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Bendroflumethiazide

HCID 2315
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Basic information

CAS
73-48-3
Standard SMILES
NS(=O)(=O)c1cc2c(cc1C(F)(F)F)NC(Cc1ccccc1)NS2(=O)=O
InChIKey
HDWIHXWEUNVBIY-UHFFFAOYSA-N
Molecular formula
C15H14F3N3O4S2
Average molar mass
421.4 g/mol
Monoisotopic mass
421.03778277

Overview

Bendroflumethiazide is a sulfonamide consisting of 7-sulfamoyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide in which the hydrogen at position 6 is substituted by a trifluoromethyl group and that at position 3 is substituted by a benzyl group. It has a role as a diuretic and an antihypertensive agent. It is a sulfonamide and a benzothiadiazine.

Names & identifiers

Preferred name
Bendroflumethiazide
IUPAC
3-benzyl-1,1-dioxo-6-(trifluoromethyl)-3,4-dihydro-2H-1λ6,2,4-benzothiadiazine-7-sulfonamide
English name
BENDROFLUMETHIAZIDE
Molecular formula
C15H14F3N3O4S2
Molecular weight
421.41

Names & synonyms

BENDROFLUMETHIAZIDEBendrofluazide73-48-3NaturetinAprinoxBenzhydroflumethiazideBenzylrodiuranCentylPlurylBentrideBristuricBristuron
Show more names
ft8bhftft81relanurleablh368nikionorsile
FlumesilNiagarilPlusurilPoliuronSinesalinSodiureticThiazidicoIntolex

Database identifiers

CAS
73-48-3
PubChem CID
2315
DTXSID
DTXSID5022647
ChEMBL
CHEMBL1684
ChEBI
CHEBI:3013
UNII
5Q52X6ICJI
EC Number
200-800-1

Properties

Computed structural properties

XLogP
1.2
Topological polar surface area
135 Ų
Hydrogen bond donors
3
Hydrogen bond acceptors
10
Rotatable bonds
3
Heavy atoms
27
Formal charge
0
Complexity
740

Experimental & physicochemical properties

DrugsPharmaceuticals -> Cardiovascular system -> Diuretics
LogP · 3 items

log Kow = 1.19

1.7

1.78

OdorODORLESS OR HAS SLIGHT, CHARACTERISTIC FLORAL ODOR
Color/Form · 2 items

Crystals from dioxane.

WHITE TO CREAM-COLORED, FINELY DIVIDED, CRYSTALLINE POWDER

Solubility · 5 items

FREELY SOL IN ALC & ACETONE

Insoluble in chloroform, benzene, ether.

In water, 108.3 mg/l at 25 °C.

2.14e-01 g/L

>63.2 [ug/mL] (The mean of the results at pH 7.4)

Human Drugs · 4 items

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Thiazide Diuretics

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

DecompositionWhen heated to decomposition it emits toxic fumes of /hydrogen fluoride/, sulfoxides, and nitroxides.
Melting Point

Safety & regulation

Safety information is for reference only and does not replace the supplier’s Safety Data Sheet (SDS), applicable regulations, or professional assessment.

GHS classification

GHS Classification · 3 items

This chemical does not meet GHS hazard criteria for 91.5% (54 of 59) of all reports.

Not Classified

Aggregated GHS information provided per 59 reports by companies from 6 notifications to the ECHA C&L Inventory.

Hazard information

Regulatory InformationBendroflumethiazide: Does not have an individual approval but may be used under an appropriate group standard
Other Safety InformationIMAP assessments - 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3,4-dihydro-3-(phenylmethyl)-6-(trifluoromethyl)-, 1,1-dioxide: Environment tier I assessment
FDA Requirements · 1 item

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

Hazard Classes and CategoriesNot Classified

Safety & protection

Storage ConditionsBendroflumethiazide tablets should be stored in tight containers at room temperature and protected from excessive heat.
Disposal Methods · 1 item

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Chemistry & industry

Pharmacology

ATC Code · 2 items

C - Cardiovascular system

QC - Cardiovascular system

Protein Binding96%
Pharmacodynamics · 1 item

Bendroflumethiazide, a thiazide diuretic, removes excess water from the body by increasing how often you urinate (pass water) and also widens the blood vessels which helps to reduce blood pressure. It inhibits Na<sup>+</sup>/Cl<sup>-</sup> reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue.

