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Cyclobenzaprine
Cyclobenzaprine
- Molecular FormulaC20H21N
- Average mass275.387 Da
- MK-130
- TNX-102
1-(3-Dimethylaminopropylidene)-2,3:6,7-dibenzo-4-suberene
1-Propanamine, 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-[ACD/Index Name]
206-145-8[EINECS]
3-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine
303-53-7[RN]
5-(3-Dimethylaminopropylidene)dibenzo[a,e]cycloheptatriene
циклобензаприн[Russian][INN]
سيكلوبنزابرين[Arabic][INN]
环苯扎林[Chinese][INN]
Cyclobenzaprine, CAS Registry Number: 303-53-7
CAS Name: 3-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine
Additional Names:N,N-dimethyl-5H-dibenzo[a,d]cyclohepten-D5,g-propylamine; 5-(3-dimethylaminopropylidene)dibenzo[a,e]cycloheptatriene; 1-(3-dimethylaminopropylidene)-2,3:6,7-dibenzo-4-suberene; proheptatriene
Manufacturers’ Codes: MK-130; Ro-4-1577; RP-9715
Molecular Formula: C20H21N, Molecular Weight: 275.39
Percent Composition: C 87.23%, H 7.69%, N 5.09%
Literature References: Prepn: GB858187 (1961 to Hoffmann-La Roche); Villani et al.,J. Med. Pharm. Chem.5, 373 (1962); Winthrop et al.,J. Org. Chem.27, 230 (1962). Pharmacology: C. D. Barnes, W. L. Adams, Neuropharmacology17, 445 (1978); N. N. Share, ibid. 721; and toxicology: J. Metysova et al.,Arch. Int. Pharmacodyn. Ther.144, 481 (1963). Metabolism: G. Belvedere et al.,Biomed. Mass Spectrom.1, 329 (1974); H. B. Hucker et al.,Drug Metab. Dispos.6, 184 (1978). Bioavailability: eidem,J. Clin. Pharmacol.17, 719 (1977). Clinical studies: J. V. Basmajian, Arch. Phys. Med. Rehabil.5, 58 (1978); B. R. Brown, J. Womble, J. Am. Med. Assoc.240, 1151 (1978). Comprehensive description: M. L. Cotton, G. R. B. Down, Anal. Profiles Drug Subs.17, 41-72 (1988).
Properties: bp1 175-180°. uv max: 224, 289 nm (log e 4.57, 4.02), (Villani et al.)
Boiling point: bp1 175-180°
Absorption maximum: uv max: 224, 289 nm (log e 4.57, 4.02), (Villani et al.)
Derivative Type: Hydrochloride
CAS Registry Number: 6202-23-9
Trademarks: Flexeril (Merck & Co.); Flexiban (Merck & Co.)
Molecular Formula: C20H21N.HCl, Molecular Weight: 311.85
Percent Composition: C 77.03%, H 7.11%, N 4.49%, Cl 11.37%
Literature References: Use as muscle relaxant: N. N. Share, FR2100873 (1972 to Frosst), C.A.78, 47801n (1973).
Properties: Crystals from isopropanol, mp 216-218°. Soly in water: >20 g/100 ml. Freely sol in water, methanol, ethanol; sparingly sol in isopropanol; slightly sol in chloroform, methylene chloride. Practically insol in hydrocarbons. uv max: 226, 295 nm (e 52300, 12000). LD50 in mice (mg/kg): 35 i.v., 250 orally (Metysova).
Melting point: mp 216-218°
Absorption maximum: uv max: 226, 295 nm (e 52300, 12000)
Toxicity data: LD50 in mice (mg/kg): 35 i.v., 250 orally (Metysova)
Therap-Cat: Muscle relaxant (skeletal).
Keywords: Muscle Relaxant (Skeletal).
Cyclobenzaprine, a centrally-acting muscle relaxant, was first synthesized in 196111 and has been available for human use since 1977.10 It was initially studied for use as antidepressant given its structural similarity to tricyclic antidepressants – it differs from Amitriptyline by only a single double bond.11,10 Since its approval, it has remained relatively popular as an adjunctive, short-term treatment for acute skeletal muscle spasms secondary to musculoskeletal injury.
Cyclobenzaprine (sold under the brand name Flexeril, among others) is a medication used for muscle spasms from musculoskeletal conditions of sudden onset.[6] It is not useful in cerebral palsy.[6] It is taken by mouth.[6] Use is not recommended for more than a few weeks.[6]
Common side effects include headache, feeling tired, dizziness, and dry mouth.[6] Serious side effects may include an irregular heartbeat.[6] There is no evidence of harm in pregnancy, but it has not been well studied in this population.[6] It should not be used with an MAO inhibitor.[6] How it works is unclear.[6]
Cyclobenzaprine was approved for medical use in the United States in 1977.[6] It is available as a generic medication.[6] In 2019, it was the 45th most commonly prescribed medication in the United States, with more than 15 million prescriptions.[7][8] It was not available in the United Kingdom as of 2012.[9]
Synthesis Reference
Villani, F.J.; US. Patent 3,409,640; November 5,1968; assigned to Schering Corporation.
Paper
By: Gowda, Narendra B.; Rao, Gopal Krishna; Ramakrishna, Ramesha A.
Tetrahedron Letters (2010), 51, (43), 5690-5693.
https://www.sciencedirect.com/science/article/abs/pii/S0040403910014668
A simple and convenient protocol for deoxygenation of aliphatic and aromatic N-oxides to the corresponding amines in good to excellent yield using sodium borohydride–Raney nickel in water is reported. Other functional moieties such as alkenes, halides, ethers, and amides are unaffected under the present reaction condition.
Graphical abstract
Cyclobenzaprine N-oxide, CAS RN: 6682-26-4
Dissolve (1 mmol) of cyclobenzaprine N-oxide in 2.5 mL of water at 60 °C. 2. Add Raney nickel (0.10 g, W6 grade) to the solution. 3. Stir the reaction mixture for 10 minutes. 4. Add (2 mmol) of sodium borohydride slowly in portions over 15-20 minutes to the reaction mixture. 5. Stir the reaction mixture at the same temperature for 2.5 hours (the completion of the reaction as monitored by TLC). 6. Once the reaction is completed, add chloroform (50 mL) to the reaction mixture. 7. Filter the resulted mixture to remove Raney nickel. 8. Dry the chloroform layer over anhydrous magnesium sulfate. 9. Filter the reaction mixture. 10. Evaporate the solvent under vacuum. 11. Purify the obtained residue through short path flash chromatography with silica gel and chloroform.
1H NMR (400 MHz, CDCl3) δ: 1.12 (s, 6H, N-CH3), 1.23- 1.34 (m, 4H, CH2), 4.58 (t, J= 4.0 Hz, 1H, CH), 5.82(d, J= 4.0 Hz, 2H, CH), 6.21- 6.33 (m, 8H, ArH).
13C NMR (100 MHz, CDCl3) δ: 27.89, 45.93, 60.12, 127.40, 127.55, 128.30, 128.59, 128.92, 129.33, 129.45, 129.67, 131.74, 131.96, 132.40, 134.63, 135.39, 137.97, 142.95, 143.30.
SYN
PATENT
https://patents.google.com/patent/WO2012098563A2/en
Cyclobenzaprine hydrochloride, chemically known as 5-(3-dimethylaminopropylidene)- dibenzo (a,e) cycloheptatriene hydrochloride (Formula I),
Formula I is a commonly prescribed tricyclic amine having muscle relaxant pharmaceutical activity. After sustaining an injury, muscle spasms may occur to stabilize the affected body part and prevent further damage. Cyclobenzaprine hydrochloride is used to treat such muscle spasm associated with acute, painful musculoskeletal conditions.
Few multistep processes for the preparation of this tricyclic amine are already available in the literature which involves isolation and purification of intermediate compounds. The conventional route of synthesis as reported in US3454643, ES8201950 includes preparation of Grignard reagent (GR) of 3-dimethylaminopropyl chloride in a first step, reacting with 5-dibenzosuberenone (Formulall) in a second step. The reaction mass was extracted with benzene, solid obtained was recrystallized from alcohol to produce 5- hydroxy intermediate (Formula III) and further dehydrated in third step using acetyl chloride or acetic anhydride in presence of chloroform as a solvent medium followed by purging HC1 gas to produce hydrochloride salt (Formula I). CH,
CI-(CH2)3 NS
CH,
Dimeth laminopropyl chloide
Di methy lam i nopropy I 5-dibenzosubrenone – y roxy compoun magnesium chloide
(Formula II) (Formula III)
Cyclobenzaprine base Cyclobenzaprine hydrochloride
(Formula IV) (Formula I)
The multistep synthesis is cumbersome and use of hazardous solvents and reagents like chloroform, benzene and acetyl chloride etc are not recommended for the preparation of pharmaceutical substances.
J. Org. Chem. Vol. 27, 230-240 (1961) also portrayed similar procedure for the synthesis of cyclobenzaprine hydrochloride, wherein 5-hydroxy compound of formula III was isolated and recrystallized before dehydration reaction.
Synthetic Comm. 11 (3), 241-246 (1981) described a process which involves isolation and purification of the intermediate at magnesium -complex stage. Hydrolysis of the isolated complex afforded desired tricyclic amine. GB858186 and GB858187 jointly described a process which comprises preparation of 5- hydroxy compound (Formula III) and subsequent conversion of the same to cyclobenzaprine hydrochloride. However the overall yield reported is significantly low.
In a different approach, a high temperature dehydrogenation of amitriptyline base resulting in formation of cyclobenzaprine hydrochloride is reported in Indian patent application 387/CHE/2005.
. EXAMPLE:
In a reaction vessel, THF (1 10ml), magnesium turnings 20gm (0.823mole) were charged and the mixture was warmed to 45-55°C for 20 min. A solution of l OOgm (0.823mole) of 3-dimethylaminopropyl chloride prepared in 1 10ml THF was added dropwise to the reaction mixture by controlling the reflux generated due to reaction initiation and maintained for 2hrs. The formed Grignard reagent was then cooled to 0-5°C and a solution of lOOgm (0.485mole) 5-dibenzosuberenone prepared in 220ml THF was charged to the reaction mass at temperature below 10°C. The reaction mass was stirred for 45 min at temperature 10-15°C. The absence of 5-dibenzosuberenone was checked by TLC and 770ml of 20% aq. HC1 was charged to the reaction mass at a temperature below 10°C. The reaction mass was then heated to 70-80°C for 3 hrs. The acidic mass was neutralized by using aqueous Na2C03 solution and extracted with 900ml methylene dichloride. The solvent was removed completely under reduced pressure and oil thus formed was dissolved in 450ml IPA and acidified with 240 ml of 20% IPA .HC1 solution and stirred for 2 hrs at 0-5°C for complete precipitation. The precipitate is filtered, recrystallized from IPA (800 ml) and dried to obtain 1 18 gm (78%) white crystalline cyclobenzaprine hydrochloride with purity 99.93% by HPLC.
PATENT
PATENT
CN 111393305
CLIP
Muscle Relaxants
R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006
Cyclobenzaprine
Cyclobenzaprine, N,N-dimethyl-3-(dibenzo[a,d]cyclohepten-5-ylidene) propylamine (15.3.9), is synthesized by reacting 5H-dibenzo[a,d]cyclohepten-5-one with 3-dimethylaminopropylmagnesium chloride and subsequent dehydration of the resulting carbinol (15.3.8) in acidic conditions into cyclobenzaprine (15.3.9) [30–32].
Cyclobenzaprine is structurally similar to tricyclic antidepressants. It acts at the brain stem level. It is used as an adjuvant agent for relieving muscle spasms associated with severe diseased conditions of the muscle. A synonym of this drug is flexeril.
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Medical use
Cyclobenzaprine is used, in conjunction with physical therapy, to treat muscle spasms that occur because of acute musculoskeletal conditions.[10] After sustaining an injury, muscle spasms to stabilize the affected body part occur, which may increase pain to prevent further damage. Cyclobenzaprine is used to treat such muscle spasms associated with acute, painful musculoskeletal conditions.[11] It decreases pain in the first two weeks,[12][13] peaking in the first few days, but has no proven benefit after two weeks.[12][14] Since no benefit is proven beyond that, therapy should not be continued long-term.[11] It is the best-studied muscle relaxer.[12] It is not useful for spasticity due to neurologic conditions such as cerebral palsy.[11][15]
A 2004 review found benefit for fibromyalgia symptoms, with a reported number needed to treat of 4.8 (meaning that 1 person out of every 4.8 benefits from treatment) for pain reduction, but no change in fatigue or tender points.[16] A 2009 Cochrane review found insufficient evidence to justify its use in myofascial pain syndrome.[17] It may also be used along with other treatments for tetanus.[18]
Side effects
Cyclobenzaprine results in increased rates of drowsiness (38%), dry mouth (24%), and dizziness (10%).[14] Drowsiness and dry mouth appear to intensify with increasing dose.[19] The sedative effects of cyclobenzaprine are likely due to its antagonistic effect on histamine, serotonin, and muscarinic receptors.[medical citation needed]
Agitation is a common side effect observed, especially in the elderly. Some experts[who?] believe that cyclobenzaprine should be avoided in elderly patients because it can cause confusion, delirium, and cognitive impairment.[20][21] In general, the National Committee for Quality Assurance recommends avoiding the use of cyclobenzaprine in the elderly because of the potential for more severe side effects.[22]
Dysphagia, a life-threatening side-effect, may rarely occur.[23] Treatment protocols and support should follow the same as for any structurally related tricyclic, such as tricyclic antidepressants.[24]
Overdose
The most common effects of overdose are drowsiness and tachycardia.[11] Rare but potentially critical complications are cardiac arrest, abnormal heart rhythms, severe low blood pressure, seizures, and neuroleptic malignant syndrome.[11] Life-threatening overdose is rare,[11] however, as the median lethal dose is about 338 milligrams/kilogram in mice and 425 mg/kg in rats.[11] The potential harm is increased when central nervous system depressants and antidepressants are also used; deliberate overdose often includes alcohol among other drugs.[11]
Interactions
Cyclobenzaprine has major contraindications with monoamine oxidase inhibitors (MAOIs). At least one study also found increased risk of serotonin syndrome when cyclobenzaprine was taken with the serotonergic drugs duloxetine or phenelzine.[25]
These substances may interact with cyclobenzaprine:
- Central nervous system depressants (e.g. alcohol, opioids, benzodiazepines, nonbenzodiazepines, phenothiazines, carbamates, barbiturates, major tranquilizers)
- Monoamine oxidase inhibitors taken within two weeks of cyclobenzaprine may result in serious, life-threatening side effects.[11]
Cyclobenzaprine may affect the medications used in surgical sedation and some surgeons request that patients temporarily discontinue its use prior to surgery.[26]
Pharmacology
Cyclobenzaprine is a centrally acting muscle relaxant.[27] Cyclobenzaprine is a 5-HT2 receptor antagonist; it relieves muscle spasm through action on the central nervous system at the brain stem, rather than targeting the peripheral nervous system or muscles themselves.[28]
Pharmacodynamics
| Site | CBP | NCBP | Action | Ref |
|---|---|---|---|---|
| 5-HT1A | 5.3 | 3.2 | Agonist | [29] |
| 5-HT2A | 5.2 | 13 | Antagonist | [29] |
| 5-HT2B | 100 | ??? | Antagonist | [29] |
| 5-HT2C | 5.2 | 43 | Antagonist | [29] |
| α1A | 5.6 | 34 | ND | [29] |
| α2A | 4.3 | 6.4 | Antagonist | [29] |
| α2B | 21 | 150 | ND | [29] |
| α2C | 21 | 48 | ND | [29] |
| H1 | 1.3 | 5.6 | ND | [29] |
| M1 | 7.9 | 30 | ND | [29] |
| Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. |
Pharmacokinetics
Cyclobenzaprine has an oral bioavailability of about 55% and approximately 93% is bound to proteins in plasma. The half-life of the drug is 18 hours and it has a plasma clearance of 0.7 litres per minute.[27][30][31]
Comparison to other medications
Cyclobenzaprine has been found to be not inferior to tizanidine, orphenadrine, and carisoprodol in the treatment of acute lower back pain, although none have been proven to be effective for long-term use (beyond two weeks of treatment). No differences in pain or spasm scores were noted among these agents, nor when compared to benzodiazepines.[32] However, nonbenzodiazepine (including cyclobenzaprine) treatment was found to have a lower risk of medication abuse and continuation of use against medical advice.[medical citation needed] Side effects such as sedation and ataxia are also less pronounced with nonbenzodiazepine antispasmodics.[medical citation needed]
In a study on the treatment of musculoskeletal pain treatment with cyclobenzaprine alone or in combination with ibuprofen, no significant differences in pain scores were noted among the three treatment groups. Peak benefit was found to occur on day seven of the treatment for all groups.[33]
Formulations
Cyclobenzaprine 10mg tablets
By mouth, cyclobenzaprine is marketed as Apo-Cyclobenzaprin, Fexmid, Flexeril and Novo-Cycloprine. It is available in generic form. A once-a-day, extended-release formulation, Amrix, is available.[34] Cyclobenzaprine is also used by compounding pharmacies in topical creams.[citation needed]
References
- ^ Micromedex® 2010 – DRUGDEX Evaluations (Cyclobenzaprine Hydrochloride)
- ^ “Cyclobenzaprine Hydrochloride Tablets USP Revised: April 2005 Rx only”. nih.gov. Retrieved 1 October 2016.
- ^ Teva Pharmaceuticals USA, Inc (May 2016). “AMR40470 (Amrix) Prescribing Information” (PDF).
- ^ U.S. Food and Drug Administration. “NDA 17-821/S-045 Flexeril (Cyclobenzaprine HCl) Tablets” (PDF).
- ^ Teva Pharmaceuticals USA, Inc (May 2016). “AMR40470 (Amrix) Prescribing Information” (PDF).
- ^ Jump up to:a b c d e f g h i j k “Cyclobenzaprine Monograph for Professionals”. Drugs.com. AHFS. Retrieved 22 December 2018.
- ^ “The Top 300 of 2019”. ClinCalc. Retrieved 16 October 2021.
- ^ “Cyclobenzaprine – Drug Usage Statistics”. ClinCalc. Retrieved 16 October 2021.
- ^ “Fibromyalgia, psychiatric comorbidity, and the somatosensory cortex”. British Journal of Medical Practitioners. 5 (2): a522. 2012.
- ^ Yang YW, Macdonald JB, Nelson SA, Sekulic A (December 2017). “Treatment of vismodegib-associated muscle cramps with cyclobenzaprine: A retrospective review”. Journal of the American Academy of Dermatology. 77 (6): 1170–1172. doi:10.1016/j.jaad.2016.12.017. PMID 29132849. S2CID 8265576.
- ^ Jump up to:a b c d e f g h i “Cyclobenzaprine- cyclobenzaprine hydrochloride tablet, film coated”. DailyMed. 30 December 2019. Retrieved 26 September 2020.
- ^ Jump up to:a b c Chou R, Peterson K, Helfand M (August 2004). “Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review”. Journal of Pain and Symptom Management. 28 (2): 140–75. doi:10.1016/j.jpainsymman.2004.05.002. PMID 15276195.
- ^ van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM (2003). Van Tulder MW (ed.). “Muscle relaxants for non-specific low back pain”. The Cochrane Database of Systematic Reviews. 2 (2): CD004252. doi:10.1002/14651858.CD004252. PMC 6464310. PMID 12804507.
- ^ Jump up to:a b Browning R, Jackson JL, O’Malley PG (July 2001). “Cyclobenzaprine and back pain: a meta-analysis”. Archives of Internal Medicine. 161 (13): 1613–20. doi:10.1001/archinte.161.13.1613. PMID 11434793.
- ^ Ashby P, Burke D, Rao S, Jones RF (October 1972). “Assessment of cyclobenzaprine in the treatment of spasticity”. Journal of Neurology, Neurosurgery, and Psychiatry. 35 (5): 599–605. doi:10.1136/jnnp.35.5.599. PMC 494138. PMID 4563483.
- ^ Tofferi JK, Jackson JL, O’Malley PG (February 2004). “Treatment of fibromyalgia with cyclobenzaprine: A meta-analysis”. Arthritis and Rheumatism. 51 (1): 9–13. doi:10.1002/art.20076. PMID 14872449.
- ^ Leite FM, Atallah AN, El Dib R, Grossmann E, Januzzi E, Andriolo RB, da Silva EM (July 2009). “Cyclobenzaprine for the treatment of myofascial pain in adults”. The Cochrane Database of Systematic Reviews (3): CD006830. doi:10.1002/14651858.CD006830.pub3. PMC 6481902. PMID 19588406.
- ^ Smith BT (2014). Pharmacology for Nurses. Jones & Bartlett Publishers. p. 122. ISBN 9781449689407.
- ^ “Flexeril: Side effects”. RxList.com. Archived from the original on 12 September 2008. Retrieved 22 February 2010.
- ^ “Long-term Use of Cyclobenzaprine for Pain: A Review of the Clinical Effectiveness”. CADTH Rapid Response Reports. Ottawa, Ontario: Canadian Agency for Drugs and Technologies in Health. 23 February 2015. PMID 25763449.
- ^ Potentially inappropriate medications for the elderly according to the revised Beers criteria. 2012. Duke Clinical Research Institute website. [1]
- ^ “High risk medications” (PDF). National Committee for Quality Assurance. Archived from the original (PDF) on 1 February 2010. Retrieved 22 February 2010.
- ^ “MEDICATIONS AND DYSPHAGIA/ SWALLOWING RISKS” (PDF).
- ^ Chabria SB (July 2006). “Rhabdomyolysis: a manifestation of cyclobenzaprine toxicity”. Journal of Occupational Medicine and Toxicology. 1 (1): 16. doi:10.1186/1745-6673-1-16. PMC 1540431. PMID 16846511.
- ^ Keegan MT, Brown DR, Rabinstein AA (December 2006). “Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs”. Anesthesia and Analgesia. 103 (6): 1466–8. doi:10.1213/01.ane.0000247699.81580.eb. PMID 17122225.
- ^ Medical Practice of William H. Gorman, M.D. (18 February 2014). “Medications to Avoid, Continue, or Stop – Before & After Surgery”.
- ^ Jump up to:a b “Cyclobenzaprine”. http://www.drugbank.ca.
- ^ Kobayashi H, Hasegawa Y, Ono H (September 1996). “Cyclobenzaprine, a centrally acting muscle relaxant, acts on descending serotonergic systems”. European Journal of Pharmacology. 311 (1): 29–35. doi:10.1016/0014-2999(96)00402-5. PMID 8884233.
- ^ Jump up to:a b c d e f g h i j k “Cyclobenzaprine (CBP) and Its Major Metabolite Norcyclobenzaprine (nCBP) Are Potent Antagonists of Human Serotonin Receptor 2a (5HT2a), Histamine Receptor H-1 and á-Adrenergic Receptors: Mechanistic and Safety Implications for Treating Fibromyalgia Syndrome by Improving Sleep Quality”. ACR Meeting Abstracts. Retrieved 27 January 2022.
- ^ “Cyclobenzaprine”. pubchem.ncbi.nlm.nih.gov.
- ^ Winchell GA, King JD, Chavez-Eng CM, Constanzer ML, Korn SH (January 2002). “Cyclobenzaprine pharmacokinetics, including the effects of age, gender, and hepatic insufficiency”. Journal of Clinical Pharmacology. 42 (1): 61–9. doi:10.1177/0091270002042001007. PMID 11808825. S2CID 7749001.
- ^ “Medscape: Medscape Access”. medscape.com. Retrieved 1 October 2016.
- ^ Childers MK, Petri M, Laudadio C, Harrison D, Silber S, Bowen D (2004). “Comparison of cyclobenzaprine alone versus cyclobenzaprine plus ibuprofen in patients with acute musculoskeletal spasm and pain”. Annals of Emergency Medicine. 44 (4): S87–S88. doi:10.1016/j.annemergmed.2004.07.286.
- ^ “Patient Web site for Amrix (Cyclobenzaprine Hydrochloride Extended‐Release Capsules)”. amrix.com. Retrieved 1 October 2016.
External links
- “Cyclobenzaprine”. Drug Information Portal. U.S. National Library of Medicine.
| Clinical data | |
|---|---|
| Trade names | Flexeril, Amrix, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682514 |
| License data | US DailyMed: Cyclobenzaprine |
| Routes of administration | By mouth |
| ATC code | M03BX08 (WHO) |
| Legal status | |
| Legal status | US: ℞-onlyIn general: ℞ (Prescription only) |
| Pharmacokinetic data | |
| Bioavailability | 33–55%[1][2] |
| Protein binding | 93% |
| Metabolism | major: CYP3A4, CYP1A2; minor: CYP2D6, N-demethylation[5] |
| Metabolites | Norcyclobenzaprine |
| Elimination half-life | 32 hours (extended-release, range 8-37 hours),[3] 18 hours (immediate release, range 8–37 hours)[4] |
| Excretion | Kidney |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 303-53-7 |
| PubChem CID | 2895 |
| IUPHAR/BPS | 7152 |
| DrugBank | DB00924 |
| ChemSpider | 2792 |
| UNII | 69O5WQQ5TI |
| KEGG | D07758 |
| ChEBI | CHEBI:3996 |
| ChEMBL | ChEMBL669 |
| CompTox Dashboard (EPA) | DTXSID0046933 |
| ECHA InfoCard | 100.005.588 |
| Chemical and physical data | |
| Formula | C20H21N |
| Molar mass | 275.395 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
| (verify) |
///////////////cyclobenzaprine, циклобензаприн , سيكلوبنزابرين , 环苯扎林 , MK-130, TNX-102, Muscle Relaxant
CN(C)CCC=C1C2=CC=CC=C2C=CC2=CC=CC=C12
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Pyritinol
Pyritinol
- Molecular FormulaC16H20N2O4S2
- Average mass368.471 Da
1098-97-1[RN]
1308
214-150-1[EINECS]
233-178-5[EINECS]
3,3′-[Dithiobis(methylene)]bis[5-hydroxy-6-methyl-4-pyridinemethanol]
4-Pyridinemethanol, 3,3′-[dithiobis(methylene)]bis[5-hydroxy-6-methyl-
пиритинол[Russian][INN]
بيريتينول[Arabic][INN]
吡硫醇[Chinese][INN]
Pyritinol, CAS Registry Number: 1098-97-1
CAS Name: 3,3¢-[Dithiobis(methylene)]bis[5-hydroxy-6-methyl-4-pyridinemethanol]
Additional Names: bis(4-hydroxymethyl-5-hydroxy-6-methyl-3-pyridylmethyl) disulfide; bis[(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methyl] disulfide; dipyridoxolyldisulfide; pyridoxine-5-disulfide; pyrithioxin
Molecular Formula: C16H20N2O4S2, Molecular Weight: 368.47
Percent Composition: C 52.15%, H 5.47%, N 7.60%, O 17.37%, S 17.40%
Literature References: Prepn: Zima, Schorre, US3010966 (1961 to E. Merck); Iwanami et al.,Bitamin36, 122 (1967); J. Vitaminol.14, 321, 326 (1968). HPLC determn in urine: K. Kitao et al.,Chem. Pharm. Bull.25, 1335 (1977). Pharmacokinetics and metabolism: Darge et al.,Arzneim.-Forsch.19, 5, 9, (1969); Nowak, Schorre, ibid. 11. Clinical trial in dementia: S. Hoyer et al.,ibid.27, 671 (1977); A. J. Cooper, R. V. Magnus, Pharmacotherapeutica2, 317 (1980); in cerebrovascular disorders: Y. Tazaki et al.,J. Int. Med. Res.8, 118 (1980).
Properties: Crystals, mp 218-220°.
Melting point: mp 218-220°
Derivative Type: Dihydrochloride monohydrate
Trademarks: Biocefalin (Benvegna); Bonifen (Merck KGaA); Enbol (Chugai); Encephabol (Merck KGaA); Enerbol (Polfa); Epocan (Merck KGaA); Life (SIT)
Molecular Formula: C16H20N2O4S2.2HCl.H2O, Molecular Weight: 459.41
Percent Composition: C 41.83%, H 5.27%, N 6.10%, O 17.41%, S 13.96%, Cl 15.43%
Properties: mp 184°. Note: Has no vitamin B6 activity.
Melting point: mp 184°
Therap-Cat: Nootropic.
Keywords: Nootropic.
