58-93-5 Usage
Uses
Used in Pharmaceutical Industry:
Hydrochlorothiazide is used as a diuretic for the treatment of edema and as an antihypertensive agent to lower blood pressure. It is also used in combination with other traditional Chinese medicines to enhance their effects.
Used in Diuretic Applications:
Hydrochlorothiazide is used as a diuretic drug of moderate effect, increasing renal excretion of sodium chloride and producing a diuretic effect. It is often used for the treatment of edema and to promote the elimination of excess fluid from the body.
Used in Antihypertensive Applications:
Hydrochlorothiazide is used as an antihypertensive agent to lower blood pressure. Its effect is enhanced when used in combination with other medications, such as Lee medicine paste, antihypertensive shen paste, or apocynum venetum.
Used in Anti-diuretic Applications:
Hydrochlorothiazide is used for the treatment of diabetes insipidus, a condition characterized by excessive urination and thirst. It helps to reduce urine output and manage the symptoms of the condition.
Used in Carbonic Anhydrase Inhibition:
Hydrochlorothiazide is used as a carbonic anhydrase inhibitor, which helps to prevent the formation of carbonic acid in the kidneys and contributes to its diuretic effect.
mechanism of action
1. Natriuretic effect: This product mainly inhibits the re-absorption of Na+, Cl-of distal tubule anterior part and proximal tubules (mild effect), and increasing urinary sodium, potassium, chlorine, phosphorus and magnesium ion excretion, and reducing urinary calcium excretion.
2. Antihypertensive effect: it has a moderate and precise antihypertensive effect and can reduce both the orthostatic, supine systolic and diastolic pressure and also enhance the hypotensive effect of other antihypertensive drugs.
3. Anti-diuretic effect: This product can reduce the amount of urine in nephrogenic diabetes insipidus, sometimes by 50% with the specific mechanism of action remaining unknown.
Pharmacokinetics
It has rapid but incomplete oral absorption with heaving meal being able to increase the absorbed amount, which may be related with the prolonged residence time of drug in the small intestine. This product can partially bind to the plasma protein with the other part getting into the red blood cells. It takes effect at 2h after oral administration with the peak reaching in 4h. It duration time is 6~12h. It is mainly secreted in the prototype through the urinary excretion with the half-life (t1/2) being 15h and the t1/2 being extended in renal dysfunction.
The above information is edited by the lookchem of Dai Xiongfeng.
Indications
1. Edema disease: including congestive heart failure, cirrhosis, nephrotic syndrome, acute and chronic nephritis edema, chronic renal failure early, adrenocorticotropic hormone and estrogen therapy caused retention of sodium and water.
2. High blood pressure: it can be used alone or in combination with other antihypertensive drugs. It is mainly used for the treatment of essential hypertension.
3. Central or nephrogenic diabetes insipidus.
4. Kidney stone disease: it is mainly used for the prevention of calcium stone formation.
Dosage
Oral ordinary tablet: the efficacy onset of oral administration is in 2h with plasma concentration reaching peak at 4 hour and the effect lasting for 6~12h.
Adults: (1) for the treatment of edema disease, a 25~50mg, qd or bid, or qod; or take drug 3~5d weekly with a interval of 3~4d. (2) For the treatment of hypertension with the dose of 25 to 100 mg per day and divided into 1-2 times for administration. It needs to be used in combination with other antihypertensive drugs and should be subject to dose adjustment according to the actual antihypertensive effect. The dose is usually reduced to 25 to 50 mg per day within one week. (3) for the treatment of diabetes insipidus, take 25mg once tid, or 50 mg once, qd.
Children: treatment of edema disease, take 1~2mg/kg per day and divided 1-2 times for administration. Adjust the dose according to the actual efficacy.
Side effects
Most adverse events are related to the dose and duration.
1. Water, electrolyte imbalance caused adverse reactions are the more common: hypokalemia is prone to occur and is related to the potassium excretion effect of thiazide diuretics. Long-term potassium deficiency can damage tubular with serious loss of potassium being able to cause vacuolar changes in the renal tubular epithelial and severe tachyarrhythmias and other ectopic rhythm. Thiazide class, especially hydrochlorothiazide can often significantly increases the excretion of chloride, causing low chlorine alkalosis or low chlorine, potassium alkalosis. In addition, hyponatremia is also not rare, causing central nervous system symptoms and aggravate kidney damage. Dehydration causes blood volume and renal blood flow reduction and can also cause reduced glomerular filtration rate. The common clinical manifestations of water, electrolyte imbalance include dry mouth, thirst, muscle cramps, nausea, vomiting and extreme fatigue, weakness and so on.
