Doxapram
- CAS NO.:309-29-5
- Empirical Formula: C24H30N2O2
- Molecular Weight: 378.51
- MDL number: MFCD00242721
- EINECS: 206-216-3
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-11-19 23:02:33
What is Doxapram?
Toxicity
Intravenous LD50 values in the mouse and rat were approximately 75 mg/kg and in the cat and dog were 40 to 80 mg/kg. Symptoms of overdosage are extensions of the pharmacologic effects of the drug. Excessive pressor effect, tachycardia, skeletal muscle hyperactivity, and enhanced deep tendon reflexes may be early signs of overdosage.
Originator
Dopram,Robins,US,1965
The Uses of Doxapram
Doxapram HCl inhibits TASK-1, TASK-3, TASK-1/TASK-3 heterodimeric channel function with EC50 of 410 nM, 37 μM, 9 μM, respectively - See more at: http://www.selleckchem.com/products/doxapram-hcl.html#sthash.SSt04Hwr.dpuf
The Uses of Doxapram
Doxapram increases the rate and depth of respiration. It is used for post-anesthetic respiratory depression, and for respiratory depression caused by drug use.
The Uses of Doxapram
Doxapram is a central respiratory stimulant.
Indications
For use as a temporary measure in hospitalized patients with acute respiratory insufficiency superimposed on chronic obstructive pulmonary disease.
Background
A central respiratory stimulant with a brief duration of action. (From Martindale, The Extra Pharmocopoeia, 30th ed, p1225)
What are the applications of Application
Doxapram is a central respiratory stimulant
Definition
ChEBI: A member of the class of pyrrolidin-2-ones that is N-ethylpyrrolidin-2-one in which both of the hydrogens at the 3 position (adjacent to the carbonyl group) are substituted by phenyl groups, and one of the hydrogens at the 4 position is ubstituted by a 2-(morpholin-4-yl)ethyl group. A central and respiratory stimulant with a brief duration of action, it is used (generally as the hydrochloride or the hydrochloride hydrate) as a temporary treatment of acute respiratory failure, particularly when superimposed on chronic obstructive pulmonary disease, and of postoperative respiratory depression. It has also been used for treatment of postoperative shivering.
Manufacturing Process
(A) Preparation of α-(1-ethyl-3-pyrrolidyl)-α,α-diphenylacetonitrile: A
suspension of the sodium salt of diphenylacetonitrile was formed by the
dropwise addition at 50°C of 193 grams (1.0 mol) of diphenylacetonitrile to a
stirred suspension of 43 grams (1.1 mols) of sodium amide in 1 liter of dry
toluene. After addition was complete, the mixture was refluxed for 4 hours
and then, to the refluxing mixture, 1.0 mol of 1-ethyl-3-chloropyrrolidine was
added at a rapid dropwise rate with continuous stirring. After addition was
complete, stirring and refluxing were continued for 3 hours. The mixture was
then cooled and extracted with one normal hydrochloric acid. The aqueous
layer together with an oil layer were separated, made basic with dilute sodium
hydroxide, and extracted with ether. The ethereal solution was dried over
sodium sulfate and concentrated and the residue was distilled in vacuo. The
material crystallized from a 4:1 ethanol-water mixture.
(B) Preparation of 4-(β-chloroethyl)-3,3-diphenyl-1-ethyl-2-pyrrolidinone: A
solution of α,α-diphenyl-α-(1-ethyl-3-pyrrolidyl)-acetonitrile in 70% sulfuric
acid was heated at 130-140°C for 48 hours, poured onto ice, made basic with
sodium hydroxide, and extracted with chloroform. The chloroform solution was
acidified with hydrogen chloride gas, dried over sodium sulfate and
concentrated. The residue was refluxed in 500 ml of thionyl chloride for 3
hours; the resulting solution was concentrated in vacuo; and the residue wascrystallized from isopropyl ether.
(C) Preparation of doxapram hydrochloride [3,3-diphenyl-1-ethyl-4-(2-
morpholino-ethyl)-2-pyrrolidinone hydrochloride monohydrate]: A solution of
25 grams (0.076 mol) of 4-(2-chloroethyl)-3,3-diphenyl-1-ethyl-2-
pyrrolidinone and 13.3 grams (0.153 mol) of morpholine in 500 ml of absolute
ethanol was heated at 95°-120°C for 21 hours in a closed system and
concentrated in vacuo. The residue was dissolved in 300 ml of two normal
hydrochloric acid and extracted with 150 ml of ethyl acetate. A solid
crystallized (13 g) during the extraction and was removed by filtration. MP
217°-219°C. The acid extracts were made basic with sodium hydroxide and
extracted with ether, and the ether solution was concentrated in vacuo and
the residue was suspended in six normal hydrochloric acid. Additional
crystalline product formed and was recrystallized from two normal
hydrochloric acid. Yield, 10 grams; MP 217°-219°C. Total yield, 23 grams
(70%).
Therapeutic Function
Respiratory stimulant
Pharmacokinetics
Doxapram is an analeptic agent (a stimulant of the central nervous system). The respiratory stimulant action is manifested by an increase in tidal volume associated with a slight increase in respiratory rate. A pressor response may result following doxapram administration. Provided there is no impairment of cardiac function, the pressor effect is more marked in hypovolemic than in normovolemic states. The pressor response is due to the improved cardiac output rather than peripheral vasoconstriction. Following doxapram administration, an increased release of catecholamines has been noted.
Synthesis
Doxapram, 1-ethyl-4-(2-morpholinoethyl)-3,3-diphenyl-2-pyrrolidinone (8.2.4), is synthesized in the following manner. Diphenylacetonitrile in the presence of sodium amide is alkylated with 1-ethyl-3-chlorpyrrolidine, giving (1-ethyl-3-pyrrolidinyl) diphenylacetonitrile (8.2.1). Acidic hydrolysis of the nitrile group gives (1-ethyl-3 pyrrolidinyl)diphenylacetic acid (8.2.2). Reacting this with phosphorous tribromide (thionyl chloride, thionyl bromide, acetic anhydride) leads to rearrangement with an opening of the pyrrolidine ring and the subsequent closing of the pyrrolidinone ring, forming 1-ethyl-4-(2-bromoethyl)-3,3-diphenyl-2-pyrrolidinone (8.2.3). Substitution of the bromine atom with a morpholine group gives doxapram (8.2.4) [15¨C18].
Metabolism
Not Available
Properties of Doxapram
Melting point: | 113 - 114°C |
Boiling point: | 506.58°C (rough estimate) |
Density | 1.1056 (rough estimate) |
refractive index | 1.5620 (estimate) |
storage temp. | 2-8°C |
solubility | Chloroform (Slightly), Methanol (Slightly) |
form | Solid |
pka | 7.30±0.10(Predicted) |
color | White to Off-White |
NIST Chemistry Reference | 2-Pyrrolidinone, 1-ethyl-4-[2-(4-morpholinyl)ethyl]-3,3-diphenyl-(309-29-5) |
Safety information for Doxapram
Signal word | Warning |
Pictogram(s) |
Exclamation Mark Irritant GHS07 |
GHS Hazard Statements |
H317:Sensitisation, Skin H319:Serious eye damage/eye irritation |
Precautionary Statement Codes |
P280:Wear protective gloves/protective clothing/eye protection/face protection. P305+P351+P338:IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing. |
Computed Descriptors for Doxapram
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