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SIBUTRAMINE
SIBUTRAMINE
- Molecular FormulaC17H26ClN
- Average mass279.848 Da
1-(4-Chlorophenyl)-N,N-dimethyl-a-(2-methylpropyl)cyclobutane methanamine
1-[1-(4-Chlorophenyl)cyclobutyl]-N,N,3-trimethyl-1-butanamine
106650-56-0[RN]
106650-56-0 (Sibutramine );
125494-59-9 (Sibutramine HCl Monohydrate);
84485-00-7 (Sibutramine HCl);
6124
UNII:WV5EC51866, WV5EC51866
сибутрамин[Russian]
سيبوترامين[Arabic]
西布曲明[Chinese]
Drug Name：Sibutramine Hydrochloride Hydrate
Research Code：BTS-54524
Trade Name：Meridia®
MOA：Serotonin-norepinephrine reuptake inhibitor
Indication：Obesity
Status：Withdrawn
Company：Abbott (Originator)
Sibutramine hydrochloride monohydrate, KES-524, BTS-54524, Meridia, Reductil
Sibutramine, formerly sold under the brand name Meridia among others, is an appetite suppressant which has been discontinued in many countries. Until 2010, it was widely marketed and prescribed as an adjunct in the treatment of obesity along with diet and exercise. It has been associated with increased cardiovascular events and strokes and has been withdrawn from the market in several countries and regions including Australia,[1] Canada,[2] China,[3] the European Union,[4] Hong Kong,[5] India,[6] Mexico, New Zealand,[7] the Philippines,[8] Thailand,[9] the United Kingdom,[10] and the United States.[11] However, the drug remains available in some countries.[12]
Sibutramine was originally developed in 1988 by Boots in Nottingham, UK,[13] and marketed by Knoll Pharmaceuticals after BASF/Knoll AG purchased the Boots Research Division in 1995, and was most recently manufactured and marketed by Abbott Laboratories before its withdrawal from most markets. It has been sold under a variety of brand names including Reductil, Meridia, Siredia, and Sibutrex. It is classified as a Schedule IV controlled substance in the United States.
Sibutramine hydrochloride hydrate was approved by the U.S. Food and Drug Administration (FDA) on Nov 16, 1997. It was developed and marketed as Meridia® by Abbott in the US.
Sibutramine hydrochloride hydrate is a serotonin-norepinephrine reuptake inhibitor, it produces its therapeutic effects by norepinephrine, serotonin and dopamine reuptake inhibition. Meridia® is indicated for the management of obesity, including weight loss and maintenance of weight loss, and should be used in conjunction with a reduced calorie diet.
Meridia® is available as capsule for oral use, containing 5, 10 or 15 mg of Sibutramine hydrochloride hydrate. The recommended dose is initiated at 10 mg once daily with or without food and may increase to 15 mg once daily.
Sibutramine has been withdrawn from the market in several countries and regions since 2010, owning to its side effect that associated with increased cardiovascular events and strokes.Route 1
Reference：1. US4746680A / US4806570A.
2. US4929629A.
SYN
SYN
SYN
PAT
https://patents.google.com/patent/KR20060019351A/en
Sibutramine hydrochloride (Sibutramine HCl: C 17 H 26 CIN HCl) is a chemical name {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -dimethylamine hydrochloride, and has the structure of Formula 1 .
Sibutramine was originally developed as a drug for the treatment of depression and was found to give weight to patients taking this drug. It was developed as an anti-obesity drug. Let your appetite decrease.
Korean Patent Publication No. 1990-274 (corresponding patent DE3212682 (Boots), filed Oct. 21, 1982; priority GB 1981.4.6.) For the preparation of 1- (1-arylcyclobutyl) alkylamine derivative comprising sibutramine It is described. The method for synthesizing sibutramine described in this document proceeds in a total of five steps as follows.
Step A
1- (4-chlorophenyl) -1-cyclobutyl cyanide is obtained from 4-Chlorobenzyl cyanide. Examples of the actual synthesis method described in this document are as follows.
After dissolving 25 g of 4-chlorobenzyl cyanide and 15 ml of 1,3-dibromopropane in 150 ml of DMSO, the solution was dissolved in nitrogen at room temperature (20-35 ° C.) and 7.5 g of NaH dispersed in mineral oil. And 200 ml of DMSO was added dropwise. The mixture was stirred at room temperature for 2 hours, 8 ml of IPA was added dropwise, and 110 ml of water was added dropwise. The mixture is filtered through CELITE ™ and the solid residue is washed with ether. The ether layer is separated, washed with water, dried, evaporated and vacuum distilled at high temperature to separate the desired 1- (4-chlorophenyl) -1-cyclobutyl cyanide. The total reaction time of this step is 5 hours and the yield from the starting material is 78%.
Step B
1- [1- (4-chlorophenyl) -cyanobutyl] -3-methyl-butan-1-one is obtained from 1- (4-chlorophenyl) -1-cyclobutyl cyanide. Specific synthesis examples are as follows. 35.2 g of 1- (4-chlorophenyl) -1-cyclobutyl cyanide are dissolved in 100 ml of ether and this solution is added to the product prepared by the reaction of 32 g of propylbromide and 6.36 g of magnesium. The ether is replaced with toluene and the mixture is heated under reflux for 1 hour. After adding water, concentrated hydrochloric acid is added, and the mixture is heated under reflux for 1 hour. The mixture obtained in the same manner as in the previous step was treated with ether, water, dried and evaporated and then vacuum distilled to give the desired 1- [1- (4-chlorophenyl) -cyanobutyl] -3-methyl-butan-1-one. To separate. The reaction time of this step is a total of 22 hours, the yield is 81%. The target product is bp 100-120 ° C / 0.2 mm / Hg.
Step C
N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl from 1- [1- (4-chlorophenyl) -cyanobutyl] -3-methyl-butan-1-one } Formamide is obtained. Specific synthesis examples are as follows. To 23.5 ml of formamide, 37 g (0.14 mol) of 1- [1- (4-chlorophenyl) -cyanobutyl] -3-methyl-butan-1-one and 9 ml of HCOOH were added dropwise at 160-170 ° C. The temperature is maintained at 175 ° C. to 180 ° C. for 24 hours. The mixture is extracted with ether and concentrated to afford an oil, which crystallizes the desired N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} formamide from petroleum ether. The reaction time of this step is a total of 24 hours, the yield is 39%. The target is mp 110-112 ° C.
Step D
1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride from N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} formamide Get Specific synthesis examples are as follows. 4 g of N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} formamide, 25 ml of 2-methoxyethyl ether, 10 ml of water and 22 ml of concentrated hydrochloric acid were refluxed for 18 hours. Stir under. Dilute with water, wash with ether, and add 35 ml of 5M aqueous NaOH solution. After completion of the process by treatment with ether, water and brine, treated with magnesium sulfate, filtered and concentrated. The concentrated crude product is saturated with hydrochloric acid dissolved in 20 ml of ether. The resulting solid is filtered, concentrated and crystallized with petroleum ether to give the desired product 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride. The reaction time of this step is a total of 20 hours, the yield is 96% oil, 46% hydrochloride. The target product is mp 163-165 ° C.
Step E
The final target from 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -dimethyl Amine hydrochloride, ie sibutramine hydrochloride, is obtained. Specific synthesis examples are as follows. 3.3 g of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride, 2.99 g of HCOOH and 1 ml of water are mixed while cooling. 3.93 ml of 37% aqueous formaldehyde is added and heated at 85-95 ° C. for 18 hours. Excess hydrochloric acid is added and the solution is evaporated to dryness. 5N NaOH solution is added, extracted with ether and concentrated to give a pale yellow oil. This oil is dissolved in a mixture of 4 mL IPA, 20 mL ether and 2 mL hydrochloric acid is added dropwise. Concentrate, repeatedly dissolve in ethanol and concentrate again. Polishing with petroleum ether gives a yellow solid and recrystallizes with acetone to give the final target sibutramine hydrochloride. The reaction time of this step is a total of 18 hours, the yield is 80%. The target product is mp 195-197 ° C. The yield in 5 steps (A to E) is 18.9%.
As described above, the conventional sibutramine synthesis method has a total of five steps, which is complicated and takes a long time, and requires high temperature vacuum distillation (step A). Since the reaction proceeds at the high temperature of the raw material there was a problem that the yield is reduced. In fact, the synthesis was performed by applying the conventional sibutramine synthesis method, the total yield was very low as 18.9%.
First step
4-Chlorobenzyl cyanide is reacted with 1,3-dibromopropane to give 1- (4-chlorophenyl) -1-cyclobutyl cyanide.
In a flask at room temperature (20-35 ° C.), 14.1 g (352 mmol) of NaH dispersed in mineral oil (200%) and 200 ml of DMSO were added. 25 g (160 mmol) of 4-chlorobenzyl cyanide and 1,3- A solution of 36 g (176 mmol) of dibromopropane dissolved in 200 ml of DMSO was added dropwise. The mixture is stirred at room temperature for 2 hours, 10 ml of IPA is added dropwise and 200 ml of water is added dropwise. The mixture is filtered through a CELITE ™ filter and the solid residue is washed with ether. The ether layer is separated, washed with water, filtered, concentrated and dried to give 34.72 g of crude product of 1- (4-chlorophenyl) -1-cyclobutyl cyanide. The yield of crude product is 109.8%.
2nd step
1- (4-chlorophenyl) -1-cyclobutyl cyanide isobutyl magnesium bromide is reacted to obtain 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine.
10 g (52 mmol) of 1- (4-chlorophenyl) -1-cyclobutyl cyanide was dissolved in 25 ml of toluene at room temperature, followed by addition of a 2.0 M solution of isobutyl magnesium bromide dissolved in 40 ml of diethyl ether. The mixture is heated at reflux at a temperature of at least 105 ° C. for 2 hours. After completion of the reaction at 0 ° C. with methanol, 2.4 g of NaBH 4 was added to the mixture at 0-25 ° C. and stirred for 1 hour or more. Concentrate, treat with ether, water, concentrate again, and vacuum dry. The yield of crude product is 91.6%.
3rd step
The amine group of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine was dimethylated to obtain {1- [1- (4-chlorophenyl) -cyclobutyl]-which is the final object of the present invention. 3-methylbutyl} -dimethylamine hydrochloride, ie sibutramine hydrochloride, is obtained.
5.02 g of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine and 10 ml of HCOOH are mixed with cooling. 6 ml of 37% aqueous formaldehyde is added and heated at 85-95 ° C. for 18 hours. Excess 2M HCl is added and the solution is evaporated to dryness. 5N NaOH solution is added, extracted with ether and concentrated to give a pale yellow oil. After dissolving in a small amount of ether, ether saturated with HCl gas is slowly added dropwise at 0 ° C. The solid obtained was filtered and dried in vacuo to give 5.12 g of sibutramine hydrochloride as the final target. Yield of the product is 92%, mp 193.5-194.8 ° C. The total yield of the first to third stages is 52.7%. The H 1 NMR results of the final product are as follows: H 1 NMR (CDCl 3 ) 1.058 (6H, dd), 1.400 (2H, m), 1.508 (2H, m), 2.193 (3H, d), 2.316 (2H , m), 2.784 (2H, m), 2.910 (3H, d), 2.967 (1H, m), 3.568 (1H, m), 7.386 (2H, d), 7.638 (2H, d), 10.771 (1H, s)
The present invention is to shorten the process that was conventionally carried out in five steps to three steps to greatly shorten the process as well as to eliminate the difficult and time-consuming high-temperature vacuum distillation process to enable mass production In addition, it is possible to greatly reduce production time and production costs by improving the process step by step, and to reduce the production cost by showing a yield improvement effect nearly three times that of the conventional synthesis method in terms of overall yield.
Claims (3)
Hide Dependent
- In the method for synthesizing {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -dimethylamine from 4-chlorobenzyl cyanide,(a) reacting 4-chlorobenzyl cyanide with 1,3-dibromopropane to obtain 1- (4-chlorophenyl) -1-cyclobutyl cyanide;(b) To isobutyl magnesium bromide dissolved in diethyl ether is added to 1- (4-chlorophenyl) -1-cyclobutyl cyanide dissolved in toluene, and the mixture is refluxed at a temperature of 105 ° C. or higher at 1-3 ° C. Heating and cooling for a period of time, followed by addition of NaBH 4 at 0-25 ° C., followed by stirring for at least 1 hour to obtain 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine;(c) Dimethylating the amine group of 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine to yield {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methyl Improved synthesis method of sibutramine consisting of a three-step reaction comprising the step of obtaining butyl} -dimethylamine.
- The method according to claim 1,In step (a), the solution of 4-chlorobenzyl cyanide and 1,3-dibromopropane dissolved in DMSO is added dropwise to the mixture of NaH and DMSO dispersed in mineral oil, followed by filtration. , Washing, concentrating and drying to obtain a crude product of 1- (4-chlorophenyl) -1-cyclobutyl cyanide, and proceeding to the next step (b) as it is without distillation at high temperature. Improved Synthesis of Sibutramine.
- The method according to claim 1,In step (c), 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine is mixed with formaldehyde in a free base state, and 37% aqueous formaldehyde is added thereto, and 85 An improved method for synthesizing sibutramine, characterized in that sibutramine hydrochloride is obtained by heating at -95 ° C for 15-22 hours followed by addition of hydrochloric acid.
SYN
DE 3212682; GB 2098602; US 4806570
4-Chlorobenzyl cyanide (I) is cycloalkylated with 1,3-dibromopropane to yield 1-(4-chlorophenyl)cyclobutyl cyanide (II). The cyclobutyl cyanide (II) is treated with 2-methylpropyl magnesium bromide te give the imine salt (III), which may be either hydrolyzed to the ketone (IV), which is then formylaminated with formamide and formic acid and subsequently hydrolyzed, or reduced with sodium borohydride in ethanol to give 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (V). Eschweiler-Clarke methylation and hydrochloride formation yield N-[1-[1-(4-chlorophenyl)cyclo butyl]-3-methylbutyl]-N,N-dimethylamine hydrochloride monohydrate
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Medical uses
Sibutramine has been used to produce appetite suppression for the purpose of attaining weight loss in the treatment of patients with obesity.
Contraindications
Sibutramine is contraindicated in patients with:
- Psychiatric conditions as bulimia nervosa, anorexia nervosa, serious depression or pre-existing mania
- Patients with a history of or a predisposition to drug or alcohol abuse
- Hypersensitivity to the drug or any of the inactive ingredients
- Patients below 18 and above 65 years of age[14]
- Concomitant treatment with a MAO inhibitor, antidepressant or other centrally active drugs, particularly other anoretics
- History of peripheral arterial disease
- Hypertension that is not sufficiently controlled (e.g., >145/90 mmHg), caution in controlled hypertension
- Existing pulmonary hypertension
- Existing damage on heart valves, coronary heart disease, congestive heart failure, serious arrhythmias, previous myocardial infarction
- A history of coronary artery disease (e.g., angina, history of myocardial infarction), congestive heart failure, tachycardia, peripheral arterial occlusive disease, arrhythmia or cerebrovascular disease (stroke or transient ischemic attack (TIA))[14]
- Stroke or transient ischemic attack (TIA)
- Hyperthyroidism (overactive thyroid gland)
- Closed angle glaucoma
- Seizure disorders
- Enlargement of the prostate gland with urinary retention (relative contraindication)
- Pheochromocytoma
- Pregnant and lactating women (relative contraindication)
Side effects
A higher number of cardiovascular events has been observed in people taking sibutramine versus control (11.4% vs. 10.0%).[15] In 2010 the FDA noted the concerns that sibutramine increases the risk of heart attacks and strokes in patients with a history of cardiovascular disease.[15]
Frequently encountered side effects are: dry mouth, paradoxically increased appetite, nausea, strange taste in the mouth, upset stomach, constipation, trouble sleeping, dizziness, drowsiness, menstrual cramps/pain, headache, flushing, or joint/muscle pain.
In a 2016 Cochrane review sibutramine was found to substantially increase blood pressure and heart rate in some patients, in the updated review in 2021 sibutramine was not included since the drug had been withdrawn from the market.[16] When used, regular blood pressure monitoring needed to be performed.
The following side effects are infrequent but serious and require immediate medical attention: cardiac arrhythmias, paresthesia, mental/mood changes (e.g., excitement, restlessness, confusion, depression, rare thoughts of suicide).
Symptoms that require urgent medical attention are seizures, problems urinating, abnormal bruising or bleeding, melena, hematemesis, jaundice, fever and rigors, chest pain, hemiplegia, abnormal vision, dyspnea and edema.
Currently, no case of pulmonary hypertension has been noted. (Fenfluramine, of the 1990s “Fen-Phen” combo, forced excess release of neurotransmitters—a different action. Phentermine was uninvolved in the rare—but clinically significant—heart issues of fenfluramine.)