Derivatives
Dihydrochloride monohydrate
- Formula:C16H20N2O4S2 • 2HCl • H2O
- MW:459.42 g/mol
- CAS-RN:10049-83-9
- EINECS:233-178-5
- LD50:221 mg/kg (M, i.v.); 5786 mg/kg (M, p.o.);
300 mg/kg (R, i.v.); 6 g/kg (R, p.o.)
Pyritinol has been used in trials studying the treatment of Dementia, Depression, Schizophrenia, Anxiety Disorders, and Psychosomatic Disorders.
Pyritinol also called pyridoxine disulfide or pyrithioxine (European drug names Encephabol, Encefabol, Cerbon 6) is a semi-synthetic water-soluble analog of vitamin B6 (Pyridoxine HCl). It was produced in 1961 by Merck Laboratories by bonding 2 vitamin B6 compounds (pyridoxine) together with a disulfide bridge. Since the 1970s, it has been a prescription and OTC drug in several countries for cognitive disorders, rheumatoid arthritis,[1] and learning disorders in children. Since the early 1990s it has been sold as a nootropic dietary supplement in the United States.
SYN
| CAS-RN | Formula | Chemical Name | CAS Index Name |
|---|---|---|---|
| 39984-49-1 | C8H10Br3NO | 3,4-bis(bromomethyl)-5-hydroxy-6-methylpyridine hydrobromide | 3-Pyridinol, 4,5-bis(bromomethyl)-2-methyl- |
| 92147-37-0 | C11H15NO3S2 | ethylxanthic acid [5-hydroxy-4-(hydroxymethyl)-6-methyl-3-pyridyl]methyl ester | Xanthic acid, ethyl-, [5-hydroxy-4-(hydroxymethyl)-6-methyl-3-pyridyl]methyl ester |
| 140-89-6 | C3H5KOS2 | potassium ethylxanthogenate | Carbonodithioic acid, O-ethyl ester, potassium salt |
PATENT
PATENT
https://patents.google.com/patent/CN103992268A/en
Pyritinol, it is the derivative of vitamin B6, for nootropic agents, can promote glucose and amino acid metabolism in brain, improve whole body assimilation, increase Flow of carotid artery, improve cerebral blood flow (CBF), be applicable to the dizzy distending pain, insomnia, hypomnesis of cerebral trauma sequela, encephalitis and meningitis sequela etc., the improvement of absent minded, emotional change; Also for cerebral arteriosclerosis, senile dementia mental symptom etc.
The pyritinol of applying clinically at present, it is pyritinol hydrochloride, be specially the monohydrate of hydrochloride, its chemical name is 3,3-(dithio methylene radical) two (5-hydroxyl-6-methyl-pyridine methane) dihydrochloride monohydrate, has recorded in < < Chinese Pharmacopoeia version > > in 2010.The preparation of this product listing has sheet, capsule and sterile powder injection, and its injection easily causes venous stimulation when clinical application, has greatly limited clinical application.The powder injection of pyritinol hydrochloride easy caking after standing storage, not soluble or dissolve and thoroughly cause liquid unclarity, particulate matter to exceed standard and easily cause the untoward reactions such as Microembolization during use.
CN101003509A discloses hydrobromate and the mesylate of pyritinol, record its stability having had, solvability and bland advantage, but in fact, Hydrogen bromide pyritinol, methylsulfonic acid pyritinol store easy moisture absorption under normal condition, in purification refine, be difficult to separate out with conventional crystallization method, need loaded down with trivial details aftertreatment technology, Hydrogen bromide and methylsulfonic acid have strong corrodibility in addition, comparatively difficult to its suitability for industrialized production.
CN101066266A discloses organic acid salt of pyritinol and preparation method thereof, wherein preferred pyritinol nicotinate.Yet, in nicotinic acid pyritinol water solvability a little less than, and nicotinic acid pyritinol preparation technology used dry-out benzene, toxicity is larger, and aftertreatment technology is complicated, is not suitable for suitability for industrialized production.
Yet, existing pyritinol or its salt, or pyritinol salt exists defect in the use, or the production technique that obtains this pyritinol salt is unsuitable for suitability for industrialized production.For this reason, need to provide a kind of safe, pyritinol salt and production method thereof of stablizing, meeting industrialization production requirements.
Embodiment 1: pyritinol maleate synthetic
Get 5.0g pyritinol powder, drop in reaction flask, add 100ml purified water, then under agitation add toxilic acid 3.8g, finish, be heated to 60-65 ℃ and stir 30min and all dissolve to solid, remove heating fluid, stirred crystallization under room temperature, separate out a large amount of white solids, use a small amount of cold water washing, 45 ℃ of vacuum-dryings, obtain white powder 5.97g, yield 72.9%.Purity: 99.5%; M.p.:134～137 ℃; Ultimate analysis (C16H20N2O4S22C4H4O4): C:47.9%, H:4.8%, N:4.6%, S:10.6%, O:32.1% (theory: C:48.0%, H:4.7%, N:4.7%, S:10.7%, O:32.0%); 1H-NMR (600MHz, DMSO) δ: 2.39 (6H, s), 3.93 (4H, s), 4.76 (4H, s), 6.18 (4H, s), 7.87 (2H, s).By the 1H-NMR (Fig. 2) of toxilic acid pyritinol and the 1H-NMR (Fig. 1) of pyritinol contrast, in a part toxilic acid pyritinol, contain 2 molecule toxilic acids.
Embodiment 2: pyritinol maleate synthetic
Get 5.0g pyritinol powder, drop in reaction flask, add 100ml ethanol, then under agitation add toxilic acid 3.0g, finish, be heated to return stirring 30min and all dissolve to solid, remove heating fluid, stirred crystallization under room temperature, separate out a large amount of white solids, use a small amount of cold water washing, 45 ℃ of vacuum-dryings, obtain white powder 5.50g, yield 67.5%.After measured, the toxilic acid pyritinol that structure makes with embodiment 1.
PATENT
https://patents.google.com/patent/CN105153021A/en
Embodiment 1
Toxilic acid 3.8g is dissolved in 100ml ethanol, be warming up to 60 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 1 hour, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid toxilic acid pyritinol crystal form A 4.9g.X-ray powder diffraction analysis, as Fig. 1, its 2 θ value is as following table.
Embodiment 2
Toxilic acid 3.8g is dissolved in 100ml acetone, be warming up to 45 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 1.5 hours, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid 5.2g.It is toxilic acid pyritinol crystal form A that dry product does X-ray powder diffraction.
Embodiment 3
Toxilic acid 3.8g is dissolved in and adds 100ml Virahol, be warming up to 60 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 2 hours, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid 5.1g.It is toxilic acid pyritinol crystal form A that dry product does X-ray powder diffraction.
PATENT
https://patents.google.com/patent/CN101066266A/en
Specific embodiment:
Embodiment 1: nicotinic acid pyritinol salt synthetic
Get nicotinic acid 24.6g, fully be dissolved in the 300ml anhydrous benzene, heated and stirred is to molten entirely, under complete molten state, add pyritinol 40.5g, reflux mixture 3 hours, TLC thin layer identification (developing solvent: ethyl acetate: ethanol: glacial acetic acid=5: 6: 0.6) fully, the cooling back adds the 200ml dehydrated alcohol slightly, mixture is put into refrigerator fully cool off, sucking filtration is separated out white crystals, with a small amount of cold absolute ether washing solid.65 ℃ of vacuum dryings get 62.1g nicotinic acid pyritinol salt, yield 89.7%.Determination of acid-basetitration nicotinic acid and pyritinol content are measured moisture with the karl Fischer method.The result is: nicotinic acid 37.2%, and pyritinol 62.0%, water 5.8%, approaching with theoretical value, contain 2 water of crystallization.Elementary analysis: theoretical value C52.8% H5.3% O25.2%N6.6% S10.1%; Measured value C52.4% H5.2% O25.1%N6.5% S10.0%.
Embodiment 2: fumaric acid pyritinol salt synthetic
Get fumaric acid 11.6g, fully be dissolved in the 300ml anhydrous benzene, heated and stirred is to molten entirely, under complete molten state, add pyritinol 40.5g, reflux mixture 3 hours, TLC thin layer identification (developing solvent: ethyl acetate: ethanol: glacial acetic acid=5: 4: 0.8) fully, the cooling back adds the 200ml dehydrated alcohol slightly, mixture is put into refrigerator fully cool off, sucking filtration is separated out white crystals, with a small amount of cold absolute ether washing solid.65 ℃ of vacuum dryings get 49.9g fumaric acid pyritinol salt, yield 88.9%.Determination of acid-basetitration fumaric acid and pyritinol content are measured moisture with the karl Fischer method.The result is: fumaric acid 20.8%, and pyritinol 72.7%, water 6.5%, approaching with theoretical value, contain 2 water of crystallization.Elementary analysis: theoretical value C49.6% H5.0%O26.4% N5.8% S13.2%; Measured value C49.4% H5.2% O26.5% N5.9%S13.1%.
PATENT
https://patents.google.com/patent/CN102516297A/en
Embodiment 1: the preparation of compd A
With Pyrithioxine hydrochloride 10g, be dissolved in the 20ml pyridine, slowly drip POCl3 solution 10ml under the room temperature; Drip and finish, stirring at room reaction 12 hours slowly adds the 100g frozen water and stirred hydrolysis reaction 2 hours; Toluene gradation extraction 30ml * 3, water layer evaporated under reduced pressure, Virahol dissolution residual substance; Filter, evaporate to dryness gets compd A 4.2g.
Embodiment 2: the preparation of compd B
With Pyrithioxine hydrochloride 10g, be dissolved in the 40ml THF, add 4gNaH, 30 ℃ were stirred 2 hours; Add the 20ml POCl3, stirring reaction 16 hours slowly adds the 100g frozen water and stirred hydrolysis reaction 2 hours; ETHYLE ACETATE gradation extraction 30ml * 3, the water layer evaporated under reduced pressure adds 80ml Virahol dissolution residual substance; Add 40ml water, freezing crystallization gets compd B 5.6g.
Embodiment 3: the preparation of Compound C
With Pyrithioxine hydrochloride 10g, be dissolved in the 40ml THF, add 4gNaH, 30 ℃ were stirred 2 hours; Add the 20ml chloroiodomethane, stirring reaction 16 hours, 60 ℃ of evaporated under reduced pressure add 20ml acetonitrile dissolution residual substance; As midbody, other gets triethylamine 9ml and is dissolved in the 10ml acetonitrile, drips 3.6ml phosphoric acid, after dropping finishes; Stir down and slowly splash into midbody, continued 60 ℃ of stirring reactions 12 hours, steaming desolventizes; Residue adds water 20ml dissolving, and water layer filters clarification, and freeze-drying promptly gets compd B 6.7g.
Embodiment 4: the preparation of Compound D
Serine 3 grams, ethylene bromohyrin 2.5g, N with the BOC protection; N-Dimethylamino pyridine 3g and NSC 57182 3g are dissolved in the THF; Stirring at room 10 hours, vacuum concentration is with the thick product of chromatography purification (with the ETHYLE ACETATE/normal hexane wash-out of normal hexane to 30%); Merging filtrate, evaporate to dryness gets intermediate A; Pyrithioxine hydrochloride 2g and intermediate A 2.5g are dissolved with THF 30ml, add triphenyl phosphorus 2g, slowly drip diethyl azodiformate solution 2ml, room temperature reaction 5 hours; Reaction is finished, and evaporated under reduced pressure adds ETHYLE ACETATE 50ml dissolving, filters insolubles; With the thick product of chromatography purification (with the ETHYLE ACETATE/normal hexane wash-out of normal hexane to 10%), merging filtrate, evaporate to dryness dissolves with methylene dichloride 20ml then; Feed hydrogen chloride gas to saturated, stirring reaction 5 hours filters; Get the hydrochloride of Compound D, transferring pH behind the use dissolved in distilled water is about 8, and the water layer lyophilize gets Compound C 0.27g.
Embodiment 5: the preparation of compd E
Get compd A 10g, be dissolved in the 30ml Virahol, add 25gBoc-Ser-OBZL in batches, 50 ℃ of stirring reactions; HPLC monitoring react to compd B less than 5%, add 0.1M hydrochloric acid soln 20ml, 60 ℃ of heating hydrolysis 5 hours are regulated pH to 7; Evaporated under reduced pressure adds anhydrous alcohol solution, removes by filter insolubles, evaporated under reduced pressure; Add the 5ml water dissolution, filtering, lyophilize get compd E 6.9g
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Availability
It is approved for “symptomatic treatment of chronically impaired brain function in dementia syndromes” and for “supportive treatment of sequelae of craniocerebral trauma” in various European countries, including Austria, Germany, France, Italy, Portugal, and Greece. In France it is also approved for rheumatoid arthritis as a disease modifying drug, on the basis of the results of clinical trials. In many countries it is available over the counter and is widely advertised on the internet as being for “memory disturbances.”
Effects
review refs needed
Adverse effects
Adverse effects include nausea, headache,[2] and rarely allergic reaction (mild skin reactions).[3] A 2004 survey of six case reports suggested a link between pyritinol and severe cholestatic hepatitis when on several drugs for certain diseases.[4]
Other rare side effects: acute pancreatitis[5] and photoallergic eruption.[6]
References
- ^ Lemmel EM (May 1993). “Comparison of pyritinol and auranofin in the treatment of rheumatoid arthritis. The European Multicentre Study Group”. British Journal of Rheumatology. 32 (5): 375–82. doi:10.1093/rheumatology/32.5.375. PMID 8495257.
- ^ Nachbar F, Korting HC, Vogl T (1993). “Erythema multiforme-like eruption in association with severe headache following pyritinol”. Dermatology. 187 (1): 42–6. doi:10.1159/000247196. PMID 8324277.
- ^ de Groot, Anton C.; Nater, Johan Pieter; Weyland, J. Willem. Unwanted Effects of Cosmetics and Drugs Used in Dermatology.[full citation needed][page needed]
- ^ Maria V, Albuquerque A, Loureiro A, Sousa A, Victorino R (March 2004). “Severe cholestatic hepatitis induced by pyritinol”. BMJ. 328 (7439): 572–4. doi:10.1136/bmj.328.7439.572. PMC 381054. PMID 15001508.
- ^ Straumann A, Bauer M, Pichler WJ, Pirovino M (August 1998). “Acute pancreatitis due to pyritinol: an immune-mediated phenomenon”. Gastroenterology. 115 (2): 452–4. doi:10.1016/S0016-5085(98)70212-4. PMID 9679051.
- ^ Tanaka M, Niizeki H, Shimizu S, Miyakawa S (October 1996). “Photoallergic drug eruption due to pyridoxine hydrochloride”. The Journal of Dermatology. 23 (10): 708–9. doi:10.1111/j.1346-8138.1996.tb02685.x. PMID 8973037. S2CID 28810619.
External links
- Media related to Pyritinol at Wikimedia Commons
| Clinical data | |
|---|---|
| ATC code | N06BX02 (WHO) |
| Pharmacokinetic data | |
| Elimination half-life | 2.5 hours |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1098-97-1 |
| PubChem CID | 14190 |
| ChemSpider | 13561 |
| UNII | AK5Q5FZH2R |
| KEGG | D02160 |
| ChEMBL | ChEMBL488093 |
| CompTox Dashboard (EPA) | DTXSID3048362 |
| ECHA InfoCard | 100.012.864 |
| Chemical and physical data | |
| Formula | C16H20N2O4S2 |
| Molar mass | 368.473 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
| (what is this?) (verify) |
//////////////Pyritinol, пиритинол , بيريتينول , 吡硫醇 , Nootropic,
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Fabomotizole
Fabomotizole
Afobazole
- Molecular FormulaC15H21N3O2S
- Average mass307.411 Da
0F8K1X115C
173352-21-1[RN], 173352-21-1 (free base) 173352-39-1 (HCl) 189638-30-0 (2HCl)
1H-Benzimidazole, 6-ethoxy-2-[[2-(4-morpholinyl)ethyl]thio]-
Obenoxazine, Afobazol, Afobazole, Aphobazole, Fabomotizole dihydrochloride, CM-346, CM346, CM 346,
фабомотизол[Russian][INN]
فابوموتيزول[Arabic][INN]
法莫替唑[Chinese][INN]
Fabomotizole dihydrochloride
CAS#: 189638-30-0 (2HCl)
Chemical Formula: C15H23Cl2N3O2S
Molecular Weight: 380.33
Fabomotizole (also known as Afobazole) is a selective non-benzodiazepine anxiolytic which was developed in Russia and launched in 2006. The drug is used for the treatment of wide range of diseases: generalized anxious disorders, neurasthenia, adaptation disorders, sleep disorders, for alleviation of withdrawal syndrome. According to the drug label (in Russian), its action is related to the interaction with sigma-1 receptors.
Fabomotizole (INN;[1] brand name Afobazole) is an anxiolytic drug launched in Russia in the early 2000s. It produces anxiolytic and neuroprotective effects without any sedative or muscle relaxant actions.[citation needed] Its mechanism of action remains poorly defined however, with GABAergic, NGF– and BDNF-release-promoting, MT1 receptor agonism, MT3 receptor antagonism, and sigma agonism suggested as potential mechanisms. Fabomotizole was shown to inhibit MAO-A reversibly and there might be also some involvement with serotonin receptors.[2][3][4][5][6] Clinical trials have shown fabomotizole to be well tolerated and reasonably effective for the treatment of anxiety.[7]
Experiments of mice have shown antimutagenic and antiteratogenic properties.[8]
Fabomotizole has found little clinical use outside Russia and has not been evaluated by the FDA.
PATENT
WO 9534304
https://patents.google.com/patent/WO1995034304A1/en
PAPER
European Journal of Medicinal Chemistry (2021), 211, 113110
https://www.sciencedirect.com/science/article/abs/pii/S0223523420310825?
A ligand-based virtual screening study to search for giardicidal compounds on a 6551 ChEMBL drugs database was carried out using molecular similarity. Three fingerprints implemented in MayaChemTools with different design and validated by ROC curves, were used. Twelve compounds were retrieved from this screening, from which, four representative compounds were selected to carry out biological assays. Whereas two compounds were commercially available, the additional two compounds were synthesized during the development of this work. The biological assays revealed that the compounds possess in vitro activity against five strains of Giardia intestinalis, each with different susceptibility/resistance rates to metronidazole, albendazole and nitazoxanide. Particularly, tenatoprazole showed the best effect against the WB and IMSS strains. Furthermore, fabomotizole, tenatoprazole and ipriflavone showed a higher activity against resistant strains than the reference drugs: metronidazole, albendazole and nitazoxanide.
Graphical abstract
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| Clinical data | |
|---|---|
| Trade names | Afobazole |
| Other names | Fabomotizole |
| Routes of administration | Oral |
| ATC code | N05BX04 (WHO) |
| Legal status | |
| Legal status | US: Unscheduled Not FDA approved |
| Pharmacokinetic data | |
| Bioavailability | 43.64%, pronounced first-pass effect |
| Metabolism | extensive hepatic |
| Onset of action | 0.85±0.13 hours |
| Elimination half-life | 0.82±0,54 hours |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 173352-39-1 |
| PubChem CID | 9862937 |
| ChemSpider | 8038633 |
| UNII | HDO6HX6NZU |
| CompTox Dashboard (EPA) | DTXSID00169606 |
| Chemical and physical data | |
| Formula | C15H21N3O2S |
| Molar mass | 307.41 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
| (what is this?) (verify) |
References
- ^ “International Nonproprietary Names for Pharmaceutical Substances (INN)” (PDF). WHO Drug Information. 26 (1): 63. 2012. Retrieved 21 March 2015.
- ^ Neznamov, GG; Siuniakov, SA; Chumakov, DV; Bochkarev, VK; Seredenin, SB (2001). “Clinical study of the selective anxiolytic agent afobazol”. Eksperimental’naia i Klinicheskaia Farmakologiia. 64 (2): 15–9. PMID 11548440.
- ^ Silkina, IV; Gan’shina, TC; Seredin, SB; Mirzoian, RS (2005). “Gabaergic mechanism of cerebrovascular and neuroprotective effects of afobazole and picamilon”. Eksperimental’naia i Klinicheskaia Farmakologiia. 68 (1): 20–4. PMID 15786959.
- ^ Seredin, SB; Melkumian, DS; Val’dman, EA; Iarkova, MA; Seredina, TC; Voronin, MV; Lapitskaia, AS (2006). “Effects of afobazole on the BDNF content in brain structures of inbred mice with different phenotypes of emotional stress reaction”. Eksperimental’naia i Klinicheskaia Farmakologiia. 69 (3): 3–6. PMID 16878488.
- ^ Antipova, TA; Sapozhnikova, DS; Bakhtina, LIu; Seredenin, SB (2009). “Selective anxiolytic afobazole increases the content of BDNF and NGF in cultured hippocampal HT-22 line neurons”. Eksperimental’naia i Klinicheskaia Farmakologiia. 72 (1): 12–4. PMID 19334503.
- ^ Seredenin, SB; Antipova, TA; Voronin, MV; Kurchashova, SY; Kuimov, AN (2009). “Interaction of afobazole with sigma1-receptors”. Bulletin of Experimental Biology and Medicine. 148 (1): 42–4. doi:10.1007/s10517-009-0624-x. PMID 19902093. S2CID 37411324.
- ^ Medvedev, VE; Trosnova, AP; Dobrovol’skiĭ, AV (2007). “Psychopharmacotherapy of anxiety disorders in patients with cardio-vascular diseases: the use of aphobazole”. Zh Nevrol Psikhiatr Im S S Korsakova. 107 (7): 25–9. PMID 18379478.
- ^ Durnev AD, Zhanataev AK, Shreder OV, Seredenin SB (Jan–Feb 2009). “Antimutagenic and antiteratogenic properties of afobazole”. Eksp Klin Farmakol. 72 (1): 46–51. PMID 19334511.
//////////////Fabomotizole, Afobazole, фабомотизол , فابوموتيزول , 法莫替唑 , Obenoxazine, Afobazol, Afobazole, Aphobazole, Fabomotizole dihydrochloride, CM-346, CM346, CM 346,
CCOc1ccc2c(c1)[nH]c(n2)SCCN3CCOCC3.Cl.Cl
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BIFONAZOLE
BIFONAZOLE
- Molecular FormulaC22H18N2
- Average mass310.392 Da
(±)-1-(p,a-Diphenylbenzyl)imidazole
(±)-Bifonazole
1-([1,1′-Biphenyl]-4-ylphenylmethyl)-1H-imidazole
1-(p,α-Diphenylbenzyl)imidazole
262-336-6[EINECS]
4887
60628-96-8[RN]
бифоназол
بيفونازول
联苯苄唑
- BAY H 4502
- BAY-H-4502
Bifonazole
CAS Registry Number: 60628-96-8
CAS Name: 1-([1,1¢-Biphenyl]-4-ylphenylmethyl)-1H-imidazole
Additional Names: (±)-1-(p,a-diphenylbenzyl)imidazole
Manufacturers’ Codes: Bay h 4502
Trademarks: Amycor (Lipha); Azolmen (Menarini); Bedriol (Andromaco); Mycospor (Bayer); Mycosporan (Bayer)
Molecular Formula: C22H18N2, Molecular Weight: 310.39
Percent Composition: C 85.13%, H 5.85%, N 9.03%
Literature References: Antimycotic deriv of imidazole. Prepn: E. Regel et al.,DE2461406; eidem,US4118487 (1976, 1978 both to Bayer). Series of articles on in vitro and in vivo antimycotic efficacy, microscopic studies, pharmacokinetics, efficacy in dermatomycoses and comparison with clotrimazole and miconazole, q.q.v.:Arzneim.-Forsch.33, 517-551, 745-754 (1983). Toxicology: G. Schlüter, ibid. 739.
Properties: Crystals from acetonitrile, mp 142°. Very lipophilic. Sol in alcohols, DMF, DMSO. Soly in water at pH 6: <0.1 mg/100 ml. Stable in aq soln at pH 1-12. LD50 in male mice, rats (mg/kg): 2629, 2854 orally (Schlüter).
Melting point: mp 142°
Toxicity data: LD50 in male mice, rats (mg/kg): 2629, 2854 orally (Schlüter)
Therap-Cat: Antifungal.
Keywords: Antifungal (Synthetic); Imidazoles.
BrandsAmycor (Merck) / Azolmen (Menarini) / Bayclear Plus (Bayer) / Bifonol (Mayado Seiyaku) / Canespor (Bayer) / Canesten (Bayer) / Mycospor (Bayer)
Bifonazole (trade name Canespor among others[1]) is an imidazole antifungal drug used in form of ointments.
It was patented in 1974 and approved for medical use in 1983.[2] There are also combinations with carbamide for the treatment of onychomycosis.
Bifonazole is an azole antifungal drug used to treat fungal skin infections, such as dermatomycosis.
- Synonyms:Bifonazolum
- ATC:D01AC10
- MW:310.40 g/mol
- CAS-RN:60628-96-8
- InChI Key:OCAPBUJLXMYKEJ-UHFFFAOYSA-N
- InChI:InChI=1S/C22H18N2/c1-3-7-18(8-4-1)19-11-13-21(14-12-19)22(24-16-15-23-17-24)20-9-5-2-6-10-20/h1-17,22H
- EINECS:262-336-6
- LD50:57 mg/kg (M, i.v.); 2629 mg/kg (M, p.o.);
63 mg/kg (R, i.v.); 1463 mg/kg (R, p.o.);
>500 mg/kg (dog, p.o.)
Derivatives
Monohydrochloride
- Formula:C22H18N2 • HCl
- MW:346.86 g/mol
- CAS-RN:60629-09-6
Sulfate
- Formula:C22H18N2 • xH2O4S
- MW:unspecified
- CAS-RN:60629-08-5
| CAS-RN | Formula | Chemical Name | CAS Index Name |
|---|---|---|---|
| 98-88-4 | C7H5ClO | benzoyl chloride | Benzoyl chloride |
| 92-52-4 | C12H10 | biphenyl | 1,1′-Biphenyl |
| 7515-73-3 | C19H15Cl | (±)-4-(chlorophenylmethyl)biphenyl | 1,1′-Biphenyl, 4-(chlorophenylmethyl)- |
| 288-32-4 | C3H4N2 | imidazole | 1H-Imidazole |
SYN
Synthesis Reference
Regal, E., Draber, W., Buchel, K.H.and Plempel, M.; U.S. Patent 4,118,487; October 3,1978; assigned to Bayer A.G.
SYN
SYN
(CAS NO.: ), with its systematic name of , 1-(alpha-(4-biphenylyl)benzyl)-, could be produced through many synthetic methods.
Following is one of the synthesis routes: (I) could be reduced with NaBH4 in ethanol to produce 4-phenylbenzhydrol (II), and the yielding product is then condensed with imidazole (III) in the presence of SOCl2 in acetonitrile.
PAT
https://patents.google.com/patent/DE10332684B3/en
- The The present invention relates to a process for the preparation of Bifonazole (1- [biphenyl-4-yl (phenyl) methyl] -1H-imidazole) by reacting 1-biphenyl-4-yl (phenyl) methanol with a chlorinating reagent in cyclohexane and subsequent coupling with imidazole.
- [0002]The compound bifonazole (1- [biphenyl-4-yl (phenyl) methyl] -1H-imidazole) is off DE-A 2 461 406 known and corresponds to the formula (I). Due to its antifungal activity, it can be used as an agent for the treatment of fungal diseases.
- [0003]Various methods for preparing this compound are known. So describes DE-A 2 461 406 the synthesis (process 1) of bifonazole (Example 1) starting from biphenyl-4-yl (phenyl) methanol by reaction with imidazole and thionyl chloride in acetonitrile with a yield of only 56% of theory. An alternative synthesis described therein (process 2) starting from 4- [chloro (phenyl) methyl] biphenyl, which is prepared from biphenyl-4-yl (phenyl) methanol by reaction with thionyl chloride in toluene, by reaction with trimethylsilylimidazole bifonazole provides only in a yield of 52% of theory.
- [0004]ES-A 2 024 363 describes also starting from 4- [chloro (phenyl) methyl] biphenyl, which is prepared from biphenyl-4-yl (phenyl) methanol by reaction with hydrogen chloride in acetonitrile, by reaction with imidazole in acetonitrile using a phase transfer catalyst, the synthesis (method 3) of bifonazole.
- [0005]AT-B 396 931 describes the preparation (method 4) of bifonazole by means of reductive amination of biphenyl-4-yl (phenyl) methanone with imidazole and formic acid. However, this requires high reaction temperatures (220 ° C.) and long reaction times. DE-A 3 538 873 describes a comparable process (process 5) with the additional use of p-toluenesulfonic acid, wherein the reaction temperature is 180 ° C.
