| Identification | Back Directory | [Name]
NEDOCROMIL SODIUM | [CAS]
69049-74-7 | [Synonyms]
Tayled
Tilade
Alocril
Tilarin
Unii-et8if4ks1t
Nedocromil sodium
NEDOCROMIL DISODIUM SALT
NEDOCROMIL SODIUM###Nedocromil
Sodium 9-ethyl-4,6-dioxo-10-propyl-6,9-dihydro-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate
4H-Pyrano[3,2-g]quinoline-2,8-dicarboxylicacid, 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-, sodium salt
[9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]quinoline]-2,8-dicarboxylic acid disodium salt
4H-Pyrano(3,2-G)quinoline-2,8-dicarboxylic acid, 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-, disodium salt
4H-Pyrano[3,2-g]quinoline-2,8-dicarboxylicacid, 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-, sodium salt (1:2) | [Molecular Formula]
C19H15NNa2O7 | [MDL Number]
MFCD00941388 | [MOL File]
69049-74-7.mol | [Molecular Weight]
415.3 |
| Hazard Information | Back Directory | [Description]
Nedocromil sodium is an antiallergic agent with broader mast cell stabilizing
properties than related cromolyn sodium. Administered as an aerosol, it is useful in
the treatment of bronchial asthma and related diseases. | [Originator]
Fisons (United Kingdom) | [Uses]
Anti-allergic (prophylactic. | [Definition]
ChEBI: Nedocromil sodium is an organic sodium salt. It contains a nedocromil(2-). | [Indications]
nedocromil sodium(Tilade) is chemically related drugs called chromones that is used for the prophylaxis of mild or moderate
asthma. It is administered by inhalation and has very good safety profiles, making them particularly useful
in treating children. | [Manufacturing Process]
4,6-Dioxo-10-propyl-4H,6H-pyrano[3,2-]quinoline-2,8-dicarbxylic acid
disodium salt was prepared in 8 steps
1. 4-Acetamido-2-allylacetophenone
4-Acetamido-2-hydroxyacetophenone (19.3 g), allyl bromide (12.1 ml) and
hydrous potassium carbonate (21.5 g) were stirred in dry dimethylformamide
(250 ml) at room temperature for 24 hours. The reaction mixture was poured
into water and the product was extracted with ethyl acetate. The organic
solution was then washed well with water dried over magnesium sulphate and
evaporated to dryness. The sub-title product was obtained as buff coloured
solid (20.5 g). The structure of the product was confirmed by NMR and mass
spectroscopy.
2. 4-Acetamido-3-allyl-2-hydroxyacetophenone
The above allyl ether (18.4 g) was heated at 200-210°C for 4 hours. 17.1 g of
the thermally rearranged sub- title product was obtained as a brown solid.
Again the structure was confirmed by NMR and mass spectroscopy.
3. 4-Acetamido-2-hydroxy-3-propyl acetophenone
The product of step 2 (17 g) was dissolved in glacial acetic acid and
hydrogenated in the presence of Adams catalyst until hydrogen uptake had
ceased. The catalyst was filtered off through a keiselguhr filter and the filtrate
was evaporated to leave 13.0 g of almost colorless solid. The mass and NMR
spectra confirmed the structure of product.
4. Ethyl-7-acetamido-4-oxo-8-propyl-4H-l-benzopyran-2-carboxylate
A mixture of diethyl oxalate (19.3 g; 17.9 ml) and the above product of step
3 (12.4 g) in dry ethanol (100 ml) was added to a stirred solution of sodium
ethoxide in ethanol (prepared by dissolving sodium (6.1 g) in dry ethanol
(200 ml)). The reaction mixture was refluxed for 3 hours and then poured into
dilute hydrochloric acid and chloroform. The chloroform layer was separated,
washed with water and dried. The solvent was evaporated to leave a brown
solid which was dissolved in ethanol (300 ml) containing concentrated
hydrochloric acid (3 ml) and the whole was refluxed for 1 hour. The reaction
mixture was poured into water and the product was extracted into ethyl
acetate which was washed with water and dried. The solvent was evaporated
to leave 10 g of a sticky solid which had mass and NMR spectra consistent
with the expected product.
5. Ethyl 7-amino-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate
A solution of the amide of step 4 (10 g) in ethanol (300 ml), containing
concentrated hydrochloric acid (5 ml), was refluxed for 8 hours. The reaction
mixture was diluted with water and extracted into ethyl acetate. The extract
was washed with water, dried and the solvent was evaporated to leave a dark
brown semi-solid. This was chromatographed on a silica gel column, using
ether as eluant to give 4.8 g of the required product whose structure was
confirmed by mass and NMR spectral evidence; mp 84-87°C.