Interactions
Sibutramine has a number of clinically significant interactions. The concomitant use of sibutramine and monoamine oxidase inhibitors (MAOIs, such as selegiline) is not indicated, as it may increase the risk of serotonin syndrome, a somewhat rare but serious adverse drug reaction.[17] Sibutramine should not be taken within two weeks of stopping or starting an MAOI. Taking both sibutramine and certain medications used in the treatment of migraines—such as ergolines and triptans—as well as opioids, may also increase the risk for serotonin syndrome, as may the use of more than one serotonin reuptake inhibitor at the same time.[17]
The concomitant use of sibutramine and drugs which inhibit CYP3A4, such as ketoconazole and erythromycin, may increase plasma levels of sibutramine.[18] Sibutramine does not affect the efficacy of hormonal contraception.[17]
Pharmacology
Pharmacodynamics
| Compound | SERT | NET | DAT |
|---|---|---|---|
| Sibutramine | 298–2,800 | 350–5,451 | 943–1,200 |
| Desmethylsibutramine | 15 | 20 | 49 |
| (R)-Desmethylsibutramine | 44 | 4 | 12 |
| (S)-Desmethylsibutramine | 9,200 | 870 | 180 |
| Didesmethylsibutramine | 20 | 15 | 45 |
| (R)-Didesmethylsibutramine | 140 | 13 | 8.9 |
| (S)-Didesmethylsibutramine | 4,300 | 62 | 12 |
| Values are Ki (nM). |
Sibutramine is a serotonin–norepinephrine reuptake inhibitor (SNRI) that, in humans, reduces the reuptake of norepinephrine (by ~73%), serotonin (by ~54%), and dopamine (by ~16%),[21] thereby increasing the levels of these substances in synaptic clefts and helping enhance satiety; the serotonergic action, in particular, is thought to influence appetite. Older anorectic agents such as amphetamine and fenfluramine force the release of these neurotransmitters rather than affecting their reuptake.[22]
Despite having a mechanism of action similar to tricyclic antidepressants, sibutramine has failed to demonstrate antidepressant properties in animal studies. It was approved by the U.S. Food and Drug Administration (FDA) in November 1997[23] for the treatment of obesity.
Sibutramine is reported to be a prodrug to two active metabolites, desmethylsibutramine (M1; BTS-54354) and didesmethylsibutramine (M2; BTS-54505), with much greater potency as MRIs.[24][25]
Unlike other serotonergic appetite suppressants like fenfluramine, sibutramine and its metabolites have only low and likely inconsequential affinity for the 5-HT2B receptor.[21]
Pharmacokinetics
Sibutramine is well absorbed from the gastrointestinal tract (77%), but undergoes considerable first-pass metabolism, reducing its bioavailability. The drug itself reaches its peak plasma level after 1 hour and has also a half-life of 1 hour. Sibutramine is metabolized by cytochrome P450 isozyme CYP3A4 into two pharmacologically-active primary and secondary amines (called active metabolites 1 and 2) with half-lives of 14 and 16 hours, respectively. Peak plasma concentrations of active metabolites 1 and 2 are reached after three to four hours. The following metabolic pathway mainly results in two inactive conjugated and hydroxylated metabolites (called metabolites 5 and 6). Metabolites 5 and 6 are mainly excreted in the urine.
Chemistry
Sibutramine has usually been used in the form of the hydrochloride monohydrate salt.
Detection in body fluids
Sibutramine and its two active N-demethylated metabolites may be measured in biofluids by liquid chromatography–mass spectrometry. Plasma levels of these three species are usually in the 1–10 μg/L range in persons undergoing therapy with the drug. The parent compound and norsibutramine are often not detectable in urine, but dinorsibutramine is generally present at concentrations of >200 μg/L.[26][27][28]
Society and culture
Regulatory approval
Studies are ongoing into reports of sudden death, heart failure, renal failure and gastrointestinal problems. Despite a 2002 petition by Ralph Nader-founded NGO Public Citizen,[29] the FDA made no attempts to withdraw the drug, but was part of a Senate hearing in 2005.[30] Similarly, David Graham, FDA “whistleblower”, testified before a Senate Finance Committee hearing that sibutramine may be more dangerous than the conditions it is used for.[31]
Between January 2003 and November 2005, a large randomized-controlled “Sibutramine Cardiovascular OUTcomes” (SCOUT) study with 10,742 patients examined whether or not sibutramine administered within a weight management program reduces the risk for cardiovascular complications in people at high risk for heart disease and concluded that use of silbutramine had a RR 1.16 for the primary outcome (composit of nonfatal MI, nonfatal CVA, cardiac arrest, and CV death).[32]
In a dissenting article, “Sibutramine: gone, but not forgotten”, David Haslam (chairman of the National Obesity Forum) says that the SCOUT study is flawed as it only covered high-risk patients and did not consider obese patients who do not have cardiovascular complications or similar contraindications [33]
On January 21, 2010, the European Medicines Agency recommended suspension of marketing authorizations for sibutramine based on the SCOUT study results.[34]
In August 2010 the FDA added a new contraindication for patients over 65 years of age due to the fact that clinical studies of sibutramine did not include sufficient numbers of such patients.[14]
Abbott Laboratories announced on October 8, 2010 that it is withdrawing sibutramine from the US market under pressure from the FDA, citing concerns over minimal efficacy coupled with increased risk of adverse cardiovascular events.[35]
Counterfeit weight-loss products
On December 22, 2008, the United States Food and Drug Administration issued an alert to consumers naming 27 different products marketed as “dietary supplements” for weight loss, that illegally contain undisclosed amounts of sibutramine.[36][37] In March 2009, Dieter Müller et al. published a study of sibutramine poisoning cases from similar Chinese “herbal supplements” sold in Europe, containing as much as twice the dosage of the legally licensed drug.[38]
An additional 34 products were recalled by the FDA on April 22, 2009, further underscoring the risks associated with unregulated “herbal supplements” to unsuspecting persons. This concern is especially relevant to those with underlying medical conditions incompatible with undeclared pharmaceutical adulterants.[39] In January 2010, a similar alert was issued for counterfeit versions of the over-the-counter weight loss drug Alli sold over the Internet. Instead of the active ingredient orlistat, the counterfeit drugs contain sibutramine, and at concentrations at least twice the amount recommended for weight loss.[40]
In March 2010 Health Canada advised the public that illegal “Herbal Diet Natural” had been found on the market, containing sibutramine, which is a prescription drug in Canada, without listing sibutramine as an ingredient.[41] In October 2010 FDA notified consumers that “Slimming Beauty Bitter Orange Slimming Capsules contain the active pharmaceutical ingredient sibutramine, a prescription-only drug which is a stimulant. Sibutramine is not listed on the product label.”[42]
In October 2010 the MHRA in the UK issued a warning regarding “Payouji tea” and “Pai You Guo Slim Capsules” which were found to contain undeclared quantities of sibutramine.[43]
On December 30, 2010 the FDA released a warning regarding “Fruta Planta” dietary products, which were found to contain undeclared amounts of sibutramine. The recall stated that “there is NO SAFE formula on the US market and that all versions of Fruta Planta contain sibutramine. All versions of the formula are UNSAFE and should not be purchased from any source.”[44]
Some illegal weight loss products imported into Ireland have been found to contain sibutramine.[45][46] Similar concerns have been raised in Australia, where illegal imported supplements have been found to contain sibutramine, resulting in public alerts from Australia’s Therapeutic Goods Administration.[47]
In October 2011, the FDA warned that 20 brands of dietary supplements were tainted with sibutramine.[48] In a 2018 study FDA has found synthetic additives including sibutramine in over 700 diet supplements marketed as “natural”, “traditional” or “herbal remedies”.[49]
References
- ^ “Sibutramine (Reductil) – withdrawal in Australia”. Therapeutic Goods Administration (Tga). Therapeutic Goods Administration, Department of Health, Australian Government. 2010. Retrieved 2014-10-06.
- ^ Health Canada Endorsed Important Safety Information on MERIDIA (Sibutramine Hydrochloride Monohydrate): Subject: Voluntary withdrawal of Meridia (sibutramine) capsules from the Canadian market.
- ^ “Notification of Termination of Production, Sale, and Usage of Sibutramine Preparations and Their Active Pharmaceutical Ingredient”. sda.gov in People’s Republic of China. October 30, 2010. Retrieved 2011-05-21.
- ^ (in German) Sibutramin-Vertrieb in der Europäischen Union ausgesetzt [1]. Abbott Laboratories in Germany. Press Release 2010-01-21. Retrieved 2010-01-27
- ^ “De-registration of pharmaceutical products containing sibutramine” (Press release). info.gov in Hong Kong. November 2, 2010. Retrieved 2010-11-08.
- ^ “Banned Medicines” (Press release). Ministry of Health and Family Welfare. February 10, 2011. Retrieved 2011-03-15.
- ^ “Withdrawal of Sibutramine (Reductil) in New Zealand” (Press release). MedSafe in New Zealand. October 11, 2010. Retrieved 2012-11-06.
- ^ “FDA warns online sellers of banned slimming pills”. January 12, 2014. Retrieved February 20, 2014.
- ^ “Thai FDA reveals voluntary withdrawal of sibutramine from the Thai market” (PDF) (Press release). Food and Drug Administration of Thailand. October 20, 2010. Retrieved 2010-12-22.
- ^ “Top obesity drug sibutramine being suspended”. BBC News. 2010-01-22. Retrieved 2010-01-22.
- ^ Rockoff JD, Dooren JC (October 8, 2010). “Abbott Pulls Diet Drug Meridia Off US Shelves”. The Wall Street Journal. Retrieved 8 October 2010.
- ^ “Sibutramine – Drugs.com”. drugs.com.
- ^ Buckett WR, Thomas PC, Luscombe GP (1988). “The pharmacology of sibutramine hydrochloride (BTS 54 524), a new antidepressant which induces rapid noradrenergic down-regulation”. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 12 (5): 575–84. doi:10.1016/0278-5846(88)90003-6. PMID 2851857. S2CID 24787523.
- ^ Jump up to:a b c “The FDA August 2010 drug safety update”. fda.gov.
- ^ Jump up to:a b “Early Communication about an Ongoing Safety Review of Meridia (sibutramine hydrochloride)”. United States Food and Drug Administration. 1 February 2010. Archived from the original on 6 January 2012.
- ^ Siebenhofer, Andrea; Winterholer, Sebastian; Jeitler, Klaus; Horvath, Karl; Berghold, Andrea; Krenn, Cornelia; Semlitsch, Thomas (2021-01-17). “Long-term effects of weight-reducing drugs in people with hypertension”. The Cochrane Database of Systematic Reviews. 1: CD007654. doi:10.1002/14651858.CD007654.pub5. ISSN 1469-493X. PMC 8094237. PMID 33454957.
- ^ Jump up to:a b c “Meridia Side Effects, and Drug Interactions”. RxList.com. 2007. Retrieved 2007-04-29.
- ^ (in Portuguese) Cloridrato de sibutramina monoidratado. Bula. [Sibutramine hydrochloride monohydrate—label information]. Medley (2007).
- ^ Nisoli E, Carruba MO (October 2000). “An assessment of the safety and efficacy of sibutramine, an anti-obesity drug with a novel mechanism of action”. Obesity Reviews. 1 (2): 127–39. doi:10.1046/j.1467-789x.2000.00020.x. PMID 12119986. S2CID 20553857.
- ^ Rothman RB, Baumann MH (May 2009). “Serotonergic drugs and valvular heart disease”. Expert Opinion on Drug Safety. 8 (3): 317–29. doi:10.1517/14740330902931524. PMC 2695569. PMID 19505264.
- ^ Jump up to:a b “Meridia (sibutramine hydrochloride monohydrate) Capsules CIV. Full Prescribing Information” (PDF). Abbott Laboratories, North Chicago, IL 60064, U.S.A. Retrieved 6 February 2016.
- ^ Heal DJ, Aspley S, Prow MR, Jackson HC, Martin KF, Cheetham SC (August 1998). “Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine”. International Journal of Obesity and Related Metabolic Disorders. 22 Suppl 1: S18–28, discussion S29. PMID 9758240.
- ^ “FDA APPROVES SIBUTRAMINE TO TREAT OBESITY” (Press release). U.S. Food and Drug Administration. November 24, 1997. Retrieved 2007-04-29.
- ^ Kim KA, Song WK, Park JY (November 2009). “Association of CYP2B6, CYP3A5, and CYP2C19 genetic polymorphisms with sibutramine pharmacokinetics in healthy Korean subjects”. Clinical Pharmacology and Therapeutics. 86 (5): 511–8. doi:10.1038/clpt.2009.145. PMID 19693007. S2CID 24789264.
- ^ Hofbauer K (2004). Pharmacotherapy of obesity : options and alternatives. Boca Raton, Fla: CRC Press. ISBN 978-0-415-30321-7.
- ^ Jain DS, Subbaiah G, Sanyal M, et al. Liquid chromatography/electrospray ionization tandem mass spectrometry validated method for the simultaneous quantification of sibutramine and its primary and secondary amine metabolites in human plasma and its application to a bioequivalence study. Rapid Comm. Mass Spec. 20: 3509-3521, 2006.
- ^ Thevis M, Sigmund G, Schiffer AK, Schänzer W. Determination of N-desmethyl- and N-bisdesmethyl metabolites of Sibutramine in doping control analysis using liquid chromatography-tandem mass spectrometry. Eur. J. Mass Spec. 12: 129-136, 2006.
- ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1426–1427.
- ^ Wolfe SM, Sasich LD, Barbehenn E (March 19, 2002). “Petition to FDA to ban the diet drug sibutramine (MERIDIA) (HRG Publication #1613)”. Public Citizen. Retrieved 2007-04-29.
- ^ Japsen B (13 March 2005). “FDA weighs decision on Meridia; Health advisory likely for Abbott obesity drug”. Chicago Tribune. Chicago, Illinois. p. 1.
- ^ Hearing of 17 November 2004. Related CBS news item 19 November 2004.
- ^ James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Shepherd GM, Rode RA, Renz CL (September 2010). “Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects” (PDF). The New England Journal of Medicine. 363 (10): 905–17. doi:10.1056/NEJMoa1003114. hdl:2437/111825. PMID 20818901.
- ^ Haslam D (April 2010). “Sibutramine: gone, but not forgotten” (PDF). Pract Diab Int. 27 (3): 96–97. doi:10.1002/pdi.1453. Archived from the original (PDF) on 26 July 2015.
- ^ “European Medicines Agency recommends suspension of marketing authorisations for sibutramine” (PDF). European Medicines Agency. January 21, 2010. Archived from the original (PDF) on 2010-04-01.
- ^ Pollack A (October 8, 2010). “Abbott Labs Withdraws Meridia From Market”. The New York Times.
- ^ “FDA warns consumers about tainted weight loss pills” (Press release). U.S. Food and Drug Administration. 22 December 2008.
- ^ “Consumer directed questions and answers about FDA’s initiative against contaminated weight loss products”. U.S. Food and Drug Administration Center for Drug Evaluation and Research. 22 December 2008.
- ^ Müller D, Weinmann W, Hermanns-Clausen M (March 2009). “Chinese slimming capsules containing sibutramine sold over the Internet: a case series”. Deutsches Ärzteblatt International. 106 (13): 218–22. doi:10.3238/arztebl.2009.0218. PMC 2680571. PMID 19471631.
- ^ 34 weight loss products recalled, WebMD, 22 April 2009.
- ^ “Fake Alli diet pills can pose health risks”. CNN.com. January 23, 2010. Retrieved 2010-01-24.
- ^ “Herbal diet product poses heart risk”. CBC News. March 26, 2010.
- ^ “FDA Alert: Slimming Beauty Bitter Orange Slimming Capsules: Undeclared Drug Ingredient”. drugs.com.
- ^ “Press release: Warning over unlicensed herbal Payouji tea and Pai You Guo Slim Capsules”. United Kingdom Medicines & Healthcare Products Regulatory Agency. 20 October 2010. Archived from the original on 9 February 2012.
- ^ “PRock Marketing, LLC Issues a Voluntary Nationwide Recall of All weight loss formulas and variation of formulas of Reduce Weight Fruta Planta/Reduce Weight Dietary Supplement”. United States Food and Drug Administration. Archived from the original on 23 March 2012.
- ^ Pope C. “Seizures of illegal medicines rise”. The Irish Times.
- ^ “FDA Alert: Slim Xtreme Herbal Slimming Capsule: Undeclared Drug Ingredient”. drugs.com.
- ^ “Majestic slimming capsules: Safety advisory”. Therapeutic Goods Administration. Australian Government. 9 November 2012.
- ^ Carroll L (19 October 2011). “‘Natural’ diet pills tainted with banned prescription drug”. MSNBC. Archived from the original on 11 January 2012.
- ^ Cohen, Ronnie (12 October 2018). “No Wonder It Works So Well: There May Be Viagra In That Herbal Supplement”. NPR.org. Retrieved 2018-10-14.