- [0006]This in ES 539 345 described method (method 6) for the preparation of bifonazole involves a Gringard reaction between 4-biphenylmagnesium bromide and benzoylated imidazole. Finally, it is tosylated and reduced to bifonazole.
- [0007]ES 549 793 describes the synthesis (method 7) of bifonazole starting from a cyclocondensation between biphenyl-4-yl (phenyl) methylamine, 2-chloro-1-aminoethane and ethyl orthoacetate. The final dehydrogenation is carried out by reaction with 2,3-dichloro-5,6-dicyano-p-benzoquinone in benzene.
- [0008]All known processes have various disadvantages which are particularly unfavorable in the preparation of the compound of the formula (I) on an industrial scale. The solvents used in processes 1 and 2 acetonitrile and toluene are of concern to health. Their use should be avoided in the manufacture of active ingredients used in medicines. By using toluene in process 2, chlorination to give 4- [chloro (phenyl) methyl] biphenyl also produces a toluene-specific, undesired by-product which can only be removed incompletely and thus deteriorates the product quality. The yield is unsatisfactory in both processes. A significant disadvantage of method 3 is, in addition to the use of acetonitrile as solvent, the use of a phase transfer catalyst, which is difficult to separate from the product during work-up. Methods 4 and 5 both operate at very high temperatures and are therefore disadvantageous in a technical use due to the energy consumption and the potential hazard. In method 6, the use of the Gringard reagent is disadvantageous, since this must be produced under considerable safety expense and difficult to handle on an industrial scale. Disadvantage in process 7 is the use of the very toxic compounds 2,3-dichloro-5,6-dicyano-p-benzoquinone and benzene. Their use should be avoided especially in the production of active ingredients used in pharmaceuticals
- Embodiment:
- Synthesis of bifonazole (1- [Biphenyl-4-yl (phenyl) methyl] -1H-imidazole)
- 1st step: 4- [chloro (phenyl) methyl] biphenyl (III)
- [0038]140 g (0.54 mol) dry (water content <0.3%) biphenyl-4-yl (phenyl) methanol (II) are suspended in 1550 ml of cyclohexane and treated with 90 g (0.76 mol) thionyl chloride at a temperature of 50 to 55 ° C added. The reaction mixture is stirred for 0.5 h at a temperature of 50 to 55 ° C stirred. Subsequently, in the Vacuum (<100 mbar) Distilled off thionyl chloride and cyclohexane. A distillation bottoms containing 4- [chloro (phenyl) methyl] biphenyl remains.
- 2nd step: 1- [biphenyl-4-yl (phenyl) methyl] -1H-imidazole (Bifonazole)
- [0039]162 g (2.4 mol) of imidazole are suspended in 1350 ml of acetone and dissolved at 50 ° C. This solution is added to the distillation bottoms from step 1 containing 4- [chloro (phenyl) methyl] biphenyl (III). The reaction mixture is heated at reflux for 3 h. After cooling, the reaction solution is mixed with 2 g of activated carbon and 2 g of bleaching earth at a temperature of 50 to 55 ° C, stirred for 0.5 h and filtered. The filtrate is cooled to about 0 ° C. The title compound crystallizes by addition of seed crystals, is filtered off and washed with a mixture of acetone / water (1: 1). For recrystallization, the product is dissolved in 1250 ml of isopropanol, treated with 0.5 g of activated charcoal and 0.5 g of bleaching earth, heated to reflux and filtered hot. The filtrate is cooled to 10 ° C. The title compound crystallizes out by addition of seed crystals, is filtered off, washed with isopropanol and dried. The yield is 101 g (61.9% of theory). The purity of the product is 98.68% by weight.
Melting point: 142 ° C - Comparative method:
- [0040]In the comparative method, instead of cyclohexane, toluene is used as solvent in step 1 as in DE-A 2 461 406 described. Step 2 is performed as described above. 1- [biphenyl-4-yl (phenyl) methyl] -1H-imidazole (bifonazole) is obtained in a purity of 97.66% by weight.
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Adverse effects
The most common side effect is a burning sensation at the application site. Other reactions, such as itching, eczema or skin dryness, are rare.[3] Bifonazole is a potent aromatase inhibitor in vitro.[4][5]
Pharmacology
Mechanism of action
Bifonazole has a dual mode of action. It inhibits fungal ergosterol biosynthesis at two points, via transformation of 24-methylendihydrolanosterol to desmethylsterol, together with inhibition of HMG-CoA. This enables fungicidal properties against dermatophytes and distinguishes bifonazole from other antifungal drugs.[3][6]
Pharmacokinetics
Six hours after application, bifonazole concentrations range from 1000 µg/cm³ in the stratum corneum to 5 µg/cm³ in the papillary dermis.[3]
References
- ^ International Drug Names: Bifonazole.
- ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 502. ISBN 9783527607495.
- ^ Jump up to:a b c Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Canesten Bifonazol-Creme.
- ^ Trösken ER, Fischer K, Völkel W, Lutz WK (February 2006). “Inhibition of human CYP19 by azoles used as antifungal agents and aromatase inhibitors, using a new LC-MS/MS method for the analysis of estradiol product formation”. Toxicology. 219 (1–3): 33–40. doi:10.1016/j.tox.2005.10.020. PMID 16330141.
- ^ Egbuta C, Lo J, Ghosh D (December 2014). “Mechanism of inhibition of estrogen biosynthesis by azole fungicides”. Endocrinology. 155 (12): 4622–8. doi:10.1210/en.2014-1561. PMC 4239419. PMID 25243857.
- ^ Berg D, Regel E, Harenberg HE, Plempel M (1984). “Bifonazole and clotrimazole. Their mode of action and the possible reason for the fungicidal behaviour of bifonazole”. Arzneimittel-Forschung. 34 (2): 139–46. PMID 6372801.
Further reading
- Lackner TE, Clissold SP (August 1989). “Bifonazole. A review of its antimicrobial activity and therapeutic use in superficial mycoses”. Drugs. 38 (2): 204–25. doi:10.2165/00003495-198938020-00004. PMID 2670516.
| Clinical data | |
|---|---|
| Trade names | Canespor, many others |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration | Topical |
| ATC code | D01AC10 (WHO) |
| Legal status | |
| Legal status | In general: Over-the-counter (OTC) |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 60628-96-8 |
| PubChem CID | 2378 |
| DrugBank | DB04794 |
| ChemSpider | 2287 |
| UNII | QYJ305Z91O |
| KEGG | D01775 |
| ChEBI | CHEBI:31286 |
| ChEMBL | ChEMBL277535 |
| CompTox Dashboard (EPA) | DTXSID9045631 |
| ECHA InfoCard | 100.056.651 |
| Chemical and physical data | |
| Formula | C22H18N2 |
| Molar mass | 310.400 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| Chirality | Racemic mixture |
| showSMILES | |
| showInChI | |
| (what is this?) (verify) |
///////////BIFONAZOLE, бифоназол , بيفونازول , 联苯苄唑 , BAY H 4502, BAY-H-4502
C1=CN(C=N1)C(C1=CC=CC=C1)C1=CC=C(C=C1)C1=CC=CC=C1
NEW DRUG APPROVALS
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$10.00
Melitracen
Melitracen
- Molecular FormulaC21H25N
- Average mass291.430 Da
10563-70-9[RN]
1568
1-Propanamine, 3-(10,10-dimethyl-9(10H)-anthracenylidene)-N,N-dimethyl-
225-858-5[EINECS], 234-150-5[EINECS]
3-(10,10-Dimethyl-9(10H)-anthracenyliden)-N,N-dimethyl-1-propanamine
Q7T0Y1109Z
Thymeol
мелитрацен[Russian][INN]
ميليتراسان[Arabic][INN]
美利曲辛[Chinese][INN]
Melitracen
CAS Registry Number: 5118-29-6
CAS Name: 3-(10,10-Dimethyl-9(10H)-anthracenylidene)-N,N-dimethyl-1-propanamine
Additional Names:N,N,10,10-tetramethyl-D9(10H),g-anthracenepropylamine; 9,10-dihydro-10,10-dimethyl-9-(3-dimethylaminopropylidene)anthracene; 9-[3-(dimethylamino)propylidene]-10,10-dimethyl-9,10-dihydroanthracene; N,N-dimethyl-3-(10,10-dimethyl-9(10H)-anthrylidene)propylamine
Molecular Formula: C21H25N, Molecular Weight: 291.43
Percent Composition: C 86.55%, H 8.65%, N 4.81%
Literature References: Prepn of the hydrochloride: Holm, Acta Chem. Scand.17, 2437 (1963); idem,GB939856 corresp to US3177209 (1963, 1965, both to Kefalas A/S). Crystal structure: J. Lopez de Lerma et al.,Acta Crystallogr.B35, 1739 (1979). Toxicity data: P. V. Petersen et al.,Acta Pharmacol. Toxicol.24, 121 (1966).
Derivative Type: Hydrochloride
CAS Registry Number: 10563-70-9
Manufacturers’ Codes: U-24973A
Trademarks: Melixeran (Lusofarmaco); Trausabun (Promonta); Dixeran (Lundbeck)
Molecular Formula: C21H25N.HCl, Molecular Weight: 327.89
Percent Composition: C 76.92%, H 7.99%, N 4.27%, Cl 10.81%
Properties: Crystals from acetone, mp 245-248°. LD50 i.v. in mice: 52 mg/kg (Petersen).
Melting point: mp 245-248°
Toxicity data: LD50 i.v. in mice: 52 mg/kg (Petersen)
Therap-Cat: Antidepressant.
Keywords: Antidepressant; Tricyclics.
Melitracen (brand names Melixeran) is a tricyclic antidepressant (TCA), for the treatment of depression and anxiety.[1][2][3][4] In addition to single drug preparations, it is also available as Deanxit, marketed by Lundbeck, a combination product containing both melitracen and flupentixol.[5][6][7][8]
The pharmacology of melitracen has not been properly investigated and is largely unknown, but it is likely to act in a similar manner to other TCAs. Indeed, melitracen is reported to have imipramine and amitriptyline-like effects and efficacy against depression and anxiety, though with improved tolerability and a somewhat faster onset of action.[9][10]
- ATC:N06AA14
- MW:291.44 g/mol
- CAS-RN:5118-29-6
- InChI Key:GWWLWDURRGNSRS-UHFFFAOYSA-N
- InChI:InChI=1S/C21H25N/c1-21(2)19-13-7-5-10-17(19)16(12-9-15-22(3)4)18-11-6-8-14-20(18)21/h5-8,10-14H,9,15H2,1-4H3
- EINECS:225-858-5
- LD50:52 mg/kg (M, i.v.); 315 mg/kg (M, p.o.);
170 mg/kg (R, p.o.)
Derivatives
hydrochloride
- Formula:C21H25N • HCl
- MW:327.90 g/mol
- CAS-RN:10563-70-9
- EINECS:234-150-5
- LD50:52 mg/kg (M, i.v.); 315 mg/kg (M, p.o.);
170 mg/kg (R, p.o.)
| CAS-RN | Formula | Chemical Name | CAS Index Name |
|---|---|---|---|
| 90-44-8 | C14H10O | anthrone | 9(10H)-Anthracenone |
| 85118-29-2 | C21H27NO | 9-[3-(dimethylamino)propyl]-9,10-dihydro-10,10-dimethyl-9-anthracenol | 9-Anthracenol, 9-[3-(dimethylamino)propyl]-9,10-dihydro-10,10-dimethyl- |
| 19070-16-7 | C5H12ClMgN | 3-dimethylaminopropylmagnesium chloride | Magnesium, chloro[3-(dimethylamino)propyl]- |
| 5447-86-9 | C16H14O | 10,10-dimethylanthrone | 9(10H)-Anthracenone, 10,10-dimethyl- |
SYN
English: DOI number: 10.3891/acta.chem.scand.17-2437 GB 939856 corresp to US 3177209 (1963, 1965, both to Kefalas A/S).
SYN
https://pubs.rsc.org/en/content/articlehtml/2020/re/d0re00087f
| Fig. 10 Synthesis of melitracen HCl-(36) by Kiil and co-workers making use of a one-flow system. Adapted with permission from Org. Process Res. Dev., 2018, 22, 228–235. Copyright 2018 American Chemical Society.35 |
Grignard reactions are commonly used for the construction of carbon–carbon bonds and show exothermic behaviour which can be dangerous in large-scale batch processes. The use of Grignard reagents in flow can be beneficial because of the high control of reaction conditions, facile heat transport and small effective reaction volume.6,34 A recent example was published by Kiil and co-workers, who synthesised melitracen (36) in a one-flow system.35 Kiil hypothesised that the seven unit operations required in batch could be decreased by combining a hydrolysis and dehydration step, and removing a phase separation (Fig. 10).
The investigation commenced with finding a suitable solvent for the Grignard reaction in which starting materials 34, 35 and intermediate products would dissolve. After having identified THF as the most suitable option, the next challenge was to find an acid that could induce both hydrolysis and dehydration in a single step. Hydrochloric acid was able to perform both transformations, however, precipitation was observed. Thus, hydrochloric acid molarities ranging from 1–12 M were tested. However, while even at the lowest molarity precipitation was observed, it also appeared that below 6 M the dehydration reaction did not proceed. Since the precipitation could not be prevented, a molarity of 12 M was eventually used. The individually optimised transformations were then combined in a one-flow continuous system. Most troublesome was that addition of HCl to the reaction mixture led to an exothermic reaction and boiling of the solvent. Therefore, a back-pressure regulator was employed so that melitracen (36) could be successfully synthesised as its HCl-salt in approximately 85% yield.
SYN
https://pubs.acs.org/doi/pdf/10.1021/acs.oprd.7b00368
A Grignard-based batch process, for the preparation of Melitracen HCl, has been redesigned to fit a continuous reactor system. The Grignard addition is carried out at room temperature, with subsequent hydrolysis of the magnesium alkoxide intermediate followed by dehydration of the resulting alcohol. The product undergoes further workup by simple gravimetric phase separation and then crystallization with 2 M HCl in diethyl ether to afford pure Melitracen HCl. All steps in the laboratory setup were concatenated, and the setup was proven capable of producing a significant portion of the commercial quantities of Melitracen HCl. The flow setup profits from a reduced footprint, lower energy consumption, fewer synthetic steps, and reduced raw material usage compared to the batch process.
As illustrated in Scheme 1, four synthetic steps are involved in the manufacturing of Melitracen HCl (6). The four steps are a classic Grignard addition to a ketone, a hydrolysis of a magnesium alkoxide, a dehydration of an alcohol and a salt precipitation to isolate the API. The Grignard addition is between 10,10-dimethylanthrone (10,10-DMA (1)) and 3-(N,N-dimethylamino)propylmagnesium chloride (DMPC-MgCl (2)), resulting in formation of the magnesium alkoxide 3. The magnesium alkoxide 3 is then hydrolyzed to the alcohol 4 and dehydrated to form product 5. The last step is a crystallization of the API as a salt, where HCl is added to obtain the Melitracen HCl (6)
Scheme 1: Syntheses of magnesium alkoxide 3, alcohol 4 and dehydrated product 5 in the manufacturing process of Melitracen HCl 6, from ketone 1 and Grignard reagent 2.
Current Batch Synthesis The current batch synthesis involves individual synthetic steps, as illustrated in Figure 1. DMPC-MgCl 2 is made in-house before it is used, due to its limited storage shelf life, in a toluene-THF solvent mixture. THF is present in trace amounts in order to stabilize the magnesium in the Grignard reagents.45 A solution of 10,10-DMA 1 is prepared in toluene and is slowly transferred to the DMPC-MgCl 2, maintaining a temperature of 50°C. DMPC-MgCl 2 is used in an equivalence of 1.6 compared to 10,10-DMA 1. The formed magnesium alkoxide 3 is hydrolyzed with water and acetic acid (80%). The aqueous phase is discarded and concentrated hydrochloric acid (37%) is used to dehydrate alcohol 4 to form dehydrated product 5. Toluene is replaced with ethanol by a solvent swap. Crystallization of the dehydrated product 5 from the ethanol phase is done with HCl gas to obtain the final Melitracen HCl (6), which is subsequently isolated by filtration.
Precipitation of Melitracen HCl from THF The dehydrated product 5 was crystallized as the final HCl salt in the THF in a batch experiment, in order to remove a solvent swap to ethanol. The crystallization was carried out with 2 M HCl in Et2O, as this was considered more suited for a later flow process and more easily implemented in the laboratory setup. An equivalence of 1.1 HCl was used and the requirement was an achievement of pH<2. The mixture was kept stirred during the crystallization and carried out at ambient temperature. After 10 minutes, fine white solids started to form, followed by a massive precipitation of Melitracen HCl 6. The Melitracen HCl 6 was filtered with a Büchner funnel and washed with THF. The isolated yield was 80% and within the specifications for the in-house analysis methods used in the routine production (CHN, TGA, UV-vis, HPLC, melting point). Figure 3 is a microscope picture of the isolated Melitracen HCl 6. For full-scale production, the HCl gas would still be more desirable for the crystallization and the 2 M HCl in Et2O merely serves as a proof of concept for the laboratory flow setup.
CLIP
PATENT
https://patents.google.com/patent/CN105418436B/en
Melitracen (Melitracen), is a kind of tricyclics, entitled 10, the 10- dimethyl -9- γ-two of chemistry Methylamino acrylic -9,10- dihydro-anthraquinone, Clinical practice is its hydrochloride.Melitracen can suppress in presynaptic membrane To the effect of the reuptake of norepinephrine and serotonin, and therefore improve containing for monoamine transmitterses in synaptic cleft Amount.
On the preparation method of melitracen, document report both domestic and external is seldom, existing as described below：
US3177209, GB939856, DK97400, are the compound patents of Lundbeck drugmaker of Denmark, it is mentioned that Synthetic method is that, with 10,10- dimethylanthracene -9- ketone and N, TMSDMA N dimethylamine base propyl group magnesium chloride is generated in the middle of melitracen Body, then by intermediate be dissolved under chloroform, reflux state lead to hydrogen chloride prepare melitracen crude product, then crystallized again with acetone Melitracen is obtained, this method needs to be passed through hydrogen chloride at reflux, there is substantial amounts of smog to produce, and reaction condition is not yet It is easy to control, it there is larger safety factor.
CN103877088A is Lundbeck drugmaker of Denmark in a kind of safe melitracen group disclosed in 2014 Compound, wherein the purity to melitracen in drug regimen proposes more strict requirements, especially to that may make in clinic Cause the impurity (formula I, formula II) of the adverse reactions such as anxiety, irritated and excitement in, even more propose：Formula I<0.1%, formula II< 0.1, I+formula of formula II<0.1% rigors.The melitracen of patent US3177209, GB939856, DK97400 method synthesis Impurity is more, and primary purification can not obtain satisfactory active pharmaceutical ingredient (API).
It is also mentioned that the preparation method of melitracen hydrochloride, this method is with 10,10- diformazans in patent CN103877088A The γ of base-9-dimethylaminopropyl-9- anthrols are raw material, add dichloromethane and hydrochloric acid, are heated to reflux, reaction system alkaline hydrolysis from The free alkali obtained afterwards, is re-dissolved in acetone and leads to hydrogen chloride into salt, obtain melitracen crude product, then isolated and purified with column chromatography Obtain the melitracen of high-purity.The melitracen yield that it is prepared into is low, and purifies and separates process needs column chromatography, it is impossible to meet The need for large-scale production.
Embodiment 1
A kind of preparation method of melitracen hydrochloride, comprises the following steps：
(1) melitracen intermediate is prepared
10,10- dimethylanthracene -9- ketone carry out grignard reaction with 3- dimethylaminos-n-propyl chloride in the presence of initiator, obtain To melitracen intermediate, detailed process is as follows：
340g magnesium rods and 17.5L absolute ethers are added in 20L glass reaction kettles, stirring is warming up to 30~35 DEG C, addition 1.75kg 3- dimethylaminos-n-propyl chloride, finish insulated and stirred, add 1g iodine and 2mL 1,2- Bromofume as initiator, 9h is stirred at reflux, magnesium rod disappears completely, reaction system is cooled into 10~20 DEG C, 1.5kg 10,10- dimethyl is slowly added to Anthracene -9- ketone, then it is warming up to 30~35 DEG C, back flow reaction 1 hour；TLC monitoring reactions are complete, and reaction system is cooled into 10~20 DEG C, then add 5.5L water, ether layer is separated, anhydrous sodium sulfate is added and is concentrated under reduced pressure drying, obtain melitracen intermediate 2.03kg, receive The ﹪ of rate 97.2, purity 98.5%.
TLC monitoring methods：Add water and be quenched after sampling, take organic layer point plate；Solvent is petroleum ether:Ethyl acetate=2:1 (volume ratio)；The Rf of 10,10- dimethylanthracene -9- ketone is 0.6, and the Rf of melitracen intermediate is 0.1.
(2) melitracen crude product is prepared
2kg melitracens intermediate, 10L chloroforms and 2.4L concentrated hydrochloric acids are put into 20L glass reaction kettles, stirred molten Solution, obtains pale yellow solution, and 60 DEG C of heating stirring reaction 2 hours, TLC monitoring reactions are complete, and separate aqueous layer, organic phase is concentrated under reduced pressure Dry, it is melitracen crude product 2.03kg, yield 95.7%, purity 99.41%, containing Formulas I to obtain white solid：0.20%, formula II：0.13%；Formulas I, II1HNMR spectrograms, melitracen crude product liquid phase spectrogram are shown in accompanying drawing 1,2,3 respectively；
TLC monitoring methods：Organic phase point plate is extracted reaction solution, solvent is dichloromethane:Methanol:Acetic acid=150:10:2 (volume ratio).
Formulas I：1H NMR(400MHz,DMSO)δ7.78-7.82(m,2H),δ7.50-7.53(m,2H),δ7.28-7.35 (m, 4H), δ 2.11 (S, 6H), δ 2.08 (d, J=6.8Hz, 2H), δ 1.96 (t, J=6.4Hz, 2H), δ 1.72 (s, 3H), δ 1.61(s,3H),δ1.26(brs,1H),δ1.02-1.09(m,2H)
Formula II：1H NMR(400MHz,DMSO)δ8.95(s,2H),δ7.47-7.63(m,4H),δ7.27-7.37(m, 4H), δ 6.06 (t, J=7.2Hz, 1H), δ 3.09 (t, J=7.2Hz, 2H), δ 2.91 (m, 2H), δ 2.54 (s, 3H), δ 1.53 (s,6H)
(3) purifying of melitracen crude product
Take 2.03kg melitracens crude product (purity 99.41%, Formulas I：0.20%, Formula II:0.13%) 4 times of amount (W/, are added V isopropanol), 20~25 DEG C of stirring 4h (mashing), is filtered, and is dried, is obtained product 2.0kg, yield is 98.5%, and purity is 99.61%, containing Formulas I：0.054%, without Formula II；Melitracen crude product is shown in accompanying drawing 4 through isopropanol mashing sample liquid chromatography(LC figure；
Product after 2kg is beaten is added in 30L glass reaction kettle, adds 16kg isopropanols, and backflow is dissolved, then Cool to 10 DEG C and stir crystallization and stay overnight, suction filtration is dried under reduced pressure, and obtains melitracen 1.89kg, and yield 94.5%, purity 99.98% contains Formulas I：0.0026%, without Formula II；See accompanying drawing 5 through isopropanol recrystallization liquid phase spectrogram.
Embodiment 2
A kind of preparation method of melitracen hydrochloride, comprises the following steps：
(1) melitracen intermediate is prepared
This step is identical with the step (1) in embodiment 1；
(2) melitracen crude product is prepared
This step is identical with the step (2) in embodiment 1；
(3) purifying of melitracen crude product
Take 10g melitracens crude product (purity 99.41%, Formulas I：0.20%, Formula II:0.13%) 4 times of amounts (W/V), are added Ethanol, 20~25 DEG C stirring 4h (mashing), filtering, drying, obtain product 9.79g, yield is 97.9%, purity 99.69% contains Formula I 0.047%, containing formula II 0.005%；Melitracen crude product is shown in accompanying drawing 6 through ethanol mashing sample liquid chromatography(LC figure；
Product after 9.0g ethanol is beaten is added in 250mL round-bottomed flask, adds the dissolving of 230mL alcohol refluxs, Then 10 DEG C are cooled to stir crystallization and stay overnight, suction filtration is dried under reduced pressure, obtain melitracen 8.4g, yield 93.3%, purity 99.98%, Containing Formulas I：0.0041%, without Formula II；See accompanying drawing 7 through ethanol recrystallization liquid phase spectrogram.
Embodiment 3
A kind of preparation method of melitracen hydrochloride, comprises the following steps：
(1) melitracen intermediate is prepared
This step is identical with the step (1) in embodiment 1；
(2) melitracen crude product is prepared
100g melitracens intermediate, 500mL chloroforms and 120mL concentrated hydrochloric acids are put into 1L three-necked bottles, stirred molten Solution, obtains pale yellow solution, and 60 DEG C of heating stirring reaction 2 hours, TLC monitoring reactions are complete, and separate aqueous layer, organic phase is concentrated under reduced pressure Dry, it is melitracen crude product 104g, yield 98.3%, purity 99.38%, containing Formulas I to obtain white solid：0.22%, Formula II： 0.15%；Melitracen crude product liquid phase spectrogram is shown in accompanying drawing 8；
TLC monitoring methods：Organic phase point plate is extracted reaction solution, solvent is dichloromethane:Methanol:Acetic acid=150:10:2 (volume ratio).
(3) purifying of melitracen crude product
Above-mentioned melitracen crude product is taken, the methanol of 4 times of amounts (W/V) is added, 20~25 DEG C of stirring 4h (mashing) obtain product Weight is 18.48g, and yield is 92.4%, and purity is 99.66%, containing Formulas I：0.05%, Formula II：0.008%, see accompanying drawing 9.
Embodiment 4
A kind of preparation method of melitracen hydrochloride, comprises the following steps：
(1) melitracen intermediate is prepared
This step is identical with the step (1) in embodiment 3；
(2) melitracen crude product is prepared
This step is identical with the step (2) in embodiment 3；
(3) purifying of melitracen crude product
Above-mentioned melitracen crude product is taken, the n-butanol of 4 times of amounts (W/V) is added, 20~25 DEG C of stirring 5h (mashing) are produced Thing weight is 19.6g, and yield is 98%, and purity is 99.54%, containing Formulas I：0.05%, Formula II：0.009%, see accompanying drawing 10.
Embodiment 5
A kind of preparation method of melitracen hydrochloride, comprises the following steps：
(1) melitracen intermediate is prepared
This step is identical with the step (1) in embodiment 3；
(2) melitracen crude product is prepared
This step is identical with the step (2) in embodiment 3；
(3) purifying of melitracen crude product
Above-mentioned melitracen crude product is taken, the isopropanol of 4 times of amounts (W/V) is added, 30~35 DEG C of stirring 5h (mashing) are produced Thing weight is 18.06g, and yield is 90.3%.
Embodiment 6
A kind of preparation method of melitracen hydrochloride, comprises the following steps：
(1) melitracen intermediate is prepared
This step is identical with the step (1) in embodiment 3；
(2) melitracen crude product is prepared
This step is identical with the step (2) in embodiment 3；
(3) purifying of melitracen crude product
Above-mentioned melitracen crude product is taken, the isopropanol of 4 times of amounts (W/V) is added, 50 DEG C of stirring 3h (mashing) obtain product weight Measure as 14.2g, yield is 71%.
Embodiment 7
A kind of preparation method of melitracen hydrochloride, comprises the following steps：
(1) melitracen intermediate is prepared
This step is identical with the step (1) in embodiment 3；
(2) melitracen crude product is prepared
This step is identical with the step (2) in embodiment 3；
(3) purifying of melitracen crude product
Above-mentioned melitracen crude product is taken, the isopropanol of 4 times of amounts (W/V) is added, 5-10 DEG C of stirring 5h (mashing) obtains product Weight is 19.7g, and yield is 98.5%, and purity is 99.53%, containing Formulas I：0.054%, Formula II：0.014%, see accompanying drawing 11.
