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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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CAS 57961-90-7


INDIA 2020, 14.05.2020, Centhaquine citrate bulk and Centhaquine citrate injection 1.0mg/vial, Add on resuscitative agent for hypovolemic shock

  • OriginatorMidwestern University; Pharmazz
  • DeveloperPharmazz
  • ClassAnalgesics; Antihaemorrhagics; Antihypertensives; Cardiovascular therapies; Piperazines; Quinolines; Small molecules
  • Mechanism of ActionAlpha 1 adrenergic receptor antagonists; Alpha 2 adrenergic receptor agonists
  • RegisteredHaemorrhagic shock
  • Phase IHeart arrest; Postoperative pain
  • 20 Jul 2020Pharmazz plans to launch centhaquin for Haemorrhagic shock (Adjuvant therapy) in India by the middle of September 2020
  • 20 Jul 2020Efficacy data from a phase III trial in Haemorrhagic shock released by Pharmazz
  • 02 Jun 2020Centhaquine is still in phase I trials for Postoperative pain in USA (Pharmazz pipeline, June 2020)

SYNCenthaquin is a compound that produces hypotension and bradycardia in higher doses and resuscitation in lower doses. It is water insoluble, and is unsuitable for intravenous use. We prepared the citrate salt of centhaquin and evaluated its cardiovascular efficacy vs. centhaquin. Centhaquin citrate was prepared and characterized; its purity was determined by HPLC. Mean arterial pressure (MAP), heart rate (HR), pulse pressure (PP), cardiac output (CO), stroke volume (SV) and stroke work (SW) following intravenous administration of centhaquin and the citrate (0.05, 0.15 and 0.45 were determined in anaesthetized male Sprague-Dawley rats. Centhaquin citrate was 99.8% pure and water soluble. Centhaquin (0.05, 0.15 and 0.45 produced a maximal decrease in MAP of 15.6, 25.2 and 28.1%, respectively; while centhaquin citrate produced a greater (p<0.001) decrease of 35.7, 47.1 and 54.3%, respectively. The decrease in PP and HR produced by the citrate was greater than centhaquin (p<0.001). At 0.45 centhaquin produced a maximal decrease of 20.9% (p<0.01) in CO, while centhaquin citrate produced a decrease of 42.1% (p<0.001). Reduction in SV (p<0.01) and SW (p<0.001) produced by centhaquin citrate were greater than centhaquin. Centhaquin citrate has greater cardiovascular activity compared to centhaquin.

Synthesis and characterization of centhaquin and its citrate salt and a  comparative evaluation of their cardiovascular actions. | Semantic Scholar


 Shock due to severe hemorrhage accounts for a large proportion of posttraumatic deaths, particularly during early stages of injury (Wu, Dai et al. 2009). A majority of deaths due to hemorrhage occur within the first six hours after trauma (Shackford, Mackersie et al. 1993), but many of these deaths can be prevented (Acosta, Yang et al. 1998).

[0003] Shock is accompanied by circulatory failure which is the primary cause of mortality and morbidity. Presently, the recommended fluid therapy uses large volumes of Lactated Ringer’s solution (LR), which is effective in restoring hemodynamic parameters, but presents logistic and physiologic limitations (Vincenzi, Cepeda et al. 2009). For example, resuscitation using a large volume of crystalloids, like LR, has been associated with secondary abdominal compartment syndrome, pulmonary edema, cardiac dysfunction, and paralytic ileus (Balogh, McKinley et al. 2003). Therefore, a need exists in the art for a resuscitation agent that improves survival time, and can be used with a small volume of resuscitation fluid, for resuscitation in hypovolemic shock.

[0004] Centhaquin (2-[2-(4-(3-methyphenyl)-l-piperazinyl) ethyl-quinoline) is a centrally acting antihypertensive drug. The structure of centhaquin was determined (Bajpai et al., 2000) and the conformation of centhaquin was confirmed by X-ray diffraction (Carpy and Saxena, 1991).