External links
- Abbott Press Release on Meridia Withdrawal
- Sibutramine drug information from Merck Manual. Includes dosage information and a comprehensive list of international brand names
- U.S. Food and Drug Administration (FDA) product safety website
/////////////SIBUTRAMINE, UNII:WV5EC51866, WV5EC51866, сибутрамин , سيبوترامين , 西布曲明 , ABOTT, OBESITY
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Olipudase alfa
| HPLSPQGHPA RLHRIVPRLR DVFGWGNLTC PICKGLFTAI NLGLKKEPNV ARVGSVAIKL CNLLKIAPPA VCQSIVHLFE DDMVEVWRRS VLSPSEACGL LLGSTCGHWD IFSSWNISLP TVPKPPPKPP SPPAPGAPVS RILFLTDLHW DHDYLEGTDP DCADPLCCRR GSGLPPASRP GAGYWGEYSK CDLPLRTLES LLSGLGPAGP FDMVYWTGDI PAHDVWHQTR QDQLRALTTV TALVRKFLGP VPVYPAVGNH ESTPVNSFPP PFIEGNHSSR WLYEAMAKAW EPWLPAEALR TLRIGGFYAL SPYPGLRLIS LNMNFCSREN FWLLINSTDP AGQLQWLVGE LQAAEDRGDK VHIIGHIPPG HCLKSWSWNY YRIVARYENT LAAQFFGHTH VDEFEVFYDE ETLSRPLAVA FLAPSATTYI GLNPGYRVYQ IDGNYSGSSH VVLDHETYIL NLTQANIPGA IPHWQLLYRA RETYGLPNTL PTAWHNLVYR MRGDMQLFQT FWFLYHKGHP PSEPCGTPCR LATLCAQLSA RADSPALCRH LMPDGSLPEA QSLWPRPLFC (Disulfide bridge: 43-119, 46-111, 74-85, 175-180, 181-204, 339-385, 538-542, 548-561) |
Olipudase alfa
Xenpozyme, Japan 2022, APPROVALS 2022, 2022/3/28
PEPTIDE, オリプダーゼアルファ (遺伝子組換え)
Alternative Names: Acid sphingomyelinase Niemann Pick disease type B – Sanofi; Acid-sphingomyelinase – Sanofi; GZ-402665; Recombinant human acid sphingomyelinase – Sanofi; rhASM – Sanofi; Sphingomyelinase-C (synthetic human) – Sanofi; Synthetic human sphingomyelinase-C – Sanofi; Xenpozyme
| Formula | C2900H4373N783O791S24 |
|---|---|
| CAS | 927883-84-9 |
| Mol weight | 63631.0831 |
| Efficacy | Lysosomal storage disease treatment, Enzyme replacement (acid sphingomyelinase) |
|---|---|
| Comment | Enzyme replacement therapy product Treatment of Niemann-Pick disease type A/B |
- OriginatorGenzyme Corporation
- DeveloperSanofi
- ClassRecombinant proteins; Sphingomyelin phosphodiesterases
- Mechanism of ActionSphingomyelin-phosphodiesterase replacements
- Orphan Drug StatusYes – Niemann-Pick diseases
- RegisteredNiemann-Pick diseases
- 28 Mar 2022Registered for Niemann-Pick diseases (In adolescents, In children, In adults) in Japan (IV) – First global approval
- 09 Feb 2022FDA assigns PDUFA action date of (03/07/2022) for Olipudase alfa (In children, In adults) for Niemann-Pick diseases
- 09 Feb 2022Adverse e
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Olipudase Alfa Improves Lung Function, Spleen Volume in ASMD
Olipudase Alfa Improves Lung Function, Spleen Volume in ASMD
Olipudase alfa was associated with significant improvements in clinically relevant disease end points among patients with chronic visceral acid sphingomyelinase (ASM) deficiency (ASMD), according to results from the phase 2/3 ASCEND trial presented at the 17th Annual WORLDSymposium.
ASMD is a rare, debilitating lysosomal storage disease characterized by a deficiency of the enzyme acid sphingomyelinase, which results in the accumulation of sphingomyelin in various tissues of the body. Olipudase alfa is an investigational enzyme replacement therapy designed to replace deficient or defective ASM.
The multicenter, randomized, double-blind, placebo-controlled ASCEND trial evaluated the efficacy and safety of olipudase alfa in 36 adults with chronic visceral ASMD. Patients were randomly assigned 1:1 to receive olipudase alfa 3mg/kg intravenously every 2 weeks or placebo for 52 weeks. The coprimary end points were the percent change in spleen volume and percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO).
At week 52, treatment with olipudase alfa resulted in a 39.45% reduction in spleen volume, compared with a 0.5% increase for placebo (P <.0001). A decrease in spleen volume of at least 30% was observed in 17 patients (94%) treated with olipudase afla compared with no patients treated with placebo. Additionally, olipudase alfa significantly improved lung function by 22% from baseline compared with 3% for patients receiving placebo (P =.0004), as measured by percent predicted DLCO.
Olipudase alfa also met key secondary end points including a 31.7% reduction in liver volume (vs a 1.4% reduction for placebo; P <.0001) and a 16.8% improvement in mean platelet counts (vs 2.5% with placebo; P =.019) at week 52. Significant improvements in HDL, LDL, AST, ALT, chitotriosidase (54% vs 12% with placebo; P =.0003), and lyso-sphingomyelin (78% vs 6% with placebo) were also observed in the olipudase alfa group at week 52.
With regard to Splenomegaly Related Score, a patient-reported outcome measurement that evaluates patient symptoms associated with an enlarged spleen, findings showed no meaningful difference between olipudase alfa and placebo (-8 point vs -9.3 points, respectively).
As for safety, olipudase alfa was well tolerated with most adverse events being mild to moderate in severity. There were no treatment-related serious adverse events and no adverse event-related discontinuations.
Disclosure: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Reference
Wasserstein M, Arash-Kaps L, Barbato A, et al. Adults with chronic acid sphingomyelinase deficiency show significant visceral, pulmonary, and hematologic improvements after enzyme replacement therapy with olipudase-alfa: 1-year results of the ASCEND placebo-controlled trial. Presented at: 17th Annual WORLDSymposium; February 8-12, 2021. Abstract 265.
CLIP
https://www.sanofi.com/en/media-room/press-releases/2021/2021-12-06-14-00-00-2346501
EMA accepts regulatory submission for olipudase alfa, the first potential therapy for ASMD
- Olipudase alfa has been granted PRIority MEdicines (PRIME) designation in Europe, Breakthrough Therapy designation in the United States, and SAKIGAKE designation in Japan
- European regulatory decision anticipated second half of 2022
DECEMBER 6, 2021
The European Medicines Agency (EMA) has accepted for review under an accelerated assessment procedure the Marketing Authorization Application (MAA) for olipudase alfa, Sanofi’s investigational enzyme replacement therapy which is being evaluated for the treatment of acid sphingomyelinase deficiency (ASMD). Historically referred to as Niemann-Pick disease (NPD) type A and type B, ASMD is a rare, progressive, and potentially life-threatening disease for which no treatments are currently approved. The estimated prevalence of ASMD is approximately 2,000 patients in the U.S., Europe (EU5 Countries) and Japan. If approved, olipudase alfa will become the first and only therapy for the treatment of ASMD.
“Today’s milestone has been decades in the making and our gratitude goes to the ASMD community who has stood by us with endless patience while olipudase alfa advanced through clinical development,” said Alaa Hamed, MD, MPH, MBA, Global Head of Medical Affairs, Rare Diseases, Sanofi. “Olipudase alfa represents the kind of potentially life-changing innovation that is possible when industry, medical professionals and the patient community work together toward a common goal.”
The MAA is based on positive results from two separate clinical trials (ASCEND and ASCEND-Peds) evaluating olipudase alfa in adult and pediatric patients with non-central nervous system (CNS) manifestations of ASMD type A/B and ASMD type B.
Olipudase alfa has received special designations from regulatory agencies worldwide, recognizing the innovation potential of the investigational therapy.
“Scientific innovation is the greatest source of hope for people living with diseases like ASMD where there are no approved treatments and is a critical component for ensuring a viable healthcare ecosystem,” said Bill Sibold, Executive Vice President of Sanofi Genzyme. “At Sanofi, we have a long history of pioneering scientific innovation, and we remain committed to finding solutions to address unmet medical needs, including those of the rare disease community.”
The EMA awarded olipudase alfa the PRIority MEdicines designation, also known as PRIME, intended to aid and expedite the regulatory process for investigational medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options.
The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to olipudase alfa. This designation is intended to expedite the development and review of drugs intended to treat serious or life-threatening diseases and conditions. The criteria for granting Breakthrough Therapy designation include preliminary clinical evidence indicating that the molecule may demonstrate substantial improvement on a clinically significant endpoint over available therapies.
In Japan, olipudase alfa was awarded the SAKIGAKE designation, which is intended to promote research and development in Japan for innovative new medical products that satisfy certain criteria, such as the severity of the intended indication. In September, Sanofi filed the J-NDA submission for olipudase alfa.
About ASMD
ASMD results from a deficient activity of the enzyme acid sphingomyelinase (ASM), which is found in special compartments within cells called lysosomes and is required to breakdown lipids called sphingomyelin. If ASM is absent or not functioning as it should, sphingomyelin cannot be metabolized properly and accumulates within cells, eventually causing cell death and the malfunction of major organ systems. The deficiency of the lysosomal enzyme ASM is due to disease-causing variants in the sphingomyelin phosphodiesterase 1 gene (SMPD1). The estimated prevalence of ASMD is approximately 2,000 patients in the U.S., Europe (EU5 Countries) and Japan.
ASMD represents a spectrum of disease caused by the same enzymatic deficiency, with two types that may represent opposite ends of a continuum sometimes referred to as ASMD type A and ASMD type B. ASMD type A is a rapidly progressive neurological form of the disease resulting in death in early childhood due to central nervous system complications. ASMD type B is a serious and potentially life-threatening disease that predominantly impacts the lungs, liver, and spleen, as well as other organs. ASMD type A/B represents an intermediate form that includes varying degrees of neurologic involvement. Patients with ASMD type A/B or ASMD type B were studied in the ASCEND trial program. Another type of NPD is NPD type C, which is unrelated to ASMD.
About olipudase alfa
Olipudase alfa is an investigational enzyme replacement therapy designed to replace deficient or defective ASM, allowing for the breakdown of sphingomyelin. Olipudase alfa is currently being investigated to treat non-CNS manifestations of ASMD. Olipudase alfa has not been studied in ASMD type A patients. Olipudase alfa is an investigational agent and the safety and efficacy have not been evaluated by the FDA, EMA, or any other regulatory authority worldwide.
About Sanofi
Sanofi is dedicated to supporting people through their health challenges. We are a global biopharmaceutical company focused on human health. We prevent illness with vaccines, provide innovative treatments to fight pain and ease suffering. We stand by the few who suffer from rare diseases and the millions with long-term chronic conditions.
With more than 100,000 people in 100 countries, Sanofi is transforming scientific innovation into healthcare solutions around the globe.
///////Olipudase alfa, japan 2022, APPROVALS 2022, Xenpozyme, PEPTIDE, オリプダーゼアルファ (遺伝子組換え) , ORPHAN DRUG, GZ-402665 , GZ 402665
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Andexanet alfa
(heavy chain)
IVGGQECKDG ECPWQALLIN EENEGFCGGT ILSEFYILTA AHCLYQAKRF KVRVGDRNTE
QEEGGEAVHE VEVVIKHNRF TKETYDFDIA VLRLKTPITF RMNVAPACLP ERDWAESTLM
TQKTGIVSGF GRTHEKGRQS TRLKMLEVPY VDRNSCKLSS SFIITQNMFC AGYDTKQEDA
CQGDAGGPHV TRFKDTYFVT GIVSWGEGCA RKGKYGIYTK VTAFLKWIDR SMKTRGLPKA
KSHAPEVITS SPLK
(light chan)
ANSFLFWNKY KDGDQCETSP CQNQGKCKDG LGEYTCTCLE GFEGKNCELF TRKLCSLDNG
DCDQFCHEEQ NSVVCSCARG YTLADNGKAC IPTGPYPCGK QTLER
(Disulfide bridge: H7-H12, H27-H43, H108-L98, H156-H170, H181-H209, L16-L27, L21-L36, L38-L47, L55-L66, L62-L75, L77-L90)
Andexanet alfa
JAPAN 2022, PEPTIDE
| Ondexxya |
| 2022/3/28 |
| Anticoagulant reversal (factor Xa inhibitors) |
CAS: 1262449-58-0
アンデキサネットアルファ (遺伝子組換え)
- Andexanet alfa
- r-Antidote
- rfXa Inhibitor Antidote
- PRT-4445
- PRT064445
Andexanet alfa, sold under the trade name Andexxa among others, is an antidote for the medications rivaroxaban and apixaban, when reversal of anticoagulation is needed due to uncontrolled bleeding.[1] It has not been found to be useful for other factor Xa inhibitors.[2] It is given by injection into a vein.[2]
Common side effects include pneumonia and urinary tract infections.[2] Severe side effects may include blood clots, heart attacks, strokes, or cardiac arrest.[2] It works by binding to rivaroxaban and apixaban.[2]
It was approved for medical use in the United States in May 2018.[1] It was developed by Portola Pharmaceuticals.[3]
ndexanet alfa is a recombinant human coagulation Factor Xa that promotes blood coagulation. It was developed by Portola Pharmaceuticals and was approved in in May 2018. It is marketed as Andexxa for intravenous injection or infusion and is indicated for the reversal of anticoagulation in combination with rivaroxaban and apixaban in cases of life-threatening or uncontrolled bleeding. Rivaroxaban and apixaban are Factor Xa inhibitors that promote anticoagulation in situations where blood clotting is unfavourable, such as in deep vein thrombosis and pulmonary embolism. However, the use of these agents is associated with a risk for uncontrollable bleeding episodes that can lead to can cause serious or fatal bleeding. Andexanet alfa is currently under regulatory review by the European Union and is undergoing clinical development in Japan 1.
Andexanet alfa works by binding to Factor Xa inhibitors and prevent them from interacting with endogenous Factor Xa. It displayed high affinity (0.53–1.53 nmol/L) to apixaban, betrixaban, edoxaban and rivaroxaban 1. However, the effectiveness of andexanet alfa on treating bleeding related to any FXa inhibitors other than apixaban and rivaroxaban was not demonstrated, thus such use is limited 7. Its pharmacokinetic properties are not reported to be affected by factor Xa inhibitors 1. Andexanet alfa retains the structural similarity to that of endogenous human factor Xa, but exists in its mature functional form without the need for activation via the intrinsic or extrinsic coagulation pathways 5 and remains catalytically inactive due to structural modification 1. The procoagulation potential of andexanet alfa is eliminated through the removal of a 34-residue fragment containing Gla: via this truncation, andexanet alfa is unable to bind to membrane surfaces and assemble the prothrombinase complex 5. It also prevents andexanet alfa from taking up space on phospholipid surface membranes, so that native FXa may bind and assemble the prothrominase complex 5. The amino acid residue modification from serine to alanine in the binding site of the catalytic domain allows more effective binding to FXa inhibitors and deters the andexanet alfa from converting prothrombin to thrombin 5.
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Structure of andexant alfa. Andexanet alfa is a modified activated human factor Xa (FXa) that binds FXa with high affinity and a 1:1 stoichiometric ratio but does not have intrinsic catalytic activity (the amino acid serine at position 419 is replaced by alanine) and lacks the membrane-binding-carboxyglutamic acid domain (Gla domain) of native FX. The Gla domains are responsible for the binding of FXa to phospholipids
Medical uses
Andexanet alfa is used to stop life threatening or uncontrollable bleeding in people who are taking rivaroxaban or apixaban.[1]
There are no randomised clinical trials as of 2019. Studies in healthy volunteers show that the molecule binds factor Xa inhibitors and counters their anti-Xa-activity.[4] The only published clinical trial is a prospective, open label, single group study.[5] This study reports results on 352 people and demonstrates a reduction of anti-Xa-activity while also showing an excellent or good hemostatic efficacy in 82%. While people who were expected to die in 30 days were excluded from the study, 14% of participants died. There was no relationship between hemostatic efficacy and reduced anti-Xa-activity.[6] The FDA has demanded a randomised clinical trial: the first results are not expected before 2023.[7]
Adverse effects
Common side effects include pneumonia and urinary tract infections.[2] Severe side effects may include blood clots or cardiac arrest.[2]
Andexanet alfa has a boxed warning that it is associated with arterial and venous blood clots, ischemic events, cardiac arrest, and sudden deaths.[1]
Pharmacology
Mechanism of action
Andexanet alfa is a biologic agent, a recombinant modified version of human activated factor X (FXa).[8] Andexanet alfa differs from native FXa due to the removal of a 34 residue fragment that contains the Gla domain. This modification reduces andexanet alfa’s procoagulant potential. Additionally, a serine to alanine (S419A) mutation in the active site eliminates its activity as a prothrombin to thrombin catalyst, but still allows the molecule to bind to FXa inhibitors.[9] FXa inhibitors bind to andexanet alfa with the same affinity as to natural FXa. As a consequence in the presence of andexanet alfa natural FXa is partially freed, which can lead to effective hemostasis.[3][10] In other words, it acts as a decoy receptor. Andexanet alfa reverses effect of all anticoagulants that act directly through FXa or by binding antithrombin III. The drug is not effective against factor IIa inhibitor dabigatran.[11]
History[edit]
It was approved in the United States in 2018 based on data from two phase III studies on reversing the anticoagulant activity of FXa inhibitors rivaroxaban and apixaban in healthy volunteers.[4] As a condition of its accelerated approval there is a study being conducted comparing it to other currently used reversal agents (“usual care”).[5][12]
Society and culture
Economics
Initial pricing (AWP) is $58,000 per reversal (800 mg bolus + 960 mg infusion, $3,300 per 100 mg vial) which is higher than reversal agents for other DOAC agents (idarucizumab for use in dabigatran reversal is $4,200 per reversal).[13]
References
- ^ Jump up to:a b c d e “Andexxa- andexanet alfa injection, powder, lyophilized, for solution”. DailyMed. 21 September 2020. Retrieved 12 November 2020.
- ^ Jump up to:a b c d e f g “Andexxa Monograph for Professionals”. Drugs.com. Retrieved 19 December 2018.
- ^ Jump up to:a b Dolgin E (March 2013). “Antidotes edge closer to reversing effects of new blood thinners”. Nature Medicine. 19 (3): 251. doi:10.1038/nm0313-251. PMID 23467222. S2CID 13340319.
- ^ Jump up to:a b Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA (December 2015). “Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity”. New England Journal of Medicine. 373 (25): 2413–24. doi:10.1056/NEJMoa1510991. PMID 26559317.
- ^ Jump up to:a b Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al. (April 2019). “Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors”. New England Journal of Medicine. 380 (14): 1326–1335. doi:10.1056/NEJMoa1814051. PMC 6699827. PMID 30730782.
- ^ Justin Morgenstern, “Andexanet Alfa: More garbage science in the New England Journal of Medicine”, First10EM blog, February 11, 2019. Available at: https://first10em.com/andexanet-alfa/.
- ^ “A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor”. 11 January 2022.