Embodiment 8
With reference to CN103877088A, crystallized using acetone, that is, take 10g melitracens intermediate and 24mL dichloromethane, 6.7mL concentrated hydrochloric acids are heated to reflux 2h and are cooled to room temperature, and pH is to 8-9 for regulation, then are extracted with dichloromethane and product, are concentrated to give free Alkali cpd, acetone is dissolved in by the free alkali compound, concentrated hydrochloric acid is added dropwise to pH=0.1, stirring, cooling separate out solid 7.1g, This solid crystallizes to obtain sample 6.4g with acetone again, and total recovery is 60.9%, and purity is 99.64%, containing Formulas I：0.09%, Formula II： 0.04%.Melitracen is shown in accompanying drawing 12 only with acetone crystallization liquid chromatography(LC figure.
Repeat literature method crystallized only with acetone obtained by product in impurity Formulas I, Formula II impurity summation be 0.13%, The adverse reactions such as anxiety, irritated and excitement may be caused in Clinical practice.
In summary, the effect of mashing is to make melitracen crude product rapid dispersion, and the effect of methanol mashing is similar with ethanol, But it is good without isopropanol effect, but methanol mashing yield is decreased obviously trend；N-butanol mashing needs the extension time to reach To the effect same with ethanol, but be not as good as isopropanol effect, and because the viscosity of n-butanol is slightly larger, melitracen crude product is at it In disperse slightly worse, invention has the granular solids that not readily dissolve after filtering, and the removal effect to other impurities is also poor；Isopropanol Temperature is raised during mashing, yield is decreased obviously, and reduces temperature, yield has no raising, though to the removal effect of impurity Formula II It can so control in the range of conforming to quality requirements, but compared to being decreased obviously in embodiment 1.
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References
- ^ Swiss Pharmaceutical Society (2000). Index Nominum 2000: International Drug Directory (Book with CD-ROM). Boca Raton: Medpharm Scientific Publishers. ISBN 3-88763-075-0.
- ^ Hall, Chapman and; Chemical Abstracts Service, American Chemical Society; Rhodes, P. H (1996). Dictionary of organic compounds. London: Chapman & Hall. ISBN 0-412-54090-8.
- ^ O’Neil, Maryadele J. (2001). The Merck index: an encyclopedia of chemicals, drugs, and biologicals. Rahway, NJ: Merck Research Laboratories. ISBN 0-911910-13-1.
- ^ José Miguel Vela; Helmut Buschmann; Jörg Holenz; Antonio Párraga; Antoni Torrens (2007). Antidepressants, Antipsychotics, Anxiolytics: From Chemistry and Pharmacology to Clinical Application. Weinheim: Wiley-VCH. ISBN 978-3-527-31058-6.
- ^ Muller, Niels F; Dessing, Rudolf P; Pharmacy, European Society of Clinical (1998). European Drug Index, 4th Edition. Boca Raton: CRC Press. ISBN 3-7692-2114-1.
- ^ Van Moffaert M, Dierick M, De Meulemeester F, Vereecken A (1983). “Treatment of depressive anxiety states associated with psychosomatic symptoms. A double-blind multicentre clinical study: mianserin versus melitracen-flupentixol”. Acta Psychiatrica Belgica. 83 (5): 525–39. PMID 6670581.
- ^ Bin Yaacob H (April 1985). “Flupenthixol and Melitracen in the management of trigeminal neuralgia”. Dental Journal of Malaysia. 8 (2): 37–8. PMID 3917005.
- ^ Hashash JG, Abdul-Baki H, Azar C, et al. (June 2008). “Clinical trial: a randomized controlled cross-over study of flupenthixol + melitracen in functional dyspepsia”. Alimentary Pharmacology & Therapeutics. 27 (11): 1148–55. doi:10.1111/j.1365-2036.2008.03677.x. PMID 18331614. S2CID 40714136.
- ^ Aronson, Jeffrey Kenneth (2008). Meyler’s Side Effects of Psychiatric Drugs (Meylers Side Effects). Amsterdam: Elsevier Science. ISBN 978-0-444-53266-4.
- ^ Author Unknown (1970). Ann Reports Medicinal Chem V5 (v. 5). Boston: Academic Press. ISBN 0-12-040505-9.
{{cite book}}:|author=has generic name (help)
| Clinical data | |
|---|---|
| Trade names | Adaptol, Dixeran, Melixeran, Thymeol, Trausabun |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration | Oral, intramuscular injection |
| ATC code | N06AA14 (WHO) |
| Legal status | |
| Legal status | In general: ℞ (Prescription only) |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 5118-29-6 |
| PubChem CID | 25382 |
| ChemSpider | 23697 |
| UNII | Q7T0Y1109Z |
| KEGG | D08171 |
| ChEMBL | ChEMBL110094 |
| CompTox Dashboard (EPA) | DTXSID4048274 |
| ECHA InfoCard | 100.023.507 |
| Chemical and physical data | |
| Formula | C21H25N |
| Molar mass | 291.438 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
| (what is this?) (verify) |
//////////Melitracen, Q7T0Y1109Z, Thymeol, мелитрацен , ميليتراسان , 美利曲辛 , U 24973A, Antidepressant, Tricyclics,
NEW DRUG APPROVALS
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$10.00
VIP 152, BAY 1251152
VIP 152, BAY 1251152
CAS RN.: 1610358-56-9
C19H18F2N4O2S
5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-[4-[(methylsulfonimidoyl)methyl]pyridin-2-yl]pyridin-2-amine
- 2-Pyridinamine, 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-[4-[(S-methylsulfonimidoyl)methyl]-2-pyridinyl]-, (+)-
(+)-BAY-1251152 is a CDK9 inhibitor extracted from patent WO 2014076091 A1, example 1.
RN: 1610408-97-3
UNII: 1255AT22ZJ
UNII-1255AT22ZJ
2-Pyridinamine, 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-[4-[[[S(S)]-S-methylsulfonimidoyl]methyl]-2-pyridinyl]-
Molecular Formula, C19-H18-F2-N4-O2-S, Molecular Weight, 404.4336
- OriginatorBayer
- DeveloperBayer; Vincerx Pharma
- ClassAntineoplastics; Fluorinated hydrocarbons; Organic sulfur compounds; Phenyl ethers; Pyridines; Small molecules
- Mechanism of ActionCyclin dependent kinase 9 inhibitors; Positive transcriptional elongation factor B inhibitors
- Orphan Drug StatusYes – Diffuse large B cell lymphoma
- Phase IChronic lymphocytic leukaemia; Haematological malignancies; Non-Hodgkin’s lymphoma; Richter’s syndrome; Solid tumours
- 17 Dec 2021Vincerx Pharma plans phase II trials for Cancer (IV, Infusion), in the second half of 2022
- 16 Dec 2021Phase-I clinical trials in Chronic lymphocytic leukaemia (Second-line therapy or greater) in USA (IV)
- 16 Dec 2021Phase-I clinical trials in Richter’s syndrome (Second-line therapy or greater) (IV) in USA
First-in-human dose escalation study of cyclin-dependent kinase-9 inhibitor VIP152 in patients with advanced malignancies shows early signs of clinical efficacyJennifer R. Diamond, Valentina Boni, Emerson Lim, Grzegorz Nowakowski, Raul Cordoba, Daniel Morillo, Ray Valencia, Isabelle Genvresse, Claudia Merz, Oliver Boix, Melanie M. Frigault, Joy M. Greer, Ahmed M. Hamdy, Xin Huang, Raquel Izumi, Harvey Wong and Victor Moreno
DOI: 10.1158/1078-0432.CCR-21-3617
Abstract
Purpose: To report on the first-in-human phase I study of VIP152 (NCT02635672), a potent and highly selective CDK9 inhibitor. Patients and Methods: Adults with solid tumors or aggressive non-Hodgkin lymphoma (NHL) who were refractory to or had exhausted all available therapies received VIP152 monotherapy as a 30-minute intravenous, once weekly infusion, as escalating doses (5, 10, 15, 22.5, or 30 mg in 21-day cycles) until the maximum tolerated dose (MTD) was determined. Results: Thirty-seven patients received {greater than or equal to} 1 VIP152 dose, with 30 mg identified as the MTD based on dose-limiting toxicity of grade 3/4 neutropenia. The most common adverse events were nausea and vomiting (75.7% and 56.8%, respectively), all of grade 1/2 severity. Of the most common events, Grade 3/4 events occurring in > 1 patient were neutropenia (22%), anemia (11%), abdominal pain (8%), increased alkaline phosphatase (8%), and hyponatremia (8%). Day 1 exposure for the MTD exceeded the predicted minimum therapeutic exposure and reproducibly achieved maximal pathway modulation; no accumulation occurred after multiple doses. Seven of 30 patients with solid tumors had stable disease (including 9.5 and 16.8 months in individual patients with pancreatic cancer and salivary gland cancer, respectively), and 2 of 7 patients with high-grade B-cell lymphoma with MYC and BCL2/BCL6 translocations (HGL) achieved durable complete metabolic remission (ongoing at study discontinuation, after 3.7 and 2.3 years of treatment). Conclusion: VIP152 monotherapy, administered intravenously once weekly, demonstrated a favorable safety profile and evidence of clinical benefit in patients with advanced HGL and solid tumors.
CLIP
Preclinical bioconjugation platform designed to overcome limitations of small–molecule and antibody–drug conjugates use to treat cancer
Vincera Pharma, Inc., a biopharmaceutical company aspiring to address the unmet medical needs of patients with cancer through paradigm-shifting therapeutics, today announced the signing of an exclusive license agreement with Bayer AG for the development and commercialization of an early development oncology portfolio. The license will become effective upon the closing of the transaction with LSAC (described below), and Vincera intends to use the funds it will receive upon closing of such transaction to initiate its clinical program.
Under the terms of the license agreement, Vincera will in-license VIP152 (formerly BAY 1251152 & CAS RN.: 1610358-56-9), a clinical-stage, highly selective, positive transcription elongation factor b (PTEFb)/cyclin-dependent kinase 9 (CDK9) inhibitor for the treatment of cancer. Additionally, Vincera will receive assets and license technology for a preclinical bioconjugation platform to address the limitations of small-molecule and antibody-drug conjugates in oncology. The preclinical assets include VIP236, a small molecule drug conjugate (SMDC) targeting advanced and metastatic cancer; as well as VIP943 (formerly BAY-943) and VIP924 (formerly BAY-924), two antibody-drug conjugates (ADC) targeting hematologic tumors; and VIP217, an oral PTEFb/CDK9 inhibitor in discovery. “This license agreement with Bayer creates the foundation of Vincera’s targeted clinical oncology pipeline, with a potentially best-in-class asset, while positioning us for long-term growth across two therapeutic platforms,” said Ahmed Hamdy M.D., Chief Executive Officer of Vincera. “Our lead asset, VIP152, is a small molecule PTEFb/CDK9 inhibitor with very encouraging data from monotherapy Phase 1 studies, including 2 of 7 patients with durable remissions of over 2 years in the very aggressive indication of relapsed/refractory double-hit DLBCL. In addition, preclinical data support our belief that VIP152 is the most selective CDK9 inhibitor in the clinic with on-target depletion of oncogenic MYC and MCL1 mRNA transcripts in patients. These results, combined with the acceptable safety profile seen to date, suggest that VIP152 could be an important new treatment option for patients with MYC- and MCL1-driven malignancies. Importantly, with proof-of-concept clinical data in hand, we are poised to execute on a strategic clinical development plan with the potential for multiple accelerated approvals in the U.S. Expansion of the current Phase 1b study to include these patient populations is expected to begin in 2021.”
IP Information:
WO2014076091A1 (Product Patent)
Assignee: Bayer Pharma Aktiengesellschaft, Germany
Application Date: 2013-11-12
Family Equivalents:
AP3872A; AR093505A1; AU2013346939A1; AU2013346939B2; BR112015010707A2; BR112015010707A8; CA2891358A1; CL2015001304A1; CN105102444A; CN105102444B; CR20150256A; CU20150052A7; CY1118441T1; DK2928878T3; DOP2015000118A; EA027226B1; EA201590890A1; EP2928878B1; ES2612978T3; HK1213255A1; HRP20161547T1; HUE032868T2; IL238322A; JO3332B1; JP2015537015A; JP6263193B2; KR20150084968A; LT2928878T; MA38090A1; MA38090B1; ME02880B; MX2015006169A; NZ707084A; PE20151071A1; PH12015501003A1; PH12015501003B1; PL2928878T3; PT2928878T; RS55580B1; SG11201503079PA; SI2928878T1; SV2015004979A; TN2015000185A1; TW201420569A; TWI613193B; UA115254C2; US2015291528A1; US2017202815A1; US9650340B2; US9877954B2; UY35141A; WO2014076091A1
Title: 5-FLUORO-N-(PYRIDIN-2-YL)PYRIDIN-2-AMINE DERIVATIVES CONTAINING A SULFOXIMINE GROUP.
Abstract
The present invention relates to 5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing a sulfoximine group of general formula (I) as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hyper-proliferative disorders and/or virally induced infectious diseases and/or of cardiovascular diseases. The invention further relates to intermediate compounds useful in the preparation of said compounds of general formula (I).
“CDK9 represents a validated target for malignancies such as CLL where other less selective CDK inhibitors have shown clinical activity in high-risk patients,” says Dr. John C. Byrd, Chair of the Scientific Advisory Board of Vincera. “VIP-152 represents an exciting new therapy for this disease, particularly those with prior resistance to ibrutinib and venetoclax where a true unmet need exists for new treatments.”
Dr. Hamdy continued, “In addition to our planned clinical program, we intend to advance, in parallel, the development of our preclinical bioconjugation platform. We believe our next-generation platform has the potential to generate first-in-class and best-in-class opportunities in oncology, improving the specificity of drug targeting and release through a modular platform with innovative warhead design and linker-payload technologies. We are thrilled that the Bayer license will allow us to pursue the commercial potential of this promising oncology portfolio and look forward to providing updates as we execute across our pipeline in the coming quarters.”
In exchange for this license, Vincera will pay Bayer an upfront license fee and development and commercial sales milestone payments. In further consideration of the rights granted, we will also pay an annual royalty on the commercial sale of licensed products in the single- to low-double-digit percentage range on net commercial sales of licensed products.
On September 29, 2020, Vincera announced that it has entered into a merger agreement with LifeSci Acquisition Corp. (“LSAC”), a publicly-traded blank check company targeting biopharma, medical technology, digital health, and healthcare services sectors. Following the completion of the merger, the combined company is expected to have approximately $60 million in cash to fund its preclinical and clinical pipeline. Additional information about the merger and related transactions, including a copy of the merger agreement, are included in a Current Report on Form 8-K filed by LSAC with the SEC on September 29, 2020, and available at www.sec.gov.
About Vincera Pharma, Inc.
Vincera is a recently formed clinical-stage life sciences company focused on leveraging its extensive development and oncology expertise to advance new therapies intended to address unmet medical needs for the treatment of cancer. Vincera’s executive team has assembled a management team of biopharmaceutical experts with extensive experience in building and operating organizations that develop and deliver innovative medicines to patients. Vincera’s current pipeline is derived from an exclusive license agreement with Bayer and includes (i) a clinical-stage and follow-on small molecule drug program and (ii) a preclinical stage bioconjugation/next-generation antibody-drug conjugate platform. The company intends to develop multiple products through clinical proof-of-concept and potentially through Accelerated Approval in the United States. For more information, please visit www.vincerapharma.com.
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Patent
US 20150291528
Example 1
(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine
Preparation of Intermediate 1.12-Chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridine
| 1H NMR (400 MHz, CDCl 3, 300K) δ=8.27 (m, 1H), 7.33 (m, 1H), 7.24 (m, 1H), 6.75 (m, 2H), 3.83 (s, 3H). |
Preparation of Intermediate 1.25-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(methylsulfanyl)methyl]pyridin-2-yl}pyridin-2-amine
| 1H NMR (400 MHz, CDCl 3, 300K) δ=8.15 (m, 2H), 7.61 (m, 1H), 7.40 (s, 1H), 7.35 (br, 1H), 7.29 (m, 1H), 6.82 (m, 1H), 6.75 (m, 2H), 3.83 (s, 3H), 3.62 (s, 2H), 2.03 (s, 3H). |
Alternative Procedure for the Preparation of Intermediate 1.25-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(methylsulfanyl)methyl]pyridin-2-yl}pyridin-2-amine
Preparation of Intermediate 1.3(2-{[5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}pyridin-4-yl)methanol
Preparation of End Product (Alternative Preparation of Intermediate 1.2)
| 1H NMR (400 MHz, CDCl 3, 300K) δ=8.15 (m, 2H), 7.61 (m, 1H), 7.40 (br, 2H), 7.29 (m, 1H), 6.82 (m, 1H), 6.75 (m, 2H), 3.83 (s, 3H), 3.62 (s, 2H), 2.03 (s, 3H). |
Alternative Procedure for the Preparation of Example 1Preparation of Intermediate 1.4(rac)-2,2,2-Trifluoro-N-{[(2-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}pyridin-4-yl)methyl](methyl)-λ4-sulfanylidene}acetamide
| 1H NMR (400 MHz, CDCl 3, 300K) δ=8.29 (m, 1H), 8.18 (m, 1H), 7.83 (s. 1H), 7.50 (br, 1H), 7.32 (m, 1H), 7.28 (m, 1H), 6.79 (m, 3H), 4.52 (d, 1H), 4.21 (d, 1H), 3.85 (s, 3H), 2.71 (s, 3H). |
Alternative Preparation of End Product (Example 1)
Example 2 and 3
Enantiomers of 5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine
| (rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine (3.47 g) was separated into the single enantiomers by preparative chiral HPLC. |
Example 2(+)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine
Example 3(−)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine
Example 4(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{6-methyl-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine
Preparation of Intermediate 4.15-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-amine
| 1H NMR (400 MHz, CDCl 3, 300K) δ=7.95 (m, 1H), 7.20 (m, 1H), 6.72 (m, 2H), 6.46 (m, 1H), 4.33 (br, 2H), 3.61 (s, 3H). |
Preparation of Intermediate 4.2(2-Chloro-6-methylpyridin-4-yl)methanol
| 1H NMR (400 MHz, CDCl 3, 300K) δ=7.18 (s, 1H), 7.09 (s, 1H), 4.72 (d, 2H), 2.55 (s, 3H), 2.17 (tr, 1H). |
Preparation of Intermediate 4.32-Chloro-6-methyl-4-[(methylsulfanyl)methyl]pyridine
| 1H NMR (400 MHz, CDCl 3, 300K) δ=7.12 (s, 1H), 7.05 (s, 1H), 3.58 (s, 2H), 2.54 (s, 3H), 2.03 (s, 3H). |
Preparation of Intermediate 4.45-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{6-methyl-4-[(methylsulfanyl)methyl]pyridin-2-yl}pyridin-2-amine
Preparation of Intermediates 4.5 and 4.6(rac)-2,2,2-Trifluoro-N-{[(2-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}-6-methylpyridin-4-yl)methyl](methyl)-λ4-sulfanylidene}acetamide and (rac)-N-{[(3-bromo-6-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}-2-methylpyridin-4-yl)methyl](methyl)-λ4-sulfanylidene}-2,2,2-trifluoroacetamide
Intermediate 4.5:
Intermediate 4.6:
| 1H NMR (400 MHz, CDCl 3, 300K) δ=8.18 (s, 1H), 7.84 (s, 1H), 7.33 (s, 1H), 7.29 (m, 1H), 7.23 (m, 1H), 6.78 (m, 2H), 4.77 (d, 1H), 4.36 (d, 1H), 3.86 (s, 3H), 2.80 (s, 3H), 2.63 (s, 3H). |
Preparation of End Product:
| 1H NMR (400 MHz, CDCl 3, 300K) δ=8.16 (s, 1H), 7.60 (s, 1H), 7.39 (m, 1H), 7.30 (m, 2H), 6.79 (m, 3H), 4.34 (d, 1H), 4.22 (d, 1H), 3.86 (s, 3H), 3.02 (s, 3H), 2.79 (br, 1H), 2.48 (s, 3H). |
Alternative Procedure for the Preparation of Example 4Preparation of Intermediate 4.15-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-amine
| 1H-NMR (300 MHz, DMSO-d 6, 300 K): δ [ppm]=7.85 (d, 1H), 7.25 (tr, 1H), 7.08-7.00 (m, 1H), 6.91-6.81 (m, 1H), 6.35 (d, 1H), 5.84 (s, 2H). |
Preparation of Intermediate 4.32-Chloro-6-methyl-4-[(methylsulfanyl)methyl]pyridine
| 1H-NMR (300 MHz, DMSO-d 6, 300 K): δ [ppm]=7.24 (s, 1H), 7.20 (s, 1H), 3.66 (s, 2H), 2.42 (s, 3H), 1.95 (s, 3H). |
Preparation of Intermediate 4.45-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{6-methyl-4-[(methylsulfanyl)methyl]pyridin-2-yl}pyridin-2-amine
| 1H-NMR (300 MHz, CDCl 3, 300 K): δ [ppm]=8.16 (d, 1H), 7.56 (d, 1H), 7.36-7.29 (m, 2H), 7.21 (s, 1H), 6.85-6.73 (m, 2H), 6.72 (s, 1H), 3.86 (s, 3H), 3.61 (s, 2H), 2.45 (s, 3H), 2.06 (s, 3H). |
Preparation of Intermediate 4.5(rac)-2,2,2-Trifluoro-N-{[(2-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}-6-methylpyridin-4-yl)methyl](methyl)-λ4-sulfanylidene}acetamide
Preparation of Intermediate 4.6(rac)-N-{[(3-bromo-6-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}-2-methylpyridin-4-yl)methyl](methyl)-λ4-sulfanylidene}-2,2,2-trifluoroacetamide
Intermediate 4.5:
Intermediate 4.6(1H-NMR was Taken from a Different Batch)
Preparation of Intermediates 4.7 and 4.8
| 3.76 g of racemic 2,2,2-trifluoro-N-{[(2-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}-6-methylpyridin-4-yl)methyl](methyl)-λ 4-sulfanylidene}acetamide were separated by chiral HPLC: |
Intermediate 4.7(+)-2,2,2-Trifluoro-N-{[(2-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}-6-methylpyridin-4-yl)methyl](methyl)-λ4-sulfanylidene}acetamide
Intermediate 4.8(−)-2,2,2-Trifluoro-N-{[(2-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}-6-methylpyridin-4-yl)methyl](methyl)-λ4-sulfanylidene}acetamide
Alternative Preparation of End Product (Example 4)(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{6-methyl-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine
Example 5
(rac)-5-Bromo-N-[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]-6-methyl-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-amine
| 1H NMR (400 MHz, CDCl 3, 300K) δ=8.14 (m, 1H), 7.80 (s, 1H), 7.32 (m, 2H), 7.29 (m, 1H), 6.78 (m, 2H), 4.87 (d, 1H), 4.59 (d, 1H), 3.85 (s, 3H), 3.07 (s, 3H), 2.99 (br, 1H), 2.62 (s, 3H). |
Example 6(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{6-methoxy-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine
Preparation of Intermediate 6.1:2-Chloro-6-methoxy-4-[(methylsulfanyl)methyl]pyridine
| 1H NMR (400 MHz, CDCl 3, 300K) δ=6.92 (s, 1H), 6.61 (s, 1H), 3.96 (s, 3H), 3.56 (s, 2H), 2.03 (s, 3H). |
Preparation of Intermediate 6.25-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{6-methoxy-4-[(methylsulfanyl)methyl]pyridin-2-yl}pyridin-2-amine
| 1H NMR (400 MHz, CDCl 3, 300K) δ=8.15 (m, 1H), 7.91 (m, 1H), 7.29 (m, 1H), 7.21 (s, 1H), 6.77 (m, 3H), 6.28 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.58 (s, 2H), 2.06 (s, 3H). |
Preparation of Intermediate 6.3(rac)-2,2,2-Trifluoro-N-{[(2-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}-6-methoxypyridin-4-yl)methyl](methyl)-λ4-sulfanylidene}acetamide
| 1H NMR (400 MHz, CDCl 3, 300K) δ=8.18 (m, 1H), 7.56 (m, 1H), 7.29 (m, 2H), 7.12 (m, 1H), 6.78 (m, 2H), 6.25 (s, 1H), 4.52 (d, 1H), 4.07 (d, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.70 (s, 3H). |
Preparation of End Product:
Alternative Procedure for the Preparation of Example 6(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{6-methoxy-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine
Example 7(rac)-N-{6-Chloro-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-amine
Preparation of Intermediate 7.12-Chloro-6-methoxy-4-[(methylsulfanyl)methyl]pyridine
| 1H NMR (400 MHz, d 6-DMSO, 300K) δ=10.06 (s, 1H), 8.25 (m, 1H), 7.71 (m, 1H), 7.56 (m, 1H), 7.35 (m, 1H), 7.10 (m, 1H), 6.93 (m, 1H), 6.85 (m, 1H), 5.47 (tr, 1H), 4.49 (d, 2H), 3.81 (s, 3H). |
Preparation of Intermediate 7.2N-{6-Chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-amine
| 1H NMR (400 MHz, CDCl 3, 300K) δ=8.17 (s, 1H), 7.50 (m, 3H), 7.32 (m, 1H), 6.90 (s, 1H), 6.79 (m, 2H), 3.87 (s, 3H), 3.62 (s, 2H), 2.07 (s, 3H). |
Preparation of Intermediate 7.3(rac)-N-{[(2-chloro-6-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}pyridin-4-yl)methyl](methyl)-λ4-sulfanylidene}-2,2,2-trifluoroacetamide
| 1H NMR (400 MHz, CDCl 3, 300K) δ=8.18 (s, 1H), 8.12 (br, 1H), 7.84 (s, 1H), 7.37 (m, 1H), 7.31 (m, 1H), 6.80 (m, 3H), 4.46 (d, 1H), 4.24 (d, 1H), 3.87 (s, 3H), 2.75 (s, 3H). |
Preparation of End Product:
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014076091
Example 1:
(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine
Preparation of Intermediate 1.1:
2-Chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridine
A batch with 2-chloro-5-fluoro-4-iodopyridine (1000 mg; 3.88 mmol; APAC Pharmaceutical, LLC), (4-fluoro-2-methoxyphenyl)boronic acid (660 mg; 3.88 mmol; Aldrich Chemical Company Inc.) and tetrakis(triphenylphosphin)palladium(0) (449 mg; 0.38 mmol) in 1,2-dimethoxyethane (10.0 mL) and 2 M aqueous solution of potassium carbonate (5.8 mL) was degassed using argon. The batch was stirred under an atmosphere of argon for 4 hours at 100 °C. After cooling, the batch was diluted with ethyl
acetate and THF and washed with a saturated aqueous solution of sodium chloride. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (hexane to hexane / ethyl acetate 50%) to give the desired product (947 mg; 3.70 mmol).
1H NMR (400MHz, CDCl3, 300K) δ = 8.27 (m, 1H), 7.33 (m, 1H), 7.24 (m, 1H), 6.75 (m, 2H), 3.83 (s, 3H).
Example 2: (+)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S- methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine
1H-NMR (300 MHz, DMSO-d6, 300 K): δ [ppm] = 9.80 (s, 1H), 8.20 (m, 1H), 8.16 (m, 1H), 7.78 (m, 1H), 7.59 (s, 1H), 7.34 (m, 1H), 7.09 (m, 1H), 6.90 (m, 2H), 4.37 (d, 1H), 4.33 (d, 1H), 3.79 (s, 3H), 3.72 (s, 1H), 2.87 (s, 3H).