2. Hyperglycemia: It can make impaired glucose tolerance, elevated blood sugar, may be associated with inhibition of insulin release.
3. Hyperuricemia: it can interfere with renal tubular excretion of uric acid with a few being able to cause gout attacks. Usually it doesn’t cause joint pain, so hyperuricemia is easily overlooked.
4. Allergy: such as rash, urticaria; relatively rare.
5. Leukopenia or deficiency, and thrombocytopenic purpura, also rare.
6. Rare cholecystitis, pancreatitis, sexual dysfunction, light sensitivity, and color vision disorders.
Drug Interaction
1. Adrenocorticotropic hormone, corticotropin, estrogens, amphotericin B (intravenous administration), can reduce the diuretic effect of this product and increase the chance of electrolyte imbalance, particularly hypokalemia.
2. Non-steroidal anti-inflammatory analgesic drugs, especially indomethacin, can reduce the diuretic effect of this product which is related with the former’s inhibition of prostaglandin synthesis.
3. Upon combination with the sympathomimetic amine drugs, its diuretic effect weakened.
4. Cholestyramine (cholestyramine) can reduce the gastrointestinal absorption of this product. Therefore, it should be taken orally at 1 h before or 4 h after taking the former drug.
5. In combination with dopamine, the diuretic effect strengthened.
6. In combination with antihypertensive drugs, both diuretic and antihypertensive effect were enhanced.
7. In combination with anti-gout drug, the dosage of the later one should be adjusted.
8. It can weaken the anticoagulant, mainly due to the decreased elevated levels of blood plasma volume after diuretic, elevated levels of blood clotting factors, together with the diuretic effect improving blood supplement in the liver, and increased synthesis of clotting factors.
9. It can reduce the role of hypoglycemic agents.
10. Upon being used combination with digitalis drugs or amiodarone, you should beware of adverse reactions caused by hypokalemia.
11. Upon being combination with lithium preparations, the product can reduce the renal clearance of lithium and increase renal toxicity of lithium.
12. The effect of methenamine is affected by this product with its conversion to formaldehyde being inhibited, decreasing the efficacy.
13. Enhance the non-depolarizing muscle relaxant effect which is related to a decline in serum potassium.
14. Upon being used in combination with sodium bicarbonate, the chances of low chlorine alkalosis increases.
Production method
It is produced by: m-Chlorosulfonated goes through chlorosulfonation to give 5-chloro-2,4-chloro-anilide, and further reacted with ammonia to form 5-chloro-2,4-sulfamoyl aniline which finally reacts with formaldehyde to obtain the final product.
Originator
Hydrodiuril,MSD,US,1959
Manufacturing Process
As described in US Patent 3,163,645, a mixture of 2.9 grams of 5-chloro-2,4-
disulfamyl aniline in 15 ml of anhydrous diethyleneglycol dimethyl ether, 0.5
ml of an ethyl acetate solution containing 109.5 grams of hydrogen chloride
per 1,000 ml and 0.33 grams (0.011 mol) of paraformaldehyde is heated to
80° to 90°C and maintained at that temperature for 1 hour. The resulting
mixture is cooled to room temperature and concentrated to one-third of its volume under reduced pressure, diluted with water, then allowed to
crystallize. The product is filtered off and recrystallized from water, to yield
the desired 6-chloro-7-sulfamyl-3,4-dihydro-2H-[1,2,4]-benzothiadiazine-1,1-
dioxide, MP 266° to 268°C, yield 1.4 grams. By replacing paraformaldehyde
by 0.84 gram of 1,1 -dimethoxymethane and proceeding as above, the same
compound is obtained.
As described in US Patent 3,025,292, the desired product may be made by
hydrogenation of chlorothiazide. Three grams of 6-chloro-7-sulfamyl-1,2,4-
benzothiadiazine-1,1-dioxide (chlorothiazide) is suspended in 100 ml of
methanol. Then 1.0 gram of a 5% ruthenium on charcoal catalyst is added,
and the mixture is reduced at room temperature and at an initial hydrogen
pressure of 39 psig. The theoretical amount of hydrogen to form the 3,4-
dihydro derivative is absorbed after a period of about 10 hours.