Figure imgf000003_0001

Structure of centhaquin (2-[2-(4-(3-methyphenyl)- 1 -piperazinyl) ethyl] -quinoline) (as free base)

[0005] Centhaquin is an active cardiovascular agent that produces a positive inotropic effect and increases ventricular contractions of isolated perfused rabbit heart (Bhatnagar, Pande et al. 1985). Centhaquin does not affect spontaneous contractions of the guinea pig right auricle, but significantly potentiates positive inotropic effect of norepinephrine (NE) (Srimal, Mason et al. 1990). The direct or indirect positive inotropic effect of centhaquin can lead to an increase in cardiac output (CO). Centhaquin produces a decrease in mean arterial pressure (MAP) and heart rate (HR) in anesthetized rats and conscious freely moving cats and rats (Srimal, Gulati et al. 1990) due to its central sympatholytic activity (Murti, Bhandari et al. 1989; Srimal, Gulati et al. 1990; Gulati, Hussain et al. 1991). When administered locally into a dog femoral artery, centhaquin (10 and 20 μg) increased blood flow, which was similar to that observed with acetylcholine and papaverine. However, the vasodilator effect of centhaquin could not be blocked by atropine or dibenamine (Srimal, Mason et al. 1990). The direct vasodilator or central sympatholytic effect of centhaquin is likely to decrease systemic vascular resistance (SVR).

[0006] It was found that centhaquin enhances the resuscitative effect of hypertonic saline (HS) (Gulati, Lavhale et al. 2012). Centhaquin significantly decreased blood lactate and increases MAP, stroke volume, and CO compared to hypertonic saline alone. It is theorized, but not relied upon, that the cardiovascular actions of hypertonic saline and centhaquin are mediated through the ventrolateral medulla in the brain (Gulati, Hussain et al. 1991 ; Cavun and Millington 2001) and centhaquin may be augmenting the effect of hypertonic saline.

[0007] A large volume of LR (i.e., about three times the volume of blood loss) is the most commonly used resuscitation fluid therapy (Chappell, Jacob et al. 2008), in part because LR does not exhibit the centrally mediated cardiovascular effects of hypertonic saline. Large volume resuscitation has been used by emergency medical personnel and surgeons to reverse hemorrhagic shock and to restore end-organ perfusion and tissue oxygenation. However, there has been a vigorous debate with respect to the optimal methods of resuscitation (Santry

Figure imgf000004_0001

ased on the molecular weight of centhaquin (free base) (MW-332) and centhaquin citrate (MW-523), for identical doses of centhaquin (as free base) and centhaquin citrate, centhaquin citrate provides only 63.5% of centhaquin free base compared to the dose of centhaquin free base, e.g., a 0.05 mg dose of centhaquin citrate contains a 0.0318 mg of centhaquin (as free base). Similarly, a dose of centhaquin citrate dihydrate (MW-559) provides 59.4% centhaquin (free base) of the same dose as centhaquin (as free base), i.e., a 0.0005 mg dose of centhaquin citrate dihydrate contains 0.030 mg of centhaquin (as free base). Surprisingly, and as demonstrated below, at the same mg/kg dose centhaquin citrate and centhaquin citrate dihydrate provides greater cardiovascular effects than centhaquin free base.

Figure imgf000013_0001

 Synthesis of Centhaquin

Figure imgf000014_0001

[0061] The synthesis of centhaquin was reported by Murthi and coworkers (Murthi et al U.S. Patent No. 3,983,121 ; Murti, Bhandari et al. 1989). In one procedure, reactants 1 and 2 were stirred at reflux for 15 hours. The resulting product was purified by evaporating the solvents to obtain an oil, which was heated in vacuo (100°C, 1 mm Hg). The remaining residue was recrystallized from ether-petroleum ether to obtain the final centhaquin product 3. The melting point reported for centhaquin was 76-77°C. In a subsequent publication (Murti, Bhandari et al. 1989), the reaction mixture was concentrated following 24 hours of reflux, diluted with water, and basified with aqueous NaOH. The basic mixture was extracted with ethyl acetate, and the ethyl acetate extracts were dried over anhydrous sodium sulfate and evaporated in vacuo to give centhaquin which was crystallized from hexane. The melting point of centhaquin (free base) obtained in this procedure was 82°C. The product obtained using either purification method is light tan in color, which is indicative of small amounts of impurities that were not completely removed using previously reported purification methods.

