Cilostazol
- Iupac Name：6-[4-(1-cyclohexyltetrazol-5-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one
- CAS No.: 73963-72-1
- Molecular Weight：369.52
- Modify Date.: 2022-10-30 08:28
- Introduction: Cilostazol is a platelet aggregation inhibitor with cerebral vasodilating activity, indicatedfor use in stroke and myocardial infarction. In patients with cerebral thrombosis, transientischemia and cerebral arteriosclerosis, cilostazol significantly inhibits ADP-, collagenandepinephrine-induced platelet aggregation. Side effects include headache andtachycardia.
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1. Names and Identifiers
- 1.1 Name
- Cilostazol
- 1.2 Synonyms
2(1H)-Quinolinone, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro- 6-[4-(1-Cyclohexyl-1H-tetrazol-5-y1)butoxy]-3，4-dihydrcr2(1H)-quinolinone 6-[4-(1-CYCLOHEXYL-1H-TETRAZOL-5-YL)BUTOXY]-3,4-DIHYDRO-2(1H)-QUINOLINONE 6-[4-(1-cyclohexyl-1h-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1h)-quinolinone additional name: 6-[4-(1-cyclohexyl-5-tetrazolyl)butoxy]-1,2,3,4- tetrahydro-2-oxoquinolinone 6-[4-(1-CYCLOHEXYL-1H-TETRAZOL-5-YL)BUTOXY]-3,4-DIHYDRO-2(1H)-QUINOLINONE(CILOSTAZOL) 6-[4-(1-Cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrochinolin-2(1H)-on 6-[4-(1-Cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydroquinolin-2(1H)-one CILASTAZOL Cilostal CILOSTAZOL INTERMEDIATES CILOSTAZOL JP CILOSTAZOLE MFCD00866780 OPC 13013, OPC 21, Pletaal, 6-[4-(1-Cyclohexyl-1H-tetrazol-5-yl)-butoxy]-3,4-dihydro-2(1H)-quinolinone OPC-13013, Pletal, 6-[4-(1-Cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone PLETAAL Pletal RETAL
- 1.3 CAS No.
- 73963-72-1
- 1.4 CID
- 2754
- 1.5 EINECS(EC#)
- 689-122-9
- 1.6 Molecular Formula
- C20H27N5O2 (isomer)
- 1.7 Inchi
- InChI=1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)
- 1.8 InChkey
- RRGUKTPIGVIEKM-UHFFFAOYSA-N
- 1.9 Canonical Smiles
- C1CCC(CC1)N2C(=NN=N2)CCCCOC3=CC4=C(C=C3)NC(=O)CC4
- 1.10 Isomers Smiles
- C1CCC(CC1)N2C(=NN=N2)CCCCOC3=CC4=C(C=C3)NC(=O)CC4
2. Properties
- 2.1 Density
- 1.34
- 2.1 Melting point
- 159-160°C
- 2.1 Boiling point
- 664.7 °C at 760 mmHg
- 2.1 Refractive index
- 1.675
- 2.1 Flash Point
- 355.8 °C
- 2.1 Precise Quality
- 369.21600
- 2.1 PSA
- 81.93000
- 2.1 logP
- 3.60270
- 2.1 Solubility
- DMSO: 18?mg/mL, soluble
- 2.2 Λmax
- 257nm(MeOH)(lit.)
- 2.3 Appearance
- off-white solid
- 2.4 Storage
- Store at RT
- 2.5 Color/Form
- off-white
- 2.6 pKa
- 14.22±0.20(Predicted)
- 2.7 Water Solubility
- DMSO: 18?mg/mL, soluble
- 2.8 Stability
- Stable under recommended storage conditions.
- 2.9 StorageTemp
- Inert atmosphere,Room Temperature
3. Use and Manufacturing
- 3.1 Definition
- ChEBI: A lactam that is 3,4-dihydroquinolin-2(1H)-one in which the hydrogen at position 6 is substiuted by a 4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy group.