Mechanism of Action · 6 items

As a diuretic, bendroflumethiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like bendroflumethiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of bendroflumethiazide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle.

...BENZOTHIADIAZIDES HAVE DIRECT EFFECT ON RENAL TUBULAR TRANSPORT OF SODIUM & CHLORIDE...INDEPENDENT OF ANY EFFECT ON CARBONIC ANHYDRASE. /THIAZIDE DIURETICS/

NATURE OF CHEM INTERACTION BETWEEN THIAZIDES & SPECIFIC RENAL RECEPTORS RESPONSIBLE FOR CHLORURETIC EFFECT IS NOT KNOWN; NO CRITICAL ENZYMATIC REACTIONS HAVE BEEN IDENTIFIED. /THIAZIDE DIURETICS/

...MAY DECR EXCRETION OF URIC ACID IN MAN, THUS INCR ITS CONCN IN PLASMA. HYPERURICEMIC EFFECT RESULTS PRIMARILY FROM INHIBITION OF TUBULAR SECRETION OF URATE. ... UNLIKE MOST OTHER NATRIURETIC AGENTS...DECR RENAL EXCRETION OF CALCIUM RELATIVE TO THAT OF SODIUM... /ENHANCE/ EXCRETION OF MAGNESIUM... /THIAZIDE DIURETICS/

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Compound notes

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On this pageBasic informationOverviewNames & identifiersPropertiesSafety & regulationChemistry & industryRelated reactionsCompound notes
· 3 items

222-223 °C

224.5 to 225.5 °C (also reported as 221 to 223 °C)

221 - 223 °C

Physical DescriptionSolid
Dissociation Constants8.5
Collision Cross Section · 2 items

188.6 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

189.03 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Physicochemical properties

Melting point
205 · 205-207°C
Boiling point
602.1 · 602.1±65.0 °C(Predicted)
Density
1.4711 · 1.4711 (estimate)
storage temp.
Refrigerator
solubility
Practically insoluble in water, freely soluble in acetone, soluble in ethanol (96 per cent).
pka
8.53 · pKa 8.53±0.05(H2O t=25 I=0.2) (Uncertain)
form
Solid
color
3 · Crystals from MeOH/CHCl3
Water Solubility
40 mg/L · 40mg/L(room temperature)
FDA UNII
5 Q52X6ICJI · 5Q52X6ICJI
ATC code
3 AA01 · C03AA01
EPA Substance Registry System
2 H-1,2,4-Benzothiadiazine-7-sulfonamide, · 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3,4-dihydro-3-(phenylmethyl)-6-(trifluoromethyl)-, 1,1-dioxide (73-48-3)
Protein binding
94 % · 94%
Excreted unchanged in urine
30 % · 30%
Volume of distribution
1.2 · 1.2-1.5(L/kg)
Biological half-life
3 · 3-9 / -
Symbol(GHS)
7 · GHS07
Signal word
Warning
Hazard statements
332 · H332-H302
Precautionary statements
261 · P261-P271-P304+P340-P312-P264-P270-P301+P312-P330-P501
WGK Germany
2 · 2
RTECS
8225000 · DK8225000
HS Code
2935904000 · 2935904000
Hazardous Substances Data
73 · 73-48-3(Hazardous Substances Data)
Toxicity
50 oral · LD50 oral in mouse: > 10gm/kg

Toxicology

Interactions · 5 items

MANY DIABETIC PATIENTS REGULATED BY CHLORPROPAMIDE OR OTHER SULFONYLUREAS EXHIBIT IMPAIRED DIABETIC CONTROL WHEN ANY THIAZIDE DIURETIC IS ADDED TO DRUG REGIMEN. /THIAZIDE DIURETICS/

...CARDIAC GLYCOSIDE & DIURETIC; DIURETIC-INDUCED HYPOKALEMIA POTENTIATES CARDIOTOXICITY OF GLYCOSIDE. /DIURETICS/

THIAZIDES ENHANCE ANTIHYPERTENSIVE ACTION OF GUANETHIDINE, ALLOWING DOSE OF GUANETHIDINE TO BE REDUCED & DECR INCIDENCE OF ADVERSE REACTIONS... /THIAZIDE DIURETICS/

...DIURETICS MAY INCR CONCN OF CLOTTING FACTORS BY LOSS OF PLASMA VOL & INCR CLOTTING FACTOR SYNTH BY REDUCING HEPATIC CONGESTION, THEREBY ANTAGONIZING EFFECT OF ORAL ANTICOAGULANTS. /DIURETICS, THIAZIDE/

For more Interactions (Complete) data for BENDROFLUMETHIAZIDE (21 total), please visit the HSDB record page.