The reduction mixture then is heated to boiling and filtered hot to remove the
catalyst. The catalyst is washed with a little methanol and the combined
filtrate is concentrated to a volume of about 25 ml by evaporation on a steam
bath. Upon cooling to room temperature, white crystals separate which are
filtered, washed with water, and dried in vacuo at room temperature over
phosphorus pentoxide overnight. The weight of 6-chloro-7-sulfamyl 3,4-
dihydro-1,2,4-benzothiadiazine-1,1-dioxide obtained is 1.26 grams; MP 268.5°
to 270°C. Dilution of the above filtrate with water to a volume of about 125
ml gives a second crop of product having the same melting point and
weighing 1.22 grams, giving a combined yield of 83%. When the product is
mixed with an authentic sample of 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-
benzothiadiazine-1,1-dioxide, prepared by another method, the melting point
is not depressed.
Therapeutic Function
Diuretic
Air & Water Reactions
Insoluble in water.
Reactivity Profile
Strong reducing agents will produce toxic gases ammonia and hydrogen sulfide.
Fire Hazard
Flash point data for Hydrochlorothiazide are not available but Hydrochlorothiazide is probably combustible.
Safety Profile
Poison bp
intraperitoneal and intravenous routes.
Moderately toxic by ingestion and
subcutaneous routes. Human systemic
effects by ingestion: sodum level changes,
chlorine level changes, acute pulmonary
edema, nausea or vomiting. Experimental
reproductive effects. Questionable
carcinogen with experimental tumorigenic
data. Mutation data reported. A duetic.
When heated to decomposition it emits very
toxic fumes of SOx, Cl-, and NOx.
Synthesis
Hydrochlorothiazide, 1,1-dioxide 6-chloro-3,4-dihydro-2H-1,2,4-
benzothiadiazin-7-sulfonamide (21.3.4), is synthesized either by cyclization of 4,6-sulfonamido-
3-chloroaniline (21.3.2) using paraformaldehyde, during which simultaneous
reduction of the double bond occurs at position C3–C4, or the drug is synthesized by reduction
of the same double bond in chlorothiazide (21.3.3) by formaldehyde. This small change
in structure increases activity of the drug in comparison with chlorothiazide, and increases
its absorbability when used orally.
Veterinary Drugs and Treatments
In veterinary medicine, furosemide has largely supplanted the use
of thiazides as a general diuretic (edema treatment). Thiazides are
still used for the treatment of systemic hypertension,
nephrogenic
diabetes insipidus, and to help prevent the recurrence of calcium
oxalate uroliths in dogs.
Check Digit Verification of cas no
The CAS Registry Mumber 58-93-5 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 8 respectively; the second part has 2 digits, 9 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 58-93:
(4*5)+(3*8)+(2*9)+(1*3)=65
65 % 10 = 5
So 58-93-5 is a valid CAS Registry Number.
InChI:InChI=1/C7H8ClN3O4S2/c8-4-1-5-7(2-6(4)16(9,12)13)17(14,15)11-3-10-5/h1-2,10H,3H2,(H3-,9,11,12,13,14,15)
58-93-5Relevant articles and documents
Different approaches in Partial Least Squares and Artificial Neural Network models applied for the analysis of a ternary mixture of Amlodipine, Valsartan and Hydrochlorothiazide
Darwish, Hany W.,Hassan, Said A.,Salem, Maissa Y.,El-Zeany, Badr A.
, p. 744 - 750 (2014)
Different chemometric models were applied for the quantitative analysis of Amlodipine (AML), Valsartan (VAL) and Hydrochlorothiazide (HCT) in ternary mixture, namely, Partial Least Squares (PLS) as traditional chemometric model and Artificial Neural Networks (ANN) as advanced model. PLS and ANN were applied with and without variable selection procedure (Genetic Algorithm GA) and data compression procedure (Principal Component Analysis PCA). The chemometric methods applied are PLS-1, GA-PLS, ANN, GA-ANN and PCA-ANN. The methods were used for the quantitative analysis of the drugs in raw materials and pharmaceutical dosage form via handling the UV spectral data. A 3-factor 5-level experimental design was established resulting in 25 mixtures containing different ratios of the drugs. Fifteen mixtures were used as a calibration set and the other ten mixtures were used as validation set to validate the prediction ability of the suggested methods. The validity of the proposed methods was assessed using the standard addition technique.
A convenient and mild cyclocondensation using water-soluble aldehydes in water
Kitanosono, Taku,Cho, Soo Min,Kobayashi, Shū
, p. 7237 - 7241 (2018/11/21)
The use of negatively charged aluminosilicate layers and Lewis acidic cations embedded therein allowed efficient cyclocondensation of bisamines with water-soluble aldehydes to be achieved in water. The protocol does not involve acidic or reflux conditions, thereby avoiding undesired byproduct formation. The use of water as a reaction medium is indispensable to ensure high reaction yields.