[0062] In accordance with the present invention, an improved purification method was found. According to the improved method, reactants 1 and 2 were stirred at reflux for 24 hours. The solvents were evaporated in vacuo and the resulting mixture was diluted with water and basified (10% NaOH). The basic mixture was extracted with ethyl acetate and the combined ethyl acetate extracts are dried over anhydrous sodium sulfate and evaporated in vacuo to obtain a residue, which was further purified with column chromatography (Si02, ethyl acetate). The resulting product can be decolorized using activated charcoal or directly crystallized from hot hexane to yield pure centhaquin. The resulting product is an off-white crystalline solid having a melting point of 94-95°C (free base). The product was

characterized using proton NMR, mass spectral, and elemental analysis and indicated high purity and superior quality.

[0063] Synthesis and characterization of centhaquin (free base): A mixture of 2- vinylquinoline (1) (5.0 g, 32.2 mmol, 98.5%) and 1 -(3-methylphenyl)piperazine (2) (5.68 g, 32.2 mmol, 99.0%) in absolute ethyl alcohol (150 ml) and glacial acetic acid (3.5 ml) was stirred at reflux for 24 hours in a round bottom flask. The reaction mixture was concentrated in vacuo, diluted with water (150 ml) and treated with 10% aqueous NaOH (150 ml). The residue was extracted with ethyl acetate (4 x 125 ml), dried with anhydrous Na2S04, and concentrated under reduced pressure to yield a crude product which was purified by column chromatography using silica gel (100-200 mesh) with ethyl acetate as an eluent. The resulting compound was recrystallized from hot hexane and filtered, to yield centhaquin as an off- white crystalline solid (7.75 g, 23.4 mmol, 73% yield); mp. 94-95°C; i? 0.30 (100% ethyl acetate); 1H NMR (300 MHz, CDC13): δ 8.07 (t, J= 7.5 Hz, 2 H), 7.78 (d, J= 7.8 Hz, 1 H), 7.70 (t, J= 7.8 Hz, 1 H), 7.50 (t, J= 7.5 Hz, 1 H), 7.36 (d, J= 8.4 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 6.77 – 6.74 (m, 2 H), 6.69 (d, J= 7.2 Hz, 1 H), 3.26- 3.21 (m, 6 H), 2.97 – 2.92 (m, 2 H), 2.76 – 2.73 (m, 4 H), 2.32 (s, 3 H); HRMS (ESI) m/z 332.2121 [M+l]+ (calcd for C22H26N3 332.2122); Anal. (C22H25N3) C, H, N.

[0064] Preparation of centhaquin citrate: Centhaquin (free base) (5.62 g, 16.98 mmol) was treated with citric acid (3.26 g, 16.98 mmol) in a suitable solvent and converted to the citrate salt obtained as an off-white solid (7.96 g, 15.2 mmol, 90%); m.p. 94-96°C ; Anal.

10065] Figs. 1(a) and 1(b) are high resolution mass spectral analyses of centhaquin free base (Fig 1(a)) and centhaquin citrate (Fig. 1(b)). Compound samples were analyzed following ionization using electrospray ionization (ESI).

[0066J For centhaquin free base in Fig 1(a), a base peak [M+l]+ was observed at m z 332.2141 (theory: 332.2121) consistent with the elemental composition of protonated centhaquin (C22H26N3).

[0067] For centhaquin citrate in Fig 1(b), the mass spectrum was identical to the mass spectrum obtained for the free base. An [M+l]+base peak was observed at m z 332.2141 (theory: 332.2121), which corresponds to the elemental composition of protonated centhaquin (C22H26N3). This result is typical of salts of organic bases to yield the [M+l]+ of the free base as observed here with centhaquin citrate.

[0068] Mass spectrometry is one of the most sensitive analytical methods, and examination of the mass spectra of Fig. 1 indicate that the samples are devoid of any extraneous peaks and are of homogeneous purity (>99.5).


