About half the absorbed dose of captopril is rapidly metabolized, mainly to captopril-cysteine disulfide and the disulfide dimer of captopril. In vitro studies suggest that captopril and its metabolites may undergo reversible interconversions. It has been suggested that the drug may be more extensively metabolized in patients with renal impairment than in patients with normal renal function.
IDENTIFICATION AND USE: Captopril is angiotensin-converting enzyme (ACE) inhibitor and antihypertensive agent. HUMAN STUDIES: Captopril prevents the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor) by competing with the physiologic substrate (angiotensin I) for the active site of ACE. The affinity of the drug for ACE is approximately 30,000 times greater than that of angiotensin I. Inhibition of ACE results in decreased plasma angiotensin II concentrations and, consequently, blood pressure may be reduced in part through decreased vasoconstriction. Captopril-induced bone marrow suppression is rare, except in certain high-risk patient populations. Severe exfoliative rashes have also been associated with captopril. A 57 year old male with mild impairment of renal function secondary to diabetic glomerulosclerosis developed acute renal failure associated with a generalized desquamative skin rash and peripheral eosinophilia shortly after initiation of antihypertensive therapy with captopril. Cholestatic jaundice is a rare complication associated with the use captopril. The severity of the disease may range from cholestasis on liver histology to overt fulminant hepatic failure. A case of a 75 year old male who committed suicide by taking an overdose of captopril was reported. He took approximately ninety 12.5 mg captopril tablets. Captopril administration over 3 months or more generates red blood cells zinc depletion. Hypogeusia (a reduced ability to taste things) is a reported side effect of captopril. Linkage of hypogeusia to zinc deficiency has been suggested. The fetal toxicity of captopril in the 2nd and 3rd trimesters is similar to other ACE inhibitors. The use of this drug during the 2nd and 3rd trimesters may cause teratogenicity and severe fetal and neonatal toxicity. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, prematurity, and patent ductus arteriosus. Still birth or neonatal death may occur. Anuria-associated oligohydramnios may product fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Sever anuria and hypotension, which is resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure. Newborn renal function and blood pressure should be closely monitored. Mutagenicity studies with captopril in fixed combination with hydrochlorothiazide have not been conducted, but the effects of the individual components in a 2:1 ratio have been studied. Captopril/hydrochlorothiazide did not exhibit mutagenic or clastogenic potential in a sister chromatid exchange test in human lymphocytes. In a cytogenetics assay in human lymphocytes exposed to captopril/hydrochlorothiazide concentrations of 5, 25, and 50 ug/mL (total concentration of both drugs) with metabolic activation, chromosomal abnormalities were not observed consistently. When such aberrations were observed, no concentration response was noted. ANIMAL STUDIES: No evidence of carcinogenesis was observed in rats or mice receiving captopril dosages of 50-1350 mg/kg daily for 2 years. Reproduction studies in hamsters and rats using large doses of captopril have not revealed evidence of teratogenic effects. However, the drug was embryocidal and was associated with a low incidence of craniofacial malformations in rabbits, probably as a result of the marked decrease in blood pressure caused by the drug in this species. Reduction in neonatal survival occurred in the offspring of rats receiving captopril continuously during gestation and lactation, and an increased incidence of stillbirths has reportedly occurred in ewes. Mutagenicity studies with captopril in fixed combination with hydrochlorothiazide have not been conducted, but the effects of the individual components in a 2:1 ratio have been studied. Captopril/hydrochlorothiazide did not exhibit mutagenic or clastogenic potential in vitro with or without metabolic activation in a bacterial reverse mutation (Ames) assays using Salmonella, a forward mutation assay in Saccharomyces pombe, and a gene conversion assay using Saccharomyces cerevisiae. Captopril and hydrochlorothiazide in a 2:1 ratio were not genotoxic in the in vivo mouse micronucleus test at an oral dose of 2,500 mg/kg (total concentration of both drugs). ECOTOXICITY STUDIES: Captopril induces oxidative stress in C. carpio.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
肝毒性
Captopril，与其他ACE抑制剂一样，与血清转氨酶升高的低发生率有关（
Captopril, like other ACE inhibitors, has been associated with a low rate of serum aminotransferase elevations (
The drug /captopril/ is metabolized and renally excreted. More than 95% of a dose is excreted renally, both as unchanged (45-50%) drug and as metabolites.