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FLUPHENAZINE
Fluphenazine
- Molecular FormulaC22H26F3N3OS
- Average mass437.522 Da
- SQ 10733
- Squibb 16144
UNIIS79426A41Z
CAS number69-23-8
Product Ingredients
| INGREDIENT | UNII | CAS | INCHI KEY |
|---|---|---|---|
| Fluphenazine decanoate | FMU62K1L3C | 5002-47-1 | VIQCGTZFEYDQMR-UHFFFAOYSA-N |
| Fluphenazine enanthate | QSB34YF0W9 | 2746-81-8 | LRWSFOSWNAQHHW-UHFFFAOYSA-N |
| Fluphenazine hydrochloride | ZOU145W1XL | 146-56-5 | MBHNWCYEGXQEIT-UHFFFAOYSA-N |
2-(Trifluoromethyl)-10-[3-[1-(b-hydroxyethyl)-4-piperazinyl]propyl]phenothiazine
200-702-9[EINECS]
4-(3-(2-(trifluoromethyl)phenothiazin-10-yl)propyl)-1-Piperazineethanol
4-[3-[2-(Trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-1-piperazineethanol
69-23-8[RN]
فلوفينازين[Arabic][INN]
氟奋乃静[Chinese][INN]
1-(2-Hydroxyethyl)-4-[3-(trifluoromethyl-10-phenothiazinyl)propyl]piperazine
10-[3′-[4”-(b-Hydroxyethyl)-1”-piperazinyl]propyl]-3-trifluoromethylphenothiazine
1-Piperazineethanol, 4-(3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)propyl)-
1-Piperazineethanol, 4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-
read https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/071413s019lbl.pdfFluphenazineCAS Registry Number: 69-23-8
CAS Name: 4-[3-[2-(Trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-1-piperazineethanol
Additional Names: 1-(2-hydroxyethyl)-4-[3-(trifluoromethyl-10-phenothiazinyl)propyl]piperazine; 10-[3¢-[4¢¢-(b-hydroxyethyl)-1¢¢-piperazinyl]propyl]-3-trifluoromethylphenothiazine; 2-(trifluoromethyl)-10-[3-[1-(b-hydroxyethyl)-4-piperazinyl]propyl]phenothiazine
Manufacturers’ Codes: S-94; SQ-4918
Molecular Formula: C22H26F3N3OS, Molecular Weight: 437.52
Percent Composition: C 60.39%, H 5.99%, F 13.03%, N 9.60%, O 3.66%, S 7.33%
Literature References: Prepn: H. L. Yale, F. Sowinski, J. Am. Chem. Soc.82, 2039 (1960); GB829246; G. E. Ullyot, US3058979 (1960, 1962 both to SKF); GB833474 (1960 to Scherico), C.A.54, 21143e (1960); E. L. Anderson et al.,Arzneim.-Forsch.12, 937 (1962); H. L. Yale, R. C. Merrill, US3194733 (1965 to Olin Mathieson). Metabolism: J. Dreyfuss, A. J. Cohen, J. Pharm. Sci.60, 826 (1971). Comprehensive description of the enanthate ester: K. Florey, Anal. Profiles Drug Subs.2, 245-262 (1973); of the dihydrochloride: idem,ibid. 263-294; of the decanoate ester: G. Clarke, ibid.9, 275-294 (1980).
Properties: Dark brown viscous oil, bp0.5 268-274°; bp0.3 250-252°.
Boiling point: bp0.5 268-274°; bp0.3 250-252°
Derivative Type: Dihydrochloride
CAS Registry Number: 146-56-5
Trademarks: Anatensol (BMS); Dapotum (BMS); Lyogen (Promonta Lundbeck); Moditen (Sanofi Winthrop); Omca (BMS); Pacinol (Schering); Permitil (Schering); Prolixin (Apothecon); Siqualone (BMS); Tensofin (BMS); Valamina (Schering)
Molecular Formula: C22H26F3N3OS.2HCl, Molecular Weight: 510.44
Percent Composition: C 51.77%, H 5.53%, F 11.17%, N 8.23%, O 3.13%, S 6.28%, Cl 13.89%
Properties: Crystals from abs ethanol, mp 235-237°. Also reported as mp 224.5-226°.
Melting point: mp 235-237°; Also reported as mp 224.5-226°
Derivative Type: Decanoate
CAS Registry Number: 5002-47-1
Manufacturers’ Codes: SQ-10733; QD-10733
Trademarks: Modecate (Sanofi Winthrop)
Molecular Formula: C32H44F3N3O2S, Molecular Weight: 591.77
Percent Composition: C 64.95%, H 7.49%, F 9.63%, N 7.10%, O 5.41%, S 5.42%
Properties: Pale yellow-orange, viscous liquid. Slowly crystallizes at room temp. mp 30-32°. Very sol in chloroform, ether, cyclohexane, methanol, ethanol. Insol in water.
Melting point: mp 30-32°
Derivative Type: Enanthate
CAS Registry Number: 2746-81-8
Manufacturers’ Codes: SQ-16144
Molecular Formula: C29H38F3N3O2S, Molecular Weight: 549.69Percent Composition: C 63.36%, H 6.97%, F 10.37%, N 7.64%, O 5.82%, S 5.83%
Properties: Pale yellow to yellow-orange viscous liquid or oily solid.
Therap-Cat: Antipsychotic.
Keywords: Antipsychotic; Phenothiazines.
Fluphenazine is a phenothiazine used to treat patients requiring long-term neuroleptic therapy.
A phenothiazine used in the treatment of psychoses. Its properties and uses are generally similar to those of chlorpromazine.
Fluphenazine, sold under the brand names Prolixin among others, is a high-potency typical antipsychotic medication.[1] It is used in the treatment of chronic psychoses such as schizophrenia,[1][2] and appears to be about equal in effectiveness to low-potency antipsychotics like chlorpromazine.[3] It is given by mouth, injection into a muscle, or just under the skin.[1] There is also a long acting injectable version that may last for up to four weeks.[1] Fluphenazine decanoate, the depot injection form of fluphenazine, should not be used by people with severe depression.[4]
Common side effects include movement problems, sleepiness, depression and increased weight.[1] Serious side effects may include neuroleptic malignant syndrome, low white blood cell levels, and the potentially permanent movement disorder tardive dyskinesia.[1] In older people with psychosis as a result of dementia it may increase the risk of dying.[1] It may also increase prolactin levels which may result in milk production, enlarged breasts in males, impotence, and the absence of menstrual periods.[1] It is unclear if it is safe for use in pregnancy.[1]
Fluphenazine is a typical antipsychotic of the phenothiazine class.[1] Its mechanism of action is not entirely clear but believed to be related to its ability to block dopamine receptors.[1] In up to 40% of those on long term phenothiazines, liver function tests become mildly abnormal.[5]
Fluphenazine came into use in 1959.[6] The injectable form is on the World Health Organization’s List of Essential Medicines.[7] It is available as a generic medication.[1] It was discontinued in Australia around mid 2017.[8]
Synthesis Reference
Ullyot, G.E.; U.S. Patent 3,058,979; October 16, 1962; assigned to Smith Kline & French Laboratories.
syn
syn
Antipsychotics (Neuroleptics)
R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006
Fluphenazine
Fluphenazine, 4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]-1-piperazineethanol (6.1.8), is synthesized by any of the methods described above [21–27]. Alkylation of 2-trifluoromethylphenothiazine using 4-formyl-1-piperazineylpropylchlo-ride in the presence of sodium amide synthesizes 2-trifluoromethyl-10-[3-(4-formyl-1-piperazinyl)propyl]phenothizine (6.1.6). Further alkaline hydrolysis removes the N-formyl group, giving 2-trifluoromethyl-10-[3-(1-piperazinyl)propyl]phenothiazine (6.1.7). This is alkylated by 2-bromethanol-1 acetate, which upon further acidic hydrolysis removes the protecting acetyl group, yielding fluphenazine (6.1.8) [27,28].
Fluphenazine is an extremely strong antipsychotic drug. A stimulatory effect accompanies the neuroleptic effect. It is used in psychiatry for treating various forms of schizophrenia and other mental illnesses. The most common synonyms are fluorphenazine, moditen, dapotum, motival, permitil, and others.SYN
Manufacturing Process
A suspension of 69.0 grams of 2-trifluoromethylphenothiazine in 1 liter of toluene with 10.9 grams of sodium amide is heated at reflux with high speed stirring for 15 minutes. A solution of 54.1 grams of 1-formyl-4-(3’chloropropyl)-piperazine, [prepared by formylating 1-(3′-hydroxypropyl)piperazine by refluxing in an excess of methyl formate, purifying the 1-formyl4-(3′-hydroxypropyl)-piperazine by vacuum distillation, reacting this compound with an excess of thionyl chloride at reflux and isolating the desired 1-formyl-4(3′-chloropropyl)-piperazine by neutralization with sodium carbonate solution followed by distillation] in 200 ml of toluene is added. The reflux period is continued for 4 hours. The cooled reaction mixture is treated with 200 ml of water. The organic layer is extracted twice with dilute hydrochloric acid. The acid extracts are made basic with ammonia and extracted with benzene. The volatiles are taken off in vacuo at the steam bath to leave a dark brown oil which is 10-[3′-(N-formylpiperazinyl)-propyl]-2trifluoromethylphenothiazine. It can be distilled at 260°C at 10 microns, or used directly without distillation if desired.
A solution of 103.5 grams of 10-[3′-(N-formylpiperazinyl)-propyl]-2trifluoromethylphenothiazine in 400 ml of ethanol and 218 ml of water containing 26 ml of 40% sodium hydroxide solution is heated at reflux for 2 hours. The alcohol is taken off in vacuo on the steam bath. The residue is swirled with benzene and water. The dried benzene layer is evaporated in vacuo. The residue is vacuum distilled to give a viscous, yellow oil, 10(3’piperazinylpropyl)-2-trifluoromethylphenothiazine, distilling at 210° to235°C at 0.5 to 0.6 mm.
A suspension of 14.0 grams of 10-(3′-piperazinylpropyl)-2trifluoromethylphenothiazine, 6.4 grams of β-bromoethyl acetate and 2.6 grams of potassium carbonate in 100 ml of toluene is stirred at reflux for 16 hours. Water (50 ml) is added to the cooled mixture. The organic layer is extracted into dilute hydrochloric acid. After neutralizing the extracts and taking the separated base up in benzene, a viscous, yellow residue is obtained by evaporating the organic solvent in vacuo. This oil is chromatographed on alumina. The purified fraction of 7.7 grams of 10-[3′-(Nacetoxyethylpiperazinyl)-propyl] -2-trifluoromethylphenothiazine is taken up in ethyl acetate and mixed with 25 ml of alcoholic hydrogen chloride. Concentration in vacuo separates white crystals of the dihydrochloride salt, MP 225° to 227°C.
A solution of 1.0 gram of 10-[3′-(N-acetoxyethylpiperazinyl)-propyl]-2trifluoromethylphenothiazine in 25 ml of 1 N hydrochloric acid is heated at reflux briefly. Neutralization with dilute sodium carbonate solution and extraction with benzene gives the oily base, 10-[3′-(N-βhydroxyethylpiperazinyl)-propyl]-2-trifluoromethylphenothiazine. The base is reacted with an excess of an alcoholic hydrogen chloride solution. Trituration with ether separates crystals of the dihydrochloride salt, MP 224° to 226°C, (from US Patent 3,058,979).
Chemical Synthesis
Fluphenazine, 4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]-1- piperazineethanol (6.1.8), is synthesized by any of the methods described above [21–27]. Alkylation of 2-trifluoromethylphenothiazine using 4-formyl-1-piperazineylpropylchloride in the presence of sodium amide synthesizes 2-trifluoromethyl-10-[3-(4-formyl- 1-piperazinyl)propyl]phenothizine (6.1.6). Further alkaline hydrolysis removes the N-formyl group, giving 2-trifluoromethyl-10-[3-(1-piperazinyl)propyl]phenothiazine (6.1.7). This is alkylated by 2-bromethanol-1 acetate, which upon further acidic hydrolysis removes the protecting acetyl group, yielding fluphenazine (6.1.8) [27,28].
SYN
Indian Pat. Appl., 2014MU02033,
PATENT
CN 105153062
https://patents.google.com/patent/CN105153062A/en
Embodiment 1(1) preparation of 2-trifluoromethyl thiodiphenylamine: by 100g(0.356mol) Tecramine adds in reaction flask, be heated to 180-190 DEG C, open and stir, treat that it melts in backward reaction flask completely and add 10g(0.178mol) iron powder, stirring reaction about 2 hours at 180-190 DEG C of temperature, after reaction terminates, reaction solution is cooled to pour in beaker by reaction solution while hot when 100 DEG C, and iron powder stays (used water flushing) bottom reaction flask.Reaction solution is added underpressure distillation in clean reaction flask, collects 134-135 DEG C of (3mmHg) cut, obtain weak yellow liquid 3-trifluoromethyl pentanoic and be about 67.5g, yield about 80%.By 3-trifluoromethyl pentanoic 60g(0.253mol), sublimed sulphur 8g(0.253mol) add in reaction flask, whipped state is warming up to about 130 DEG C, after the complete melting of sulphur, in reaction flask, add 3g elemental iodine, continue to be warming up to 185-190 DEG C, react about 1 hour at this temperature.There is hydrogen sulfide to release in reaction process, note tail gas absorption.After reaction terminates, reaction solution is cooled to about 100 DEG C, adds 200g toluene in reaction flask, about raised temperature to 100 DEG C, in reaction flask, add 100g water, stir layering while hot after 5 minutes, water layer discarded, toluene layer returns reaction flask, and whipped state borehole cooling, to 15-18 DEG C, filters, filtrate retains (to be recycled apply mechanically 3-trifluoromethyl pentanoic), filter cake adopts 60 DEG C, vacuum to dry 10 hours, and obtain 29g intermediate 2-trifluoromethyl thiodiphenylamine, yield is about 85%(and calculates by sulphur)(2) preparation of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine: by 79g(0.5mol) 1,3-bromo-chloropropane, 320g toluene add in reaction flask, 130g(1.0mol is dripped under control 32-35 DEG C condition) 1-(2-hydroxyethyl) piperazine, time for adding about 2 hours.After dropwising, 32-35 DEG C of stirring reaction 10 hours, after reaction terminates, passes into hydrogen chloride gas to reaction system, regulate PH=8, solids removed by filtration, filtrate decompression distillation and concentration removing toluene solvant and unreacted complete 1,3-bromo-chloropropane, obtains viscous liquid product 95g, yield about 92%.(3) fluorine puts forth energy to be the preparation of nearly alkali: by 2-trifluoromethyl thiodiphenylamine 28g(0.105mol), toluene 140g, granular sodium hydroxide 28g(0.7mol) drop in reaction flask, whipped state is warming up to reflux state (110-112 DEG C), drip (the mixing solutions solution of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine and 50g toluene, the dropping process lasts about 1.5 hours of 26g (0.126mol) at reflux.After dropwising, reflux state reaction about 8 hours, whole reflux course notices that system moisture removes by timely water trap.After reaction terminates, be cooled to room temperature, solids removed by filtration insolubles, 150g purifying moisture three washing organic phases.Add the 10% concentration aqueous hydrochloric acid of 100g to organic phase, stir static layering after 10 minutes, discard upper toluene organic phase, retain lower floor’s aqueous phase, wash aqueous phase at twice with 150g toluene.In aqueous phase, add toluene 140g, drip the sodium hydroxide solution of 20% of 62g under whipped state, in process, hierarchy of control temperature is no more than 45 DEG C, after dropwising, stir 20 minutes, static layering, discard lower floor’s aqueous phase, retain upper organic phase, organic phase 15g anhydrous sodium sulfate drying, underpressure distillation removing toluene solvant, residue carries out underpressure distillation, collect 230 DEG C of (0.5mmHg) cuts, obtain 33g fluorine and put forth energy to be nearly alkali, yield 72%.(4) preparation of fluophenazine hydrochloride: 32g alkali is dissolved in 128g dehydrated alcohol, stirring is dissolved backward system completely and is led to hydrogen chloride gas, process temperature is no more than 20 DEG C, logical hydrogen chloride gas is stopped as PH=2, stir after 30 minutes and filter, filter cake 50g absolute ethanol washing, product puts into vacuum drying oven, dry after 10 hours for 45 DEG C and obtain fluophenazine hydrochloride 36g, yield about 95%.embodiment 2.(1) preparation of 2-trifluoromethyl thiodiphenylamine: by 500g(1.78mol) Tecramine adds in reaction flask, be heated to 180-190 DEG C, open and stir, treat that it melts in backward reaction flask completely and add 50g(0.89mol) iron powder, stirring reaction about 2 hours at 180-190 DEG C of temperature, after reaction terminates, reaction solution is cooled to pour in beaker by reaction solution while hot when 100 DEG C, and iron powder stays (used water flushing) bottom reaction flask.Reaction solution is added underpressure distillation in clean reaction flask, collects 134-135 DEG C of (3mmHg) cut, obtain weak yellow liquid 3-trifluoromethyl pentanoic and be about 346g, yield about 82%.By 3-trifluoromethyl pentanoic 300g(1.265mol), sublimed sulphur 40g(1.265mol) add in reaction flask, whipped state is warming up to about 130 DEG C, after the complete melting of sulphur, in reaction flask, add 15g elemental iodine, continue to be warming up to 185-190 DEG C, react about 1 hour at this temperature.There is hydrogen sulfide to release in reaction process, note tail gas absorption.After reaction terminates, reaction solution is cooled to about 100 DEG C, adds 1000g toluene in reaction flask, about raised temperature to 100 DEG C, in reaction flask, add 1000g water, stir layering while hot after 5 minutes, water layer discarded, toluene layer returns reaction flask, and whipped state borehole cooling, to 15-18 DEG C, filters, filtrate retains (to be recycled apply mechanically 3-trifluoromethyl pentanoic), filter cake adopts 60 DEG C, vacuum to dry 10 hours, and obtain 147g intermediate 2-trifluoromethyl thiodiphenylamine, yield is about 86%(and calculates by sulphur)(2) preparation of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine: by 395g(2.5mol) 1,3-bromo-chloropropane, 1600g toluene add in reaction flask, 650g(5.0mol is dripped under control 32-35 DEG C condition) 1-(2-hydroxyethyl) piperazine, time for adding about 2 hours.After dropwising, 32-35 DEG C of stirring reaction 10 hours, after reaction terminates, passes into hydrogen chloride gas to reaction system, regulate PH=8, solids removed by filtration, filtrate decompression distillation and concentration removing toluene solvant and unreacted complete 1,3-bromo-chloropropane, obtains viscous liquid product 470g, yield about 91%.(3) fluorine puts forth energy to be the preparation of nearly alkali: by 2-trifluoromethyl thiodiphenylamine 140g(0.525mol), toluene 700g, granular sodium hydroxide 140g(3.5mol) drop in reaction flask, whipped state is warming up to reflux state (110-112 DEG C), drip (the mixing solutions solution of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine and 300g toluene, the dropping process lasts about 1.5 hours of 130g (0.63mol) at reflux.After dropwising, reflux state reaction about 8 hours, whole reflux course notices that system moisture removes by timely water trap.After reaction terminates, be cooled to room temperature, solids removed by filtration insolubles, 750g purifying moisture three washing organic phases.Add the 10% concentration aqueous hydrochloric acid of 500g to organic phase, stir static layering after 10 minutes, discard upper toluene organic phase, retain lower floor’s aqueous phase, wash aqueous phase at twice with 750g toluene.In aqueous phase, add toluene 720g, drip the sodium hydroxide solution of 20% of 310g under whipped state, in process, hierarchy of control temperature is no more than 45 DEG C, after dropwising, stir 20 minutes, static layering, discard lower floor’s aqueous phase, retain upper organic phase, organic phase 75g anhydrous sodium sulfate drying, underpressure distillation removing toluene solvant, residue carries out underpressure distillation, collect 230 DEG C of (0.5mmHg) cuts, obtain 168g fluorine and put forth energy to be nearly alkali, yield 73%.(4) preparation of fluophenazine hydrochloride: 160g alkali is dissolved in 640g dehydrated alcohol, stirring is dissolved backward system completely and is led to hydrogen chloride gas, process temperature is no more than 20 DEG C, logical hydrogen chloride gas is stopped as PH=2, stir after 30 minutes and filter, filter cake 300g absolute ethanol washing, product puts into vacuum drying oven, dry after 10 hours for 45 DEG C and obtain fluophenazine hydrochloride 182g, yield about 96%.embodiment 3.(1) preparation of 2-trifluoromethyl thiodiphenylamine: by 1000g(3.56mol) Tecramine adds in reaction flask, be heated to 180-190 DEG C, open and stir, treat that it melts in backward reaction flask completely and add 100g(1.78mol) iron powder, stirring reaction about 2 hours at 180-190 DEG C of temperature, after reaction terminates, reaction solution is cooled to pour in beaker by reaction solution while hot when 100 DEG C, and iron powder stays (used water flushing) bottom reaction flask.Reaction solution is added underpressure distillation in clean reaction flask, collects 134-135 DEG C of (3mmHg) cut, obtain weak yellow liquid 3-trifluoromethyl pentanoic and be about 1029g, yield about 82%.By 3-trifluoromethyl pentanoic 600g(2.53mol), sublimed sulphur 80g(2.53mol) add in reaction flask, whipped state is warming up to about 130 DEG C, after the complete melting of sulphur, in reaction flask, add 30g elemental iodine, continue to be warming up to 185-190 DEG C, react about 1 hour at this temperature.There is hydrogen sulfide to release in reaction process, note tail gas absorption.After reaction terminates, reaction solution is cooled to about 100 DEG C, adds 2000g toluene in reaction flask, about raised temperature to 100 DEG C, in reaction flask, add 1000g water, stir layering while hot after 5 minutes, water layer discarded, toluene layer returns reaction flask, and whipped state borehole cooling, to 15-18 DEG C, filters, filtrate retains (to be recycled apply mechanically 3-trifluoromethyl pentanoic), filter cake adopts 60 DEG C, vacuum to dry 10 hours, and obtain 294g intermediate 2-trifluoromethyl thiodiphenylamine, yield is about 86%(and calculates by sulphur)(2) preparation of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine: by 790g(5mol) 1,3-bromo-chloropropane, 3200g toluene add in reaction flask, 1300g(10mol is dripped under control 32-35 DEG C condition) 1-(2-hydroxyethyl) piperazine, time for adding about 2 hours.After dropwising, 32-35 DEG C of stirring reaction 10 hours, after reaction terminates, passes into hydrogen chloride gas to reaction system, regulate PH=8, solids removed by filtration, filtrate decompression distillation and concentration removing toluene solvant and unreacted complete 1,3-bromo-chloropropane, obtains viscous liquid product 940g, yield about 91%.(3) fluorine puts forth energy to be the preparation of nearly alkali: by 2-trifluoromethyl thiodiphenylamine 280g(1.05mol), toluene 1400g, granular sodium hydroxide 280g(7mol) drop in reaction flask, whipped state is warming up to reflux state (110-112 DEG C), drip (the mixing solutions solution of 1-(3-chloropropyl)-4-(2-hydroxyethyl) piperazine and 500g toluene, the dropping process lasts about 1.5 hours of 260g (1.26mol) at reflux.After dropwising, reflux state reaction about 8 hours, whole reflux course notices that system moisture removes by timely water trap.After reaction terminates, be cooled to room temperature, solids removed by filtration insolubles, 1500g purifying moisture three washing organic phases.Add the 10% concentration aqueous hydrochloric acid of 1000g to organic phase, stir static layering after 10 minutes, discard upper toluene organic phase, retain lower floor’s aqueous phase, wash aqueous phase at twice with 1500g toluene.In aqueous phase, add toluene 1400g, drip the sodium hydroxide solution of 20% of 620g under whipped state, in process, hierarchy of control temperature is no more than 45 DEG C, after dropwising, stir 20 minutes, static layering, discard lower floor’s aqueous phase, retain upper organic phase, organic phase 150g anhydrous sodium sulfate drying, underpressure distillation removing toluene solvant, residue carries out underpressure distillation, collect 230 DEG C of (0.5mmHg) cuts, obtain 344g fluorine and put forth energy to be nearly alkali, yield 75%.(4) preparation of fluophenazine hydrochloride: 320g alkali is dissolved in 1280g dehydrated alcohol, stirring is dissolved backward system completely and is led to hydrogen chloride gas, process temperature is no more than 20 DEG C, logical hydrogen chloride gas is stopped as PH=2, stir after 30 minutes and filter, filter cake 500g absolute ethanol washing, product puts into vacuum drying oven, dry after 10 hours for 45 DEG C and obtain fluophenazine hydrochloride 364g, yield about 96%.
PATENT
WO 2015103587
https://patents.google.com/patent/WO2015103587A2/no
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Medical use
A 2018 Cochrane review found that fluphenazine was an imperfect treatment and other inexpensive drugs less associated with side effects may be an equally effective choice for people with schizophrenia.[9]
Side effects
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[10] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[11] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[11] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[11] Symptoms generally resolve after a short period of time.[11]
There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[12] It may also result in reoccurrence of the condition that is being treated.[13] Rarely tardive dyskinesia can occur when the medication is stopped.[11]
Pharmacology
Pharmacodynamics
See also: Antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
Fluphenazine acts primarily by blocking post-synaptic D2 receptors in the basal ganglia, cortical and limbic system. It also blocks alpha-1 adrenergic receptors, muscarinic-1 receptors, and histamine-1 receptors.[14][15]
| Site | Ki (nM) | Action | Ref |
|---|---|---|---|
| 5-HT1A | 145-2829 | ND | [16] |
| 5-HT1B | 334 | ND | [16] |
| 5-HT1D | 334 | ND | [16] |
| 5-HT1E | 540 | ND | [16] |
| 5-HT2A | 3.8-98 | ND | [16] |
| 5-HT2B | ND | ND | [16] |
| 5-HT2C | 174–2,570 | ND | [16] |
| 5-HT3 | 4,265- > 10,000 | ND | [16] |
| 5-HT5A | 145 | ND | [16] |
| 5-HT6 | 7.9 – 38 | ND | [16] |
| 5-HT7 | 8 | ND | [16] |
| D1 | 14.45 | ND | [16] |
| D2 | 0.89 | ND | |
| D2L | ND | [16] | |
| D3 | 1.412 | ND | [16] |
| D4 | 89.12 | ND | [16] |
| D5 | 95–2,590 | ND | [16] |
| α1A | 6.4-9 | ND | [16] |
| α1B | 13 | ND | [16] |
| α2A | 304-314 | ND | [16] |
| α2B | 181.6-320 | ND | [16] |
| α2C | 28.8-122 | ND | [16] |
| β1 | > 10,000 | ND | [16] |
| β2 | > 10,000 | ND | [16] |
| H1 | 7.3-70 | ND | [16] |
| H2 | 560 | ND | [16] |
| H3 | 1,000 | ND | [16] |
| H4 | > 10,000 | ND | [16] |
| M1 | 1,095-3,235.93 | ND | [16] |
| M2 | 2,187.76-7,163 | ND | [16] |
| M3 | 1441–1445.4 | ND | [16] |
| M4 | 5,321 | ND | [16] |
| M5 | 357 | ND | [16] |
| SERT | ND | ND | [16] |
| NET | ND | ND | [16] |
| DAT | ND | ND | [16] |
| NMDA (PCP) | ND | ND | [16] |
| Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except 5-HT3 (rat), D4 (human/rat), H3 (guinea pig), and NMDA/PCP (rat).[16] |
Pharmacokinetics
History
Fluphenazine came into use in 1959.[6]
Availability
The injectable form is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[7] It is available as a generic medication.[1] It was discontinued in Australia around mid 2017.[8]
Other animals
In horses, it is sometimes given by injection as an anxiety-relieving medication, though there are many negative common side effects and it is forbidden by many equestrian competition organizations.[27]
References
- ^ Jump up to:a b c d e f g h i j k l m n o “fluphenazine decanoate”. The American Society of Health-System Pharmacists. Archived from the original on 8 December 2015. Retrieved 1 December 2015.
- ^ “Product Information: Modecate (Fluphenazine Decanoate Oily Injection )” (PDF). TGA eBusiness Services. Bristol-Myers Squibb Australia Pty Ltd. 1 November 2012. Archived from the original on 2 August 2017. Retrieved 9 December 2013.
- ^ Tardy M, Huhn M, Engel RR, Leucht S (August 2014). “Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia”. The Cochrane Database of Systematic Reviews. 8 (8): CD009230. doi:10.1002/14651858.CD009230.pub2. PMID 25087165.
- ^ “Modecate Injection 25mg/ml – Patient Information Leaflet (PIL) – (eMC)”. http://www.medicines.org.uk. Retrieved 6 November 2017.
- ^ “Fluphenazine”. livertox.nih.gov. Retrieved 6 November 2017.
- ^ Jump up to:a b McPherson EM (2007). Pharmaceutical Manufacturing Encyclopedia (3rd ed.). Burlington: Elsevier. p. 1680. ISBN 9780815518563.
- ^ Jump up to:a b World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
- ^ Jump up to:a b Rossi S, ed. (July 2017). “Fluphenazine – Australian Medicines Handbook”. Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd. Retrieved 8 August 2017.
- ^ Matar HE, Almerie MQ, Sampson SJ (June 2018). “Fluphenazine (oral) versus placebo for schizophrenia”. The Cochrane Database of Systematic Reviews. 6: CD006352. doi:10.1002/14651858.CD006352.pub3. PMC 6513420. PMID 29893410.