- ^ Lu, Genmin; DeGuzman, Francis R.; Lakhotia, Sanjay; Hollenbach, Stanley J.; Phillips, David R.; Sinha, Uma (2008-11-16). “Recombinant Antidote for Reversal of Anticoagulation by Factor Xa Inhibitors”. Blood. 112 (11): 983. doi:10.1182/blood.V112.11.983.983. ISSN 0006-4971.
- ^ Kaatz, Scott; Bhansali, Hardik; Gibbs, Joseph; Lavender, Robert; Mahan, Charles E.; Paje, David G. (2017-09-13). “Reversing factor Xa inhibitors – clinical utility of andexanet alfa”. Journal of Blood Medicine. 8: 141–149. doi:10.2147/JBM.S121550. PMC 5602457. PMID 28979172.
- ^ Lu G, Deguzman FR, Hollenbach SJ, et al. (March 2013). “A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa”. Nature Medicine. 19 (4): 446–51. doi:10.1038/nm.3102. PMID 23455714. S2CID 11235887.
- ^ H. Spreitzer (23 December 2013). “Neue Wirkstoffe – Andexanet Alfa”. Österreichische Apothekerzeitung (in German) (26/2013): 40.
- ^ “Trial of Andexanet in ICH Patients Receiving an Oral FXa Inhibitor”. ClinicalTrials.gov. 11 January 2022.
- ^ “Lexi Comp Drug Information Online”. 24 May 2018.
Further reading
- Connolly SJ, Milling TJ, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al. (September 2016). “Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors”. New England Journal of Medicine. 375 (12): 1131–41. doi:10.1056/NEJMoa1607887. PMC 5568772. PMID 27573206.
External links
- “Andexanet alfa”. Drug Information Portal. U.S. National Library of Medicine.
- “Ondexxya (andexanet alfa): Avoid use of andexanet prior to heparinization”. European
| Clinical data | |
|---|---|
| Trade names | Andexxa, Ondexxya, others |
| Other names | Coagulation factor Xa (recombinant), inactivated-zhzo, PRT06445, r-Antidote, PRT4445 |
| AHFS/Drugs.com | Monograph |
| License data | US DailyMed: Andexanet_alfa |
| Routes of administration | Intravenous injection |
| ATC code | V03AB38 (WHO) |
| Legal status | |
| Legal status | UK: POM (Prescription only)US: ℞-only [1]EU: Rx-only |
| Pharmacokinetic data | |
| Metabolism | Not studied |
| Elimination half-life | 5 h to 7 h |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1262449-58-0 |
| IUPHAR/BPS | 7576 |
| DrugBank | DB14562 |
| ChemSpider | none |
| UNII | BI009E452R |
| KEGG | D11029 |
| ChEMBL | ChEMBL3301583 |
//////////Andexanet alfa, JAPAN 2022, APPROVALS 2022, アンデキサネットアルファ (遺伝子組換え) , Ondexxya , PRT-4445, PRT064445
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Ferric derisomaltose
Ferric derisomaltose
WeightAverage: 562.297
Monoisotopic: 562.117975Chemical FormulaC18H34FeO16
Monover, JAPAN 2022, 2022/3/28
Monoferric (TN);
Monover (TN)
Anti-anemic, Hematinic, Supplement (iron)
CAS 1345510-43-1
デルイソマルトース第二鉄
- NS32
- WHO 9712
- UNII-AHU547PI9H
| Originator Company | Pharmacosmos |
| Active Companies | Nippon Shinyaku Co Ltd;Pharmacosmos A/S;Wasserburger Arzneimittelwerk Gmbh;Zealand University Hospital |
iron(3+) (2S,3R,4R,5R)-6-{[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-({[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}methyl)oxan-2-yl]oxy}hexane-1,2,3,4,5-pentol
- alpha-D-Glucan, (1-6)-, reduced, reaction products with iron hydroxide (Fe(OH)3)
Ferric derisomaltose is an iron injection used in the treatment of iron deficiency anemia.
Ferric derisomaltose, sold under the brand name Monoferric, is a medication for the treatment of iron deficiency anemia (IDA) in adults who have intolerance to oral iron or have had unsatisfactory response to oral iron or who have non-hemodialysis dependent chronic kidney disease (NDD-CKD).[1] It was approved for use in the United States in January 2020.[1][2][3] It is given intravenously.[1]
Iron deficiency is an extremely common condition and is the most frequent cause of anemia worldwide. Iron deficiency results when iron intake, iron stores, and loss of iron from the body do not adequately support production of erythrocytes, also known as red blood cells. Though it is generally considered non life-threatening, iron deficiency may considerably affect quality of life.3
Ferric derisomaltose is a form of iron used in the treatment of iron deficiency. This drug is a complex of iron (III) hydroxide and derisomaltose. The latter is an iron carbohydrate oligosaccharide that works to release iron. Ferric derisomaltose was developed by Pharmacosmos Therapeutics ad was granted FDA approval in January 2020.8,9 Clinical trials show that it is non-inferior to iron sucrose, another form of iron that is often administered in iron deficiency, and less likely to cause serious hypersensitivity that is associated with other forms of injectable iron.1,4
This drug is indicated for the treatment of iron deficiency anemia in adult patients who have experienced intolerance to oral iron preparations or insufficient clinical response to orally administered iron. Ferric derisomaltase is also indicated for patients with non-hemodialysis dependent chronic kidney disease.8 In Australia and United Kingdom, ferric derisomaltase is indicated for cases in which rapid delivery of iron is required.10,11
Iron deficiency is an extremely common condition and is the most frequent cause of anemia worldwide. Iron deficiency results when iron intake, iron stores, and loss of iron from the body do not adequately support production of erythrocytes, also known as red blood cells. Though it is generally considered non life-threatening, iron deficiency may considerably affect quality of life. Ferric derisomaltose is a form of iron used in the treatment of iron deficiency. This drug is a complex of iron (III) hydroxide and derisomaltose. The latter is an iron carbohydrate oligosaccharide that works to release iron. Ferric derisomaltose was developed by Pharmacosmos Therapeutics ad was granted FDA approval in January 2020. Clinical trials show that it is non-inferior to [iron sucrose], another form of iron that is often administered in iron deficiency, and less likely to cause serious hypersensitivity that is associated with other forms of injectable iron.
Monoferric is an iron replacement product containing ferric derisomaltose for intravenous infusion. Ferric derisomaltose is an iron carbohydrate complex with a matrix structure composed of interchanging layers of ferric hydroxide and the carbohydrate derisomaltose. Derisomaltose consists of linear, hydrogenated isomaltooligosaccharides with an average molecular weight of 1000 Da and a narrow molecular weight distribution that is almost devoid of mono-and disaccharides.
Ferric derisomaltose has an average molecular weight of 155,000 Da and has the following empirical formula:
{FeO(1-3X) (OH)(1+3X) (C6H5O73-)X}, (H20)T, –
(C6H10O6)R(-C6H10O5-)Z(C6H13O5)R, (NaCl)Y
X= 0.0311; T = 0.25; R = 0.14; Z = 0.49; Y = 0.14
Iron atoms placed in the electronegative cavities of the 3-D structure between and within the derisomaltose molecules. A schematic representation is presented below
 |
Monoferric is a sterile, dark brown, non-transparent aqueous solution with pH 5.0-7.0, containing ferric derisomaltose dissolved in water for injections and filled into Type I glass vials.
Each 1 mL of solution contains 100 mg of elemental iron as ferric derisomaltose in water for injection.
Each 1 mL of solution contains 100 mg of elemental iron as ferric derisomaltose in water for injection.
| Mkt. Status | Active Ingredient | Proprietary Name | Appl. No. | Dosage Form | Route | Strength | TE Code | RLD | RS | Applicant Holder |
|---|---|---|---|---|---|---|---|---|---|---|
| RX | FERRIC DERISOMALTOSE | MONOFERRIC | N208171 | SOLUTION | INTRAVENOUS | 1GM/10ML (100MG/ML) | RLD | RS | PHARMACOSMOS AS | |
| DISCN | FERRIC DERISOMALTOSE | MONOFERRIC | N208171 | SOLUTION | INTRAVENOUS | 100MG/ML (100MG/ML) | RLD | PHARMACOSMOS AS | ||
| DISCN | FERRIC DERISOMALTOSE | MONOFERRIC | N208171 | SOLUTION | INTRAVENOUS | 500MG/5ML (100MG/ML) | RLD | PHARMACOSMOS AS | ||
| Mkt. Status | Active Ingredient | Proprietary Name | Appl. No. | Dosage Form | Route | Strength | TE Code | >RLD | RS | Applicant Holder |
MONOFERRIC (FERRIC DERISOMALTOSE)
1GM/10ML (100MG/ML)
Marketing Status: Prescription
Active Ingredient: FERRIC DERISOMALTOSE
Proprietary Name: MONOFERRIC
Dosage Form; Route of Administration: SOLUTION; INTRAVENOUS
Strength: 1GM/10ML (100MG/ML)
Reference Listed Drug: Yes
Reference Standard: Yes
TE Code:
Application Number: N208171
Product Number: 003
Approval Date: Jan 16, 2020
Applicant Holder Full Name: PHARMACOSMOS AS
Marketing Status: Prescription
Patent and Exclusivity Information
Patent and Exclusivity for: N208171
Product 003
FERRIC DERISOMALTOSE (MONOFERRIC) SOLUTION 1GM/10ML (100MG/ML)
Patent Data
| Product No | Patent No | Patent Expiration | Drug Substance | Drug Product | Patent Use Code | Delist Requested | Submission Date |
|---|---|---|---|---|---|---|---|
| 003 | 8815301 | 08/14/2029 | DS | DP | U-2734 | 02/14/2020 | |
| 003 | 10414831 | 03/25/2029 | DS | DP | 02/14/2020 |
PATENT
AU2009342799B2
US10414831B2
US2012010166A1
US2014303364A1
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References
- ^ Jump up to:a b c d “Monoferric- ferric derisomaltose solution”. DailyMed. 24 January 2020. Retrieved 16 February 2020.
- ^ “Monoferric approval letter” (PDF). U.S. Food and Drug Administration (FDA). 16 January 2020. Retrieved 16 February 2020.
This article incorporates text from this source, which is in the public domain. - ^ “Drug Approval Package: Monoferric Injection”. U.S. Food and Drug Administration (FDA). 7 May 2020. Retrieved 13 August 2020.
External links
- “Ferric derisomaltose”. Drug Information Portal. U.S. National Library of Medicine.
| Clinical data | |
|---|---|
| Trade names | Monoferric |
| AHFS/Drugs.com | Monograph |
| License data | US DailyMed: Ferric_derisomaltose |
| Routes of administration | Intravenous (IV) |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only [1] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1345510-43-1 |
| PubChem CID | 86278348 |
| DrugBank | DB15617 |
| UNII | AHU547PI9H |
| KEGG | D11808 |
| Chemical and physical data | |
| Formula | C18H34FeO16+3 |
| Molar mass | 562.299 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI |
/////////////Ferric derisomaltose, デルイソマルトース第二鉄 , APPROVALS 2022, JAPAN 2022, NS32, WHO 9712
[Fe+3].OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@H](O)[C@H]1O
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Difamilast
Difamilast
PMDA Moizerto, JAPAN APPROVED 2021/9/27
ジファミラスト
ディファミラスト;
地法米司特
N-({2-[4-(difluoromethoxy)-3-(propan-2-yloxy)phenyl]-1,3- oxazol-4-yl}methyl)-2-ethoxybenzamide
OPA-15406
| Formula |
C23H24F2N2O5
|
|---|---|
| CAS |
937782-05-3
|
| Mol weight |
446.4439
|
MM 36; MM-36-Medimetriks-Pharmaceuticals; Moizerto; OPA-15406
| Efficacy |
Anti-inflammatory, Phosphodiesterase IV inhibitor
|
|---|---|
| Comment |
Treatment of atopic dermatitis
|
OriginatorOtsuka Pharmaceutical Development & Commercialization- DeveloperMedimetriks Pharmaceuticals; Otsuka Pharmaceutical Development & Commercialization
- ClassBenzamides; Nonsteroidal anti-inflammatories; Oxazoles; Skin disorder therapies
- Mechanism of ActionType 4 cyclic nucleotide phosphodiesterase inhibitors
- RegisteredAtopic dermatitis
- 27 Sep 2021Registered for Atopic dermatitis (In adolescents, In children, In adults) in Japan (Topical)
- 11 Nov 2020Otsuka Pharmaceutical completes a phase III trial in Atopic dermatitis (In children, In adolescents, In adults) in Japan (Topical) (NCT03961529)
- 28 Sep 2020Preregistration for Atopic dermatitis in Japan (In children, In adolescents, In adults) (Topical)
Difamilast is under investigation in clinical trial NCT01702181 (A Safety Study to Evaluate the Use and Effectiveness of a Topical Ointment to Treat Adults With Atopic Dermatitis).
PATENT
JP 2021059538
https://patentscope.wipo.int/search/en/detail.jsf?docId=JP322244172&_cid=P20-L1WXG6-04592-1
patcit 2 : International Publication No. 2014/034958 (Japanese Publication No. 2015-528433 )
patcit 3 : International Publication No. 2017/115780
Compound (5) (white powder) was prepared by the method described in Example 352 of Patent Document 1 (International Publication No. 2007/088383).
Ｎ−（｛２−［４−（ｄｉｆｌｕｏｒｏｍｅｔｈｏｘｙ）−３−ｉｓｏｐｒｏｐｏｘｙｐｈｅｎｙｌ］ｏｘａｚｏｌ−４−ｙｌ｝ｍｅｔｈｙｌ）−２−ｅｔｈｏｘｙｂｅｎｚａｍｉｄｅ
： ｗｈｉｔｅ ｐｏｗｄｅｒ．
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３）： δ ＝ ８．５６ （ｂｒ ｓ，
１Ｈ， ＮＨ）， ８．２３ （ｄｄ， Ｊ ＝ ７．６ Ｈｚ， １．６ Ｈｚ， １Ｈ， ＡｒＨ）， ７．６６ （ｓ， １Ｈ， ＡｒＨ）， ７．６３ （ｄ， Ｊ ＝ ２．０ Ｈｚ， １Ｈ， ＡｒＨ）， ７．５８ （ｄｄ， Ｊ ＝ ８．４ Ｈｚ， ２．０ Ｈｚ， １Ｈ， ＡｒＨ）， ７．４４−７．３９ （ｍ， １Ｈ， ＡｒＨ）， ７．２１ （ｄ， Ｊ ＝ ８．０ Ｈｚ， １Ｈ， ＡｒＨ）， ７．０８−７．０４ （ｍ， １Ｈ， ＡｒＨ）， ６．９４ （ｄ， Ｊ ＝ ８．０ Ｈｚ， １Ｈ， ＡｒＨ）， ６．６１ （ｔ， Ｊ ＝ ７５．２ Ｈｚ， １Ｈ， ＣＨＦ ２）， ４．６８ （ｓｅｐｔ， Ｊ ＝ ６．０ Ｈｚ， １Ｈ， ＣＨ）， ４．６２
（ｄ， Ｊ ＝ ６．０ Ｈｚ， ２Ｈ， ＣＨ ２）， ４．１７ （ｑ， Ｊ ＝ ６．９３， ２Ｈ， ＣＨ ２）， １．４８ （ｔ， Ｊ ＝ ７．２ Ｈｚ， ３Ｈ，
ＣＨ ３）， １．３９ （ｄ， Ｊ ＝ ５．６ Ｈｚ， ６Ｈ， ２ＣＨ ３）．
Using the obtained B-type crystal as a seed crystal, it was examined to further prepare a B-type crystal. Specifically,
B-type crystals were prepared as follows according to the method described in Patent Document 3 (International Publication No. 2017/115780).
aqueous sodium hydroxide solution were added to the organic layer, the temperature was adjusted again to 40 to 50 ° C., the liquid was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% aqueous sodium hydroxide solution, and 0.6 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. Activated carbon was removed by filtration, washed with 12 mL of ethanol, the filtrate was cooled, and 10 mg of B-type crystals (seed crystals) were added to precipitate crystals. Precipitated crystals were collected by filtration and dried at 60 ° C. to obtain 18.38 g (yield 88.18%) of crystals of compound (5).
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017115780
Compound (3) was produced in accordance with the following reaction scheme.
1H-NMR (CDCl 3) δ: 7.70 (2H,dd,J = 6.4 Hz,2.0 Hz),7.22 (1H,d,J = 9.2 Hz),6.66 (1H,t,J = 74.8 Hz),4.66(1H,sept,J = 6.0 Hz),1.39 (6H,d,J = 6.0 Hz).
Production Example 2: Production 2 of Compound (3)
Compound (3) was produced in accordance with the following reaction scheme.
Compound (7) was produced in accordance with the following reaction scheme.
Compound (11) was produced in accordance with the following reaction scheme.
20.00 g (66.8 mmol) of compound (7) and 17.28 g (134 mmol) of N,N-diisopropylethylamine were added to 300 ml of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added thereto and reacted at 20 to 35°C for 1 hour. 100 ml of water was added to the reaction solution, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 300 ml of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 ml of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue and reacted at 75 to 85°C for 1 hour. 200 ml of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 25.90 g (yield: 90.5%) of compound (9) as a white powder.
15.00 g (35.0 mmol) of compound (9) was mixed with 30 ml of a 40% methylamine aqueous solution, 30 ml of methanol, and 75 ml of water, and reacted under reflux for 30 minutes. 150 ml of cyclopentyl methyl ether (CPME) and 15 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75°C, followed by partitioning. A mixture of 150 ml of water and 7.50 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65 to 75°C again, followed by partitioning. 3.75 ml of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 11.95 g (yield: quant.) of compound (10) as a white powder.