In dogs, approximately 75% of an oral dose is absorbed but food in the GI tract reduces bioavailability by 30-40%. It is distributed to most tissues (not the CNS) and is 40% bound to plasma proteins in dogs.
Approximately 60-75% of an oral dose of captopril is rapidly absorbed from the GI tract in fasting healthy individuals or hypertensive patients. Food may decrease absorption of captopril by up to 25-40%, although there is some evidence that this effect is not clinically important. Following oral administration of a single 100-mg dose of captopril in fasting healthy individuals in one study, average peak blood drug concentrations of 800 ng/mL were attained in 1 hour.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
/MILK/ 人体乳汁中的卡托普利浓度大约是母体血液中浓度的百分之一。
/MILK/ Concentrations of captopril in human milk are approximately one percent of those in maternal blood.
Various carboxylic acids are converted into the corresponding acid chlorides by treatment with trichloroacetonitrile and triphenylphosphine in methylene chloride at room temperature. Aryl acids show higher reactivity than alkyl acids under the conditions. (C) 1999 Elsevier Science Ltd. All rights reserved.
DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
申请人：BAYER PHARMA AKTIENGESELLSCHAFT
公开号：US20160221965A1
公开（公告）日：2016-08-04
The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
[EN] SULFONYL COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN<br/>[FR] COMPOSÉS DE SULFONYLE QUI INTERAGISSENT AVEC LA PROTÉINE RÉGULATRICE DE LA GLUCOKINASE
申请人：AMGEN INC
公开号：WO2013123444A1
公开（公告）日：2013-08-22
The present invention relates to sulfonyl compounds that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.
SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
申请人：BLUM Andreas
公开号：US20140135309A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I
wherein Ar, R
1
and R
2
are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
[EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2014072244A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
申请人：Ryono Denis E.
公开号：US20080009465A1
公开（公告）日：2008-01-10
Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure
wherein
is a heteroaryl ring;
R
4
is —(CH
2
)
n
-Z-(CH
2
)
m
—PO(OR
7
)(OR
8
), —(CH
2
)
n
Z-(CH
2
)
m
—PO(OR
7
)R
g
, —(CH
2
)
n
-Z-(CH
2
)
m
—OPO(OR
7
)R
g
, —(CH
2
)
n
Z—(CH
2
)
m
—OPO(R
9
)(R
10
), or —(CH
2
)
n
Z—(CH
2
)
m
—PO(R
9
)(R
10
);
R
5
and R
6
are independently selected from H, alkyl and halogen;
Y is R
7
(CH
2
)
s
or is absent; and
X, n, Z, m, R
4
, R
5
, R
6
, R
7
, and s are as defined herein; or a pharmaceutically acceptable salt thereof.
A method for treating diabetes and related diseases employing the above compounds is also provided.
提供了磷酸酯和磷酸酯激活剂，因此在治疗糖尿病和相关疾病方面非常有用，并具有以下结构：
其中
是杂环芳基环；
R
4
为—(CH
2
)
n
-Z-(CH
2
)
m
—PO(OR
7
)(OR
8
)、—(CH
2
)
n
Z-(CH
2
)
m
—PO(OR
7
)R
g
、—(CH
2
)
n
-Z-(CH
2
)
m
—OPO(OR
7
)R
g
、—(CH
2
)
n
Z—(CH
2
)
m
—OPO(R
9
)(R
10)
或—(CH
2
)
n
Z—(CH
2
)
m
—PO(R
9
)(R
10)
；
R
5
和R
6
分别选择自H、烷基和卤素；
Y为R
7
(CH
2
)
s
或不存在；以及
X、n、Z、m、R
4
、R
5
、R
6
、R
7
和s如本文所定义；或其药用盐。
还提供了一种利用上述化合物治疗糖尿病和相关疾病的方法。
