IN RATS & MICE, HEXAMETHYLPHOSPHORAMIDE UNDERGOES A SEQUENCE OF N-DEMETHYLATION REACTIONS TO YIELD PENTAMETHYLPHOSPHORAMIDE, N',N',N'',N'''-TETRAMETHYLPHOSPHORAMIDE & N', N'',N''-TRIMETHYLPHOSPHORAMIDE. IN VITRO STUDIES WITH RAT LIVER SLICES INDICATED OXIDATIVE DEMETHYLATION, WITH SIMULTANEOUS FORMATION OF FORMALDEHYDE.
The metabolism of hexamethylphosphoramide (HMPA), aminopyrine, ethoxycoumarin, ethoxyrsorufin, and pentoxyresorufin, by the monooxygenase cytochrome p450 dependent system, was studied in microsomes from nasal epithelial membranes and liver tissue of Sprague-Dawley rats. Nasal metabolism rates for the different substrates ranged from 9% of liver values for aminopyrine to 83% for ethoxycoumarin. HMPA-demethylase activity followed Michaelis-Menten kinetics in nasal mucosa microsomes but was biphasic in those from liver. SKF 525A, metyrapone, dioxolane and alpha-naphthoflavone (ANF), inhibitors of various p450 monoxygenase, were examined with regard to inhibition of nasal and liver ethoxycoumarin deethylase. In addition, activity of epoxide hydrolase, glutathione S-transferase, DT-diaphorase and UDP-glucuronyltransferase (UDP-GT) in nasal tissue homogenates were investigated. These activities were lower than those present in the liver. Various attempts to increase the activity of oxidative enzymes in nasal tissue by PB, 3-MC and ethanol failed, 3-MC and PB doubled the microsomal UDP-GT and the epoxide hydrolase activities. The results together with data from the literature sugggest that the balance between p450 isozymes and detoxifying enzymes differs in the nose compared with the liver. The activities of these enzymes in nasal tissue of different strains of rats also varies substantially with implications regarding the metabolic fate and activation of inhaled xenobiotics.
Two unique forms of cytochrome p450 (p450), designated NMa and NMb, were recently isolated in this laboratory from nasal microsomes of rabbits. In the present study, polyclonal antibodies to the pruified nasal cytochrome were prepared. Immunochemical analysis with specific rabbit anti-NMa and sheep anti-NMb antibodies indicated that p450 isozymes identical to or having a high structural homology with NMa are present in both olfactory and respiratory mucosa, as well as in liver, but NMb was detected only in the olfactory mucosa. Neither form was detected in other tissues examined, including brain, esophageal mucosa, heart, intestinal mucosa, kidney, and lung. The specific occurrence of NMb in the olfactory mucosa was further substantiated by the detection and specific inhibition by anti-NMb of the formation of unique NMb-dependent metabolites of testosterone in olfactory microsomes but not in microsomes from liver or respiratory mucosa. Similar experiments with antibody to previously purified rabbit hepatic p450 isozymes indicated that not all of the hepatic cytochromes are expressed in the nasal tissues. Thus, p450 isozymes structurally homologous to hepatic forms 2, 3a, and 4, but not 3b and 6, were found in the olfactory mucosa. On the other hand, only form 2 was detected in the respiratory mucosa. Immunoquantitation experiments revealed that NMa nd NMb are the major p450 forms in olfactory microsomes, whereas NMa and P450 form 2 (or its homolog) constitute the major portion of the respiratory nasal microsomal p450. The level of NMa in the liver is relatively low, accounting for less than 3% of total microsomal p450 in this tissue. In addition, evidence is provided that NMa is the major catalyst in the dealkylation of two nasal carcinogens, hexamethylphosphoramide and phenacetin, in both olfactory and respiratory nasal microsomes.
Possible roles of chtochrome p450 monooxygenases in nasal tissues are discussed. Nasal cytochrome p450 is known to occur in dogs, rats, monkeys mice, guinea pigs, and Syrian hamsters, and possible other species. The concentrations of cytochrome p450 in the olfactory mucosa of monkeys, dogs, and rats is much higher than in the nasal rspiratory mucosa. The substrate specificity of nasal cytochrome p450 is different from that of the liver. For example, whereas liver cytochrome p450 oxidizes benoz(a)pyrene faster than nasal cytochrome, the reverse is true for hexamethylphosphoramide (HMPA). Nasal cytochrome p450 may be involved in producing toxic or carcinogenic metabolites from inhaled compounds. For exampe, HMPA may be demethylated to formaldehyde by nasal cytochrome p450. Nasal cytochrome p450 may have a role in protecting lungs, since nasal metabolism of inhaled organic vapors can reduce the concentration of the vapors reaching the lungs. Nasal cytochrome p450 may help maintain acuity of the sense of smell through removal of odorants by metabolizing them. Without this function, odorants remaining in the mucus covering of the sensory organs might produce an unacceptably high background odor, thereby decreasing acuity. In species that are highly dependent on the sense of smell, the lack of olfactory acuity could have serious debilitating effects.