13.30 g (39.7 mmol) of compound (10) was mixed with 3.83 g (37.8 mmol) of triethylamine and 108 ml of ethyl acetate, and stirred at 20 to 30°C for 1 hour. 9.78 g (58.9 mmol) of 2-ethoxybenzoic acid and 11.28 g (58.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 54 ml of water and 5.4 ml of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by partitioning. 54 ml of water and 5.4 ml of a 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was adjusted to 40 to 50°C again. The mixture was partitioned, and the organic layer was concentrated under reduced pressure. 45 ml of ethanol, 18 ml of water, 5.4 ml of a 25% sodium hydroxide aqueous solution, and 0.54 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 11 ml of ethanol. The filtrate was cooled, and a seed crystal was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 35°C, thereby obtaining 12.88 g (72.6%) of compound (11) as a white powder.
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019194211
*DIPEA: Diisopropylethylamine, CPME: Cyclopentyl methyl ether,
DMF: N,N-dimethylformamide, 2-EBA: 2-Ethoxybenzoic acid,
WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
Analysis was conducted to further prepare the type B crystal using the obtained type B crystal as a seed crystal. More specifically, the type B crystal was prepared as follows, in accordance with the method disclosed in PTL 3 (WO2017/115780).
PATENT
WO2014034958A1
WO2007058338A2
WO2007058338A9
WO2007058338A3
US9181205B2
US2015239855A1
USRE46792E
US2020078340A1
US2017216260A1
US2019070151A1
US2009221586A1
US8637559B2
US2014100226A1
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/////////////Difamilast, JAPAN 2021, APPROVALS 2021, ジファミラスト , MM 36, MM-36-Medimetriks-Pharmaceuticals, Moizerto, OPA-15406, OPA 15406, 地法米司特
O=C(NCC1=COC(C2=CC=C(OC(F)F)C(OC(C)C)=C2)=N1)C3=CC=CC=C3OCC
INTrmediate No.CAS No.DIFAM-001177429-27-5DIFAM-00293652-48-3DIFAM-0031574285-26-9DIFAM-00470-23-5DIFAM-0051574285-28-1DIFAM-0061574285-30-5DIFAM-0071574285-32-7DIFAM-0081574285-36-1DIFAM-0091574285-38-3DIFAM-010DIFAM-0111574285-40-7DIFAM-0121574285-43-0DIFAM-013134-11-2Difamilast937782-05-3
TOLDIMFOS SODIUM
TOLDIMFOS SODIUM
C9H12NNaO2P+ , 220.16
Toldimfos sodium
575-75-7
Sodium (4-(dimethylamino)-2-methylphenyl)phosphinate
UNII-6139240O1E
sodium;[4-(dimethylamino)-2-methylphenyl]-oxido-oxophosphanium
Sodium (4-(dimethylamino)-2-methylphenyl)phosphinate
sodium;[4-(dimethylamino)-2-methylphenyl]-oxido-oxophosphanium
Phosphinic acid, [4-(dimethylamino)-2-methylphenyl]-, sodium salt
Phosphinic acid, (4-(dimethylamino)-2-methylphenyl)-, sodium salt
Phosphinic acid, P-(4-(dimethylamino)-2-methylphenyl)-, sodium salt (1:1)
Toldimfos is an aromatic phosphorus compound which falls between phosphorous itself and phosphoric acid in the stages of oxidation. Toldimfos sodium is the sodium salt of 2- methyl-4-(dimethylamino)phenylphosphinic acid. It is used to treat and prevent diseases associated with parturition and peri-partum period, developmental and nutritional disorders in young animals, and bone growth disorders and tetany or paresis caused by calcium, magnesium, and phosphorus metabolism disorders. Toldimfos has been used as a human medicine since 1920. While it is no longer indicated for human use, it is used in horses, cattle, sheep, pigs, and goats, and administered by intravenous, intramuscular, or subcutaneous injection. No specific data on the pharmacodynamic action of toldimfos was submitted. The precise mode of action of toldimfos is unknown and it is questionable whether the effect of toldimfos is simply a matter of the substitution of deficient phosphorus. It appears more likely that the effect of toldimfos arises due to multiple stimulation of metabolism with the body.
Toldimfos sodium trihydrate
5787-63-3
Toldimfos [INN:BAN]
57808-64-7
Toldimfos Sodium
CAS Registry Number: 575-75-7
CAS Name: (4-Dimethylamino-o-tolyl)phosphonous acid sodium salt
Additional Names: sodium (4-dimethylamino-o-tolyl)phosphonate; p-dimethylamino-o-toluenephosphonous acid sodium salt
Trademarks: Foston (Hoechst); Tonofosfan (Hoechst)
Molecular Formula: C9H13NNaO2P, Molecular Weight: 221.17
Percent Composition: C 48.87%, H 5.92%, N 6.33%, Na 10.39%, O 14.47%, P 14.00%
Literature References: Prepd from N,N-dimethyl-m-toluidine and phosphorus trichloride: Benda, Schmidt, DE397813 (1924 to Cassella), Frdl.14, 1409.
Derivative Type: Trihydrate
CAS Registry Number: 5787-63-3
Properties: Scales, needles, or prisms from alc. Freely sol in cold water, hot alcohol.
Therap-Cat-Vet: Phosphorus source.
SYN
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011026571
PATENT
https://patents.google.com/patent/CN103830261A/en
China’s animal husbandry fast development is the important motivity that promotes China’s agricultural and rural economy development, improves farmers’ income.The disease relevant with Nutrition and Metabolism of serious harm animal health is in rising trend in recent years, the direct economic loss that raising poultry nutritive metabolic disease causes over ten billion to China’s animal husbandry every year, and indirect economic loss is difficult to estimate.
Due to the life-time service of chemicals, will cause some poultrys, poultry product drug residue is serious, this is harm humans healthy not only, also affecting the export of farm produce earns foreign exchange, therefore, tackle this problem, research and development are efficient, the new Nutrition and Metabolism medicine of low toxicity, wide spectrum will have huge market.
Toldimfos (Toldimfos Sodium) belongs to the nutritional supplementation medicine of phosphorus supplement, can be used as benzenephosphonic acid (Phenylphosphinicacid, BPA) succedaneum uses, can be used for treating the disease relevant with childbirth and perinatal stage of the food animals such as horse, cattle, pig, sheep, the diseases such as the bone lengthening obstacle being caused by calcium, magnesium, phosphorus metabolism obstacle.
Toldimfos has higher water solublity, mainly excretes through urine rapidly with the former medicine form of not metabolism in animal body, and the half-life is short, can in tissue, not accumulate.
Toldimfos is developed by German Hoechst company, the symptom such as since nineteen twenty, once physical weakness, chronic stress, depression, mental muscle power postoperative for human treatment, that catch was overtired.Now be not used in the mankind, be mainly used in animal.Its commodity are called onofosfan.
In sum, toldimfos, as a kind of nutritional supplementation medicine of new and effective noresidue, has wide market prospect in China.The development of this product will be made outstanding contributions to the sound development of China’s animal husbandry, remarkable economic and social benefits with application.
PATENT
https://patents.google.com/patent/WO2004003198A1/ja
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//////////TOLDIMFOS SODIUM, HOECHST, Foston, Tonofosfan,
O.O.O.[Na+].CN(C)c1ccc(c(C)c1)P(=O)[O-]
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Carotegrast methyl
Carotegrast methyl
| Formula | C28H26Cl2N4O5 |
|---|---|
| CAS | 401905-67-7 |
| Mol weight | 569.4358 |
PMDA APROVED, CAROGRA, カロテグラストメチル
| ON 2022/3/28 |
Antiasthmatic, Integrin alpha 4 inhibitor
- An alpha4 integrin antagonist.
401905-67-7[RN]
L-Phenylalanine, N-(2,6-dichlorobenzoyl)-4-[6-(dimethylamino)-1,4-dihydro-1-methyl-2,4-dioxo-3(2H)-quinazolinyl]-, methyl ester
methyl (2S)-2-[(2,6-dichlorophenyl)formamido]-3-{4-[6-(dimethylamino)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl]phenyl}propanoate
Methyl N-(2,6-dichlorobenzoyl)-4-[6-(dimethylamino)-1-methyl-2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl]-L-phenylalaninate
Carotegrast Methyl
Methyl (2S)-2-(2,6-dichlorobenzamido)-3-{4-[6-(dimethylamino)-1-methyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]phenyl}propanoate
C28H26Cl2N4O5 : 569.44
[401905-67-7]
PATENT
WO 2008062859
https://patents.google.com/patent/WO2008062859A1/en
Step 1
(Method 2): The title compound was prepared starting from 2-amino-5-dimethylamino- benzoic acid methyl ester dihydrochloride through the hydrolysis under basic condition To 5.0 g of 2-amino-5-dimethylamino-benzoic acid methyl ester di-hydrochloride, there were added 15 mL of water and 15.6 mL of a 6M aqueous solution of sodium hydroxide and the resulting mixture was heated to 40°C for 2 hours. After the confirmation of the progress of the reaction according to HPLC, the reaction system was cooled to room temperature, a 6M hydrochloric acid aqueous solution was dropwise added to the reaction system to thus neutralize the same and to separate out crystals (pH 4.9) and then the reaction system was stirred at 10°C for 2 hours. The solid thus obtained was isolated through the filtration under reduced pressure, washed with 30 mL of water and then dried under reduced pressure at 60°C for 14 hours. Title compound 3.14 g was obtained as gray-colored solid. The physical properties determined were almost identical to those observed for the same compound prepared in the above-mentioned synthesis example. H-NMR (400MHz, DMSO-d6): δ 8.21 (bs, 3H), 7.10 (d, 1H, J=2.8Hz), 6.97 (dd, 1H, J=9.1, 2.8Hz), 6.70 (d, 1H, J=9.1 Hz), 2.72 (s, 6H); 13C-NMR (100MHz, DMSO-d6): δ168.89, 144.55, 141.61, 123.29, 117.90, 114.78, 110.11,41.95; MS (ESI+): m/z 181.3 (MH+), (ESI-): m/z 179.2 (M-H–).
Step 2
Step 1: Synthesis of Nα-(2,6-dichlorobenzoyl) -4-{2-ethoxycarbonylamino-5-dimethyl- amino-benzoylamino}-L-phenylalanine methyl ester To 1.96 g of 2-amino-5-dimethylaminobenzoic acid, there were added 12 mL of acetonitrile and 5.29 mL of pyridine to form a suspension and then the resulting suspension was cooled to 4°C. To this suspension there was dropwise added 4.17 mL of ethyl chloroformate over 5 minutes and then the mixture was stirred at 25°C for one hour. After confirming the disappearance of the starting material by HPLC, 0.7 mL of ethanol was added to the mixture to thus decompose the excess ethyl chloroformate and the mixture was further stirred for additional one hour. To this reaction solution there were added 4.0 g of 4-amino-Nα-(2,6-dichlorobenzoyl)-L-phenylalanine methyl ester and 12 mL of N,Ndimethylformamide, and the resulting mixture was stirred overnight. Subsequently, 48 mL of methanol was drop-wise added, the resulting mixture was stirred at 10°C overnight and then the solid separated from the mixture was isolated through filtration under reduced pressure. The solid was then washed with 8 mL of methanol and dried at 70°C for 5 hours under reduced pressure. Title compound 5.50 g was obtained as pale yellow solid. 1H-NMR (400MHz, DMSO-d6): δ 10.29 (s, 1H), 9.42 (bs, 1H), 9.24 (d, 1H, J=7.9Hz), 7.73 (bs, 1H), 7.62 (d, 2H, J=8.4Hz), 7.48-7.44 (m, 2H), 7.41 (dd, 1H, J=9.5, 6.2Hz), 7.27 (d, 2H,J=8.4Hz), 7.01 (d, 1H, J=2.7Hz), 6.93 (dd, 1H, J=9.1, 2.9Hz), 4.71 (ddd, 1H, J=9.2, 8.1, 5.7Hz), 4.05 (q, 2H, J=7.0Hz), 3.66 (s, 3H), 3.10 (dd, 1H, J=14.0, 5.6Hz), 2.96 (dd, 1H, J=14.0, 9.2Hz), 2.93 (s, 6H), 1.18 (t, 3H, J=7.2Hz); MS (ESI+): m/z 601.2 (MH+) and 623.2 (M+Na), (ESI–): m/z 599.1 (M-H–).
Step 3
Step2: Synthesis of Na-(2,6-dichlorobenzoyl)-4-{6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine methyl ester To 2.0 g of Na-(2,6-dichlorobenzoyl)-4-{2-ethoxycarbonylamino -5-dimethyl- amino-benzoylamino}-L-phenylalanine methyl ester prepared in above-mentioned step 1, were added 16 mL of N,N-dimethylfbrmamide, 0.8 mL of methanol and 0.91 g of potassium carbonate, followed by the stirring of the resulting mixture at 25°C overnight. To this reaction solution, there was added 0.75 mL of methyl p-toluenesulfonate for subjecting the methyl ester to alkylation at 25~40°C. After confirming the disappearance of the starting material by HPLC, 0.75 mL of acetic acid was added to quench the reaction, 16 mL of water was dropped and the solid was separated. Further, 8 mLof N,N-dimethylformamide/water = 1/1 mixed liquid was added to the resulting mixture, followed by the stirring of the mixture at 25°C. Then the solid thus separated was isolated through filtration under reduced pressure and then washed with 8 mL of water. Thereafter, the isolated solid was dried at 70°C for 4 hours under reduced pressure. Desired compound 1.77 g was obtained as pale yellow solid. 1H-NMR (400MHz, DMSO-d6): δ 9.28 (d, 1H, J=8.1 Hz), 7.48-7.36 (m, 6H), 7.31 (dd, 1H, J=3.0, 9.0Hz), 7.24 (d, 1H, J=3.0Hz), 7.20-7.15 (m, 2H), 4.18 (ddd, 1H, J=10.2, 8.1,4.8Hz), 3.69 (s, 3H), 3.49 (s, 3H), 3.22 (dd, 1H, J=14.1, 4.8Hz), 3.02 (dd, 1H, J=14.2, 10.5Hz), 2.94 (s, 6H); MS (ESI+): m/z 569.2 (MH+) and 591.1 (M+Na), (ESI-): m/z 567.2 (M-H–).
PATENT
https://patents.google.com/patent/WO2004074264A1/en
PATENT’ WO 2003070709
https://patents.google.com/patent/WO2003070709A1/en
PATENT
WO 2002016329
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/////////////Carotegrast methyl, CAROGRA, カロテグラストメチル , JAPAN 2022, APPROVALS 2022,
COC(=O)[C@H](Cc1ccc(cc1)N2C(=O)N(C)c3ccc(cc3C2=O)N(C)C)NC(=O)c4c(Cl)cccc4Cl
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RISPERIDONE
Risperidone
EU APPROVED 2022/2/14, Okedi
- R-64,766
- R-64766
- RCN-3028
- RCN3028
Risperidone, R-64766, Risperdal M-Tab, Risperdal Consta, Rispolept, Belivon, Risperdal
| Formula | C23H27FN4O2 |
|---|---|
| CAS | 106266-06-2 |
| Mol weight | 410.4845 |
3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-2-methyl-4H,6H,7H,8H,9H-pyrido[1,2-a]pyrimidin-4-one
Product Ingredients
| INGREDIENT | UNII | CAS | INCHI KEY |
|---|---|---|---|
| Risperidone tartrate | 0S6B72E3LK | 666179-92-6 | KSWIOGDSXUFKOC-LREBCSMRSA-N |
Risperidone
CAS Registry Number: 106266-06-2
CAS Name: 3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
Manufacturers’ Codes: R-64766
Trademarks: Belivon (Organon); Risperdal (J & J)
Molecular Formula: C23H27FN4O2, Molecular Weight: 410.48
Percent Composition: C 67.30%, H 6.63%, F 4.63%, N 13.65%, O 7.80%
Literature References: Combined serotonin (5-HT2) and dopamine (D2) receptor antagonist. Prepn: L. E. J. Kennis, J. Vandenberk, EP196132; eidem,US4804663 (1986, 1989 both to Janssen). Pharmacology: P. A. J. Janssen et al.,J. Pharmacol. Exp. Ther.244, 685 (1988). Receptor binding studies: J. E. Leysen et al.,ibid.247, 661 (1988). HPLC determn in plasma: A. Avenoso et al.,J. Chromatogr. B746, 173 (2000). Clinical study in psychoses: Y. G. Gelders et al.,Pharmacopsychiatry23, 206 (1990); in autism: L. Scahill et al., N. Engl. J. Med.347, 314 (2002). Brief review: M. G. Livingston, Lancet343, 457-460 (1994). Review of pharmacology and therapeutic potential: S. Grant, A. Fitton, Drugs48, 253-273 (1994); B. Green, Curr. Med. Res. Opin.16, 57-65 (2000); of clinical experience in schizophrenia: H.-J. Möller, Expert Opin. Pharmacother.6, 803-818 (2005),
Properties: Crystals from DMF + 2-propanol, mp 170.0°. LD50 in male, female mice, rats, dogs (mg/kg): 29.7, 26.9, 34.3, 35.4, 14.1, 18.3 i.v.; 82.1, 63.1, 113, 56.6, 18.3, 18.3 orally (Janssen, 1988).
Melting point: mp 170.0°
Toxicity data: LD50 in male, female mice, rats, dogs (mg/kg): 29.7, 26.9, 34.3, 35.4, 14.1, 18.3 i.v.; 82.1, 63.1, 113, 56.6, 18.3, 18.3 orally (Janssen, 1988)
Therap-Cat: Antipsychotic.
Keywords: Antipsychotic; Benzisoxazoles; Serotonin-Dopamine Antagonist.
Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic[2] used to treat schizophrenia and bipolar disorder.[2] It is taken either by mouth or by injection (subcutaneous or intramuscular).[2] The injectable versions are long-acting and last for 2-4 weeks.[6]
Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight.[2][7] Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, as well as neuroleptic malignant syndrome, an increased risk of suicide, and high blood sugar levels.[2][6] In older people with psychosis as a result of dementia, it may increase the risk of death.[2] It is unknown if it is safe for use in pregnancy.[2] Its mechanism of action is not entirely clear, but is believed to be related to its action as a dopamine and serotonin antagonist.[2]
Study of risperidone began in the late 1980s and it was approved for sale in the United States in 1993.[2][8][4] It is on the World Health Organization’s List of Essential Medicines.[9] It is available as a generic medication.[6] In 2019, it was the 149th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[10][11]
Synthesis ReferenceUS4804663
SYN
| EP 0196132; ES 8705881; JP 1986221186; US 4804663 |
The Friedel-Crafts condensation of 1,3-difluorobenzene (I) with 1-acetylpiperidine-4-carbonyl chloride (II) by means of AlCl3 in dichloromethane gives 1-acetyl-4-(2,4-difluorobenzoyl)piperidine (III), which is hydrotyzed with refluxing 6N HCl to yield 4-(2,4-difluorobenzoyl)piperidine (IV). The reaction of (IV) with hydroxylamine in refluxing ethanol affords the corresponding oxime (V), which is cyclized by means of KOH in boiling water giving 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (VI). Finally, this compound is condensed with 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (VII) by means of K2CO3 and Kl in a variety of solvents.
SYN
ES 2050069
The intermediate 3-(2-chloroethyl)-2-methyl-6, 7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (V) has been obtained as follows: The cyclization of 2-aminopyridine (I) with 3-acetyltetrahydrofuran-2-one (II) by means of polyphosphoric acid (PPA) at 160 C gives 3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (III), which is hydrogenated with H2 over Pd/C in ethanol/water to yield the tetrahydro derivative (IV). Finally, the OH group of (IV) is treated with SOCl2 in dichloromethane to afford the target 2-chloroethyl intermediate (V).
SYN
The condensation of piperidine-4-carboxylic acid (VI) with ethyl chloroformate (VII) by means of Na2CO3 in toluene/water gives 1-(ethoxycarbonyl)piperidine-4-carboxylic acid (VIII), which is treated with SOCl2 to yield the corresponding acyl chloride (IX). The Friedel-Crafts condensation of (IX) with refluxing 1,3-difluorobenzene (X) by means of AlCl3 gives 4-(2,4-difluorobenzoyl)piperidine-1-carboxylic acid ethyl ester (XI), which is treated with concentrated HCl at 100 C to yield 4-(2,4-difluorobenzoyl)piperidine (XII). The condensation of piperidine (XII) with the 2-chloroethyl intermediate (V) by means of KI and NaHCO3 in refluxing acetonitrile affords the adduct (XIII), which is treated with hydroxylamine hydrochloride and KOH in refluxing pyridine/ethanol to provide the corresponding oxime (XIV). Finally, this compound is cyclized by means of KOH in refluxing water or with NaH in refluxing THF to afford in both cases the target 1,2-benzisoxazole.
SYN
The intermediate 3-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (IV) has been obtained as follows: The condensation of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (I) with dibenzylamine (II) by means of NaHCO3 in refluxing acetonitrile gives the tertiary amine (III), which is debenzylated by hydrogenation with H2 over Pd/C in warm ethanol to afford the target intermediate (IV).
SYN
The condensation of tetrahydropyran-4-carbonyl chloride (V) with refluxing 1,3-difluorobenzene (VI) by means of AlCl3 gives 1-(2,4-difluorophenyl)-1-(tetrahydropyran-4-yl)methanone (VII), which is treated with hydroxylamine hydrochloride and sodium acetate in refluxing ethanol/water to yield the corresponding oxime (VIII). The cyclization of (VIII) by means of KOH in refluxing methanol affords 6-fluoro-3-(tetrahydropyran-4-yl)-1,2-benzisoxazole (IX), which is treated with NaI and Ac-Cl and then with K2CO3 in refluxing acetonitrile to provide the 5-iodopentanol derivative (X). The reaction of the OH group of (X) with Ms-Cl and TEA in dichloromethane gives the corresponding mesylate (XI), which is finally cyclized with the intermediate amine (IV) by means of NaHCO3 in refluxing acetonitrile to yield the target piperidine.
SYN
SYN
Eur. Pat. Appl. 196132
SYN
- Production Route of Risperidone
- (CAS NO.: ), with other name of 4H-Pyrido(1,2-a)pyrimidin-4-one, 6,7,8,9-tetrahydro-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)ethyl)-2-methyl-, could be produced through many synthetic methods.Following is one of the synthesis routes:
The Friedel-Crafts condensation of 1,3-di (I) with 1-acetylpiperidine-4-carbonyl chloride (II) by means of AlCl3 in dichloromethane gives 1-acetyl-4-(2,4-difluorobenzoyl)piperidine (III), which is hydrotyzed with refluxing 6N HCl to yield 4-(2,4-difluorobenzoyl)piperidine (IV). The reaction of (IV) with hydroxylamine in refluxing ethanol affords the corresponding oxime (V), which is cyclized by means of KOH in boiling water giving 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (VI). Finally, this compound is condensed with 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (VII) by means of K2CO3 and Kl in a variety of solvents.
- SYN
Piperidine-Based Nonfused Biheterocycles With C–N and C–C Coupling
Ruben Vardanyan, in Piperidine-Based Drug Discovery, 2017
Risperidone (15970)
Risperidone (7.2.1) (Risperdal) is the first second-generation antipsychotic that was specifically designed as a combined D2 and serotonin 5-HT(2A) receptor antagonist, thus following the pharmacological mechanism thought to be responsible for the antipsychotic effects. After its advent in the 1990s as the first novel second-generation antipsychotic, risperidone has achieved worldwide acceptance. It was initially approved for use in schizophrenia, mania of bipolar disorder, and irritability and aggression of autism. But it is also effectively used in other instances of psychosis, including schizoaffective disorder, depression with psychotic features, and psychosis secondary to general medical conditions. Risperidone may be effective in other conditions such as major depression, various anxiety disorders, delirium, dementia, for Alzheimer’s dementia, which occurs in 6–8% of persons older than 65 and increases to 30% among those 85 years or older, and substance abuse disorders [84–113].
Risperidone is proposed for inclusion in the WHO Model List of Essential Medications for treatment of schizophrenia, mania, and autism.
Risperidone (7.2.1) was synthesized starting from 1-acetyl-4-piperidine-carbonyl chloride (7.2.4), which was used to acylate 1,3-difluorobenzene (7.2.5) in dichloromethane using aluminum chloride as Lewis acid. The reaction gave 1-(4-(2,4-difluorobenzoyl)piperidin-1-yl)ethan-1-one (7.2.6). The protecting acetyl group of the last was removed off by hydrolysis in 6 N hydrochloric acid on reflux, which gave (2,4-difluorophenyl)(piperidin-4-yl)methanone (7.2.7). The obtained product was converted further to corresponding oxime (7.2.8) on reaction with hydroxylamine hydrochloride in ethanol in the presence of N,N-diethylenethanamine. Synthesized oxime (7.2.8) was cyclized to 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (7.2.9) on reflux with 50% potassium hydroxide solution in water. At the final stage the obtained product (7.2.9) was alkylated with 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (7.2.10) on heating at 85–90°C in dimethylformamide in the presence of sodium carbonate and potassium iodide, which gave the desired product, risperidone (7.2.1) [114,115]. Later, another method of (7.2.7) → (7.2.1) transformation was proposed, which involved the reductive alkylation of (2,4-difluorophenyl)(piperidin-4-yl)methanone (7.2.7) with aldehyde (7.2.11) and sodium cyanoborohydride, which gave compound (7.2.12), coherently converted to oxime (7.2.13) and further to the desired compound, risperidone (7.2.1) [116] (Scheme 7.7).
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Medical uses
Risperidone is mainly used for the treatment of schizophrenia, bipolar disorder, and irritability associated with autism.[12]
Schizophrenia
Risperidone is effective in treating psychogenic polydipsia and the acute exacerbations of schizophrenia.[13][14]
Studies evaluating the utility of risperidone by mouth for maintenance therapy have reached varying conclusions. A 2012 systematic review concluded that evidence is strong that risperidone is more effective than all first-generation antipsychotics other than haloperidol, but that evidence directly supporting its superiority to placebo is equivocal.[15] A 2011 review concluded that risperidone is more effective in relapse prevention than other first- and second-generation antipsychotics with the exception of olanzapine and clozapine.[16] A 2016 Cochrane review suggests that risperidone reduces the overall symptoms of schizophrenia, but firm conclusions are difficult to make due to very low-quality evidence. Data and information are scarce, poorly reported, and probably biased in favour of risperidone, with about half of the included trials developed by drug companies. The article raises concerns regarding the serious side effects of risperidone, such as parkinsonism.[17] A 2011 Cochrane review compared risperidone with other atypical antipsychotics such as olanzapine for schizophrenia:[18]
| Summary |
|---|
| Risperidone seems to produce somewhat more extrapyramidal side effects and clearly more prolactin increase than most other atypical antipsychotics. It may also differ from other compounds in the occurrence of other adverse effects such as weight gain, metabolic problems, cardiac effects, sedation, and seizures. Nevertheless, the large proportion of participants leaving studies early and incomplete reporting of outcomes makes drawing firm conclusions difficult.[18] |
| showOutcomeFindings in wordsFindings in numbersQuality of evidence |
Long-acting injectable formulations of antipsychotic drugs provide improved compliance with therapy and reduce relapse rates relative to oral formulations.[19][20] The efficacy of risperidone long-acting injection appears to be similar to that of long acting injectable forms of first generation antipsychotics.[21]
Bipolar disorder
Second-generation antipsychotics, including risperidone, are effective in the treatment of manic symptoms in acute manic or mixed exacerbations of bipolar disorder.[22][23][24] In children and adolescents, risperidone may be more effective than lithium or divalproex, but has more metabolic side effects.[25] As maintenance therapy, long-acting injectable risperidone is effective for the prevention of manic episodes but not depressive episodes.[26] The long-acting injectable form of risperidone may be advantageous over long acting first generation antipsychotics, as it is better tolerated (fewer extrapyramidal effects) and because long acting injectable formulations of first generation antipsychotics may increase the risk of depression.[27]
Autism
Compared to placebo, risperidone treatment reduces certain problematic behaviors in autistic children, including aggression toward others, self-injury, challenging behaviour, and rapid mood changes.[28] The evidence for its efficacy appears to be greater than that for alternative pharmacological treatments.[29] Weight gain is an important adverse effect.[4][30] Some authors recommend limiting the use of risperidone and aripiprazole to those with the most challenging behavioral disturbances in order to minimize the risk of drug-induced adverse effects.[31] Evidence for the efficacy of risperidone in autistic adolescents and young adults is less persuasive.[32]
Other uses
Risperidone has shown promise in treating therapy-resistant obsessive–compulsive disorder, when serotonin reuptake inhibitors alone are not sufficient.[33]
Risperidone has not demonstrated a benefit in the treatment of eating disorders or personality disorders, except for limited evidence in schizotypal personality disorder.[34]
While antipsychotic medications such as risperidone have a slight benefit in people with dementia, they have been linked to higher incidence of death and stroke.[34] Because of this increased risk of death, treatment of dementia-related psychosis with risperidone is not FDA approved and carries a black box warning.[4]
Forms
Available forms of risperidone include tablet, oral dissolving tablet, oral solution, and powder and solvent for suspension for injection.[35]
Adverse effects
See also: List of adverse effects of risperidone
Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight.[2][7] About 9 to 20% of people gained more than 7% of the baseline weight depending on the dose.[2] Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, as well as neuroleptic malignant syndrome, an increased risk of suicide, and high blood sugar levels.[2][6] In older people with psychosis as a result of dementia, it may increase the risk of death.[2]
While atypical antipsychotics appear to have a lower rate of movement problems as compared to typical antipsychotics, risperidone has a high risk of movement problems among the atypicals.[36][37] Atypical antipsychotics however are associated with a greater amount of weight gain.[37]
Drug interactions
- Carbamazepine and other enzyme inducers may reduce plasma levels of risperidone.[4] If a person is taking both carbamazepine and risperidone, the dose of risperidone will likely need to be increased. The new dose should not be more than twice the patient’s original dose.[4]
- CYP2D6 inhibitors, such as SSRI medications, may increase plasma levels of risperidone and those medications.[4]
- Since risperidone can cause hypotension, its use should be monitored closely when a patient is also taking antihypertensive medicines to avoid severe low blood pressure.[4]
- Risperidone and its metabolite paliperidone are reduced in efficacy by P-glycoprotein inducers such as St John’s wort[38][39]
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[40] Some have argued the additional somatic and psychiatric symptoms associated with dopaminergic super-sensitivity, including dyskinesia and acute psychosis, are common features of withdrawal in individuals treated with neuroleptics.[41][42][43][44] This has led some to suggest the withdrawal process might itself be schizomimetic, producing schizophrenia-like symptoms even in previously healthy patients, indicating a possible pharmacological origin of mental illness in a yet unknown percentage of patients currently and previously treated with antipsychotics. This question is unresolved, and remains a highly controversial issue among professionals in the medical and mental health communities, as well as the public.[45]
Dementia
Older people with dementia-related psychosis are at a higher risk of death if they take risperidone compared to those who do not. Most deaths are related to heart problems or infections.[4]
Pharmacology
Pharmacodynamics
See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
| Site | Ki (nM) | Action |
|---|---|---|
| 5-HT1A | 423 | Antagonist |
| 5-HT1B | 14.9 | Antagonist |
| 5-HT1D | 84.6 | Antagonist |
| 5-HT2A | 0.17 | Inverse agonist |
| 5-HT2B | 61.9 | Inverse agonist |
| 5-HT2C | 12.0 | Inverse agonist |
| 5-HT5A | 206 | Antagonist |
| 5-HT6 | 2,060 | Antagonist |
| 5-HT7 | 6.60 | Irreversible antagonist[47] |
| α1A | 5.0 | Antagonist |
| α1B | 9.0 | Antagonist |
| α2A | 16.5 | Antagonist |
| α2B | 108 | Antagonist |
| α2C | 1.30 | Antagonist |
| D1 | 244 | Antagonist |
| D2 | 3.57 | Antagonist |
| D2S | 4.73 | Antagonist |
| D2L | 4.16 | Antagonist |
| D3 | 3.6 | Inverse agonist |
| D4 | 4.66 | Antagonist |
| D5 | 290 | Antagonist |
| H1 | 20.1 | Inverse agonist |
| H2 | 120 | Inverse agonist |
| mACh | >10,000 | Negligible |
Risperidone pharmacodynamics excluding D-amino acid oxidase inhibition
Risperidone has been classified as a “qualitatively atypical” antipsychotic agent with a relatively low incidence of extrapyramidal side effects (when given at low doses) that has more pronounced serotonin antagonism than dopamine antagonism. Risperidone contains the functional groups of benzisoxazole and piperidine as part of its molecular structure. Although not a butyrophenone, it was developed with the structures of benperidol and ketanserin as a basis. It has actions at several 5-HT (serotonin) receptor subtypes. These are 5-HT2C, linked to weight gain, 5-HT2A, linked to its antipsychotic action and relief of some of the extrapyramidal side effects experienced with the typical neuroleptics.[48]
It has been found that D-amino acid oxidase, the enzyme that catalyses the breakdown of D-amino acids (e.g. D-alanine and D-serine — the neurotransmitters) is inhibited by risperidone.[49]
Risperidone acts on the following receptors:
Dopamine receptors: This drug is an antagonist of the D1 (D1, and D5) as well as the D2 family (D2, D3 and D4) receptors, with 70-fold selectivity for the D2 family. This drug has “tight binding” properties, which means it has a long half-life and like other antipsychotics, risperidone blocks the mesolimbic pathway, the prefrontal cortex limbic pathway, and the tuberoinfundibular pathway in the central nervous system. Risperidone may induce extrapyramidal side effects, akathisia and tremors, associated with diminished dopaminergic activity in the striatum. It can also cause sexual side effects, galactorrhoea, infertility, gynecomastia and, with chronic use reduced bone mineral density leading to breaks, all of which are associated with increased prolactin secretion.[48]
Serotonin receptors: Its action at these receptors may be responsible for its lower extrapyramidal side effect liability (via the 5-HT2A/2C receptors) and improved negative symptom control compared to typical antipsychotics such as haloperidol for instance. Its antagonistic actions at the 5-HT2C receptor may account, in part, for its weight gain liability.[medical citation needed]
Alpha α1 adrenergic receptors: This action accounts for its orthostatic hypotensive effects and perhaps some of the sedating effects of risperidone.[48]
Alpha α2 adrenergic receptors: Perhaps greater positive, negative, affective and cognitive symptom control.[50]
Histamine H1 receptors: effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain.[48]
Voltage-gated sodium channels: Because it accumulates in synaptic vesicles, Risperidone inhibits voltage-gated sodium channels at clinically used concentrations.[51]
Though this medication possesses similar effects to other typical and atypical antipsychotics, it does not possess an affinity for the muscarinic acetylcholine receptors. In many respects, this medication can be useful as an “acetylcholine release-promoter” similar to gastrointestinal drugs such as metoclopramide and cisapride.[medical citation needed]
Pharmacokinetics
Risperidone undergoes hepatic metabolism and renal excretion. Lower doses are recommended for patients with severe liver and kidney disease.[4] The active metabolite of risperidone, paliperidone, is also used as an antipsychotic.[52]
Society and culture
Risperdal (risperidone) 4 mg tablets (UK)
Legal status
Risperidone was approved by the United States Food and Drug Administration (FDA) in 1993 for the treatment of schizophrenia.[63] In 2003, the FDA approved risperidone for the short-term treatment of the mixed and manic states associated with bipolar disorder. In 2006, the FDA approved risperidone for the treatment of irritability in autistic children and adolescents.[64] The FDA’s decision was based in part on a study of autistic people with severe and enduring problems of violent meltdowns, aggression, and self-injury; risperidone is not recommended for autistic people with mild aggression and explosive behavior without an enduring pattern.[65] On 22 August 2007, risperidone was approved as the only drug agent available for treatment of schizophrenia in youths, ages 13–17; it was also approved that same day for treatment of bipolar disorder in youths and children, ages 10–17, joining lithium.
