78919-13-8

Basic information

• Product Name: ILOPROST
• Synonyms: (16r,s)-methyl-18,18,19,19-tetradehydro-6a-carbaprostaglandini(sub2);1h)-pentalenylidene)-;pentanoicacid,5-(hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-1-octen-6-ynyl)-2(;zk36374;6,9ALPHA-METHYLENE-11ALPHA,15S-DIHYDROXY-16-METHYL-PROSTA-5E,13E-DIEN-18-YN-1-OIC ACID;CILOPROST;5-[Hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-1-octen-6-ynyl)-2(1H)-pentalenylidene]pentanoic acid;Endoprost
• CAS NO: 78919-13-8
• Molecular Formula: C22H32O4
• Molecular Weight: 360.49
• Product Categories: Chiral Reagents;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 78919-13-8.mol

Chemical Properties

• Boiling Point: 539.2oC at 760 mmHg
• Flash Point: 294oC
• Appearance: colorless oil
• Density: 1.21g/cm3
• Vapor Pressure: 7.06E-14mmHg at 25°C
• Refractive Index: 1.629
• Storage Temp.: Desiccate at -20°C
• Solubility: Soluble in methyl acetate
• PKA: 4.77±0.10(Predicted)
• CAS DataBase Reference: ILOPROST(CAS DataBase Reference)
• NIST Chemistry Reference: ILOPROST(78919-13-8)
• EPA Substance Registry System: ILOPROST(78919-13-8)

Safety Data

• Hazardous Substances Data: 78919-13-8(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Iloprost is used as a therapeutic agent for the treatment of pulmonary arterial hypertension (PAH), scleroderma, Raynaud's phenomenon, and ischemia. It acts through the elevation of cAMP by binding to the prostacyclin receptor (IP receptor), which helps in managing these conditions.
Used in Cardiovascular Applications:
Iloprost is used as a vasodilator, hypotensive, and antidiuretic agent, which aids in the treatment of peripheral vascular diseases. It has been reported to have beneficial effects in Buerger's and Raynaud's diseases, as well as peripheral artery occlusive disease.
Used in Hemostasis Regulation:
Iloprost is used as an inhibitor of platelet aggregation, with an ED50 of about 13 nM for ADP, thrombin, and collagen-induced aggregation of human platelets. This property helps in preventing excessive clotting and maintaining proper blood flow.
Brand Names:
Ventavis (Schering) and Iiomedin are some of the brand names under which Iloprost is marketed for its various applications.

Health Hazard

Exposures to quinine vapor are highly irritating to the eyes and may be followed by corneal opacities, structural changes in the cornea, and loss of vision. Solid quinone may produce discoloration, severe irritation, swelling, and form papules and vesicles.

Biological Activity

Prostacyclin (PGI 2 ) analog that binds with high affinity to IP, EP 1 and EP 3 receptors (K i values are 11, 11, 56, 284, 619, 1035, 1870 and 6487 nM for IP, EP 1 , EP 3 , EP 4 , FP, DP, EP 2 and TP receptors respectively). Inhibits platelet aggregation induced by collagen, thrombin and ADP (IC 50 values are 0.24, 0.71 and 1.07 nM respectively).

Biochem/physiol Actions

Iloprost is used to treat children with PH (pulmonary hypertension) after the surgery to clear CHD (congenital heart disease). In transplant patients, this prostacyclin analogue is used to inhibit renal dysfunction. Iloprost performs various functions like vasodilatation and cytoprotection. It has higher stability than prostacyclin.

InChI:InChI=1/C22H32O4/c1-3-4-7-15(2)20(23)11-10-18-19-13-16(8-5-6-9-22(25)26)12-17(19)14-21(18)24/h8,10-11,15,17-21,23-24H,5-7,9,12-14H2,1-2H3,(H,25,26)/b11-10+,16-8+/t15?,17-,18?,19-,20+,21+/m0/s1