////////////Centhaquine, PMZ-2010, PMZ 2010, INDIA 2020, 2020 APPROVALS




  • Molecular FormulaC13H16ClNO
  • Average mass237.725 Da

(S)-Ketamine33643-46-8[RN]7884Cyclohexanone, 2-(2-chlorophenyl)-2-(methylamino)-, (2S)-Cyclohexanone, 2-(2-chlorophenyl)-2-(methylamino)-, (S)-
KetamineCAS Registry Number: 6740-88-1CAS Name: 2-(2-Chlorophenyl)-2-(methylamino)cyclohexanoneMolecular Formula: C13H16ClNOMolecular Weight: 237.73Percent Composition: C 65.68%, H 6.78%, Cl 14.91%, N 5.89%, O 6.73%Literature References: Prepn: C. L. Stevens, BE634208idem,US3254124 (1963, 1966 both to Parke, Davis). Isoln of optical isomers: T. W. Hudyma et al.,DE2062620 (1971 to Bristol-Myers), C.A.75, 118119x (1971). Clinical pharmacology of racemate and enantiomers: P. F. White et al.,Anesthesiology52, 231 (1980). Toxicity: E. J. Goldenthal, Toxicol. Appl. Pharmacol.18, 185 (1971). Enantioselective HPLC determn in plasma: G. Geisslinger et al.,J. Chromatogr.568, 165 (1991). Comprehensive description: W. C. Sass, S. A. Fusari, Anal. Profiles Drug Subs.6, 297-322 (1977). Review of pharmacology and use in veterinary medicine: M. Wright, J. Am. Vet. Med. Assoc.180, 1462-1471 (1982). Review of pharmacology and clinical experience: D. L. Reich, G. Silvay, Can. J. Anaesth.36, 186-197 (1989); in pediatric procedures: S. M. Green, N. E. Johnson, Ann. Emerg. Med.19, 1033-1046 (1990).Properties: Crystals from pentane-ether, mp 92-93°. uv max (0.01N NaOH in 95% methanol): 301, 276, 268, 261 nm (A1%1cm 5.0, 7.0, 9.8, 10.5). pKa 7.5. pH of 10% aq soln 3.5.Melting point: mp 92-93°pKa: pKa 7.5Absorption maximum: uv max (0.01N NaOH in 95% methanol): 301, 276, 268, 261 nm (A1%1cm 5.0, 7.0, 9.8, 10.5) 
Derivative Type: HydrochlorideCAS Registry Number: 1867-66-9Manufacturers’ Codes: CI-581Trademarks: Ketalar (Pfizer); Ketanest (Pfizer); Ketaset (Fort Dodge); Ketavet (Gellini); Vetalar (Bioniche)Molecular Formula: C13H16ClNO.HClMolecular Weight: 274.19Percent Composition: C 56.95%, H 6.25%, Cl 25.86%, N 5.11%, O 5.84%Properties: White crystals, mp 262-263°. Soly in water: 20 g/100 ml. LD50 in adult mice, rats (mg/kg): 224 ±4, 229 ±5 i.p. (Goldenthal).Melting point: mp 262-263°Toxicity data: LD50 in adult mice, rats (mg/kg): 224 ±4, 229 ±5 i.p. (Goldenthal) 
NOTE: This is a controlled substance (depressant): 21 CFR, 1308.13.Therap-Cat: Anesthetic (intravenous).Therap-Cat-Vet: Anesthetic (intravenous).Keywords: Anesthetic (Intravenous).Esketamine hydrochloride, S enantiomer of ketamine, is in phase III clinical trials by Johnson & Johnson for the treatment of depression.Drug Name:Esketamine HydrochlorideResearchCode:JNJ-54135419MOA:Dopamine reuptake inhibitor; NMDA receptor antagonistIndication:DepressionStatus:Phase III (Active)Company:Johnson & Johnson (Originator)

Molecular Weight274.19
CAS No.33643-46-8 (Esketamine);
33643-47-9 (Esketamine Hydrochloride);

Route 1

Reference:1. US6040479.