On 16 December 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Okedi, intended for the treatment of schizophrenia in adults for whom tolerability and effectiveness has been established with oral risperidone.[66] The applicant for this medicinal product is Laboratorios Farmacéuticos Rovi, S.A.[66]
Availability
Janssen’s patent on risperidone expired on 29 December 2003, opening the market for cheaper generic versions from other companies, and Janssen’s exclusive marketing rights expired on 29 June 2004 (the result of a pediatric extension). It is available under many brand names worldwide.[1]
Risperidone is available as a tablet, an oral solution, and an ampule, which is a depot injection.[1]
Lawsuits
On 11 April 2012, Johnson & Johnson (J&J) and its subsidiary Janssen Pharmaceuticals Inc. were fined $1.2 billion by Judge Timothy Davis Fox of the Sixth Division of the Sixth Judicial Circuit of the U.S. state of Arkansas.[67] The jury found the companies had downplayed multiple risks associated with risperidone (Risperdal). The verdict was later reversed by the Arkansas State Supreme court.[68]
In August 2012, Johnson & Johnson agreed to pay $181 million to 36 U.S. states in order to settle claims that it had promoted risperidone and paliperidone for off-label uses including for dementia, anger management, and anxiety.[69]
In November 2013, J&J was fined $2.2 billion for illegally marketing risperidone for use in people with dementia.[70]
In 2015, Steven Brill posted a 15-part investigative journalism piece on J&J in The Huffington Post, called “America’s most admired lawbreaker”, which was focused on J&J’s marketing of risperidone.[71][72]
J&J has faced numerous civil lawsuits on behalf of children who were prescribed risperidone who grew breasts (a condition called gynecomastia); as of July 2016 there were about 1,500 cases in Pennsylvania state court in Philadelphia, and there had been a February 2015 verdict against J&J with $2.5 million awarded to a man from Alabama, a $1.75M verdict against J&J that November, and in 2016 a $70 million verdict against J&J.[73] In October 2019, a jury awarded a Pennsylvania man $8 billion in a verdict against J&J.[74]
Names
Brand names include Risperdal, Risperdal Consta, Risperdal M-Tab, Risperdal Quicklets, Risperlet, Okedi, and Perseris.[75]
References
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Further reading
- Dean L (2017). “Risperidone Therapy and CYP2D6 Genotype”. In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520384. Bookshelf ID: NBK425795.
“Risperidone”. Drug Information Portal. U.S. National Library of Medicine.
| Clinical data | |
|---|---|
| Trade names | Risperdal, others[1] |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a694015 |
| License data | US DailyMed: Risperidone |
| Pregnancy category | AU: C |
| Routes of administration | By mouth, intramuscular, subcutaneous |
| Drug class | Atypical antipsychotic[2] |
| ATC code | N05AX08 (WHO) |
| Legal status | |
| Legal status | AU: S4 (Prescription only)CA: ℞-onlyUK: POM (Prescription only) [3]US: ℞-only [4]EU: Rx-only [5] |
| Pharmacokinetic data | |
| Bioavailability | 70% (by mouth)[2] |
| Metabolism | Liver (CYP2D6 mediated to 9-hydroxyrisperidone)[2] |
| Elimination half-life | 20 hours (by mouth), 3–6 days (IM)[2] |
| Excretion | Urinary (70%) feces (14%)[2] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 106266-06-2 |
| PubChem CID | 5073 |
| PubChem SID | 475100 |
| IUPHAR/BPS | 96 |
| DrugBank | DB00734 |
| ChemSpider | 4895 |
| UNII | L6UH7ZF8HC |
| KEGG | D00426 |
| ChEBI | CHEBI:8871 |
| ChEMBL | ChEMBL85 |
| PDB ligand | 8NU (PDBe, RCSB PDB) |
| CompTox Dashboard (EPA) | DTXSID8045193 |
| ECHA InfoCard | 100.114.705 |
| Chemical and physical data | |
| Formula | C23H27FN4O2 |
| Molar mass | 410.493 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
| (verify) |
//////////////Risperidone, R-64,766, R-64766, RCN-3028, RCN3028
NEW DRUG APPROVALS
ONE TIME
$10.00
Lutetium Lu 177 vipivotide tetraxetan
Lutetium Lu 177 vipivotide tetraxetan
FDA APPROVED 2022/3/23, Pluvicto
To treat prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer following other therapies
| Formula | C49H65N9O16. Lu. 3H |
|---|---|
| CAS | 1703749-62-5 |
| Mol weight | 1214.0819 |
| Antineoplastic, Radioactive agent | |
| Disease | Prostate cancer (PSMA positive) |
|---|
ルテチウム(177Lu)ビピボチドテトラキセタン;
UNII-G6UF363ECX, WHO 11429
G6UF363ECX
177Lu-Psma-617
Vipivotide tetraxetan Lu-177
177Lu-Labeled PSMA-617
2-[4-[2-[[4-[[(2S)-1-[[(5S)-5-carboxy-5-[[(1S)-1,3-dicarboxypropyl]carbamoylamino]pentyl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]carbamoyl]cyclohexyl]methylamino]-2-oxoethyl]-7,10-bis(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate;lutetium-177(3+)
(177Lu)Lutetium 2,2′,2”-[10-(2-{[(trans-4-{[(2S)-1-{[(5S)-5-carboxy-5-({[(1S)-1,3-dicarboxypropyl]carbamoyl}amino)pentyl]amino}-3-(2-naphthyl)-1-oxo-2-propanyl]carbamoyl}cyclohexyl)methyl]amino}-2- oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl]triacetate (non-preferred name)
1983157-55-6[RN]
PSMA-617 LU-177
Lutetium Lu 177 Vipivotide Tetraxetan is a radioconjugate composed of PSMA-617, a human prostate-specific membrane antigen (PSMA)-targeting ligand, conjugated to the beta-emitting radioisotope lutetium Lu 177 (177Lu), with potential antineoplastic activity against PSMA-expressing tumor cells. Upon intravenous administration of lutetium Lu 177 vipivotide tetraxetan, vipivotide tetraxetan targets and binds to PSMA-expressing tumor cells. Upon binding, PSMA-expressing tumor cells are destroyed by 177Lu through the specific delivery of beta particle radiation. PSMA, a tumor-associated antigen and type II transmembrane protein, is expressed on the membrane of prostatic epithelial cells and overexpressed on prostate tumor cells.
Lutetium (177Lu) vipivotide tetraxetan, sold under the brand name Pluvicto, is a radiopharmaceutical medication used for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC).[2] Lutetium (177Lu) vipivotide tetraxetan is a targeted radioligand therapy.[2][3]
The most common adverse reactions include fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation.[2]
Lutetium (177Lu) vipivotide tetraxetan is a radioconjugate composed of PSMA-617, a human prostate-specific membrane antigen (PSMA)-targeting ligand, conjugated to the beta-emitting radioisotope lutetium Lu 177 (177Lu), with potential antineoplastic activity against PSMA-expressing tumor cells.[4] Upon intravenous administration of lutetium Lu 177 vipivotide tetraxetan, vipivotide tetraxetan targets and binds to PSMA-expressing tumor cells.[4] Upon binding, PSMA-expressing tumor cells are destroyed by 177Lu through the specific delivery of beta particle radiation.[4] PSMA, a tumor-associated antigen and type II transmembrane protein, is expressed on the membrane of prostatic epithelial cells and overexpressed on prostate tumor cells.[4]
Lutetium (177Lu) vipivotide tetraxetan was approved for medical use in the United States in March 2022.[2][5]
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History[edit]
Efficacy was evaluated in VISION (NCT03511664), a randomized (2:1), multicenter, open-label trial that evaluated lutetium (177Lu) vipivotide tetraxetan plus best standard of care (BSoC) (n=551) or BSoC alone (n=280) in men with progressive, prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC).[2] All participants received a GnRH analog or had prior bilateral orchiectomy.[2] Participants were required to have received at least one androgen receptor pathway inhibitor, and 1 or 2 prior taxane-based chemotherapy regimens.[2] Participants received lutetium (177Lu) vipivotide tetraxetan 7.4 GBq (200 mCi) every 6 weeks for up to a total of 6 doses plus BSoC or BSoC alone.[2]
The U.S. Food and Drug Administration granted the application for lutetium (177lu) vipivotide tetraxetan priority review and breakthrough therapy designations.[2]
References
- ^ “Highlights of prescribing information: PLUVICTOTM (lutetium Lu 177 vipivotide tetraxetan) injection, for intravenous use” (PDF). Advanced Accelerator Applications USA, Inc. Novartis. March 2022.
- ^ Jump up to:a b c d e f g h i j “FDA approves Pluvicto for metastatic castration-resistant prostate can”. U.S. Food and Drug Administration. 23 March 2022. Retrieved 23 March 2022. This article incorporates text from this source, which is in the public domain.
- ^ Neels OC, Kopka K, Liolios C, Afshar-Oromieh A (December 2021). “Radiolabeled PSMA Inhibitors”. Cancers. 13 (24): 6255. doi:10.3390/cancers13246255. PMC 8699044. PMID 34944875.
- ^ Jump up to:a b c d “Lutetium Lu 177 Vipivotide Tetraxetan (Code C148145)”. NCI Thesaurus. 28 February 2022. Retrieved 23 March 2022. This article incorporates text from this source, which is in the public domain.
- ^ “Novartis Pluvicto approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer” (Press release). Novartis. 23 March 2022. Retrieved 23 March 2022.
External links
- “Lutetium lu 177 vipivotide tetraxetan”. Drug Information Portal. U.S. National Library of Medicine.
| Clinical data | |
|---|---|
| Trade names | Pluvicto |
| Other names | 177Lu-PSMA-617, Lutetium Lu 177 vipivotide tetraxetan (USAN US) |
| License data | US DailyMed: Pluvicto |
| Routes of administration | Intravenous |
| Drug class | Radiopharmaceutical |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only [1][2] |
| Identifiers | |
| CAS Number | 1703749-62-5 |
| PubChem CID | 122706785 |
| ChemSpider | 58828499 |
| UNII | G6UF363ECX |
| KEGG | D12335 |
| Chemical and physical data | |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| show |
////////////Lutetium Lu 177 vipivotide tetraxetan, ルテチウム(177Lu)ビピボチドテトラキセタン, FDA 2022, APPROVALS 2022, PROSTRATE CANCER, WHO 11429
C1CC(CCC1CNC(=O)CN2CCN(CCN(CCN(CC2)CC(=O)[O-])CC(=O)[O-])CC(=O)[O-])C(=O)NC(CC3=CC4=CC=CC=C4C=C3)C(=O)NCCCCC(C(=O)O)NC(=O)NC(CCC(=O)O)C(=O)O.[Lu+3]
Vipivotide tetraxetan (Synonyms: PSMA-617)
CAS No. : 1702967-37-0
Vipivotide tetraxetan (PSMA-617) is a high potent prostate-specific membrane antigen (PSMA) inhibitor, with a Ki of 0.37 nM.
NEW DRUG APPROVALS
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CRENOLANIB
Crenolanib
- Molecular FormulaC26H29N5O2
- Average mass443.541 Da
1-(2-{5-[(3-Methyl-3-oxetanyl)methoxy]-1H-benzimidazol-1-yl}-8-quinolinyl)-4-piperidinamine
1-(2-{5-[(3-methyloxetan-3-yl)methoxy]-1H-benzimidazol-1-yl}quinolin-8-yl)piperidin-4-amine
1-[2-[5-[(3-methyl-3-oxetanyl)methoxy]-1H-benzimidazol-1-yl]-8-quinolinyl]-4-piperidinamine
4-Piperidinamine, 1-[2-[5-[(3-methyl-3-oxetanyl)methoxy]-1H-benzimidazol-1-yl]-8-quinolinyl]-
670220-88-9[RN]
9459
UNII-LQF7I567TQ
креноланиб
كرينولانيب
克拉尼布
CP-868,596-26 or AR-868,596-26
Crenolanib besylate
CAS#: 670220-93-6 (besylate)
Chemical Formula: C32H35N5O5S
Molecular Weight: 601.72
Crenolanib besylate (CP-868,596-26 or AR-868,596-26, 4-piperidinamine, 1-[2-[5-[(3-Methyl-3-oxetanyl) methoxy]-1H-benzimidazol-1-yl]- 8-quinolinyl]-, monobenzenesulfonate) is an investigational inhibitor being developed by AROG Pharmaceuticals, LLC. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including acute myeloid leukemia (AML),[1][2] gastrointestinal stromal tumor (GIST),[3] and glioma.[4] Crenolanib is an orally bioavailable benzamidazole that selectively and potently inhibits signaling of wild-type and mutant isoforms of class III receptor tyrosine kinases (RTK) FLT3 (FMS-like Tyrosine Kinase 3), PDGFR α (Platelet-Derived Growth Factor Receptor), and PDGFR β. Unlike most RTK inhibitors, crenolanib is a type I mutant-specific inhibitor that preferentially binds to phosphorylated active kinases with the ‘DFG in’ conformation motif.[5]
CN 109678849
PATENT
WO/2022/060421CRENOLANIB FOR TREATING TRK KINASE ASSOCIATED PROLIFERATIVE DISORDERS
PATENT
WO/2022/060422CRENOLANIB FOR TREATING PAIN
PAPER
https://www.nature.com/articles/s41598-018-21839-3
PAPER
Chembiochem : a European journal of chemical biology (2019), 20(14), 1783-1788.
PATENT
CN 109678849
PATENT
WO 2018118598
https://patents.google.com/patent/WO2018118598A1/en
PAT
US 20170121321
PAT
CN 107382984
https://patents.google.com/patent/CN107382984A/en
Embodiment is as follows：
The synthesis of the chloro- 8- trifluoromethanesulfonic acids base quinoline (Ι) of 2-
Compound 2- chloro-8-hydroxyquinolines 50g, DMF150ml, trifluoromethanesulfchloride chloride 53g, triethylamine 25g are added to 250ml In three-necked bottle, stir.Temperature control reacts 20~30h at 25~30 DEG C.After reaction completely, the solid of precipitation is filtered, filter cake is used Wash washing, 40 DEG C of forced air dryings, the chloro- 8- trifluoromethanesulfonic acids base benzimidazoles of gained off-white powder 2- in n-hexane 20ml × 3 83.39g yield 95.78%.
The synthesis of (base of piperidines -4) the quinoline t-butyl carbamates of 2- chloro- 8 (II)
BINAP 0.2g, toluene 70ml are added into 250ml three-necked bottles, temperature control stirs 1h at 20~25 DEG C.Added again into bottle The chloro- 8- trifluoromethanesulfonic acids base quinoline 10g of 2-, piperidin-4-yl t-butyl carbamate 6.41g, potassium carbonate 7.8g, stir lower by instead Answer liquid to be heated to 80 DEG C~100 DEG C, keep 20~30h of this thermotonus.TLC is detected, and whether reaction is complete.Reaction is complete, stops Only heat.20~30 DEG C are cooled to, dichloroethanes 50ml is added, adds diatomite to filter out the solid in reaction solution, filter cake second Acetoacetic ester 150ml is washed., 20~25 DEG C of stirring 8h.The solid separated out in solution is filtered out, filtrate is molten with 5% disodium hydrogen phosphate Liquid 2x50ml is washed.Organic phase is concentrated to dryness again, adds acetonitrile 50ml, 20~25 DEG C of 10~20h of stirring and crystallizing.Filtering analysis The solid gone out, 40 DEG C of forced air dryings obtain the tertiary fourth of yellow solid 10.69g, 2- chloro- 8 (piperidin-4-yl) benzimidazole carbamic acid Ester, yield 92.3%.
The synthesis of 5- (3- methy oxetane -3- methoxyl groups) benzimidazole (III)
Compound 3- methyl -3- oxetane methanols 30.77g, THF140ml, metallic sodium 6.95g are added to the necks of 250ml tri- In bottle, 66 DEG C of backflow 4h are heated under stirring, 55 DEG C is cooled to, then adds 5- hydroxybenzimidazole 40.4g, stir lower heat Backflow, react 20~24h.
Ethyl acetate 100ml is added into reaction bulb, 0.5h dissolvings are stirred at 30~50 DEG C, are then reduced to -5 DEG C, are added dropwise just Hexane 30ml, stirs 1h, and suction filtration obtains light yellow solid, 40 DEG C of dryings to constant weight, obtains 56.41 grams, yield 85.8%.
(1- { 2- [5- (3- methvl-oxetan -3- ylmethoxies)-benzimidazole -1- bases]-quinoline-8-yl }-piperazine The synthesis of pyridine -4- bases-t-butyl carbamate (IV)
II (50 grams), III (30.14 grams), potassium carbonate 80g, DIPHOS 4.3g, toluene 700ml, are added in 2L three-necked bottles, add Enter acid chloride 0.9g, stir.Stirring is lower to heat up, and temperature control reacts 24~30h at 80~100 DEG C.After the completion of reaction, it is cooled to 55 DEG C add dichloroethanes 700ml.10min is stirred, adds the solid in diatomite filtering reacting liquid, the filter cake chloroethenes of 500ml bis- Alkane rinses.Concentrate the filtrate to it is dry, add ethyl acetate 480ml, be heated to flowing back, be cooled to 20~25 DEG C of 10~20h of crystallization. The solid separated out is filtered, 50 DEG C of forced air dryings, obtains white solid, the amount of obtaining 70.51g, yield 93.90%.