来源:Hazardous Substances Data Bank (HSDB)
代谢
己内酰胺已知的代谢物包括戊内酰胺。
Hexamethylphosphoramide has known human metabolites that include Pentamethylphosphoramide.
Evaluation: No epidemiological data relevant to the carcinogeniciy of hexamethylphosphoramide were available. There is sufficient evidence in experimental animals for the carcinogenicity of hexamethylphosphoramide. Overall evaluation: Hexamethylphosphoramide is possibly carcinogenic to humans (Group 2B).
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
A3；已确认对动物有致癌性，但对人类的相关性未知。
A3; Confirmed animal carcinogen with unknown relevance to humans.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
六甲基磷酰胺：合理预期为人类致癌物。
Hexamethylphosphoramide: reasonably anticipated to be a human carcinogen.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌物分类
国际癌症研究机构致癌物：六甲基磷酰胺
IARC Carcinogenic Agent:Hexamethylphosphoramide
来源:International Agency for Research on Cancer (IARC)
毒理性
致癌物分类
国际癌症研究机构（IARC）致癌物分类：2B组：可能对人类致癌
IARC Carcinogenic Classes:Group 2B: Possibly carcinogenic to humans
来源:International Agency for Research on Cancer (IARC)
SEVENTY PERCENT OF (32)P-LABELED HEXAMETHYLPHOSPHORAMIDE GIVEN IP WAS EXCRETED WITHIN 20 HR BY RATS & MICE AS (32)P. HEXAMETHYLPHOSPHORAMIDE IS EXCRETED IN MILK OF COWS FOLLOWING ITS ORAL ADMIN.
Novel processes for the preparation of adenosine compounds and intermediates thereto
申请人：——
公开号：US20030069423A1
公开（公告）日：2003-04-10
Novel processes for the preparation of adenosine compounds and intermediates thereto. The adenosine compounds prepared by the present processes may be useful as cardiovascular agents, more particularly as antihypertensive and anti-ischemic agents, as cardioprotective agents which ameliorate ischemic injury or myocardial infarct size consequent to myocardial ischemia, and as an antilipolytic agents which reduce plasma lipid levels, serum triglyceride levels, and plasma cholesterol levels. The present processes may offer improved yields, purity, ease of preparation and/or isolation of intermediates and final product, and more industrially useful reaction conditions and workability.
[EN] COMPOUNDS FOR THE TREATMENT OF AMYLOID-ASSOCIATED DISEASES<br/>[FR] COMPOSÉS POUR LE TRAITEMENT DE MALADIES ASSOCIÉES À LA SUBSTANCE AMYLOÏDE
申请人：REMYND NV
公开号：WO2016083490A1
公开（公告）日：2016-06-02
This invention provides novel compounds of formulae (I) or (II) or a stereoisomer, enantiomer, racemic, or tautomer thereof, (I) (II) wherein the substituents are as defined in the specification. The present invention also relates to the novel compounds for use as a medicine, more in particular for the prevention or treatment of amyloid-related diseases, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, disorders characterized by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such amyloid-related diseases. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds.
[EN] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
申请人：TAKEDA PHARMACEUTICAL
公开号：WO2010144486A1
公开（公告）日：2010-12-16
Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.
SULFONAMIDE, SULFAMATE, AND SULFAMOTHIOATE DERIVATIVES
申请人：Wang Zhong
公开号：US20120077814A1
公开（公告）日：2012-03-29
The disclosure provides biologically active compounds of formula (I):
and pharmaceutically acceptable salts thereof, compositions containing these compounds, and methods of using these compounds in a variety applications, such as treatment of diseases or disorders associated with E1 type activating enzymes, and with Nedd8 activating enzyme (NAE) in particular.
Compounds that have agonist activity at one or more of the SlP receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at SlP receptors.