- 3.2 Usage
- It can significantly inhibit the platelet aggregation caused by various inducers and aggregates and can dissociate the aggregates without causing secondary aggregation. It has significant antithrombotic effect on the brain circulation and peripheral circulatory disturbance caused by collagen, ADP, arachidonic acid and sodium laurate. It can also be used for treating ischemic diseases such as chronic arterial occlusive ulcer, pain and coldness.
4. Safety and Handling
- 4.1 Hazard Codes
- Xi
- 4.1 RIDADR
- NONH for all modes of transport
- 4.1 WGK Germany
- 2
- 4.1 RTECS
- VC8277500
- 4.1 Safety
-
Possible side effects of cilostazole use include headache (the most common), diarrhea, abnormal stools, increased heart rate, and palpitations. Although drugs similar to cilostazol have increased the risk of death in patients with congestive heart failure, studies of significant size have not addressed people without the disease.
Hazard Codes:?
Xi
WGK Germany: 2
RTECS: VC8277500
- 4.2 Specification
-
? Cilostazol , with CAS number of 73963-72-1, can be called 3,4-Dihydro-6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-
2(1H)-quinolinone ; 6-(4-(1-Cyclohexyl-1H-tetrazol-5-yl)butoxy)-3,4-dihydro-2(1H)-quinolinone ; 6-(4-(1-Cyclohexyl-1H-tetrazol-5-yl)butoxy)-3,4-dihydrocarbostyril ; Pletal ; Cilostazolum . It is an?off-white solid,?Cilostazol (CAS NO.73963-72-1) is a medication used in the alleviation of the symptom of intermittent claudication in individuals with peripheral vascular disease. Besides cilostazol is a selective PDE3 phosphodiesterase inhibitor with therapeutic focus on cAMP. It inhibits platelet aggregation and is a direct arterial vasodilator. Its main effects are dilation of the arteries supplying blood to the legs and decreasing platelet coagulation.
- 4.3 Toxicity
-
| Organism |
Test Type |
Route |
Reported Dose (Normalized Dose) |
Effect |
Source |
| dog |
LD50 |
oral |
> 2gm/kg (2000mg/kg) |
? |
Drugs in Japan Vol. -, Pg. 504, 1990. |
| man |
TDLo |
oral |
1248ug/kg (1.248mg/kg) |
BEHAVIORAL: HEADACHE |
Arzneimittel-Forschung. Drug Research. Vol. 35, Pg. 1173, 1985. |
| mouse |
LD50 |
intramuscular |
> 1gm/kg (1000mg/kg) |
? |
Drugs in Japan Vol. -, Pg. 504, 1990. |
| mouse |
LD50 |
intraperitoneal |
> 2gm/kg (2000mg/kg) |
? |
Drugs in Japan Vol. -, Pg. 504, 1990. |
| mouse |
LD50 |
oral |
> 5gm/kg (5000mg/kg) |
? |
Drugs in Japan Vol. -, Pg. 504, 1990. |
| rat |
LD50 |
intramuscular |
> 1gm/kg (1000mg/kg) |
? |
Drugs in Japan Vol. -, Pg. 504, 1990. |
| rat |
LD50 |
intraperitoneal |
> 2gm/kg (2000mg/kg) |
? |
Drugs in Japan Vol. -, Pg. 504, 1990. |
| rat |
LD50 |
oral |
> 5gm/kg (5000mg/kg) |
? |
Drugs in Japan Vol. -, Pg. 504, 1990. |
5. MSDS
2.Hazard identification
2.1 Classification of the substance or mixture
Reproductive toxicity, Category 2
2.2 GHS label elements, including precautionary statements
| Pictogram(s) |  |
| Signal word | Warning |
| Hazard statement(s) | H361 Suspected of damaging fertility or the unborn child |
| Precautionary statement(s) | |
| Prevention | P201 Obtain special instructions before use. P202 Do not handle until all safety precautions have been read and understood. P280 Wear protective gloves/protective clothing/eye protection/face protection. |
| Response | P308+P313 IF exposed or concerned: Get medical advice/ attention. |
| Storage | P405 Store locked up. |
| Disposal | P501 Dispose of contents/container to ... |
2.3 Other hazards which do not result in classification
none
7. Synthesis Route
73963-72-1Total: 7 Synthesis Route
9. Other Information
- 9.0 Usage
- An inhibitor of phosphodiesterase III
- 9.1 Merck
- 14,2277
- 9.2 Pharmacological effects
- Cilostazol is commonly used clinically anti-platelet and anti-clotting drugs. It belongs to a phosphodiesterase inhibitor and can inhibit the activity of phosphodiesterase of platelet and smooth muscle cells, leading to increase of the cAMP concentration in platelets and vascular smooth muscle. It can significantly inhibit the platelet aggregation induced by various kinds of aggregation inducers, and can cause the dissociation of the aggregates. Its major metabolite, epoxide has a three to four fold activity of the prototype drug. It has significant antithrombotic effect on the brain circulation and peripheral circulatory disturbance caused by collagen, ADP, arachidonic acid and sodium laurate. Artery injection of this product can increase the blood flow rate with the strongest effect on the peripheral blood vessels but the weakest effect on the cerebral blood vessels.
