydrochloride With potassium hydroxide; copper(II) sulfate In water; isopropyl alcohol at 32℃; for 1h; Alkylation; Stage #2: With sodium nitrite In water at 0℃; for 1h; Nitrosation;	4.21 g

1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8) + D-ornithine hydrochloride (16682-12-5) → Nδ-nitroso-Nδ-(2-chloroethyl)carbamoyl-D-ornithine; Nδ-(2-chloroethyl)nitrosocarbamoyl-D-ornithine; mixture of

Conditions	Yield
Stage #1: 1,3-bis(2-chloroethyl)-1-nitrosourea; D-ornithine hydrochloride With potassium hydroxide; copper(II) sulfate In water; isopropyl alcohol at 32℃; for 1h; Alkylation; Stage #2: With sodium nitrite In water at 0℃; for 1h; Nitrosation;	6.25 g

1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8) + L-Lysine hydrochloride (657-27-2, 10098-89-2) → Nε-nitroso-Nε-(2-chloroethyl)carbamoyl-L-lysine; Nε-(2-chloroethyl)nitrosocarbamoyl-L-lysine; mixture of

Conditions	Yield
Stage #1: 1,3-bis(2-chloroethyl)-1-nitrosourea; L-Lysine hydrochloride With potassium hydroxide; copper(II) sulfate In water; isopropyl alcohol at 32℃; for 1h; Alkylation; Stage #2: With sodium nitrite In water at 0℃; for 1h; Nitrosation;	9.7 g

1,3-bis(2-chloroethyl)-1-nitrosourea (154-93-8) + diethyl 1-aminoethyl phosphate → C9H20ClN2O5P

Conditions	Yield
In water at 60℃; for 2h; Concentration;

Upstream product

• 2214-72-4 1,3-bis(2-chloroethyl)urea 
• 113900-20-2 1,2,2,2-Tetrachloroethyl N-(2-chloroethyl) N-nitroso-carbamate 
• 689-98-5 chloroethylamine 

Downstream Products

• 2214-72-4 1,3-bis(2-chloroethyl)urea 
• 71353-16-7 2-<(2-chloroethyl)amino>-2-oxazoline 
• 2387-20-4 1-(2-chloroethyl)imidazolidin-2-one 
• 64-17-5 ethanol 
• 75-04-7 ethylamine 
• 107-21-1 ethylene glycol 
• 75-07-0 acetaldehyde 
• 107-07-3 2-chloro-ethanol 

Relevant articles and documents

Method for preparing high-purity carmustine

The invention provides a method for preparing high-purity carmustine. Specifically, the preparation method comprises a step of recrystallizing a crude carmustine product with an organic solvent, wherein the organic solvent is a mixed solvent of an alcohol solvent and water, and the alcohol solvent is preferably at least one selected from the group consisting of methanol, ethanol and isopropanol. The method can be used for preparing high-purity carmustine.

SAFE AND EFFICIENT PROCESS FOR THE PREPARATION OF CARMUSTINE

Carmustine may be safely and efficiently produced by reacting 2-chloroethylamine hydrochloride and 1,1′-carbonyldiimidazole to afford 1,3-bis(2-chloroethyl)-1-urea, followed by nitrosation to give the final product.

AN IMPROVED PROCESS FOR THE PREPARATION OF 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA

The present invention relates to an improved process for the preparation of 1,3-bis(2-chloroethyl)-1 -nitrosourea compound of formual-1 which is represented by the following structural formula:

PROCESS FOR PREPARATION OF CARMUSTINE

The present invention relates to an improved process for preparation of carmustine (I). The present invention also relates to preparation of 1,3-bis(2-chloroethyl)urea (II) an intermediate used in preparation of carmustine.

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Tin(IV) chloride-sodium nitrite as a new nitrosating agent for N-nitrosation of amines, amides and ureas under mild and heterogeneous conditions

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1,2,2,2-Tetrachloroethyl Carbamates: Versatile Intermediates for the Synthesis of N-Nitrosoureas

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