50 g (0.21 mol) R,S-ketamine are dissolved in 613 ml of acetone at the boiling point and subsequently mixed with 31.5 g (0.21 mol) L-(+)-tartaric acid. In order to obtain a clear solution, 40 ml of water are added thereto at the boiling point and subsequently the clear solution is filtered off while still hot. After the addition of seed crystals obtained in a small preliminary experiment, the whole is allowed to cool to ambient temperature while stirring. After standing overnight, the crystals formed are filtered off with suction and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.).

Yield (tartrate): 64.8 g

m.p.: 161° C.

[α]D : +26.1° (c=2/H2 O)

Thereafter, the crystallisate is recrystallised in a mixture of 1226 ml acetone and 90 ml water. After cooling to ambient temperature and subsequently stirring for 4 hours, the crystals are filtered off with suction and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C). There are obtained 38.8 g of tartrate (95.29% of theory).

m.p.: 175.3° C.

[α]D : +68.9° (c=2/H2 O)

The base is liberated by taking up 38.8 g of tartrate in 420 ml of aqueous sodium hydroxide solution and stirring with 540 ml of diethyl ether. The ethereal phase is first washed with water and subsequently with a saturated solution of sodium chloride. The organic phase is dried over anhydrous sodium sulphate. After filtering, the solution is evaporated to dryness on a rotary evaporator, a crystalline, colourless product remaining behind.

Yield (crude base): 21.5 g=86.0% of theory

m.p.: 118.9° C. (literature: 120-122° C.)

[α]D : -55.8° (c=2/EtOH) (literature: [α]D : -56.35° ).

In order possibly to achieve a further purification, the base can be recrystallised from cyclohexane. For this purpose, 10.75 g of the crude base are dissolved in 43 ml cyclohexane at the boiling point. While stirring, the clear solution is slowly cooled to about 10° C. and then stirred at this temperature for about 1 hour. The crystallisate which precipitates out is filtered off with suction and dried to constant weight.

Yield (base): 10.3 g=82.4% of theory

m.p.: 120° C. (literature: 120-122° C.)

[α]D : -56.8° (c=2/EtOH) (literature: [α]D : -56.35° )


125 ml of water are taken and subsequently 31.5 g (0.21 mol) L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine added thereto. While stirring, this mixture is warmed to 50-60° C. until a clear solution results. After cooling to ambient temperature while stirring and subsequently stirring overnight, the crystals formed are filtered off with suction. Subsequently, the crystallisate is first washed with water (1-6° C.) and subsequently washed twice with, in each case, 20 ml of acetone. Drying in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.) gives 31.79 g of tartrate (78.23%) of theory).


150 ml of water are taken and subsequently mixed with 39.8 g (0.27 mol) L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine. While stirring, this mixture is warmed to 50-60° C. until a clear solution results.

After cooling to ambient temperature while stirring and subsequently stirring overnight, the crystals formed are filtered off with suction. Subsequently, the crystallisate is successively washed with 8 ml of water (1-6° C.) and thereafter twice with, in each case, 20 ml acetone.

Drying in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.) gives 32.58 g of tartrate (80.02% of theory).


150 ml of water and 50 ml isopropanol are taken. After the addition of 39.8 g (0.21 mol) L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine, the mixture is heated to reflux temperature while stirring until a solution results (possibly add water until all is dissolved).

Subsequently, while stirring, the solution is allowed to cool to ambient temperature and stirred overnight. The crystals are filtered off with suction and subsequently washed with a 1:2 mixture of 20 ml of water/isopropanol and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.). There are obtained 24.45 g of tartrate (62.63% of theory).


50 g (0.21 mol) R,S-ketamine are dissolved at the boiling point in 300 ml acetone and subsequently mixed with 31.5 g (0.21 mol) L-(+)-tartaric acid and 100 ml of water. The whole is allowed to cool while stirring and possibly seeded.

After standing overnight, the crystals formed are filtered off with suction, then washed twice with, in each case, 20 ml acetone and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.). There are obtained 30.30 g of tartrate (74.57% of theory).