This product is rapidly absorbed in the intestine after oral administration with the Tmax being 3h, PPB being about 95%. Consecutive administration of four days by twice per day caused no increase in the plasma concentration accumulation. It has good tissue distribution with especially high level in the stomach, liver and kidney. At 72h after administration, 42.75% of the administered drug is excreted via urine and 61.7% is subject to fecal excretion. After 48 hour of administration, bile excretion rate is 31.7%. T1/2α is 2.2h and T1/2β is 18h.
- 9.3 Clinical application
- It can be used to alleviate the ischemic symptom such as ulcers, limb pain, cold sensation and intermittent claudication caused by chronic arterial occlusive disease. It can also be applied to the adjuvant treatment of atherosclerosis, arteritis, thromboangiitis obliterans, diabetes-induced ischemia of extremity and takayasu arteritis. Cilostazol also be used as a complementary therapy after surgical treatment to help alleviate the symptoms, improve the circulation and inhibiting thrombosis in transplanted blood vessel.
- 9.4 Side effects
- There may be occasionally rash, hives, itching, palpitations, pulse frequency, low blood pressure, fever, dizziness, dizziness, vertigo, insomnia or drowsiness, swelling, pain, fatigue, weakness, stomach discomfort, nausea, vomiting, loss of appetite, diarrhea, upper abdominal pain, abdominal fullness, increased level of GOT (serum alanine aminotransferase), ALP (serum alkaline phosphatase), LDH (serum lactate dehydrogenase), BUN (blood urea nitrogen), creatinine and uric acid, gastrointestinal bleeding, epistaxis, subcutaneous bleeding, retinal hemorrhage, hematuria, bleeding tendencies and thrombocytopenia.
- 9.5 Precautions
- Patients of hemophilia, capillary fragility syndrome, upper gastrointestinal bleeding and urinary tract bleeding as well as vitreous hemorrhage should be disabled. Women of pregnancy or possible pregnancy should be disabled.
This product is should be taken cautious when being applied to patients in the use of anticoagulants (warfarin) or antiplatelet drugs (aspirin, Ticlid) patients. When using cilostazol, the patients should be subject to blood coagulation performance test.
Women in menstrual period, patients of bleeding tendency or with severe hepatic and renal dysfunction as well as elderly should administer with caution; breast-feeding women should avoid breast-feeding.
- 9.6 Chemical Properties
- It is colorless, needle-like crystals obtained from methanol with the m.p. being 159.4~160.3 ℃ and the UV absorption maximum (methanol) being 257nm (ε15200). It is easily soluble in acetic acid, chloroform, N-methyl-2-pyrrolidone or dimethyl sulfoxide and almost insoluble in ether, water, 0.1mol/L hydrochloric acid or 0.1mol/L sodium hydroxide.
- 9.7 Uses
- It can significantly inhibit the platelet aggregation caused by various inducers and aggregates and can dissociate the aggregates without causing secondary aggregation. It has significant antithrombotic effect on the brain circulation and peripheral circulatory disturbance caused by collagen, ADP, arachidonic acid and sodium laurate. It can also be used for treating ischemic diseases such as chronic arterial occlusive ulcer, pain and coldness.