Human Toxicity Excerpts · 3 items

BORDERLINE RENAL &/OR HEPATIC INSUFFICIENCY MAY BE UNPREDICTABLY AGGRAVATED BY THIAZIDES. ... IN CIRRHOSIS OF LIVER, DETERIORATION OF MENTAL FUNCTION, INCL ONSET OF COMA, HAS BEEN ATTRIBUTED TO THIAZIDE THERAPY. ... THIAZIDES MAY INDUCE HYPERGLYCEMIA & AGGRAVATE PREEXISTING DIABETES MELLITUS. /THIAZIDE DIURETICS/

In addition to diuresis and resultant dehydration, overdosage of thiazides may produce lethargy, nausea, weakness, and electrolyte imbalance; lethargy may progress to coma within a few hours with minimal depression of respiratory and cardiovascular function and without evidence of dehydration or serum electryolye change. The mechanism of thiazide-induced CNS depression is unknown. GI irritation and hypermotility may occur, and temporary elevation of the BUN has been reported. Serum electrolyte changes (e.g., hypokalemia, hypochloremia, hyponatremia) may occur, especially in patients with impaired renal function. /Thiazides/

May suppress lactation, but compatible /SRP: with breast feeding/. /Thiazide diuretics, from table/

Drug Induced Liver Injury · 6 items

Drug Induced Liver Injury Rank (DILIrank 2.0)

Bendroflumethiazide

vLess-DILI-concern

5

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

Antidote and Emergency TreatmentThiazide diuretic overdose should be treated by immediate evacuation of the stomach followed by supportive symptomatic treatment and monitoring of serum electrolyte concentrations and renal function. /Thiazide diuretic/
Effects During Pregnancy and Lactation◉ Summary of Use during Lactation
Non-Human Toxicity Values · 4 items

LD50 MOUSE ORAL EXCEEDS 8000 MG/KG

LD50 MOUSE INTRAPERITONEAL 8000 MG/KG

LD50 Mouse ip 4800 mg/kg

LD50 Mouse iv 395 mg/kg

EPA Human Health Benchmarks for Pharmaceuticals · 6 items

Bendroflumethiazide

0.1

0.5

Bendroflumethiazide is given in combination with nadolol in a tablet. Each tablet contains 40 mg or 80 mg nadolol combined with 5 mg bendroflumethiazide. Bendroflumethiazide is usually given at a dose of 5 mg daily.

Data used to generate the benchmarks include the following: Lowest Daily Dose (LDD): 5 mg/day, Lowest Therapeutic Dose (LTD): 0.1 mg/kg-day, and Screening Dose: 0.00002 mg/kg-day.

15-Apr-16

Regulatory information

FDA Requirements · 1 item

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

Safety data

wgk
2
rtecs
DK8225000
hs_code
2935904000
Toxicity
LD50 oral in mouse: > 10gm/kg
Signal word
Warning
Symbol(GHS)
GHS07
Hazard statements
H332-H302
Precautionary statements
P261-P271-P304+P340-P312-P264-P270-P301+P312-P330-P501
Hazardous Substances Data
73-48-3(Hazardous Substances Data)

THIAZIDES INHIBIT REABSORPTION OF SODIUM &...CHLORIDE IN DISTAL SEGMENT. ... AS CLASS...HAVE IMPORTANT ACTION ON EXCRETION OF POTASSIUM THAT RESULTS FROM INCR SECRETION OF CATION BY DISTAL TUBULE. ... GLOMERULAR FILTRATION RATE MAY BE REDUCED BY THIAZIDES, PARTICULARLY WITH IV ADMIN FOR EXPTL PURPOSES. /THIAZIDE DIURETICS/

For more Mechanism of Action (Complete) data for BENDROFLUMETHIAZIDE (11 total), please visit the HSDB record page.