- ^ Joint Formulary Committee, BMJ, ed. (March 2009). “4.2.1”. British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 978-0-85369-845-6.
Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
- ^ Jump up to:a b c d e Haddad P, Haddad PM, Dursun S, Deakin B (2004). Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. pp. 207–216. ISBN 9780198527480.
- ^ Moncrieff J (July 2006). “Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse”. Acta Psychiatrica Scandinavica. 114 (1): 3–13. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655. S2CID 6267180.
- ^ Sacchetti E, Vita A, Siracusano A, Fleischhacker W (2013). Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. p. 85. ISBN 9788847026797.
- ^ Siragusa S, Saadabadi A (2020). “Fluphenazine”. StatPearls. PMID 29083807.
- ^ PubChem. “Fluphenazine”. pubchem.ncbi.nlm.nih.gov. Retrieved 30 September 2019.
- ^ Jump up to:a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al Roth, BL; Driscol, J. “PDSP Ki Database”. Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
- ^ Parent M, Toussaint C, Gilson H (1983). “Long-term treatment of chronic psychotics with bromperidol decanoate: clinical and pharmacokinetic evaluation”. Current Therapeutic Research. 34 (1): 1–6.
- ^ Jump up to:a b Jørgensen A, Overø KF (1980). “Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. III. Serum levels”. Acta Psychiatrica Scandinavica. Supplementum. 279: 41–54. doi:10.1111/j.1600-0447.1980.tb07082.x. PMID 6931472.
- ^ Jump up to:a b Reynolds JE (1993). “Anxiolytic sedatives, hypnotics and neuroleptics.”. Martindale: The Extra Pharmacopoeia (30th ed.). London: Pharmaceutical Press. pp. 364–623.
- ^ Ereshefsky L, Saklad SR, Jann MW, Davis CM, Richards A, Seidel DR (May 1984). “Future of depot neuroleptic therapy: pharmacokinetic and pharmacodynamic approaches”. The Journal of Clinical Psychiatry. 45 (5 Pt 2): 50–9. PMID 6143748.
- ^ Jump up to:a b Curry SH, Whelpton R, de Schepper PJ, Vranckx S, Schiff AA (April 1979). “Kinetics of fluphenazine after fluphenazine dihydrochloride, enanthate and decanoate administration to man”. British Journal of Clinical Pharmacology. 7 (4): 325–31. doi:10.1111/j.1365-2125.1979.tb00941.x. PMC 1429660. PMID 444352.
- ^ Young D, Ereshefsky L, Saklad SR, Jann MW, Garcia N (1984). Explaining the pharmacokinetics of fluphenazine through computer simulations. (Abstract.). 19th Annual Midyear Clinical Meeting of the American Society of Hospital Pharmacists. Dallas, Texas.
- ^ Janssen PA, Niemegeers CJ, Schellekens KH, Lenaerts FM, Verbruggen FJ, van Nueten JM, et al. (November 1970). “The pharmacology of fluspirilene (R 6218), a potent, long-acting and injectable neuroleptic drug”. Arzneimittel-Forschung. 20 (11): 1689–98. PMID 4992598.
- ^ Beresford R, Ward A (January 1987). “Haloperidol decanoate. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis”. Drugs. 33 (1): 31–49. doi:10.2165/00003495-198733010-00002. PMID 3545764.
- ^ Reyntigens AJ, Heykants JJ, Woestenborghs RJ, Gelders YG, Aerts TJ (1982). “Pharmacokinetics of haloperidol decanoate. A 2-year follow-up”. International Pharmacopsychiatry. 17 (4): 238–46. doi:10.1159/000468580. PMID 7185768.
- ^ Larsson M, Axelsson R, Forsman A (1984). “On the pharmacokinetics of perphenazine: a clinical study of perphenazine enanthate and decanoate”. Current Therapeutic Research. 36 (6): 1071–88.
- ^ Loving NS (31 March 2012). “Effects of Behavior-Modifying Drug Investigated (AAEP 2011)”. The Horse Media Group. Archived from the original on 6 January 2017. Retrieved 13 December 2016.
External links
- “Fluphenazine”. Drug Information Portal. U.S. National Library of Medicine.
| Clinical data | |
|---|---|
| Trade names | Prolixin, Modecate, Moditen others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682172 |
| License data | US DailyMed: Fluphenazine |
| Pregnancy category | AU: C |
| Routes of administration | By mouth, Intramuscular injection, depot injection (fluphenazine decanoate) |
| Drug class | Typical antipsychotic |
| ATC code | N05AB02 (WHO) |
| Legal status | |
| Legal status | AU: DiscontinuedCA: ℞-onlyUK: POM (Prescription only)US: ℞-only |
| Pharmacokinetic data | |
| Bioavailability | 2.7% (by mouth) |
| Metabolism | unclear[1] |
| Elimination half-life | IM 15 hours (HCL), 7–10 days (decanoate)[1] |
| Excretion | Urine, feces |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 69-23-8 |
| PubChem CID | 3372 |
| IUPHAR/BPS | 204 |
| DrugBank | DB00623 |
| ChemSpider | 3255 |
| UNII | S79426A41Z |
| KEGG | D07977 |
| ChEBI | CHEBI:5123 |
| ChEMBL | ChEMBL726 |
| CompTox Dashboard (EPA) | DTXSID2023068 |
| ECHA InfoCard | 100.000.639 |
| Chemical and physical data | |
| Formula | C22H26F3N3OS |
| Molar mass | 437.53 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
| (verify) |
////////////Fluphenazine, فلوفينازين , 氟奋乃静 , SQ 10733, Squibb 16144
OCCN1CCN(CCCN2C3=CC=CC=C3SC3=C2C=C(C=C3)C(F)(F)F)CC1
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TAUROLIDINE
TAUROLIDINE
- Molecular FormulaC7H16N4O4S2
- Average mass284.356 Da
19388-87-5[RN]
243-016-5[EINECS]
2H-1,2,4-Thiadiazine, 4,4′-methylenebis[tetrahydro-, 1,1,1′,1′-tetraoxide
4,4′-methanediylbis(1,2,4-thiadiazinane) 1,1,1′,1′-tetraoxide
UNII-8OBZ1M4V3V
тауролидин
توروليدين
牛磺利定
NMR https://www.apexbt.com/downloader/document/C4559/NMR-2.pdf
MS https://www.apexbt.com/downloader/document/C4559/MS-2.pdf
Taurolidine
CAS Registry Number: 19388-87-5
CAS Name: 4,4¢-Methylenebis(tetrahydro-1,2,4-thiadiazine) 1,1,1¢,1¢-tetraoxide
Additional Names: 4,4¢-methylenebis(perhydro-1,2,4-thiadiazine 1,1-dioxide); bis(1,1-dioxoperhydro-1,2,4-thiadiazin-4-yl)methane
Trademarks: Drainasept (Geistlich); Taurolin (HMR); Tauroflex (Geistlich)
Molecular Formula: C7H16N4O4S2, Molecular Weight: 284.36
Percent Composition: C 29.57%, H 5.67%, N 19.70%, O 22.51%, S 22.55%
Literature References: Broad spectrum, synthetic formaldehyde carrier formed by the condensation of two molecules of taurine and three molecules of formaldehyde. Prepn: FR1458701; R. W. Pfirrmann, US3423408 (1966, 1969 both to Ed. Geistlich Söhne). Antibacterial activity in mice: M. K. Browne et al.,J. Appl. Bacteriol.41, 363 (1976). Anti-endotoxin activity in lab animals: R. W. Pfirrmann, G. B. Leslie, ibid.46, 97 (1979). Mechanism of action: E. Myers et al.,ibid.48, 89 (1980). HPLC determn of metabolites in plasma: A. D. Woolfson et al.,Int. J. Pharm.49, 135 (1989). Pharmacokinetics: C. Steinbach-Lebbin et al.,Arzneim.-Forsch.32, 1542 (1982). Metabolism in humans: B. I. Knight et al.,Br. J. Clin. Pharmacol.12, 695 (1981). Clinical trials in peritonitis: M. K. Browne et al.,Surg. Gynecol. Obstet.146, 721 (1978); G. Wesch et al.,Fortschr. Med.101, 545 (1983); in wound sepsis: A. K. Halsall et al.,Pharmatherapeutica2, 673 (1981); in pleural infection: A. A. Conlan et al.,S. Afr. Med. J.64, 653 (1983).
Properties: White crystals, mp 154-158°. Sol in water.
Melting point: mp 154-158°
Therap-Cat: Antibacterial.
Keywords: Antibacterial (Synthetic).
Taurolidine is an antimicrobial that is used to try to prevent infections in catheters.[1] Side effects and the induction of bacterial resistance is uncommon.[1] It is also being studied as a treatment for cancer.[2]
It is derived from the endogenous amino acid taurine. Taurolidine’s putative mechanism of action is based on a chemical reaction. During the metabolism of taurolidine to taurinamide and ultimately taurine and water, methylol groups are liberated that chemically react with the mureins in the bacterial cell wall and with the amino and hydroxyl groups of endotoxins and exotoxins. This results in denaturing of the complex polysaccharide and lipopolysaccharide components of the bacterial cell wall and of the endotoxin and in the inactivation of susceptible exotoxins.[3]
PATENT
https://patents.google.com/patent/WO2012070066A1/en
Taurolidine is an antibacterial drug and also has antiendotoxic substance, which is used as an antiseptic solution in surgery for washing out the abdominal cavity and it also prevents septic shock. It is commercially sold as Taurolidine (Formula I). The present invention relates to a process for the preparation of Taurolidine which provides significant advantages over the existing processes.
Formula I
The current process for the preparation of Taurolidine is depicted in Scheme 1
Formula II
Formula IVFormula IThe present inventors thus propose an industrially viable procedure for isolation of Taurolidine in substantially pure form.Taurolidine is dissolved in a suitable solvent to obtain a clear solution. The product starts to precipitate and an anti solvent is added optionally to maximize the precipitation procedure. The solvents employed for the purification are non -aqueous aprotic solvents comprising DMSO, DMAc, DMF, Acetonitirle, DMSO being the most preferred solvent. The antisolvents employed are toluene, ethyl acetate, dichloromethane, ether; toluene being the most preferred.Taurolidine obtained by the instant procedure has purity greater than or equal to 99.5 %. The process of the invention is illustrated by the following examples to obtain Taurolidine. Example ICbz-Taurine sodium salt (Formula II)To 1000ml of water in the RBF charge 192gm of (3.0 eq) of sodium hydroxide under cooling followed by 200gm of Taurine and dissolve it until clear solution is obtained. Cool to 0°C to 5°C, and Charge 50% CBZ-C1 in toluene at 0°C to 5°C. After completion of addition, maintain at room temperature for 14h. Separate the toluene layer and wash the aqueous layer with 2x200ml of ethyl acetate. Add slowly 27gm of sodium hydroxide in 60ml of water to the aqueous layer and adjust pH to 12- 14. Cool to 0°C to 5°C and a white solid separates from the solution. Filter the solid and dry the solid at 60 -70 °C. Weight of the solid: 320 gExample 2Cbz-Taurinamide (Formula III)To a clean dry flask charge 1500ml of toluene and charge 320gm of Formula II and cool to 0°C to 5°C. Charge 308 gm of PC15 slowly at 0°C to 5°C for 2hrs. Maintain at 0°C to 5°C up to completion of reaction. Quench the RM into another flask containing 2 ltr of water at 0°C to 5°C. Separate the organic layer, wash and extract the aqueous layer with toluene. Dry the organic layer with sodium sulphate and cool to 0°C to 5°C. Purge ammonia gas into the reaction mass till the reaction is complete. Filter the solid and dissolve the solid in 21tr of water and extract the aqueous layer with 2x600ml of ethyl acetate. Dry the organic layer with sodium sulphate and concentrate it under reduced pressure to obtain a white solid. Weight of the solid: 150 gExample 3Taurinamide Succinate (Formula IV)Take a suspension of 100 g of Cbz-Taurinamide in 1000 ml methanol, and 10% Pd/C (1 .0 g) and subject to hydrogenation at 45-50 psi. Upon completion of the reaction filter the catalyst and add succinic acid (1 .0 eq) to the solvent and distill off the solvent under vacuum to provide the title compound in about 90% yield as a white solid.Example 4Taurolidine (Formula I)To a solution of 100 g Taurinamide succinate in water is added sat sodium bicarbonate solution and pH adjusted to 7-8. To the solution was added formaldehyde (50 ml) and allowed to stir for 4 h. The solid obtained was filtered and washed with water to give Taurolidine. The title compound was obtained in about 70% yield and about 98% purity.Example 5Purification of TaurolidineTaurolidine (100 g) was dissolved in DMSO (400 ml) and a clear solution is obtained and a precipitate is obtained immediately. The solid is filtered and washed with toluene and dried to give a white solid in 40 % yield. The product obtained was >99.5% pure.Example 6Purification of TaurolidineTaurolidine (100 g) was dissolved in DMSO (400 ml) and a clear solution is obtained and a precipitate is obtained immediately. To the solution, toluene (1000 ml) is added. The solid is filtered and washed with toluene and dried to give a white solid in 70 % yield. The product obtained was >99.5% pure by HPLC and passed elemental analysis within 0.4% of the theoretical values.Example 7Purification of TaurolidineTaurolidine (100 g) was dissolved in DMAc (800 ml) and to the solution, toluene (1000 ml) is added. The solid is filtered and washed with toluene and dried to give a white solid in 70% yield.
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022007713&_cid=P12-KYJIDL-52672-1Taurolidine (English name Taurolidine, chemical name is 4,4′-methylenebis[tetrahydro-2H-1,2,4-thiadiazine] 1,1,1′,1′-tetraoxide , the molecular formula is C 7 H 16 N 4 O 4 S 2 ) is a derivative of the amino acid taurine, and its structure is as follows:
Taurolidine has anti-endotoxin, anti-bacterial and anti-adherent properties. In terms of bacteria, taurolidine can chemically react with cell walls, endotoxins and exotoxins to inhibit microbial adhesion and play an antibacterial role. In addition, in terms of anti-tumor, taurolidine can induce cytotoxicity of tumor cells by inducing apoptosis, autophagy and necrosis. The extent to which these processes are involved may vary with the type of tumor cell. Until July 2020, there were more than 260 foreign literature searches on taurolidine research reports, most of which focused on the exploration of the effect of taurolidine on tumor-related signaling pathways, while the application of taurolidine in antiviral activity was not yet available. See research reports.
PATENThttps://patents.google.com/patent/CN101274921B/en
Taurolidine synthetic operation step:1. the preparation of tauryl villaumite hydrochlorate
In being housed, ventpipe, escape pipe, thermometer and churned mechanically 300ml four-necked bottle add Mercaptamine 25g, 200ml methylene dichloride and 32ml dehydrated alcohol, under ice-water bath (below the 10 ℃) mechanical stirring, feed dry appropriate chlorine, reaction begins and heat release immediately, the thick solid of adularescent generates, and temperature remains on below 50 ℃ and stirs, reaction 5h.The whole process HCl gas and the monochloroethane gas of alkali lye absorption reaction process.Stop logical chlorine after reacting end, get yellow mercury oxide, suction filtration is used washed with dichloromethane four times, and vacuum-drying gets white solid 50g, 152～154 ℃ of fusing points.2. the preparation of tauryl azide salt hydrochlorate
The reaction flask ice-water bath of containing 45ml water is cooled to-15 ℃, adds NaN 3(2g), after stirring is molten entirely, add slightly pinkiness of tauryl villaumite hydrochlorate (9g) solution in batches, the water-bath of 20 minutes recession deicings, room temperature continues stirring 60 minutes.3. the preparation of tauryl amine hydrochlorate
Above-mentioned reaction solution is joined in the 500ml autoclave, add 0.5g 5%Pd/C, feed hydrogen, pressure is 7Mpa, stirring at room 6h.Turn off hydrogen, pour out reaction solution, elimination Pd/C gets colourless reaction solution.The reaction solution that takes a morsel adds in the nuclear-magnetism pipe, adds deuterated reagent D 2O, with 1HNMR determines the transformation efficiency of hydrogenation reaction.Two kinds of CH of tauryl amine hydrochlorate 2D 1The HNMR peak is 3.29～3.31 and 3.40～3.42ppm place, and two kinds of CH of reactant tauryl azide salt hydrochlorate 2D 1The HNMR peak is 3.37～3.38 and 3.82～3.84ppm place.Determine that with the peak height ratio of two kinds of compounds the 4th step added the amount of formaldehyde.4. the preparation of taurolidine
With the above-mentioned reaction solution that removes by filter Pd/C, add 5g NaHCO 3, be stirred to molten entirely, frozen water cooling, stir slowly splash into down formaldehyde solution (37%, 2ml), have milky white precipitate to produce after 30 minutes, continue to stir 1h, suction filtration, filter cake is washed 3 times with frozen water.Vacuum-drying gets white powdery solid 2.3g, 170～174 ℃ of fusing points.Embodiment 2:Making with extra care of taurolidine:The above-mentioned taurolidine white powder 5～10g that obtains adds 50～200ml acetonitrile, and heating for dissolving removes by filter a small amount of insolubles, concentrates, and cooling below 10 ℃ gets white powder 5～10g, 172～174 ℃ of fusing points.Embodiment 3:Proton nmr spectra ( 1H-NMR) data are as follows:1HNMR(DMSO-D6，TMS7.26-7.28(t，2H，NH)，4.09-4.10(d，4H，N-CH 2)，3.53(s，2H，N-CH 2-N)，3.28-3.29(t，4H，N-CH 2-CH 2)，2.96-2.97(t，4H，S-CH 2-CH 2)。The infrared absorption spectrum data are as follows:IR (KBr compressing tablet cm -1): 3425,3263,1633,1450,1404,1317,1278,1228,1160,1134,1073,1026,993,958,924,830,757,667,532,511.See Fig. 3.The ultimate analysis analytical value:C, 29.04%, N, 18.55%, H, 5.85%; Calculated value: C, 29.57%, N, 19.71%, H, 5.67%Embodiment 4:Taurolidine formulation optimizing injection type of the present invention, as: infusion solution, injection liquid, freeze-dried powder injection or powder ampoule agent for injection etc., more preferably infusion solution.The preparation of infusion solution[prescription 1] taurolidine 10.0～30.0gPVP 40.0～80.0gNaCl 2～5gAdd water to 1000ml[method for making] takes by weighing taurolidine, is dissolved in water, and stirs, and adds the PVP dissolving, and adjust pH to 7.0 is crossed the moisture film of 0.22 μ m, packing, and 121 ℃ of sterilizations 20 minutes, promptly.[prescription 2] taurolidine 10.0～30.0gCitric acid 0.1～1.0gLemon enzyme sodium 10.0～20.0gAdd water to 1000ml[method for making] takes by weighing taurolidine, is dissolved in water, stir, and the dissolving of adding citric acid sodium, adjust pH to 7.0, the moisture film of mistake 0.22 μ m, packing was sterilized 20 minutes for 121 ℃, promptly.
PATENThttps://patents.google.com/patent/US8952148B2/en
Example ICbz-Taurine Sodium Salt (Formula II)To 1000 ml of water in the RBF charge 192 gm of (3.0 eq) of sodium hydroxide under cooling followed by 200 gm of Taurine and dissolve it until clear solution is obtained. Cool to 0° C. to 5° C., and Charge 50% CBZ-Cl in toluene at 0° C. to 5° C. After completion of addition, maintain at room temperature for 14 h. Separate the toluene layer and wash the aqueous layer with 2×200 ml of ethyl acetate. Add slowly 27 gm of sodium hydroxide in 60 ml of water to the aqueous layer and adjust pH to 12-14. Cool to 0° C. to 5° C. and a white solid separates from the solution. Filter the solid and dry the solid at 60-70° C. Weight of the solid: 320 g
Example 2Cbz-Taurinamide (Formula III)To a clean dry flask charge 1500 ml of toluene and charge 320 gm of Formula II and cool to 0° C. to 5° C. Charge 308 gm of PCl5 slowly at 0° C. to 5° C. for 2 hrs. Maintain at 0° C. to 5° C. up to completion of reaction. Quench the RM into another flask containing 2 ltr of water at 0° C. to 5° C. Separate the organic layer, wash and extract the aqueous layer with toluene. Dry the organic layer with sodium sulphate and cool to 0° C. to 5° C. Purge ammonia gas into the reaction mass till the reaction is complete. Filter the solid and dissolve the solid in 2 ltr of water and extract the aqueous layer with 2×600 ml of ethyl acetate. Dry the organic layer with sodium sulphate and concentrate it under reduced pressure to obtain a white solid. Weight of the solid: 150 g
Example 3Taurinamide Succinate (Formula IV)Take a suspension of 100 g of Cbz-Taurinamide in 1000 ml methanol, and 10% Pd/C (1.0 g) and subject to hydrogenation at 45-50 psi. Upon completion of the reaction filter the catalyst and add succinic acid (1.0 eq) to the solvent and distill off the solvent under vacuum to provide the title compound in about 90% yield as a white solid.
Example 4Taurolidine (Formula I)To a solution of 100 g Taurinamide succinate in water is added sat sodium bicarbonate solution and pH adjusted to 7-8. To the solution was added formaldehyde (50 ml) and allowed to stir for 4 h. The solid obtained was filtered and washed with water to give Taurolidine. The title compound was obtained in about 70% yield and about 98% purity.
Example 5Purification of TaurolidineTaurolidine (100 g) was dissolved in DMSO (400 ml) and a clear solution is obtained and a precipitate is obtained immediately. The solid is filtered and washed with toluene and dried to give a white solid in 40% yield. The product obtained was >99.5% pure.
Example 6Purification of TaurolidineTaurolidine (100 g) was dissolved in DMSO (400 ml) and a clear solution is obtained and a precipitate is obtained immediately. To the solution, toluene (1000 ml) is added. The solid is filtered and washed with toluene and dried to give a white solid in 70% yield. The product obtained was >99.5% pure by HPLC and passed elemental analysis within 0.4% of the theoretical values.
Example 7Purification of TaurolidineTaurolidine (100 g) was dissolved in DMAc (800 ml) and to the solution, toluene (1000 ml) is added. The solid is filtered and washed with toluene and dried to give a white solid in 70% yield.
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SYN
European Journal of Medicinal Chemistry 265 (2024) 116124
Defencath, a product created by CorMedix, Inc., was granted FDA approval on November 15, 2023. Its purpose is to decrease the occur rence of catheter-related bloodstream infections (CRBSI) in a limited
population of adult individuals who have chronic renal failure and undergo hemodialysis (HD) using a central venous catheter (CVC) [11]. Defencath is the first and only FDA-approved antimicrobial catheter
locking solution (CLS) in the United States. It is composed of the anticoagulant Heparin and the broad-spectrum non-antibiotic antimicrobial and antifungal agent Taurolidine. Taurolidine has been proven to have activity against the following microorganisms: Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Serratia marcescens, Candida albicans, Candida glabrata [12,13].
The synthesis route of Taurolidine is showed in Scheme 4 [14].
Benzyl (2-sulfamoylethyl)carbamate (TAUR-001) was removed benzy
loxycarbonyl (Cbz) group under the action of palladium carbon to obtain
TAUR-002. After the reaction with formaldehyde, the product Taur
olidine was obtained.
[11] A.K. Agarwal, P. Roy-Chaudhury, P. Mounts, E. Hurlburt, A. Pfaffle, E.C. Poggio,
Taurolidine/Heparin lock solution and catheter-related bloodstream infection in
hemodialysis: a randomized, double-blind, active-control, phase 3 study, Clin. J.
Am. Soc. Nephrol. 18 (2023) 1446–1455.
[12] C.H. van den Bosch, B. Jeremiasse, J.T. van der Bruggen, F.N.J. Frakking, Y.G.
T. Loeffen, C.P. van de Ven, A.F.W. van der Steeg, M.F. Fiocco, M.D. van de
Wetering, M. Wijnen, The efficacy of taurolidine containing lock solutions for the
prevention of central-venous-catheter-related bloodstream infections: a
systematic review and meta-analysis, J. Hosp. Infect. 123 (2022) 143–155.
[13] Y. Wouters, G.R.H. Mennen, R.H.M. Te Morsche, H.M.J. Roelofs, G.J.A. Wanten,
The antiseptic and antineoplastic agent taurolidine modulates key leukocyte
functions, In Vivo 36 (2022) 2074–2082.
[14] R.M. Berrios, Synthesis of Taurolidine, Purity Profiles and Polymorphs, 2023.
US11738120B1
Medical uses
Taurolidine is an antimicrobial agent used in an effort to prevent catheter infections. It however is not approved for this use in the United States as of 2011.[4]
- Catheter lock solution in home parenteral nutrition (HPN) or total parenteral nutrition (TPN): catheter-related blood stream infections (CRBSI) remains the most common serious complication associated with long-term parenteral nutrition. The use of taurolidine as a catheter lock solution shows a reduction of CRBSI.[1][5] The overall quality of the evidence however is not strong enough to justify routine use.[1][5]
- Catheter lock solution: Taurolidine decreases the adherence of bacteria and fungi to host cells by destructing the fimbriae and flagella and thus prevent the biofilm formation.[6][7] Taurolidine is the active ingredient of antimicrobial catheter lock solutions for the prevention and treatment of catheter related bloodstream infections (CRBSIs) and is suitable for use in all catheter based vascular access devices.[8][1] Bacterial resistance against taurolidine has never been observed in various studies.[9][10]
- The use of a taurolidine lock solution may decrease the risk of catheter infection in children with cancer but the evidence is tentative.[11]
Side effects
No systemic side effects have been identified. The safety of taurolidine has also been confirmed in clinical studies with long-term intravenous administration of high doses (up to 20 grams daily). In the body, taurolidine is metabolized rapidly via the metabolites taurultam and methylol taurinamide, which also have a bactericidal action, to taurine, an endogenous aminosulphonic acid, carbon dioxide and water. Therefore, no toxic effects are known or expected in the event of accidental injection. Burning sensation while instilling, numbness, erythema, facial flushing, headache, epistaxis, and nausea have been reported.[12]
Toxicology
Taurolidine has a relatively low acute and subacute toxicity.[1] Intravenous injection of 5 grams taurolidine into humans over 0.5–2 hours produce only burning sensation while instilling, numbness, and erythema at the injection sites.[12] For treatment of peritonitis, taurolidine was administered by peritoneal lavage, intraperitoneal instillation or intravenous infusion, or by a combination thereof. The total daily dose ranged widely from 0.5 to 50 g. The total cumulative dose ranged from 0.5 to 721 g. In those patients who received intravenous taurolidine, the daily intravenous dose was usually 15 to 30 g but several patients received up to 40 g/day. Total daily doses of up to 40 g and total cumulative doses exceeding 300 g were safe and well tolerated.[12][13][14][15][16]
Pharmacology
- Metabolism: Taurolidine and taurultam are quickly metabolized to taurinamide, taurine, carbon dioxide and water. Taurolidine exists in equilibrium with taurultam and N-methylol-taurultam in aqueous solution.[17]
- Pharmacokinetic (elimination): The half-life of the terminal elimination phase of taurultam is about 1.5 hours, and of the taurinamide metabolite about 6 hours. 25% of the taurolidine dose applied is renally eliminated as taurinamide and/or taurine.[13][14][18]
Mechanism of action
Following administration of taurolidine, the antimicrobial and antiendotoxin activity of the taurolidine molecule is conferred by the release of three active methylol (hydroxymethyl) groups as taurolidine is rapidly metabolized by hydrolysis via methylol taurultam to methylol taurinamide and taurine. These labile N-methylol derivatives of taurultam and taurinamide react with the bacterial cell-wall resulting in lysis of the bacteria, and by inter- and intramolecular cross-linking of the lipopolysaccharide-protein complex, neutralization of the bacterial endotoxins which is enhanced by enzymatic activation. This mechanism of action is accelerated and maximised when taurolidine is pre-warmed to 37 °C (99 °F). Microbes are killed and the resulting toxins are inactivated; the destruction time in vitro is 30 minutes.[19]
The chemical mode of action of taurolidine via its reactive methylol groups confers greater potency in vivo than indicated by in vitro minimum inhibitory concentration (MIC) values, and also appears to preclude susceptibility to resistance mechanisms.[14]
Taurolidine binding to lipopolysaccharides (LPS) prevents microbial adherence to host epithelial cells, thereby prevents microbial invasion of uninfected host cells. Although the mechanism underlying its antineoplastic activity has not been fully elucidated, it may be related to this agent’s anti-adherence property.[6][7] Taurolidine has been shown to block interleukin 1 (IL-1) and tumour necrosis factor (TNF) in human peripheral blood mononuclear cells (PBMC).[20] In addition, taurolidine also promotes apoptosis by inducing various apoptotic factors and suppresses the production of vascular endothelial growth factor (VEGF), a protein that plays an important role in angiogenesis.[21]
Taurolidine is highly active against the common infecting pathogens associated with peritonitis and catheter sepsis, this activity extends across a wide-spectrum of aerobic and anaerobic bacteria and fungi (with no diminution of effect in the presence of biological fluids, e.g. blood, serum, pus).[15][16][22]
- Gram-positive bacteria (MIC of 1–2 mg/mL): Staphylococcus (including multiple-antibiotic resistant coagulase negative strains, methicillin-resistant S. aureus), Streptococcus, Enterococcus.