Metal-free oxidative cyclization of 2-amino-benzamides, 2-aminobenzenesulfonamide or 2-(aminomethyl)anilines with primary alcohols for the synthesis of quinazolinones and their analogues
Sun, Jinwei,Tao, Tao,Xu, Dan,Cao, Hui,Kong, Qinggang,Wang, Xinyu,Liu, Yun,Zhao, Jianglin,Wang, Yi,Pan, Yi
, p. 2099 - 2102 (2018/05/04)
A general metal-free oxidative cyclization process has been developed for the synthesis of quinazolinones, benzothiadiazines and quinazolines. By this protocol, a range of substituted 2-aminobenzamides, 2-aminobenzenesulfonamide and 2-(aminomethyl)anilines react with various alcohols, leading to the desired annulated products smoothly. This protocol features many advantages as broad substrate scope, mild reaction conditions, low environmental pollution, high atom-economy and good to excellent yields.
Synthesis method of hydrochlorothiazide
-
Paragraph 0063; 0067-0069; 0075; 0081; 0088; 0095; 0101, (2018/11/03)
The invention relates to a synthesis method of hydrochlorothiazide. The synthesis method of the hydrochlorothiazide comprises the following steps: taking chlorothiazide as a reactant; carrying out reduction reaction under the action of organic acid and a hydroboration reagent, so as to generate a hydrochlorothiazide crude product. Borohydride is used as a reducing agent and is used for reducing acarbon-nitrogen double bond in chlorothiazide to generate hydrochlorothiazide; in a whole process, no formaldehyde or analogue participates in, so that compared with an existing synthesis method, thesynthesis method is safer and more environmentally friendly; the yield and purity of the synthesis method are improved.
A method for production of hydrogen chlorothiazide
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Paragraph 0027-0030, (2017/03/08)
The invention belongs to the technical field of medicine production, and particularly relates to a production method for hydrochlorothiazide. Hydrochlorothiazide is prepared by using 4-amino-6-chloro-1,3-benzenedisulfonamide and formaldehyde as raw materials, reacting for 0.5-1.5 hours at a temperature of 90-100 DEG C; cooling a reaction liquid, de-coloring and adjusting a pH value to 5.5-7.0, and carrying out separation and purification. The production method is simple in process and suitable for industrialized production. The whole process is carried out in an aqueous phase; reaction conditions are mild; security coefficient is greatly increased; production period is short and is largely controlled at about 50 hours; the whole production process has small pollution to the environment; and the purity of the synthetic hydrochlorothiazide is high.
A process for the preparation of hydrogen chlorothiazide (by machine translation)
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Paragraph 0014-0015, (2017/03/08)
The invention belongs to the field of medical technology, in particular to a method for production of hydrogen of DCT, to 4-amino-6-chloro -1,3-benzene sulfonamide and formaldehyde as raw materials, and ammonia and for refining of sodium hydroxide, the production process is simple, and is suitable for industrial production, the obtained hydrochiorothiazide high purity, accords with the medical requirement. (by machine translation)
Synthesis and hydrolysis kinetic study of few co-drugs of propranolol and other antihypertensive drugs
Baidya, Mayukh,Das, Amit Kumar
body text, p. 173 - 178 (2012/01/13)
The different acyl halide analogs of propranolol were synthesized by reacting Propanolol with different acyl anhydrides in toluene medium. The derivatives were reacted with thionyl chloride to get propranolol hemi acyl chloride. Finally the co-drugs were synthesized by reacting propranolol hemi acyl chloride with different classes of antihypertensive drugs like Nifedepine (PSN,PMN,PPN), Hydrochlorthiazide (PSH, PMH, PPH) and Acetazolamide(PSA, PMA, PPA) by ester linkage. The structure of the synthesized derivative of propranolol analogs were confirmed by M P, TLC, IR and NMR data.
A PROCESS FOR PREPARATION OF HIGHLY PURE HYDROCHLOROTHIAZIDE
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Page/Page column 9, (2010/01/07)
The present invention relates to an improved process for the preparation of Hydrochlorothiazide of formula (I) having purity of at least 99.9% and OVI content below detectable limit. The present invention further provides a new polymorphic form of Hydrochlorothiazide. (Formula I).
A NOVEL PROCESS FOR PREPARATION OF HIGHLY PURE CRYSTALLINE HYDROCHLOROTHIAZIDE
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Page/Page column 7, (2008/06/13)
This invention relates to a process for the preparation and purification of a pure crystalline Hydrochlorothiazide with overall purity 99.9% or greater and single impurity below 0.1%. This is a two step process. In first step crude hydrochlorothiazide is prepared which is in second step purified to get highly pure crystalline hydrochlorothiazide.