(1- { 2- [5- (3- methvl-oxetan -3- ylmethoxies)-benzimidazole -1- bases]-quinoline-8-yl } -4- The synthesis of amino piperidine (V)
By compound (1- { 2- [5- (3- methvl-oxetan -3- ylmethoxies)-benzimidazole -1- bases]-quinoline -8- Base }-piperidin-4-yl-t-butyl carbamate 5g, caustic alcohol 2.8g, 2- methyltetrahydrofuran 30ml and water 0.08ml be added to In 100ml three-necked bottles, stir.The mixture is heated to flowing back, and stirs 3~4h under reflux.
TLC is detected, and reaction is complete.Stop heating, add purified water 60ml, extracting and demixing.Aqueous phase is extracted with 2 × 20ml of ethyl acetate Take, merge organic phase, washed with saturated nacl aqueous solution 20ml.Be concentrated under reduced pressure organic phase, and 30ml is added into condensate residue Ethyl acetate, in 20~25 DEG C of stirring and crystallizing 6h.The solid separated out is filtered, filtrate decompression is concentrated to dryness.Added into residue 24ml ethyl acetate, in 20~25 DEG C of 10~12h of stirring and crystallizing.Filter the solid separated out, dry white solid product, the amount of obtaining 3.68g, yield 90.3%.
1H NMR test (referring to accompanying drawing)
(d6-DMSO):δ 9.176 (s, 1H), δ 8.88-8.91 (d, 1H, J=8.7Hz), δ 8.51-8.53 (d, 1H, J= 9.0Hz), δ 8.13-8.15 (d, 1H, J=9.0Hz), δ 7.6 (d, 1H, J=7.5Hz), 7.49 (t, 1H, J=7.9Hz) 7.39 (d, 1H, J=2.4Hz), 7.29 (d, 1H, J=7.6Hz), 7.19 (dd, 1H, J=9.2hz, 2.5Hz) 4.56 (d, 2H, J= 5.6Hz), 4.34 (d, 2H, J=5.7Hz), 4.14 (s, 2H), 3.74 (d, 2H, J=10.1Hz), 2.77 (m, 3H), 1.91 (d, 2H, J=11.1Hz), 1.68 (m, 2H), 1.41 (s, 3H)
SET 2
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Background
Type III Receptor tyrosine kinase, including FLT3, PDGFRα and PDGFRβ, have been directly implicated in the pathogenesis of epithelial, mesenchymal, and hematological malignancies.[6]
Mutations of FLT3 comprise one of the most frequently identified types of genetic alterations in Angiomyolipoma.[7][8] Approximately one-third of AML patients present with a mutation in this gene.[9] The majority of these mutations result in constitutive activation of downstream signaling pathways and aberrant cell growth.[7] Mutations in FLT3 have also been reported in acute lymphoblastic leukemia (ALL)[10] and myelodysplastic syndrome (MDS).[11]
Activating mutations in PDGFRA have been detected in 5-12% of Gastrointestinal stromal tumor.[12] Fusion of PDGFRA has been found to be responsible for hematological malignances like hypereosinophilic syndrome.[13] The amplification of chromosome 4q12, the site of the PDGFRA gene[citation needed], has been identified in 13-29% of adult gliomas[citation needed] and in 29% to 36% of diffuse intrinsic pontine gliomas (DIPG)[citation needed], a subset of high-grade gliomas (HGG) in pediatric patients. Activation of PDGFRB, a third member of the type III RTK family, has been implicated in the development of chronic myelomonocytic leukemia due to the fusion of PDGFRB with the TEL gene.[13] Furthermore, PDGFB translocation to the COL1A1 gene locus has been identified to be responsible for dermatofibrosarcoma protuberans (DFSP).[13] In cancer cells, PDGFR promotes tumor development and migration via proto-oncogenic downstream mediators like AKT and MEK[citation needed]. In stromal fibroblasts, PDGFRα activation leads to local tissue invasion, production and secretion of VEGF, and elevated intratumoral interstitial pressure[citation needed]. In stromal pericytes, PDGFRβ activation mediates vascular stability.[13] Thus, either FLT3 or PDGF/PDGFR pathway is the primary driver of oncogenesis in the above malignancies and can be targeted by crenolanib therapy[citation needed].
Mechanism
FLT3: wild-type and mutant
Crenolanib inhibits both wild type FLT3 and its constitutively active mutations. In vitro studies have shown that crenolanib has low Kd for the FLT3 enzyme with constitutively activating internal tandem duplication (ITD) mutations and tyrosine kinase domain (TKD) mutations, D835H and D835Y, as compared to wild type. Crenolanib tightly binds to FLT3-ITD, FLT3-D835H and FLT3-D835Y with Kd of 0.74 nM, 0.4 nM, and 0.18 nM, respectively.[14] Crenolanib inhibits the phosphorylation of the FLT3-ITD receptor in transfected TF-1 cells and the FLT3-D835Y TKD mutation in transfected Ba/F3 cells at nanomolar IC50 concentrations of 1.3 nM and 8.8 nM, respectively.[15] Immunoblot experiments performed in the Molm14 FLT3-ITD positive cell line show that crenolanib inhibits downstream signaling of FLT3 at a concentration of 10 nM.[15] MTT assay measurements of crenolanib cytotoxicity evaluated in the FLT3-ITD expressing cell lines Molm14 and MV411, showed that crenolanib is toxic at IC50 concentrations of 7 nM and 8 nM, respectively.[15]
PDGFRα: wild-type and mutant
Crenolanib has been shown to inhibit PDGFRα with an IC50 of 0.4 ng/mL in porcine aortic epithelial cell lines. In Chinese hamster ovary (CHO) cells expressing PDGFRα, crenolanib inhibited the phosphorylation of wild type PDGFRα at an IC50 of 10 nM.[16] Additionally, crenolanib completely blocked PDGFRα phosphorylation and downstream AKT signaling at a concentration between 0.1 and 1 uM in Ink4a/Arf-/- mouse astrocytes transfected to stably co-express both human PDGFRα and PDGF AA.[17] The lung cancer cell line H1703, which is reported to have amplification of both PDGFRA (4q12) and PDGFC (4q32) genes on chromosome 4, and also overexpress PDGFRα, was sensitive to crenolanib with an IC50 of ~80 nM.[18] In CHO cells expressing an activating exon 18 (D842V) PDGFRα mutation, crenolanib was effective at an IC50 of 6nM and IC90 of 25nM. In addition, crenolanib also inhibited phosphorylation of the double mutants PDGFRα (V561D + D842V and T674I + D842V).[16]
PDGFRβ: wild-type
Crenolanib has been shown to inhibit PDGFRβ with an IC50 of 0.8 ng/mL in porcine aortic epithelial cell lines. Crenolanib inhibits the ability of recombinant PDGFRβ to phosphorylate a synthetic tyrosine substrate (poly-glutamic acid-tyrosine), with an IC50 of 0.4 ng/mL. Evaluation of the antitumor activity of crenolanib in a genetically engineered BSG DIPG mouse model showed that it is highly selective for PDGFRβ with an IC50 of 10 nM when measured by BrdU assay and 1.25 uM by MTT assay.
C-Kit: wild-type and mutant
Crenolanib has been shown to have IC50 and Kd values of 67 nM and 78 nM, respectively, for wild type c-KIT in in vitro assays[citation needed]. Similar assays show that crenolanib inhibits c-KIT activating mutations D816H and D816V with IC50 concentrations of 5.4 and 2.5 nM, respectively.[14][citation needed] Human bone marrow progenitor cell growth assays showed that crenolanib has modest effects on GM-CSF and BFUE driven colony formation at the IC50 concentration of 20 nM.[15]
Clinical
Phase I single-agent[19] and Phase Ib combination[20] studies have investigated the clinical pharmacology of crenolanib in patients with cancer. Pharmacokinetic and safety studies of Crenolanib administered alone or in combination with docetaxel with or without axitinib have been completed. Results suggest that Crenolanib is well tolerated as a single agent, and can also be safely combined with docetaxel and axitinib due to their non-overlapping toxicity profiles.
Clinical trials
- Clinical trial number NCT01229644 for “A Phase II Study of Crenolanib (CP-868,596), a Selective and Potent Inhibitor of PDGFR, for the Treatment of Adult Gliomas” at ClinicalTrials.gov
- Clinical trial number NCT01243346 for “Phase II Study of Crenolanib (CP-868,596), for the Treatment of Patients With Advanced Gastrointestinal Stromal Tumors With the D842-related Mutations and Deletions in the PDGFRA Gene” at ClinicalTrials.gov
- Clinical trial number NCT01393912 for “PDGFR Inhibitor Crenolanib in Children/Young Adults With Diffuse Intrinsic Pontine Glioma or Recurrent High-Grade Glioma” at ClinicalTrials.gov
- Clinical trial number NCT01522469 for “Phase II Study of Crenolanib in Subjects With Relapsed/Refractory AML With FLT3 Activating Mutations” at ClinicalTrials.gov
- Clinical trial number NCT01657682 for “A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations” at ClinicalTrials.gov
References
- ^ “A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations – Full Text View”. ClinicalTrials.gov. Retrieved 2014-04-08.
- ^ “Phase II Study of Crenolanib in Subjects With Relapsed/Refractory AML With FLT3 Activating Mutations – Full Text View”. ClinicalTrials.gov. Retrieved 2014-04-08.
- ^ “Phase II Study of Crenolanib (CP-868,596), for the Treatment of Patients With Advanced Gastrointestinal Stromal Tumors With the D842-related Mutations and Deletions in the PDGFRA Gene – Full Text View”. ClinicalTrials.gov. Retrieved 2014-04-08.
- ^ “PDGFR Inhibitor Crenolanib in Children/Young Adults With Diffuse Intrinsic Pontine Glioma or Recurrent High-Grade Glioma – Full Text View”. ClinicalTrials.gov. Retrieved 2014-04-08.
- ^ A. Ramachandran; H. Marshall; V. Jain. “CRENOLANIB, A NOVEL TYPE I, MUTANT -SPECIFIC INHIBITOR OF CLASS III RECEPTOR TYROSINE KINASES, PREFERENTIALLY BINDS TO PHOSPHORYLATED KINASES” (PDF). gistsupport.org. Retrieved 2014-04-08.
- ^ Lemmon, Mark A.; Schlessinger, Joseph (2010). “Cell Signaling by Receptor Tyrosine Kinases”. Cell. 141 (7): 1117–34. doi:10.1016/j.cell.2010.06.011. PMC 2914105. PMID 20602996.
- ^ Jump up to:a b Takahashi, S (2011-04-01). “Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications”. J Hematol Oncol. 4: 13. doi:10.1186/1756-8722-4-13. PMC 3076284. PMID 21453545.
- ^ Cancer Genome Atlas Research Network; Ley, T. J.; Miller, C.; Ding, L.; Raphael, B. J.; Mungall, A. J.; Robertson, A.; Hoadley, K.; Triche Jr, T. J.; Laird, P. W.; Baty, J. D.; Fulton, L. L.; Fulton, R.; Heath, S. E.; Kalicki-Veizer, J.; Kandoth, C.; Klco, J. M.; Koboldt, D. C.; Kanchi, K. L.; Kulkarni, S.; Lamprecht, T. L.; Larson, D. E.; Lin, L.; Lu, C.; McLellan, M. D.; McMichael, J. F.; Payton, J.; Schmidt, H.; Spencer, D. H.; et al. (2013). “Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia”. New England Journal of Medicine. 368 (22): 2059–2074. doi:10.1056/NEJMoa1301689. ISSN 0028-4793. PMC 3767041. PMID 23634996.
- ^ “The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias”. Hindawi.com. Retrieved 2014-04-08.
- ^ Xu, F; Taki, T; Yang, HW; Hanada, R; Hongo, T; Ohnishi, H; Kobayashi, M; Bessho, F; Yanagisawa, M; Hayashi, Y (2014-01-24). “Tandem duplication of the FLT3 gene is found in acute lymphoblastic leukaemia as well as acute myeloid leukaemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukaemia in children”. Br. J. Haematol. 105 (1): 155–62. doi:10.1111/j.1365-2141.1999.01284.x. PMID 10233379. S2CID 40898615.
- ^ Yokota, S; Kiyoi, H; Nakao, M; Iwai, T; Misawa, S; Okuda, T; Sonoda, Y; Abe, T; Kahsima, K; Matsuo, Y; Naoe, T (2014-01-24). “Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines”. Leukemia. 11 (10): 1605–9. doi:10.1038/sj.leu.2400812. PMID 9324277.
- ^ Heinrich, M. C.; Corless, CL; Duensing, A; McGreevey, L; Chen, CJ; Joseph, N; Singer, S; Griffith, DJ; Haley, A; Town, A; Demetri, GD; Fletcher, CD; Fletcher, JA (2003). “PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors”. Science. 299 (5607): 708–10. doi:10.1126/science.1079666. PMID 12522257. S2CID 11725958.
- ^ Jump up to:a b c d Östman, Arne; Heldin, Carl‐Henrik (2007). PDGF Receptors as Targets in Tumor Treatment. Advances in Cancer Research. Vol. 97. pp. 247–274. doi:10.1016/S0065-230X(06)97011-0. ISBN 9780120066971. PMID 17419949.
- ^ Jump up to:a b Muralidhara, C.; Ramachandran, A.; Jain, V. K. (2012). “Abstract 3683: Crenolanib, a novel Type I, mutant-specific inhibitor of Class III receptor tyrosine kinases, preferentially binds to phosphorylated kinases”. Cancer Research. 72 (8 Supplement): 3683. doi:10.1158/1538-7445.AM2012-3683.
- ^ Jump up to:a b c d Galanis, A.; Rajkhowa, T.; Muralidhara, C.; Ramachandran, A.; Levis, M. (2012). “Abstract 3660: Crenolanib: A next generation FLT3 inhibitor”. Cancer Research. 72 (8 Supplement): 3660. doi:10.1158/1538-7445.am2012-3660.
- ^ Jump up to:a b Heinrich, M. C.; Griffith, D.; McKinley, A.; Patterson, J.; Presnell, A.; Ramachandran, A.; Debiec-Rychter, M. (2012). “Crenolanib Inhibits the Drug-Resistant PDGFRA D842V Mutation Associated with Imatinib-Resistant Gastrointestinal Stromal Tumors”. Clinical Cancer Research. 18 (16): 4375–84. doi:10.1158/1078-0432.CCR-12-0625. PMID 22745105.
- ^ Yang, X.-L.; Mashimo, T.; Su, Y.; Vemireddy, V.; Guntipalli, P.; Ramachandran, A.; Chaudhary, P.; Mickey, B.; Hatanpaa, K.; Maher, E.; Bachoo, R. M. (2011). “Abstract 1111: Preclinical evaluation of CP868,596, a novel PDGFR Inhibitor for treatment of glioblastoma”. Cancer Research. 71 (8 Supplement): 1111. doi:10.1158/1538-7445.am2011-1111.
- ^ Peyton, M.; Chaudhary, P.; Ramachandran, A.; Minna, J. (2011). “Abstract 3601: CP-868,596, a highly potent and selective PDGFR TKI inhibits growth of PDGFR -driven lung cancer cells”. Cancer Research. 71 (8 Supplement): 3601. doi:10.1158/1538-7445.am2011-3601.
- ^ Lewis, N. L.; Lewis, L. D.; Eder, J. P.; Reddy, N. J.; Guo, F.; Pierce, K. J.; Olszanski, A. J.; Cohen, R. B. (2009). “Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients with Advanced Cancers”. Journal of Clinical Oncology. 27 (31): 5262–9. doi:10.1200/jco.2009.21.8487. PMC 2773478. PMID 19738123.
- ^ Michael, M; Vlahovic, G; Khamly, K; Pierce, K J; Guo, F; Olszanski, A J (2010). “Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor”. British Journal of Cancer. 103 (10): 1554–61. doi:10.1038/sj.bjc.6605941. PMC 2990584. PMID 20959830.
External links
- “PDGFR Inhibitor CP-868596 (Code C64639)”, National Cancer Institute Thesaurus.
- “PDGFR and Human Cancer” , AROG Pharmaceuticals LLC.
| Names | |
|---|---|
| IUPAC name1-(2-{5-[(3-methyloxetan-3-yl)methoxy]-1H-benzimidazol-1-yl}quinolin-8-yl)piperidin-4-amine | |
| Other namesCP-868,596; AR-868,596-26 | |
| Identifiers | |
| CAS Number | 670220-88-9 |
| 3D model (JSmol) | Interactive image |
| ChEBI | CHEBI:145365 |
| ChEMBL | ChEMBL2105728 ChEMBL2146086 |
| ChemSpider | 8541584 |
| IUPHAR/BPS | 7882 |
| KEGG | D10102 |
| PubChemCID | 10366136 |
| UNII | LQF7I567TQ |
| CompTox Dashboard (EPA) | DTXSID50985873 |
| showInChI | |
| showSMILES | |
| Properties | |
| Chemical formula | C26H29N5O2 |
| Molar mass | 443.551 g·mol−1 |
| Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). | |
 verify (what is ?) | |
| Infobox references |
//////////Crenolanib, UNII-LQF7I567TQ, креноланиб , كرينولانيب , 克拉尼布, CP-868,596-26, AR-868,596-26
CC1(COc2ccc3c(c2)ncn3c4ccc5cccc(N6CCC(N)CC6)c5n4)COC1.OS(=O)(=O)c7ccccc7
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