Biological Half-Life · 2 items

8.5 hours

Halflife is 3-3.9 hrs. /From table/

FDA Pharmacological Classification · 6 items

5Q52X6ICJI

BENDROFLUMETHIAZIDE

Physiologic Effects [PE] - Increased Diuresis

Established Pharmacologic Class [EPC] - Thiazide Diuretic

Chemical Structure [CS] - Thiazides

Bendroflumethiazide is a Thiazide Diuretic. The physiologic effect of bendroflumethiazide is by means of Increased Diuresis.

MeSH Pharmacological Classification · 3 items

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Agents that promote the excretion of urine through their effects on kidney function.

Agents that inhibit SODIUM CHLORIDE SYMPORTERS. They act as DIURETICS. Excess use is associated with HYPOKALEMIA.

Absorption, Distribution and Excretion · 6 items

Absorbed relatively rapidly after oral administration

MOST CMPD ARE RAPIDLY EXCRETED WITHIN 3-6 HR. BENDROFLUMETHIAZIDE...LONGER DURATION OF ACTION THAT IS CORRELATED WITH...SLOWER EXCRETION.

THIAZIDES ARE ABSORBED FROM GI TRACT & OWE THEIR USEFULNESS LARGELY TO THEIR EFFECTIVENESS BY ORAL ROUTE. ABSORPTION IS RELATIVELY RAPID. MOST AGENTS SHOW DEMONSTRABLE DIURETIC EFFECT WITHIN HR AFTER ORAL ADMIN. /BENZOTHIADIAZIDES/

IN GENERAL, THIAZIDES WITH RELATIVELY LONG DURATIONS OF ACTION SHOW PROPORTIONATELY HIGH DEGREE OF BINDING TO PLASMA PROTEINS & ARE REABSORBED... BY RENAL TUBULES. ... DRUG PASSES READILY THROUGH PLACENTAL BARRIER TO FETUS. ALL THIAZIDES PROBABLY UNDERGO ACTIVE SECRETION IN PROXIMAL TUBULE. /THIAZIDE DIURETICS/

BENDROFLUMETHIAZIDE WAS ADMIN ORALLY TO 9 HEALTHY VOLUNTEERS. PEAK PLASMA LEVELS REACHED @ 1 + OR - 0.4 HR. CONCN DECLINED WITH MEAN T/2 OF 3 HR. APPARENT VOL OF DISTRIBUTION AVG 1.48 L/KG. MAJOR PART ELIMINATED VIA NONRENAL MECHANISMS. URINARY RECOVERY AVG 30%.

Bendroflumethiazide appears to be well absorbed from the GI tract. The drug is excreted unchanged in urine, and excretion is essentially complete within 24 hours.

Cellular LocationsCytoplasm
Metabolite PathwaysBendroflumethiazide Action Pathway

Uses & manufacturing

Uses · 2 items

MEDICATION

THERAP CAT: Diuretic, antihypertensive.

Methods of ManufacturingPrepn: C.T. Holdrege et al., J Am Chem Soc 81, 4807 (1959); F. Lund, W.O. Godtfredsen, Brit pat 863,474; eidem, U.S. pat 3,392,168 (1961, 1968 both to Lovens Kemiske Fabrik)..
Formulations/PreparationsDOSAGE FORMS- TABLETS NF: 2.5, 5, & 10 MG.
Use ClassificationPharmaceuticals
Applications · 4 items

DescriptionBendroflumethiazide (Item No. 21311) is an analytical reference standard categorized as a diuretic. Diuretics, including bendroflumethiazide, have been abused as performance-enhancing drugs and masking agents in sports doping. This product is intended for research and forensic applications.

UsesBendroflumethiazide may be used for the same indications as the aforementioned drugs; however, it is primarily used as an adjuvant agent for relieving edema associated with cardiac insufficiency, liver cirrhosis, and edema caused by taking corticosteroids.

Usesexpectorant

UsesDiuretic; antihypertensive.

Upstream & downstream products

Upstream raw materials

3-NitrobenzotrifluorideBenzotrifluorideAminosulfonateBenzotrichloridePhenylacetaldehydeIron3-AminobenzotrifluorideAmmoniaChlorosulfonic acid

Additional notes

DefinitionChEBI: A sulfonamide consisting of 7-sulfamoyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide in which the hydrogen at position 6 is substituted by a trifluoromethyl group and that at position 3 is substituted by a benzyl group.