- Gram-negative bacteria (MIC of 0.5–5 mg/mL): Aerobacter species, Citrobacter species, Enterobacter species, Escherichia coli, Proteus species (indole negative), Proteus mirabilis, Pseudomonas species (including P. aeruginosa), Salmonella species, Serratia marcescans, Klebsiella species.
- Anaerobes (MIC 0.03–0.3 mg/mL): Bacteroides species (including B. fragilis), Fusobacteria, Clostridium species, Peptostreptococcus anaerobius.
- Fungi (MIC 0.3–5 mg/mL): Candida albicans, Cryptococcus neoformans, Aspergillus species, Trichophyton rubrum, Epidermophyton floccosum, Pityrosporum ovale.[10][17][22]
Chemical properties
The chemical name for taurolidine is 4,4′-Methylene-bis(1,2,4-thiadiazinane)-1,1,1’,1′-tetraoxide.
It is a white to off white odourless crystalline powder. It is practically insoluble in chloroform, slightly soluble in boiling acetone, ethanol, methanol, and ethyl acetate, sparingly soluble in water 8 at 20° and ethyl alcohol, soluble in dilute hydrochloric acid, and dilute sodium hydroxide, and freely soluble in N,N-dimethylformamide (at 60 °C).
History
Taurolidine was first synthesized in the laboratories of Geistlich Pharma AG, Switzerland in 1972. Clinical trials begun in 1975 in patients with severe peritonitis.
Research
Taurolidine demonstrates some anti-tumor properties, with positive results seen in early-stage clinical investigations using the drug to treat gastrointestinal malignancies and tumors of the central nervous system.[23] More recently, it has been found to exert antineoplastic activity. Taurolidine induces cancer cell death through a variety of mechanisms. Even now, all the antineoplastic pathways it employs are not completely elucidated. It has been shown to enhance apoptosis, inhibit angiogenesis, reduce tumor adherence, downregulate pro-inflammatory cytokine release, and stimulate anticancer immune regulation following surgical trauma. Apoptosis is activated through both a mitochondrial cytochrome-c-dependent mechanism and an extrinsic direct pathway. A lot of in vitro and animal data support taurolidine’s tumoricidal action.[24][25][26] Taurolidine has been used as an antimicrobial agent in the clinical setting since the 1970s and thus far appears nontoxic. The nontoxic nature of taurolidine makes it a favorable option compared with current chemotherapeutic regimens. Few published clinical studies exist evaluating the role of taurolidine as a chemotherapeutic agent. The literature lacks a gold-standard level 1 randomized clinical trial to evaluate taurolidine’s potential antineoplastic benefits. However, these trials are currently underway. Such randomized control studies are vital to clarify the role of taurolidine in modern cancer treatment.[21][2]
References
- ^ Jump up to:a b c d e f Liu Y, Zhang AQ, Cao L, Xia HT, Ma JJ (2013). “Taurolidine lock solutions for the prevention of catheter-related bloodstream infections: a systematic review and meta-analysis of randomized controlled trials”. PLOS ONE. 8 (11): e79417. Bibcode:2013PLoSO…879417L. doi:10.1371/journal.pone.0079417. PMC 3836857. PMID 24278133.
- ^ Jump up to:a b Neary PM, Hallihan P, Wang JH, Pfirrmann RW, Bouchier-Hayes DJ, Redmond HP (April 2010). “The evolving role of taurolidine in cancer therapy”. Annals of Surgical Oncology. 17 (4): 1135–43. doi:10.1245/s10434-009-0867-9. PMID 20039217. S2CID 23807182.
- ^ Waser PG, Sibler E (1986). “Taurolidine: A new concept in antimicrobial chemotherapy”. In Harms AF (ed.). Innovative Approaches in Drug Research. Elsevier Science Publishers. pp. 155–169.
- ^ O’Grady NP, Alexander M, Burns LA, Dellinger EP, Garland J, Heard SO, et al. (May 2011). “Guidelines for the prevention of intravascular catheter-related infections”. Clinical Infectious Diseases. 52 (9): e162-93. doi:10.1093/cid/cir257. PMC 3106269. PMID 21460264.
- ^ Jump up to:a b Bradshaw JH, Puntis JW (August 2008). “Taurolidine and catheter-related bloodstream infection: a systematic review of the literature”. Journal of Pediatric Gastroenterology and Nutrition. 47 (2): 179–86. doi:10.1097/MPG.0b013e318162c428. PMID 18664870. S2CID 19136945.
- ^ Jump up to:a b Gorman SP, McCafferty DF, Woolfson AD, Jones DS (April 1987). “Reduced adherence of micro-organisms to human mucosal epithelial cells following treatment with Taurolin, a novel antimicrobial agent”. The Journal of Applied Bacteriology. 62 (4): 315–20. doi:10.1111/j.1365-2672.1987.tb04926.x. PMID 3298185.
- ^ Jump up to:a b Blenkharn JI (July 1989). “Anti-adherence properties of taurolidine and noxythiolin”. Journal of Chemotherapy. 1 (4 Suppl): 233–4. PMID 16312382.
- ^ Liu H, Liu H, Deng J, Chen L, Yuan L, Wu Y (2014). “Preventing catheter-related bacteremia with taurolidine-citrate catheter locks: a systematic review and meta-analysis”. Blood Purification. 37 (3): 179–87. doi:10.1159/000360271. PMID 24777144.
- ^ Olthof ED, Rentenaar RJ, Rijs AJ, Wanten GJ (August 2013). “Absence of microbial adaptation to taurolidine in patients on home parenteral nutrition who develop catheter related bloodstream infections and use taurolidine locks”. Clinical Nutrition. 32 (4): 538–42. doi:10.1016/j.clnu.2012.11.014. PMID 23267744.
- ^ Jump up to:a b Torres-Viera C, Thauvin-Eliopoulos C, Souli M, DeGirolami P, Farris MG, Wennersten CB, et al. (June 2000). “Activities of taurolidine in vitro and in experimental enterococcal endocarditis”. Antimicrobial Agents and Chemotherapy. 44 (6): 1720–4. doi:10.1128/aac.44.6.1720-1724.2000. PMC 89943. PMID 10817739.
- ^ Simon A, Bode U, Beutel K (July 2006). “Diagnosis and treatment of catheter-related infections in paediatric oncology: an update”. Clinical Microbiology and Infection. 12 (7): 606–20. doi:10.1111/j.1469-0691.2006.01416.x. PMID 16774556.
- ^ Jump up to:a b c Gong L, Greenberg HE, Perhach JL, Waldman SA, Kraft WK (June 2007). “The pharmacokinetics of taurolidine metabolites in healthy volunteers”. Journal of Clinical Pharmacology. 47 (6): 697–703. doi:10.1177/0091270007299929. PMID 17395893. S2CID 31059736.
- ^ Jump up to:a b Knight BI, Skellern GG, Browne MK, Pfirrmann RW (November 1981). “Peritoneal absorption of the antibacterial and antiendotoxin taurolin in peritonitis”. British Journal of Clinical Pharmacology. 12 (5): 695–9. doi:10.1111/j.1365-2125.1981.tb01292.x. PMC 1401955. PMID 7332737.
- ^ Jump up to:a b c Stendel R, Scheurer L, Schlatterer K, Stalder U, Pfirrmann RW, Fiss I, et al. (2007). “Pharmacokinetics of taurolidine following repeated intravenous infusions measured by HPLC-ESI-MS/MS of the derivatives taurultame and taurinamide in glioblastoma patients”. Clinical Pharmacokinetics. 46 (6): 513–24. doi:10.2165/00003088-200746060-00005. PMID 17518510. S2CID 33321671.
- ^ Jump up to:a b Browne MK, MacKenzie M, Doyle PJ (May 1978). “C controlled trial of taurolin in established bacterial peritonitis”. Surgery, Gynecology & Obstetrics. 146 (5): 721–4. PMID 347606.
- ^ Jump up to:a b Browne MK (1981). “The treatment of peritonitis by an antiseptic – taurolin”. Pharmatherapeutica. 2 (8): 517–22. PMID 7255507.
- ^ Jump up to:a b Knight BI, Skellern GG, Browne MK, Pfirrmann RW (September 1981). “The characterisation and quantitation by high-performance liquid chromatography of the metabolites of taurolin”. British Journal of Clinical Pharmacology. 12 (3): 439–40. doi:10.1111/j.1365-2125.1981.tb01245.x. PMC 1401804. PMID 7295478.
- ^ Browne MK, Leslie GB, Pfirrmann RW (December 1976). “Taurolin, a new chemotherapeutic agent”. The Journal of Applied Bacteriology. 41 (3): 363–8. doi:10.1111/j.1365-2672.1976.tb00647.x. PMID 828157.
- ^ Braumann C, Pfirrman RW, et al. (2013). “Taurolidine, an Effective Multimodal Antimicrobial Drug Versus Traditional Antiseptics and Antibiotics”. In Willy C (ed.). Antiseptics in Surgery – Update 2013. Lindqvist Book Publishing. pp. 119–125.
- ^ Bedrosian I, Sofia RD, Wolff SM, Dinarello CA (November 1991). “Taurolidine, an analogue of the amino acid taurine, suppresses interleukin 1 and tumor necrosis factor synthesis in human peripheral blood mononuclear cells”. Cytokine. 3 (6): 568–75. doi:10.1016/1043-4666(91)90483-t. PMID 1790304.
- ^ Jump up to:a b Jacobi CA, Menenakos C, Braumann C (October 2005). “Taurolidine–a new drug with anti-tumor and anti-angiogenic effects”. Anti-Cancer Drugs. 16 (9): 917–21. doi:10.1097/01.cad.0000176502.40810.b0. PMID 16162968. S2CID 33876185.
- ^ Jump up to:a b Nösner K, Focht J (1994). “In-vitro Wirksamkeit von Taurolidin und 9 Antibiotika gegen klinische Isolate aus chirurgischem Einsendegut sowie gegen Pilze”. Chirurgische Gastroenterologie. 10 (Suppl 2): 10.
- ^ Stendel R, Picht T, Schilling A, Heidenreich J, Loddenkemper C, Jänisch W, Brock M (2004-04-01). “Treatment of glioblastoma with intravenous taurolidine. First clinical experience”. Anticancer Research. 24 (2C): 1143–7. PMID 15154639.
- ^ Calabresi P, Goulette FA, Darnowski JW (September 2001). “Taurolidine: cytotoxic and mechanistic evaluation of a novel antineoplastic agent”. Cancer Research. 61 (18): 6816–21. PMID 11559556.
- ^ Clarke NW, Wang JH, et al. (2005). “Taurolidine inhibits colorectal adenocarcinoma metastases in vivo and in vitro by inducing apoptosis”. Ir J Med Sci. 174 (Supplement 3): 1.
- ^ Stendel R, Scheurer L, Stoltenburg-Didinger G, Brock M, Möhler H (2003-06-01). “Enhancement of Fas-ligand-mediated programmed cell death by taurolidine”. Anticancer Research. 23 (3B): 2309–14. PMID 12894508.
| Clinical data | |
|---|---|
| ATC code | B05CA05 (WHO) |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 19388-87-5 |
| ChemSpider | 27486 |
| UNII | 8OBZ1M4V3V |
| CompTox Dashboard (EPA) | DTXSID00173001 |
| ECHA InfoCard | 100.039.090 |
| Chemical and physical data | |
| Formula | C7H16N4O4S2 |
| Molar mass | 284.35 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI |
////////////////////TAUROLIDINE, UNII-8OBZ1M4V3V, тауролидин ,توروليدين , 牛磺利定 ,
C1CS(=O)(=O)NCN1CN2CCS(=O)(=O)NC2
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I’m happy to share that I’m starting a new position as Consultant Glenmark Lifesciences at Glenmark Life Sciences!
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I retired 16th Jan 2022 at 58 yrs from Glenmark . completed 16 yrs 2 months
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DIPYRIDAMOLE
Dipyridamole
- Molecular FormulaC24H40N8O4
- Average mass504.626 Da
2,2′,2”,2”’-{[4,8-Di(piperidin-1-yl)pyrimido[5,4-d]pyrimidine-2,6-diyl]dinitrilo}tetraethanol
200-374-7[EINECS]
58-32-2[RN]
Ethanol, 2,2′,2”,2”’-[(4,8-di-1-piperidinylpyrimido[5,4-d]pyrimidine-2,6-diyl)dinitrilo]tetrakis-
дипиридамол [Russian] [INN]
ديبيريدامول [Arabic] [INN]
双嘧达莫 [Chinese] [INN]
0068373 [Beilstein]
DipyridamoleCAS Registry Number: 58-32-2
CAS Name: 2,2¢,2¢¢,2¢¢¢-[(4,8-Di-1-piperidinylpyrimido[5,4-d]pyrimidine-2,6-diyl)dinitrilo]tetrakisethanol
Additional Names: 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido-[5,4-d]pyrimidine
Manufacturers’ Codes: NSC-515776; RA-8
Trademarks: Anginal (Yamanouchi); Cardoxin (RAFA); Cleridium (Marcofina); Coridil (Delalande); Coronarine (NEGMA); Curantyl (Berlin-Chemie); Dipyridan (Hokuriku); Gulliostin (Taiyo); Natyl (Interdelta); Peridamol (Boehringer, Ing.); Persantine (Boehringer, Ing.); Piroan (Towa Yakuhin); Prandiol (Bottu); Protangix (Lefrancq)
Molecular Formula: C24H40N8O4
Molecular Weight: 504.63
Percent Composition: C 57.12%, H 7.99%, N 22.21%, O 12.68%
Literature References: Phosphodiesterase inhibitor that reduces platelet aggregation; also acts as a coronary vasodilator. Prepn: GB807826; F. G. Fischer, et al.,US3031450 (1959, 1962 both to Thomae). Activity studies: Saraf, Seth, Indian J. Physiol. Pharmacol.15, 135 (1971). Toxicological study: F. Takenaka et al.,Arzneim.-Forsch.22, 892 (1972). Symposium on pharmacology and clinical experience as antithrombotic: Thromb. Res.60, Suppl. 12, 1-99 (1990). Review of use as pharmacological stress agent in echocardiography: M. B. Buchalter et al.,Postgrad. Med. J.66, 531-535 (1990); in 201Tl cardiac imaging: S. G. Beer et al.,Am. J. Cardiol.67, Suppl., 18D-26D (1991).
Properties: Deep yellow needles from ethyl acetate, mp 163°. Bitter taste. Slightly sol in H2O; sol in dil acid having a pH of 3.3 or below; very sol in methanol, ethanol, chloroform; not too sol in acetone, benzene, ethyl acetate. Solns are yellow and show strong blue-green fluorescence. LD50 in rats: 8.4 g/kg orally; 208 mg/kg i.v. (Takenaka).Melting point: mp 163°
Toxicity data: LD50 in rats: 8.4 g/kg orally; 208 mg/kg i.v. (Takenaka)
Derivative Type: Combination with aspirin
Trademarks: Aggrenox (Boehringer, Ing.)
Literature References: Review of pharmacology and clinical efficacy in secondary prevention of stroke: P. S. Hervey, K. L. Goa, Drugs58, 469-475 (1999).
Therap-Cat: Antithrombotic; diagnostic aid (cardiac stress testing).
Keywords: Antithrombotic; Diagnostic Aid; Phosphodiesterase Inhibitor.
Dipyridamole (trademarked as Persantine and others) is a nucleoside transport inhibitor and a PDE3 inhibitor medication that inhibits blood clot formation[3] when given chronically and causes blood vessel dilation when given at high doses over a short time.
PATENT
https://patents.google.com/patent/WO2011151640A1/enDipyridamole, represented by structural formula (I), possesses platelet aggregation inhibiting, anti-thrombotic and vasodilator properties and it is marketed as an anti-platelet therapy for the treatment and prevention of disorders such as thrombo-embolisms.
A process for the preparation of dipyridamole, disclosed in patent US 3031450, involves the reaction of 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine (see Scheme 1). The preparation of 2,6-dichloro-4,8-dipiperidino- pyrimido(5,4-d)pyrimidine is also reported in US 3031450 and is incorporated herein by reference. The reaction to prepare dipyridamole does not employ an additional reaction solvent and is a neat mixture of the two reactants carried out at a very high temperature of 190 to 195°C. The process also involves a cumbersome work-up to isolate dipyridamole, since the crude product obtained is a pasty mass which needs decantation of the mother liquor and further purification. This decantation process is not practical on commercial scale.
2,6-dichloro-4,8-dipiperidino- dipyridamole (Ί) pyflmido(5,4-d)pyrimidineScheme 1A similar process for the production of dipyridamole is described in patent DD 117456 wherein the reaction conditions exemplified are heating 2,6-dichloro-4,8-dipiperidino- pyrimido(5,4-d)pyrimidine and diethanolamine at 155 to 160°C under vacuum. However, this process again requires a high temperature which leads to the formation of impurities.A process for the preparation and purification of dipyridamole is disclosed in patent DE 1812918, wherein 2,6-dicMoro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine and diethanolamine are heated to 150 to 200°C. After completion of the reaction, the reaction mixture is dissolved in chloroform, which is further separated into an upper layer of diethanolamine and its hydrochloride and a chloroform solution. The chloroform solution obtained is separated and reduced to dryness after stirring with water. This process also requires a high temperature which can lead to the formation of impurities. In addition, the solvent used for the isolation of dipyridamole, chloroform, is inconvenient as it is a restricted solvent and its permitted limit in the final marketed dipyridamole is very low.A similar process, wherein dipyridamole is manufactured by the reaction of diethanolamine with 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine is disclosed in patent RO 104718. However, this process again requires high temperatures of 180 to 200°C which leads to the formation of impurities and, consequently, the yield of the final product is very low (58%) with a purity of less than 98%.A process is disclosed in patent DD 115670, wherein the purification of dipyridamole involves refluxing it in butyl acetate, AcOBu, for 2 hours in the presence of an equal amount of silica gel or column chromatography on silica gel at 60-100°C. However, purification by column chromatography is not economical and not feasible on industrial scale. Moreover, this purification process only removes one specific impurity, 2,4,6-tris- (diethanolamino) – 8 -pip eridino-pyrimido (5,4-d)pyrimidine .The processes described above to prepare dipyridamole do not employ an additional reaction solvent but involve neat mixtures of the two reactants, 2,6-dichloro-4,8- dipiperidino-pyrimido(5,4-d)pyrimidine and diethanolamine, which are heated at very high temperatures. The use of neat reaction mixtures and/ or high temperatures means that it is very difficult to control the levels of impurities formed.Another process for the preparation of dipyridamole, disclosed in patent application WO 2007/080463, involves reacting diethanolamine with 2,6-dichloro-4,8-dipiperidino- pyrimido(5,4-d)pyrimidine in a solvent selected from the group consisting of l-methyl-2- pyrrolidinone, sulpholane and polyethylene glycol. However, the exemplified reaction temperatures are very high at 190 to 200°C and the HPLC purity of the crude dipyridamole is reported to be only 90-94%. A purification method is disclosed using first a ketonic solvent and then an alcohol and water. Even though the process disclosed in this patent application uses a solvent in the reaction, the temperature of reaction is still very high and the purification in ketonic solvent is reported at high temperature (100 to 120°C). The HPLC purity after purification is reported as only 99.0-99.5%.As discussed above, all the processes disclosed in the prior art for the preparation of dipyridamole suffer from serious disadvantages with respect to commercial production. The prior art synthetic and purification processes employ high temperatures in the preparation of dipyridamole which leads to inefficiency and high processing costs. The high temperatures also lead to higher levels of impurities being formed during manufacture with the consequence that further cumbersome and expensive purification procedures are required.The high quality dipyridamole prepared by the processes according to the present invention can be used for the preparation of a pharmaceutical composition to use in the manufacture of a medicament for anti-platelet therapy. A preferred embodiment of the present invention, illustrated in Scheme 2, provides a process for the preparation of dipyridamole comprising reacting 2,6-dichloro-4,8- dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine at 113-115°C. This reaction temperature is significantly lower than that used in the prior art processes to prepare dipyridamole.
Another preferred embodiment of the present invention, illustrated in Scheme 3, also provides a process for the preparation of dipyridamole by the reaction of 2,6-dichloro-4,8- dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine in dimethylsulfoxide at 120- 125°C to afford the mono-substituted intermediate, 2-chloro-6-diethanolamino-4,8- dipiperidino-pyrimido(5,4-d)pyrimidine, which is isolated and then further converted to dipyridamole by heating in diethanolamine at 113-115°C.Although the solvent used in this preferred embodiment of the present invention is preferably dimethylsulfoxide (DMSO), other solvents can alternatively be used. Preferred alternative solvents are other polar aprotic solvents, such as dimethylformamide (DMF), dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP). Alternatively, hydrocarbon solvents can be used. Preferred hydrocarbon solvents are aromatic hydrocarbon solvents such as toluene or xylene.
Example 1Preparation of crude dipyridamoleDiethanolamine (10 vol) and 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine (1 eq) were mixed at 25-30°C, stirred for 10 minutes and then heated at 113-115°C for 45-48 hours. After completion of the reaction, the mixture was cooled to 75-80°C. Ethanol (5 vol) was added at 75-80°C and the mixture was stirred at 75-80°C for 10 minutes. Toluene (10 vol) was added at 70-75°C and the mixture was stirred at 70-75°C for 15 minutes. Purified water (15 vol) was added at 70-75°C and the mixture was stirred at 60-65°C for 30 minutes. The mixture was then cooled and stirred at 25-30°C for 30 minutes. The precipitated solid was filtered and washed with purified water (2 x 5 vol) before drying at 75-80°C under reduced pressure afforded crude dipyridamole as a yellow crystalline solid. Yield (w/w) = 80-85%Yield (molar) = 58-62%HPLC purity > 98%Example 2Stage 1: Preparation of 2-chloro-6-diemanolamino-4,8-dipiperidino-pyrimido(5,4-d) pyrimidineDiethanolamine (3 eq) and 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine (1 eq) were added to dimefhylsulfoxide (10 vol) at 25-30°C, stirred for 10 minutes and then heated at 120-125°C for 4-5 hours. After completion of the reaction, the reaction mixture was cooled to 55-60°C. Acetone (5 vol) was added at 55-60°C and the mixture was stirred at 55-60°C for 10 minutes. Purified water (15 vol) was added at 55-60°C and the mixture was stirred at 50-55°C for 15 minutes. The mixture was cooled to 25-30°C and stirred at 25-30°C for 30 minutes. The precipitated solid was filtered, washed with purified water (2 x 5 vol) and dried at 75-80°C under reduced pressure to afford crude 2-chloro-6- diethanolamino-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine as a yellow crystalline solid. Yield (w/w) = 110-120%Yield (molar) = 93-100%HPLC purity > 96%Stage 2: Preparation of crude dipyridamoleDiethanolamine (10 vol) and 2-chloro-6-diemanolamino-4,8-dipiperidino-pyrimido(5,4-d) pyrimidine (1 eq) were mixed at 25-30°C, stirred for 10 minutes and then heated at 113- 115°C for 45-48 hours. After completion of the reaction, the mixture was cooled to 75- 80°C. Ethanol (5 vol) was added and the mixture was stirred at 75-80°C for 10 minutes. Toluene (10 vol) was added and the mixture was stirred at 70-75°C for 15 minutes. Purified water (15 vol) was added and the mixture was stirred at 60-65°C for 30 minutes. The mixture was then cooled to 25-30°C and stirred for 30 minutes. The precipitated solid was filtered, washed with purified water (2 x 5 vol) and dried at 75-80°C under reduced pressure to afford crude dipyridamole as a yellow crystalline solid.Yield (w/w) = 95-97%Yield (molar) = 82-84%HPLC purity > 98%Example 3Crystallization of crude dipyridamoleCrude dipyridamole (1 eq) and diefhanolamine (8 vol) were stirred together at 25-30°C for 10 minutes and then heated to about 80°C for 10 minutes. The clear solution was cooled to 75-80°C, ethanol (5 vol) was added and the mixture was stirred at 75-80°C for 10 minutes. Toluene (10 vol) was added and the mixture was stirred at 70-75°C for 15 minutes. The mixture was cooled to 25-30°C, stirred at 25-30°C for 10 minutes and filtered. The filtrate was heated to 70-75°C for 10 minutes, purified water (15 vol) was added and the mixture was stirred at 60-65°C for 30 minutes before cooling to 25-30°C with stirring for 30 minutes. The precipitated solid was filtered, washed with purified water (2 x 5 vol) and dried at 75-80°C under reduced pressure to afford dipyridamole as a yellow crystalline solid.Yield (w/w and molar) = 90-95%HPLC purity > 99.9%
PATENT
https://patents.google.com/patent/WO2007080463A1/enDipyridamole which is chemically known as 4,8-Bis(piperidino)-N,N,N’,N’- tetra(2-hydroxyethyl)pyrimido[5,4-d]pyrimidine-2,6-diamine is a platelet adhesion inhibitor. It is useful in anti-platelet therapy and it is marketed as Persantin ® by Boehringer Ingelheim.The platelet aggregation inhibiting properties, anti-thrombotic and vasodilator properties of Dipyridamole is reported in US patent 3031450 which also describe a process for its preparation by reacting 2-chloro-6-diethanolamino-4, 8-dipiperidyl- pyrimido-pyrimidine with diethanolamine.German patent 117456 describes the process for the production of Dipyridamole from 2,6-dichloro-4,8-dipiperidinopyrimido[5,4-d]pyrimidine and diethanolamine at 130 to 200° C under vacuum. German patent 1812918 describes the process for the preparation and purification of Dipyridamole. According to this patent 2,6-dichloro-4,8,- dipiperidinopyrimido[5,4-d]pyrimidine and diethanolamine are heated to 150 to 2000C to obtain Dipyridamole. This is characterized by the fact that after the completion of the reaction, the reaction mixture is dissolved in chloroform, which is further separated into the upper layer of diethanolamine and its hydrochloride and the chloroform solution. Thus obtained chloroform solution is reduced to dryness after stirring with water.RO 104718 Bl describes a process where Dipyridamole is manufactured and purified by reaction of diethanolamine with 2,6-dichloro-4,8-dipiperidinopyrimido[5,4- d]pyrimidine. In this process the yield is very low (58%) and purity is only 98%.Another patent DDl 15670 Z describes a process for the purification of Dipyridamole by refluxing it in AcOBu for 2 h in the presence of an equal amount of silica gel or by column chromatography on silica gel at 60-1000C. The purification by column chromatography is not economical and feasible at industrial scale.All the above mentioned prior art are neat reaction in which it is difficult to control the impurity and is not easy to scale up. In the prior art process the obtained product is pasty which needs decanting the mother liquor and further purification.We focused our research to develop an improved and efficient process for the preparation and purification of Dipyridamole of formula (I) which will overcome the above mentioned prior art problems and will produce Dipyridamole in substantially good yield, high purity and with no mixture of solvents.Objectives of the InventionThe main objective of the present invention is to provide an improved process for the preparation and purification of compound of formula (I), which gives better purity and high yield of the product. Another objective of the present invention is to provide a process for the preparation and purification of compound of formula (I), which would be easy to scale up and implement at industrial level.Yet another objective of the present invention is to provide a process for the preparation and purification of compound of formula (I), which avoids, use of hazardous gas (SO2) and corrosive chemicals like HCl, H2SO4, acetic acid, NaOH, NH3 etc.Summary of the InventionAccordingly, the present invention provides a process for the preparation ofDipyridamole of formula (I) comprising reacting 2,6-Dichloro-4,8- dipiperidinopyrimido- (5,4-d)pyrimidine (DDH) of formula (II) with Diethanolamine (DEA) of formula (III) using a solvent. This process can be represented by the scheme given below:
(II) (III) (I)The obtained wet or optionally dried crude Dipyridamole is purified by using ketonic solvent and aqueous alcoholic solvent or mixture thereof.Description of the InventionIn an embodiment of the present invention the solvent is selected from the group consisting of l-Methyl-2-pyrrolidinone, Sulpholane and Polyethylene glycol, preferably l-Methyl-2-pyrrolidinone (NMP). In another embodiment of the present invention, the polyethylene glycol used is PEG-20Q or PEG-400, preferably PEG-400.In yet another embodiment of the present invention, the reaction is carried out at a temperature of about 25° C to reflux temperature, preferably at a temperature of about 150° C to 2000C.In still another embodiment of the present invention the starting material of this invention is prepared according to the literature available in the prior art.In yet another embodiment the ketonic solvent is acetone, methyl ethyl ketone, methyl vinyl ketone or methyl isobutyl ketone (MIBK), preferably MIBK.In yet another embodiment the alcoholic solvent is selected from the group having Ci to C4 alkanol preferably isopropyl alcohol (IPA) or methanol.The present invention is illustrated with the following examples, which should not be construed for limiting the scope of the invention.Example 1Preparation of Dipyridamole (Crude)250 mL of l-Methyl-2-pyrrolidinone (NMP), 50g of 2,6-Dichloro-4,8 dipiperidinopyrimido(5,4-d)pyrimidine (DDH) and 136g of Diethanolamine (DEA) were charged into a 2.0 L four-necked RBF at 25-35 0C. The reaction mass was heated to 190 – 2000C and maintained for 1.5 to 2.5 hrs under stirring. The reaction mass was cooled to 25-350C and 450 mL of purified water was charged slowly into it and stirred for lhr. The solid reaction mass was filtered and washed with 500ml-purified water and dried the solid under vacuum at 50-550C for 8 to 10 hrs to get 55-60 g of crude Dipyridamole of 90-94% HPLC purity.Purification Of DipyridamoleMethyl isobutyl ketone (750 ml) and 50 g of Dipyridamole (crude) were charged into a clean 2.0 L four-necked RBF at 25-3O0C and heated to 100-1200C. It was stirred to dissolve and cooled to 25-350C and stirred for 30-60 min. The solid was Filtered and washed with 100 ml MIBK. The product was dried at 45-50 0C under vacuum. The obtained material was further purified as follows:Isopropyl alcohol (200 mL) and 40-45 g of Dipyridamole were charged into a clean 1.0 lit four-necked RBF at 25-350C. It was heated to 60-650C. Carbon (Ig) was added at 30-350C and filtered through celite and washed with 50 mL IPA. Water (500 mL) was charged slowly and stirred for 30 min. The solid was filtered and washed with a mixture of IPA : Water (1 :2) and dried the product at 45-50 0C under vacuum to obtain 43-5Og of Dipyridamole having HPLC purity 99.0 – 99.5%Example 2Sulpholane (15 mL), 5.0g of 2,6-Dichloro-4,8-dipiperidinopyrimido(5,4-d) pyrimidine (DDH) and 8.6g Diethanolamine (DEA) were charged into 100 mL four- necked RBF at 25-35°C. It was heated to 190-2000C and stirred for 2-3 hrs. The reaction mass was cooled to 25-35°C and 45 mL of water was added into it. The reaction mass was stirred. The solid was filtered and washed with water. The solid was purified with MIBK,IPA-Water as given in example 1.Example 3Polyethylene glycol-400 (15 mL), 5g of 2,6-Dichloro-4,8-dipiperidinopyrimido (5,4-d) pyrimidine (DDH) and 8.6 gm Diethanolamine (DEA) were charged into 10OmL four necked RBF at 25-35°C. The reaction mass was heated to 190-2000C and maintained for 2-3 hrs. The mixture was cooled to 25-350C. Water (45 mL) was added to the reaction mixture and stirred. The solid was filtered and washed with water. The solid was purified with MIBK,IPA- Water as given in example 1.Example 4 (Azeotrophic removal of water in MIBK purification)Preparation of Dipyridamole (Crude*) l-Methyl-2-pyrrolidinone (150 mL), 50g of 2,6-Dichloro-4,8-dipiperidinopyrimido(5,4-d)pyrimidine (DDH) and 136g Diethanolamine (DEA) was charged into a 2.0 L four-necked RBF at 25-35 0C. The reaction mass was stirred & heated to 190 – 2000C and stirring was continued for 1.5 to 2.5 hrs. The reaction mass was cooled to 25-350C and 450 mL of purified water was charged slowly into it and stirred for lhr. The solid reaction mass was filtered and washed with 500ml-purified water to obtain 110-13Og of wet crude Dipyridamole.Purification Of DipyridamoleMethyl isobutyl ketone (750 ml) and 65 g of Dipyridamole (wet crude) were charged into a clean 2.0 L four-necked RBF at 25-3O0C and heated to 100-1200C followed by azeotrophic separation of water. It was cooled to 25-350C and stirred for30-60 min. The solid was filtered and washed with 100 ml MIBK. The product was dried at 45-50 0C under vacuum. The obtained material was further purified as follows:Isopropyl alcohol (200 mL) and 45-48 g of Dipyridamole were charged into a clean 1.0 L four-necked RBF at 25-350C. It was heated to 60-650C and stirred to dissolve. Carbon (Ig) was added at 30-350C and filtered through celite and washed with 50 mL IPA. Water (500 mL) was charged slowly and stirred for 30 min. The solid was filtered and washed with a mixture of IPA : Water (1:2) and dried the product at 45-50 0C under vacuum to obtain 43-5Og of Dipyridamole having HPLC purity 99.0-99.5%Purification with Methaanol-waterMethanol (200 mL) and 45-48 g of Dipyridamole were charged into a clean 1.0 L four-necked RBF at 25-350C. It was heated to 60-650C and stirred to dissolve. Carbon (Ig) was added at 30-350C and filtered through celite and washed with 50 mL methanol. Water (500 mL) was charged slowly and stirred for 30 min. The solid was filtered and washed with a mixture of methanol : Water (1 :2) and dried the product at 45-50 0C under vacuum to obtain 45g of Dipyridamole having HPLC purity 99%.