75 ml of water and 50 ml isopropanol are taken and subsequently 39.8 g (0.27 mol) L-(+)-tartaric acid added thereto. While stirring, the mixture is heated to reflux temperature until a clear solution results. After cooling to ambient temperature while stirring and subsequently stirring overnight, the crystals formed are filtered off with suction. Subsequently, the crystallisate is washed with a 1:2 mixture of 20 ml water/isopropanol. After drying in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.), there are obtained 34.84 g of tartrate (85.74% of theory).


20 g of the S-(+)-tartrate obtained in Example 4 are dissolved in 100 ml of water at 30-40° C. With about 7 ml of 50% sodium hydroxide solution, an S-(-)-ketamine base is precipitated out up to about pH 13. It is filtered off with suction and washed neutral with water to pH 7-8. Subsequently, it is dried for about 24 hours at 50° C. in a circulating air drying cabinet. There are obtained 11.93 g S-(-)-ketamine (97.79% of theory).


5 g of the S-(-)-ketamine obtained in Example 7 are dissolved in 50 ml isopropanol at about 50° C. and possibly filtered off with suction over kieselguhr. Subsequently, gaseous hydrogen chloride is passed in at 50-60° C. until a pH value of 0-1 is reached. The reaction mixture is allowed to cool to ambient temperature, filtered off with suction and washed with about 5 ml isopropanol. The moist product is dried overnight at about 50° C. in a circulating air drying cabinet. There are obtained 5.09 g S-(+)-ketamine hydrochloride (88.06% of theory).

Route 2

Reference:1. J. Am. Chem. Soc. 2015137, 3205-3208.

Here we report the direct asymmetric amination of α-substituted cyclic ketones catalyzed by a chiral phosphoric acid, yielding products with a N-containing quaternary stereocenter in high yields and excellent enantioselectivities. Kinetic resolution of the starting ketone was also found to occur on some of the substrates under milder conditions, providing enantioenriched α-branched ketones, another important building block in organic synthesis. The utility of this methodology was demonstrated in the short synthesis of (S)-ketamine, the more active enantiomer of this versatile pharmaceutical.

Abstract Image


Initial reagent: cyclopentyl Grignard Step 0: Producing cyclopentyl Grignard Reacting cyclopentyl bromide with magnesium in solvent (ether or THF) Best results: distill solvent from Grignard under vacuum and replace with hydrocarbon solvent (e.g. benzene) Step 1: processing to (o-chlorophenyl)-cyclopentyl ketone Adding o-chlorobenzonitrile to cyclopentyl Grignard in solvent, stirring for long period of time (typically three days) Hydrolyzing reaction with mixture containing crushed ice, ammonium chloride and some ammonium hydroxide Extraction with organic solvent gives (o-chlorophenyl)-cyclopentyl ketone

Step 2: processing to alpha-bromo (o-chlorophenyl)-cyclopentyl ketone ketone processed with bromine in carbon tetrachloride at low temperature (typical T = 0°C), addition of bromine dropwise forming orange suspension Suspension washed in dilute aquerous solution of sodium bisufide and evaporated giving 1-bromocyclopentyl-(o-chlorophenyl)-ketone Note: bromoketone is unstable, immeadiate usage. Bromination carried out with NBromosuccinimide result higher yield (roughly 77%) Step 3: processing to 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone-N-methylimine Dissolving bromoketone in liquid methylamine freebase (or benzene as possible solvent) After time lapse (1h): excess methylamine evaporated, residue dissolved in pentane and filtered evaporation of solvent yields 1-hydroxy-cyclopentyl-(o-chlorophenyl)-ketone N-methylimine Note: longer time span (4-5d) for evaporation of methylaminemay increase yield Step 4: processing to 2-Methylamino-2-(o-chlorophenyl)-cyclohexanone (Ketamine) Method: Thermal rearragement (qualitative yield after 30min in 180°C) N-methylimine dissolved in 15ml decalin, refluxed for 2.5h Evaporation of solvent under reduced temperature followed by extraction of residue with dilute hydrochloric acid Treatment with decolorizing charcoal (solution: acidic => basic) Recrystallization from pentane-ether Note – alternative to use of decalin: pressure bomb

racemic compound, in pharmaceutical preparation racemic more active enantiomere esketamine (S-Ketamine) available as Ketanest S, but Arketamine (R-Ketamine) never marketed for clinical use, Optical rotation: varies between salt and free base form free base form: (S)-Ketamine dextrorotation  (S)-(+)-ketamine hydrochloridesalt: levorotation(S)-(-)-ketamine  Reason found in molecular level: different orientation of substituents: freebase: o-chlorophenyl equatorial, methylamino axia