6.8-Ethoxycarbonyl-2-methoxycarbonyl-4,6-dioxo-10-propyl-4H,6Hpyrano[3.2-g]quinoline
The amino benzopyran of step 5 (2.0 g) and dimethyl acetylene dicarboxylate
(1.24 g; 1.01 ml) were refluxed in ethanol (30 ml) for 26 hours. The reaction
mixture was cooled to 0°C and the insoluble yellow-brown solid was collected
by filtration and washed with a little ethanol and dried to give 2.0 g of a
product which was a mixture of maleic and fumaric esters obtained by Michael
addition of the amine to the acetylene. This mixture of esters (2.0 g) was
treated with polyphosphoric acid (30 ml) and heated on the steam bath with
stirring for 20 minutes. The reaction mixture was then poured onto ice and
stirred with ethyl acetate. The organic layer was separated, washed with
water and dried. The solvent was evaporated to leave 1.6 g of a yellow orange
solid. Recrystallisation of this solid from ethyl acetate gave the required
product as fluffy orange needles, mp 187°-188°C.
7. 4,6-Dioxo-10-propyl-4H,6H-pyrano[3.2-g]quinoline-2,8-dicarboxylic acid
The above bis ester (2.5 g) was refluxed with sodium bicarbonate (1.64 g) in
ethanol (100 ml) and water (50 ml) for 1.5 hours. The whole was poured into
water and acidified to precipitate a gelatinous solid. This was collected by
filtration, refluxed with ethanol and the product was separated by
centrifugation (1.4 g), mp 303°-304°C dec. The structure of the product was
confirmed by mass and NMR evidence.
8. Disodium 4,6-dioxo-10-propyl-4H,6H-pyrano[3,2-g]quinoline-2,8-
dicarboxylate
The bis acid from step 6 (1.35 g) and sodium bicarbonate (0.661 g) in water
(150 ml) were warmed and stirred until a clear solution was obtained. This
solution was filtered and the filtrate was freeze dried to give 1.43 g of the
required disodium salt. | [Brand name]
Alocril (Allergan); Tilade (King); Tilade (Sanofi Aventis). | [Therapeutic Function]
Antiallergic, Anti-asthmatic | [General Description]
Nedocromil sodium, disodium9-ethyl-6, 9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3, 2-g]quinoline-2,8-dicarboxylate (Tilade), is structurally relatedto cromolyn and displays similar, but broader, pharmacologicalactions. It was available as an aerosol in ametered-dose inhaler for asthma treatment, and currently remainsavailable as ophthalmic solution for the treatmentof itching associated with allergic conjunctivitis. The inhalationformulation was marketed for maintenance therapyin the management of patients with mild-to-moderatebronchial asthma, but since has been withdrawn. | [Pharmacokinetics]
Nedocromil sodium was developed by changing the furan ring of khellin to a piperidinone ring. In vitro, nedocromil sodium inhibits the release of inflammatory response mediators from a variety of cells, including neutrophils, mast cells, macrophages, and platelets. Inhaled nedocromil sodium is poorly absorbed into the systemic circulation, with approximately 3% of an inhaled dose excreted in the urine during the first 6 hours after administration. Only 2% of orally dosed nedocromil sodium is bioavailable, 89% of which is protein bound. When administered IV, nedocromil sodium is not metabolized and is excreted unchanged in the bile and the urine. Nedocromil sodium is available in aerosol canisters for oral inhalation via a mouthpiece. | [Clinical Use]
nedocromil sodium is used almost
exclusively for the prophylactic treatment of mild
to moderate asthma and should not be used for the control
of acute bronchospasm. This agent is effective
in about 60 to 70% of children and adolescents with
asthma. Unfortunately, there is no reliable means to
predict which patients will respond.It is less effective
in older patients and in patients with severe
asthma. It may take up to 4 to 6 weeks of treatment for
cromolyn sodium to be effective in chronic asthma, but
it is effective after a single dose in exercise-induced
asthma. With respect to clinical efficacy, cromolyn
sodium and nedocromil sodium do not differ in a substantial
way. | [Side effects]
nedocromil sodium is the least
toxic of available therapies for asthma. Adverse reactions
are rare and generally minor. Those occurring in
fewer than 1 in 10,000 patients include transient bronchospasm,
cough or wheezing, dryness of throat, laryngeal
edema, swollen parotid gland, angioedema, joint
swelling and pain, dizziness, dysuria, nausea, headache,
nasal congestion, rash, and urticaria.
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| Company Name: |
LGM Pharma
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| Tel: |
1-(800)-881-8210 |
| Website: |
www.lgmpharma.com |
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