PATENThttps://patents.google.com/patent/CN108069972A/enEmbodiment 1Weigh urea 120g（2mol）, ethylene glycol 62g（1mol）120 DEG C are heated in a kettle, in Catalyzed by p-Toluenesulfonic Acid Effect is lower to carry out step（1）Reaction, generate compound 3；Then 2,3- diamino succinic acid 37g is weighed（0.25mol）With step The compound 3 generated in rapid 1 carries out the reaction generation compound 5 of step 2,220 DEG C, reaction time 3h of reaction temperature, catalyst For the nickel-base catalyst of support type, catalyst is filtered out after the completion of reaction；Exist in phosphorus oxychloride, phosphorus trichloride and lead to chlorine In the case of, compound 5 carries out chlorination reaction generation compound 6,110 DEG C of reaction temperature, reaction time 30h；Weigh piperidines 85g （1mol）Step is carried out with compound（4）Reaction, after reaction liquid hydrolysis, cooling filtering, be dried to obtain compound 9；Claim Take 105g（1mol）Diethanol amine and compound 9 carry out step（6）Reaction, 220 DEG C of reaction temperature, reaction time 3h fills 1.5 MPa of Hydrogen Vapor Pressure, catalyst are the crude product of the nickel-base catalyst, after reaction cold filtration of support type, and crude product passes through It is refining to obtain Dipyridamole finished product, quality 62.10g, purity 99.21%, product yield 48.74%（Yield is with 2,3- diamino fourths Diacid is calculating benchmark）.Embodiment 2Weigh urea 120g（2mol）, ethylene glycol 62g（1mol）120 DEG C are heated in a kettle, in Catalyzed by p-Toluenesulfonic Acid Effect is lower to carry out step（1）Reaction, generate compound 3；Then 2,3- diamino succinic acid 30g is weighed（0.2mol）With step The compound 3 generated in rapid 1 carries out the reaction generation compound 5 of step 2,220 DEG C, reaction time 3h of reaction temperature, catalyst For the nickel-base catalyst of support type, catalyst is filtered out after the completion of reaction；Exist in phosphorus oxychloride, phosphorus trichloride and lead to chlorine In the case of, compound 5 carries out chlorination reaction generation compound 6,110 DEG C of reaction temperature, reaction time 30h；Weigh piperidines 85g （1mol）Step is carried out with compound（4）Reaction, after reaction liquid hydrolysis, cooling filtering, be dried to obtain compound 9；Claim Take 105g（1mol）Diethanol amine and compound 9 carry out step（6）Reaction, 220 DEG C of reaction temperature, reaction time 3h fills 1.5 MPa of Hydrogen Vapor Pressure, catalyst are the crude product of the nickel-base catalyst, after reaction cold filtration of support type, and crude product passes through It is refining to obtain Dipyridamole finished product, quality 50.34g, purity 99.3%, product yield 49.53%（Yield is with 2,3- diamino fourth two Acid is calculating benchmark）.Embodiment 3Other steps are the same as embodiment 2, step（6）In reaction temperature for 240 DEG C, product yield 50.31%.Comparative example 1Weigh urea 36g（0.6mol）, ethyl acetoacetate 26g（0.2mol）, add in ethanol-hydrogen chloride liquid（30% hydrochloric acid：95% second Alcohol=1:4）Then 200ml, drying and dehydrating after stirring add in sodium hydroxide solution and are warming up to 95 DEG C, then cool to 75 DEG C, add Hydrochloric acid adjusts PH=1, cold filtration, the 6- methyluracils of washing filtering；Nitric acid is added in reaction pot, is cooled to less than 10 DEG C, Stirring adds in 6- methyluracils, be warming up to 30 DEG C of heat preservations 1 it is small when the nitro whey liquid that filters；Take a policy powder in water, stirring After dissolving plus nitro whey liquid, temperature control keep the temperature 30min at 35 DEG C, add the static 3h of hydrochloric acid, stir 2h, filtration drying obtains amino breast Clear liquid；Again weigh urea 36g and add in reaction kettle with amino whey liquid, stirring is warming up to 100 DEG C of heat preservation 20min, cools to 90 DEG C add in 2mol/L sodium hydroxide solution, be warming up to 100 DEG C heat preservation dissolving 1h.Cool to 40 DEG C, filter tetrahydroxy pyrimidine- [4,5d] and pyrimidine sodium salt, adds water, 60 DEG C of heat preservation 30min add hydrochloric acid to adjust PH=4, is cooled to 15 DEG C of filterings, washing, dries 2,4,6,8- tetrahydroxys pyrimidine-[4,5d] and pyrimidine；Tetrahydroxy object, phosphorus oxychloride, phosphorus trichloride are added in reaction kettle, is stirred, 10 DEG C of similarly hereinafter chlorine are warming up to 110 DEG C of reflux for 24 hours, be cooled to 15 DEG C of filterings, washing, dry 2,4,6,8- tetrachloro-pyrimidines- [4,5d] and pyrimidine；Acetone, tetrachloride are sequentially added, piperidines-acetone mixture, 30 DEG C of heat preservations are added dropwise in 20 DEG C of heat preservation 30min 1h, adds water to stir 1h, and filtration drying obtains 2,6- bis- chloro- 4,8 ,-two piperidines-pyrimidine（Dichloride）；Weigh diethanol amine 63g with Dichloride is mixed, and is warming up to 200 DEG C of heat preservation 15min, is cooled to less than 25 DEG C plus acetone and stirs 30min, then 30 DEG C 4h is kept the temperature, filtration drying obtains Dipyridamole crude product, then carries out refined Dipyridamole finished product 13.53, purity 98.5%, yield 13.21%（Using ethyl acetoacetate as calculating standard）.It is found by being compared with comparative example：The method of the production Dipyridamole of the present invention is short with synthetic route, into The characteristics of product high income, production cost is low.
SYN
GB 807826 U.S. Patent 3,031,450
SYN
SYN
R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006
Dipyridamole
Dipyridamole, 2,2′,2″,2′″-[(4,8-dipiperidinopirimido[5,4-d]pirimidin-2,6-diyl)-diimino]-tetraethanol (19.4.13), is easily synthesized from 5-nitroorotic acid (19.4.8), easily obtained, in turn, by nitrating of 2,4-dihydroxy-6-methylpyrimidine, which is usually synthesized by the condensation of urea with acetoacetic ether. Reduction of the nitro group in 5-nitroorotic acid by various reducing agents gives 5-aminoorotic acid (19.4.9), which is reacted with urea or with potassium cyanide to give 2,4,6,8-tetrahydroxypyrimido[5,4-d]pyrimidine (19.4.10). This undergoes a reaction with a mixture of phosphorous oxychloride and phosphorous pentachloride, which forms 2,4,6,8- tetra-chloropyrimido[5,4-d]pyrimidine (19.4.11). Reacting the resulting tetrachloride with piperidine replaces the chlorine atoms at C4 and C8 of the heterocyclic system with piperidine, giving 2,6-dichloropyrimido-4,8-dipiperidino[5,4-d]pyrimidine (19.4.12). Reacting the resulting product with diethanolamine gives dipyridamole (19.4.13) [32,33].
Dipyridamole increases coronary blood circulation, increases oxygen flow to the myocardium, potentiates adenosine activity, and impedes its metabolization. It inhibits aggregation of thrombocytes, blocks phosphodiesterase, increases microcirculation, and inhibits the formation of thrombocytes.
It is used for chronic coronary insufficiency, as well as for preventing and treating thrombosis. Synonyms of this drug are anginal, curantyl, stenocor, thrompresantin, and many others.SYN
Chemical Synthesis
Dipyridamole, 2,2′,2”,2”’-[(4,8-dipiperidinopirimido[5,4-d]pirimidin-2,6- diyl)-diimino]-tetraethanol (19.4.13), is easily synthesized from 5-nitroorotic acid (19.4.8), easily obtained, in turn, by nitrating of 2,4-dihydroxy-6-methylpyrimidine, which is usually synthesized by the condensation of urea with acetoacetic ether. Reduction of the nitro group in 5-nitroorotic acid by various reducing agents gives 5-aminoorotic acid (19.4.9), which is reacted with urea or with potassium cyanide to give 2,4,6,8- tetrahydroxypyrimido[5,4-d]pyrimidine (19.4.10). This undergoes a reaction with a mixture of phosphorous oxychloride and phosphorous pentachloride, which forms 2,4,6,8- tetrachloropyrimido[ 5,4-d]pyrimidine (19.4.11). Reacting the resulting tetrachloride with piperidine replaces the chlorine atoms at C4 and C8 of the heterocyclic system with piperidine, giving 2,6-dichloropyrimido-4,8-dipiperidino[5,4-d]pyrimidine (19.4.12). Reacting the resulting product with diethanolamine gives dipyridamole (19.4.13).
clipA general outline of the procedure for synthesizing dipyridamole is shown in Scheme 1. Reaction of the pyrimidino pyrimidine-2,4,6,8- tetraol (1) with a mixture of phosphorous oxychloride and phosphorous pentachloride gives the tetrachloro derivative (2). The halogens at the peri positions 4 and 8 are more reactive to substitution than are the remaining halogen pairs 2 and 6, which are in effect the two positions of the pyrimidines. Thus, reaction with piperidine at ambient temperature gives the 4, 8 diamine (3). Subsequent reaction with bis-2-hydroxy ethylamine under more strenuous conditions gives dipyridamole (4) [12, 13].12. F.G. Fischer, J. Roch, and A. Kottler, U.S. Patent 3, 031, 450 (1962). 13. D. Lednicer and L.A. Mitscher, The Organic Chemistry of Drug Synthessis Volume 1, John Wiley and Sons, New York, p. 428 (1977).
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Medical uses
- Dipyridamole is used to dilate blood vessels in people with peripheral arterial disease and coronary artery disease[4]
- Dipyridamole has been shown to lower pulmonary hypertension without significant drop of systemic blood pressure
- It inhibits formation of pro-inflammatory cytokines (MCP-1, MMP-9) in vitro and results in reduction of hsCRP[clarification needed] in patients.
- It inhibits proliferation of smooth muscle cells in vivo and modestly increases unassisted patency of synthetic arteriovenous hemodialysis grafts.[5]
- It increases the release of tissue plasminogen activator from brain microvascular endothelial cells.
- It results in an increase of 13-hydroxyoctadecadienoic acid and decrease of 12-hydroxyeicosatetraenoic acid in the subendothelial matrix and reduced thrombogenicity of the subendothelial matrix.
- Pretreatment it reduced reperfusion injury in volunteers.
- It has been shown to increase myocardial perfusion and left ventricular function in patients with ischemic cardiomyopathy.
- It results in a reduction of the number of thrombin and PECAM-1 receptors on platelets in stroke patients.
- Cyclic adenosine monophosphate impairs platelet aggregation and also causes arteriolar smooth muscle relaxation. Chronic therapy did not show significant drop of systemic blood pressure.
- It inhibits the replication of mengovirus RNA.[6]
- It can be used for myocardial stress testing as an alternative to exercise-induced stress methods such as treadmills.
Stroke
A combination of dipyridamole and aspirin (acetylsalicylic acid/dipyridamole) is FDA-approved for the secondary prevention of stroke and has a bleeding risk equal to that of aspirin use alone.[4] Dipyridamole absorption is pH-dependent and concomitant treatment with gastric acid suppressors (such as a proton pump inhibitor) will inhibit the absorption of liquid and plain tablets.[7][8] Modified release preparations are buffered and absorption is not affected.[9][10]
However, it is not licensed as monotherapy for stroke prophylaxis, although a Cochrane review suggested that dipyridamole may reduce the risk of further vascular events in patients presenting after cerebral ischemia.[11]
A triple therapy of aspirin, clopidogrel, and dipyridamole has been investigated, but this combination led to an increase in adverse bleeding events.[12]
- Vasodilation occurs in healthy arteries, whereas stenosed arteries remain narrowed. This creates a “steal” phenomenon where the coronary blood supply will increase to the dilated healthy vessels compared to the stenosed arteries which can then be detected by clinical symptoms of chest pain, electrocardiogram and echocardiography when it causes ischemia.
- Flow heterogeneity (a necessary precursor to ischemia) can be detected with gamma cameras and SPECT using nuclear imaging agents such as Thallium-201, Tc99m–Tetrofosmin and Tc99m–Sestamibi. However, relative differences in perfusion do not necessarily imply any absolute decrease in blood supply in the tissue supplied by a stenosed artery.
Other uses
Dipyridamole also has non-medicinal uses in a laboratory context, such as the inhibition of cardiovirus growth in cell culture.[citation needed]
Drug interactions
Due to its action as a phosphodiesterase inhibitor, dipyridamole is likely to potentiate the effects of adenosine. This occurs by blocking the nucleoside transporter (ENT1) through which adenosine enters erythrocyte and endothelial cells.[13]
According to Association of Anaesthetists of Great Britain and Ireland 2016 guidelines, dipyridamole is considered to not cause risk of bleeding when receiving neuroaxial anaesthesia and deep nerve blocks. It does not therefore require cessation prior to anaesthesia with these techniques, and can continue to be taken with nerve block catheters in place.[14]
Overdose
Dipyridamole overdose can be treated with aminophylline[2]: 6 or caffeine which reverses its dilating effect on the blood vessels. Symptomatic treatment is recommended, possibly including a vasopressor drug. Gastric lavage should be considered. Since dipyridamole is highly protein bound, dialysis is not likely to be of benefit.
Mechanisms of action
Dipyridamole has two known effects, acting via different mechanisms of action:
- Dipyridamole inhibits the phosphodiesterase enzymes that normally break down cAMP (increasing cellular cAMP levels and blocking the platelet aggregation, response[4] to ADP) and/or cGMP.
- Dipyridamole inhibits the cellular reuptake of adenosine into platelets, red blood cells, and endothelial cells, leading to increased extracellular concentrations of adenosine.
Experimental studies[
Dipyridamole is currently undergoing repurposing for treatment of ocular surface disorders. These include pterygium and dry eye disease. The first report of topical dipyridamole’s benefit in treating pterygium was published in 2014.[15] A subsequent report of outcomes in 25 patients using topical dipyridamole was presented in 2016.[16]
See also
References
- ^ Nielsen-Kudsk, F; Pedersen, AK (May 1979). “Pharmacokinetics of Dipyridamole”. Acta Pharmacologica et Toxicologica. 44 (5): 391–9. doi:10.1111/j.1600-0773.1979.tb02350.x. PMID 474151.
- ^ Jump up to:a b “Aggrenox (aspirin/extended-release dipyridamole) Capsules. Full Prescribing Information” (PDF). Boehringer Ingelheim Pharmaceuticals, Inc. Retrieved 1 December 2016.
- ^ “Dipyridamole” at Dorland’s Medical Dictionary
- ^ Jump up to:a b c Brown DG, Wilkerson EC, Love WE (March 2015). “A review of traditional and novel oral anticoagulant and antiplatelet therapy for dermatologists and dermatologic surgeons”. Journal of the American Academy of Dermatology. 72 (3): 524–34. doi:10.1016/j.jaad.2014.10.027. PMID 25486915.
- ^ Dixon BS, Beck GJ, Vazquez MA, et al. (2009). “Effect of dipyridamole plus aspirin on hemodialysis graft patency”. N Engl J Med. 360 (21): 2191–2201. doi:10.1056/nejmoa0805840. PMC 3929400. PMID 19458364.
- ^ Dipyridamole in the laboratory: Fata-Hartley, Cori L.; Ann C. Palmenberg (2005). “Dipyridamole reversibly inhibits mengovirus RNA replication”. Journal of Virology. 79 (17): 11062–11070. doi:10.1128/JVI.79.17.11062-11070.2005. PMC 1193570. PMID 16103157.
- ^ Russell TL, Berardi RR, Barnett JL, O’Sullivan TL, Wagner JG, Dressman JB. pH-related changes in the absorption of “dipyridamole” in the elderly. Pharm Res (1994) 11 136–43.
- ^ Derendorf H, VanderMaelen CP, Brickl R-S, MacGregor TR, Eisert W. “Dipyridamole” bioavailability in subjects with reduced gastric acidity. J Clin Pharmacol (2005) 45, 845–50.
- ^ “Archived copy”. Archived from the original on 2009-07-05. Retrieved 2010-02-06.
- ^ Stockley, Ivan (2009). Stockley’s Drug Interactions. The Pharmaceutical Press. ISBN 978-0-85369-424-3.
- ^ De Schryver EL, Algra A, van Gijn J (2007). Algra A (ed.). “Dipyridamole for preventing stroke and other vascular events in patients with vascular disease”. Cochrane Database of Systematic Reviews (2): CD001820. doi:10.1002/14651858.CD001820.pub3. PMID 17636684.
- ^ Sprigg N, Gray LJ, England T, et al. (2008). Berger JS (ed.). “A randomised controlled trial of triple antiplatelet therapy (aspirin, clopidogrel and dipyridamole) in the secondary prevention of stroke: safety, tolerability and feasibility”. PLOS ONE. 3 (8): e2852. Bibcode:2008PLoSO…3.2852S. doi:10.1371/journal.pone.0002852. PMC 2481397. PMID 18682741.
- ^ Gamboa A, Abraham R, Diedrich A, Shibao C, Paranjape SY, Farley G, et al. Role of adenosine and nitric oxide on the mechanisms of action of dipyridamole. Stroke. 2005;36(10):2170-2175.
- ^ AAGBI Guidelines Neuraxial and Coagulation June 2016
- ^ Carlock, Beth H.; Bienstock, Carol A.; Rogosnitzky, Moshe (2014-03-25). “Pterygium: Nonsurgical Treatment Using Topical Dipyridamole – A Case Report”. Case Reports in Ophthalmology. 5 (1): 98–103. doi:10.1159/000362113. ISSN 1663-2699. PMC 3995373. PMID 24761148.
- ^ “Topical Dipyridamole for Treatment of Pterygium and Associated Dry Eye Symptoms: Analysis of User-Reported Outcomes”. ResearchGate. Retrieved 2019-05-19.
| Clinical data | |
|---|---|
| Trade names | Persantine, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682830 |
| Pregnancy category | B |
| Routes of administration | By mouth, IV |
| ATC code | B01AC07 (WHO) |
| Legal status | |
| Legal status | UK: POM (Prescription only)US: ℞-only |
| Pharmacokinetic data | |
| Bioavailability | 37–66%[1] |
| Protein binding | ~99% |
| Metabolism | Liver (glucuronidation)[2] |
| Elimination half-life | α phase: 40 min, β phase: 10 hours |
| Excretion | Biliary (95%), urine (negligible) |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 58-32-2 |
| PubChem CID | 3108 |
| IUPHAR/BPS | 4807 |
| DrugBank | DB00975 |
| ChemSpider | 2997 |
| UNII | 64ALC7F90C |
| KEGG | D00302 |
| ChEBI | CHEBI:4653 |
| ChEMBL | ChEMBL932 |
| CompTox Dashboard (EPA) | DTXSID6040668 |
| ECHA InfoCard | 100.000.340 |
| Chemical and physical data | |
| Formula | C24H40N8O4 |
| Molar mass | 504.636 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| hideSMILESOCCN(CCO)C(N=C1N2CCCCC2)=NC3=C1N=C(N(CCO)CCO)N=C3N4CCCCC4 | |
| showInChI | |
| (verify) |
Patent
Publication numberPriority datePublication dateAssigneeTitleUS3031450A1959-04-301962-04-24Thomae Gmbh Dr KSubstituted pyrimido-[5, 4-d]-pyrimidinesDE1812918A11968-04-251969-11-06Dresden Arzneimittel2,6-Bis (diethanolamino-4,8-dipiperidino-pyrimido (5,4-d)-pyrimidine – purification by simple procedure giving good yieldsDD115670A11974-02-191975-10-12DD117456A11975-02-131976-01-12DE2927539A1 *1979-07-071981-01-08Margineanu Dan Axente Dipl IngBis:di:ethanol-amino-di:piperidino-pyrimido-pyrimidine prepn. – from methyl acetoacetate and urea via amino-orotic acidRO104718B11989-08-091994-09-30Medicamente DePRODUCTION METHOD OF PURE 2,6-bis-(DIETHANOL AMIDE)-4,8-DI- PIPERIDINE-PYRIMIDO-(5,4-d)-PYRIMIDINEWO2007080463A12006-01-122007-07-19Orchid Chemicals & Pharmaceuticals LimitedAn improved process for the preparation of dipyridamoleFamily To Family CitationsDE115670C *JPS5191295A *1975-02-051976-08-10Jipiridamooruno kairyoseizohoJPS5757038B2 *1977-09-301982-12-02Yamanouchi Pharma Co LtdJPS57209291A *1981-06-171982-12-22Kyowa Hakko Kogyo Co LtdPurification of dipyridamoleUS6232312B1 *1995-06-072001-05-15Cell Pathways, Inc.Method for treating patient having precancerous lesions with a combination of pyrimidopyrimidine derivatives and esters and amides of substituted indenyl acetic acidesCN1425461A *2003-01-032003-06-25贵州益佰制药股份有限公司Injection preparation for resisting platelet aggregation and its producing methodCN1634085A *2004-11-242005-07-06崔晓廷Injectio of aspirin and dipyridamole and its preparing process
Non-Patent
TitleCURTIN, NICOLA J. ET AL: “Resistance-Modifying Agents of Pyrimido[5,4-d]pyrimidine Modulators of Antitumor Drug Activity. Synthesis and Structure-Activity Relationships for Nucleoside Transport Inhibition and Binding to .alpha.1-Acid Glycoprotein”, JOURNAL OF MEDICINAL CHEMISTRY , 47(20), 4905-4922 CODEN: JMCMAR; ISSN: 0022-2623, 26 August 2004 (2004-08-26), XP002651697 *
CN104710431B *2015-03-182017-03-01常州康普药业有限公司A kind of purifying process of dipyridamoleCN107782805B *2016-08-252021-02-02亚宝药业集团股份有限公司HPLC analysis method for key intermediate impurity synthesized by dipyridamoleCN106380471B *2016-08-312018-11-06广州市桐晖药业有限公司A kind of preparation method of DipyridamoleCN108069972A *2016-11-162018-05-25湖南尔康制药股份有限公司A kind of production method of Dipyridamole bulk pharmaceutical chemicalsCN106946887B *2017-03-242019-05-28大连万福制药有限公司A kind of preparation method introducing catalyst optimization synthesis Dipyridamole
/////////////////Dipyridamole, дипиридамол , ديبيريدامول , 双嘧达莫 , 0068373 , NSC-515776, RA-8
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