- 9.8 Production method
- Take 5-chloro-N-cyclohexyl pentanamide as the raw material. Under ice-cooling, to 15 mL of benzene solution containing 1.75g ??5-chloro-N-cyclohexyl-pentyl amide solution, slowly add 1.9 g of phosphorus pentachloride and stir at room temperature for 1h. At room temperature and stirring, add 1.4mol/L HN3 to 1 mL of the benzene solution. After stirring overnight, continue the reflux for 2h. The solvent was distilled off under reduced pressure with the residue being poured into ice water and subject to chloroform extraction. The extract was successively washed with water, dilute sodium bicarbonate solution and water, further dried by anhydrous sodium sulfate. After the chloroform was distilled off, the residue was subject to isopropanol-water recrystallization to obtain 1.7 g of 5-(4-chlorobutyl)-l-cyclohexyl-tetrazole, being as colorless needle-like crystals with the yield being 87% and the m.p. being 48-49 ℃.
Dissolve 3.2 g 6-hydroxy-3, 4-dihydrogen-2(1H)-quinolinone and 1.4 g of potassium hydroxide in 20 mL of isopropanol. Under reflux, add drop wise of the isopropanol solution containing 5.7 g of the tetrazole obtained above. Continue stirring and reflux for 4h. Evaporate to dryness with the residue being extracted with chloroform. The extract was washed with l mol/L sodium hydroxide solution, dilute hydrochloric acid and water, dried by anhydrous sodium sulfate. Chloroform was distilled off with the residual liquid being subject to chromatograph on silica gel. Use chloroform-methanol (30: 1) for elution. Then apply methanol-water recrystallization to obtain 6.0 g of colorless needles cilostazol with the yield being 74% and the melting point being 158 ??~ 159 ℃.
- 9.9 Description
- Cilostazol is a platelet aggregation inhibitor with cerebral vasodilating activity, indicated for use in stroke and myocardial infarction. In patients with cerebral thrombosis, transient ischemia and cerebral arteriosclerosis, cilostazol significantly inhibits ADP-, collagenand epinephrine-induced platelet aggregation. Side effects include headache and tachycardia.
- 9.10 Chemical Properties
- Colourless Needles
- 9.11 Originator
- Otsuka (Japan)
- 9.12 Uses
- antibacterial; LD50(iv) 280mg/kg(mouse)
- 9.13 Uses
- A potent phosphodiesterase III A (PDE3A) inhibitor (IC50=0.2uM) and inhibitor of adenosine uptake. Has antimitogeni, antithrombotic, vasodilatory and cardiotonic properties in vivo. Also affects lipid levels in vivo
- 9.14 Definition
- ChEBI: A lactam that is 3,4-dihydroquinolin-2(1H)-one in which the hydrogen at position 6 is substiuted by a 4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy group.
- 9.15 Brand name
- Pletal (Otsuka);Reta.
- 9.16 General Description
-
Cilostazol is a potent cyclic nucleotide phosphodiesterase inhibitor. It is mainly used as antiplatelet agent.
10. Computational chemical data
- Molecular Weight: 369.52g/mol
- Molecular Formula: C20H27N5O2
- Compound Is Canonicalized: True
- XLogP3-AA: 3.1
- Exact Mass: 369.21647512
- Monoisotopic Mass: 369.21647512
- Complexity: 485
- Rotatable Bond Count: 7
- Hydrogen Bond Donor Count: 1
- Hydrogen Bond Acceptor Count: 5
- Topological Polar Surface Area: 81.9
- Heavy Atom Count: 27
- Defined Atom Stereocenter Count: 0
- Undefined Atom Stereocenter Count: 0
- Defined Bond Stereocenter Count: 0
- Undefined Bond Stereocenter Count: 0
- Isotope Atom Count: 0
- Covalently-Bonded Unit Count: 1
- CACTVS Substructure Key Fingerprint: AAADceB7sAAAAAAAAAAAAAAAAAAAAWAAAAA8YIAAAAAAAACxwAAAHgAYAAAADCzhmwYx1obIBACqAidydACCCAMhooAdyAE+bIiMJjLEuZuGOCjk1BPI6Ae42bKeAEABAAACAAAAgAIAAAQAAAAAAAAAAA==
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