Upstream product

• 101314-09-4 Methyl (1R,5S,6S,7R)-6-Hydroxymethyl-7-tetrahydropyranyloxybicyclo<3.3.0>oct-2-ene-3-γ-pentenoate 
• 101314-12-9 (E)-5-[(3aS,5R,6R,6aS)-6-Formyl-5-(tetrahydro-pyran-2-yloxy)-1,3a,4,5,6,6a-hexahydro-pentalen-2-yl]-pent-4-enoic acid methyl ester 
• 17814-85-6 (4-carboxybutyl)triphenylphosphonium bromide 
• 146380-17-8 (3aS,4R,5R,6aR)-5-(tert-Butyl-dimethyl-silanyloxy)-4-((E)-(S)-3-hydroxy-4-methyl-oct-1-en-6-ynyl)-hexahydro-pentalen-2-one 
• 79812-95-6 (3aS,4R,5R,6aR)-5-hydroxy-4-((3S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-one 
• 74818-68-1 (3aS,5R,6aR)-4-[(E)-(S)-4-Methyl-3-(tetrahydro-pyran-2-yloxy)-oct-1-en-6-ynyl]-5-(tetrahydro-pyran-2-yloxy)-hexahydro-pentalen-2-one 
• 74818-49-8 (3aS,5R,6aR)-5-Hydroxy-4-((E)-(S)-3-hydroxy-4-methyl-oct-1-en-6-ynyl)-hexahydro-pentalen-2-one 
• 79745-58-7 5-[(3aS,5R,6aS)-4-[(E)-(S)-4-Methyl-3-(tetrahydro-pyran-2-yloxy)-oct-1-en-6-ynyl]-5-(tetrahydro-pyran-2-yloxy)-hexahydro-pentalen-(2E)-ylidene]-pentanoic acid 
• 79745-58-7 5-[(3aS,5R,6aS)-4-[(E)-(S)-4-Methyl-3-(tetrahydro-pyran-2-yloxy)-oct-1-en-6-ynyl]-5-(tetrahydro-pyran-2-yloxy)-hexahydro-pentalen-(2Z)-ylidene]-pentanoic acid 
• 126436-91-7 5-[(3aS,4R,5R,6aS)-5-(tert-Butyl-dimethyl-silanyloxy)-4-((E)-(S)-3-hydroxy-4-methyl-oct-1-en-6-ynyl)-hexahydro-pentalen-(2E)-ylidene]-pentanoic acid 
• 871095-04-4 (3aS,4S,5R,6aR)-5-((tert-butyldimethylsilyl)oxy)-4-(hydroxymethyl)hexahydropentalen-2(1H)-one 
• 32233-40-2 (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one 
• 70073-58-4 dimethyl (2-oxo-3-methylhept-5-ynyl)-phosphonate 
• 116484-93-6 (+/-)-2-methylhex-4-ynoic acid ethyl ester 

Relevant articles and documents

An alternative synthesis for iloprost via a key bicyclic aldehyde intermediate

An alternative synthesis for iloprost has been accomplished in 14 steps via a convergent synthesis starting from commercially available (?)-Corey lactone diol. The syntheses employ a new and key chiral bicyclic aldehyde (4) intermediate, which is primed for attachment of the required α-side chain and ω-side chain.

Preparation method of iloprost

The invention belongs to the field of medicine synthesis, and relates to a preparation method of iloprost. Particularly, the preparation method comprises the steps of by taking a compound in a formula II shown in the description as a raw material, carrying out Wittig reaction and valeric acid side chain splicing to obtain a compound in a formula III shown in the description, carrying out liquid-phase separation to obtain a single E type, carrying out Dess-Martin oxidation to generate aldehyde, namely, a compound in a formula IV shown in the description, splicing with an alkynyl side chain compound VIII through a Wittig-Hornor reaction to obtain a compound V, carrying out chiral reduction to obtain a compound VI, and finally removing a hydroxyl protecting group to obtain iloprost. Compared with other routes, the method has the advantages of few reaction steps, simple and easily-controlled process, high total yield, easy industrial production and the like.

PROCESS FOR THE PREPARATION OF ILOPROST

The present invention relates to a process for the preparation of iloprost of formula I through new intermediates, isolation of iloprost of formula I in solid form, as well as preparation of the 16(S)-iloprost and 16(R)-iloprost isomers of formulae (S)-I and (R)-I and isolation of iloprost of formula I and 16(S)-iloprost of formula (S)-I in solid, crystalline form.

THERAPY FOR COMPLICATIONS OF DIABETES

A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.

ANTIHYPERTENSIVE THERAPY

A new use of darusentan is provided in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy with one or more drugs. The composition comprises darusentan in an amount providing a therapeutically effective daily dose; wherein (a) the composition is orally deliverable and/or (b) the daily dose of darusentan is effective to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures. Further provided is a new use of darusentan in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy, wherein the composition is administered adjunctively with at least one diuretic and at least one antihypertensive drug selected from ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers.

Method for treating resistant hypertension

A method is provided for lowering blood pressure in a patient having clinically diagnosed resistant hypertension. The method comprises administering darusentan to the patient adjunctively with a baseline antihypertensive regimen that comprises administration of at least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers. The darusentan is orally administered at a dose and frequency effective, in combination with the baseline regimen, to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures.

Keto reduction of carbacyclin intermediates

The invention relates to a new process for the reduction of 15-keto carbacyclin intermediates in the presence of cerium(III) Salts.

E- OR Z-SELECTIVE WITTIG REACTIONS IN THE SYNTHESIS OF THE CARBACYCLIN ILOPROST

Wittig reaction of ketones 3 with 4-carboxybutyltriphenyl-phosphonium bromide generates the exocyclic 5,6 double bond of iloprost (1) in E/Z ratios between 35:65 and 90:10 depending on substituents and reaction conditions.