Process Research and Impurity Control Strategy of Esketamine Organic Process Research & Development ( IF 3.023
Pub Date: 2020-03-18 , DOI: 10.1021/acs.oprd.9b00553
Shenghua Gao; Xuezhi Gao; Zhezhou Yang; Fuli Zhang
An improved synthesis of ( S )-ketamine (esketamine) has been developed, which was cost-effective, and the undesired isomer could be recovered by racemization. Critical process parameters of each step were identified as well as the process-related impurities. The formation mechanisms and control strategies of most impurities were first discussed. Moreover, the ( S )-ketamine tartrate is a dihydrate, which was disclosed for the first time. The practicable racemization catalyzed by aluminum chloride was carried out in quantitative yield with 99% purity . The ICH-grade quality ( S)-ketamine hydrochloride was obtained in 51.1% overall yield (14.0% without racemization) by chiral resolution with three times recycling of the mother liquors. The robust process of esketamine could be industrially scalable.

Process Research and ketamine impurity control strategy

has been developed an improved ( S ) – ketamine (esketamine) synthesis, the high cost-effective way, the undesired isomer may be recycled by racemization. Determine the key process parameters and process-related impurities for each step. First, the formation mechanism and control strategy of most impurities are discussed. In addition, ( S )-ketamine tartrate is a dihydrate, which is the first time it has been published. The feasible racemization catalyzed by aluminum chloride proceeds in a quantitative yield with a purity of 99%. ICH grade quality ( S) 5-ketamine hydrochloride can be obtained through chiral resolution and three times the mother liquor recovery rate. The total yield is 51.1% (14.0% without racemization). The robust process of ketamine can be used in Industrial promotion.


Ketamine - Wikiwand


Taghizadeh, M.J., Gohari, S.J.A., Javidan, A. et al. A novel strategy for the asymmetric synthesis of (S)-ketamine using (S)-tert-butanesulfinamide and 1,2-cyclohexanedione. J IRAN CHEM SOC 15, 2175–2181 (2018).

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We present a novel asymmetric synthesis route for synthesis of (S)-ketamine using a chiral reagent according to the strategy (Scheme 1), with good enantioselectivity (85% ee) and yield. In this procedure, the (S)-tert-butanesulfinamide (TBSA) acts as a chiral auxiliary reagent to generate (S)-ketamine. A series of new intermediates were synthesized and identified for the first time in this work (2–4). The monoketal intermediate (1) easily obtained after partial conversion of one ketone functional group  of 1,2-cyclohexanedione into a ketal using ethylene glycol. The sulfinylimine (2) was obtained by condensation of (S)-tert-butanesulfinamide (TBSA) with (1), 4-dioxaspiro[4.5]decan-6-one in 90% yield. The (S)-Ntert-butanesulfinyl ketamine (3) was prepared on further reaction of sulfinylimine (2) with appropriate Grignard reagent (ArMgBr) in which generated chiral center in 85% yield and with 85% diastereoselectivity. Methylation of amine afforded the product (4). Finally, the sulfinyl- and ketal-protecting groups were removed from the compound (4) by brief treatment with stoichiometric quantities of HCl in a protic solvent gave the (S)-ketamine in near quantitative yield.

Esketamine, sold under the brand name Spravato[4] among others,[6][7] is a medication used as a general anesthetic and for treatment-resistant depression.[4][1] Esketamine is used as a nasal spray or by injection into a vein.[4][1]

Esketamine acts primarily as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist.[1][8] It also acts to some extent as a dopamine reuptake inhibitor but, unlike ketamine, does not interact with the sigma receptors.[1] The compound is the S(+) enantiomer of ketamine, which is an anesthetic and dissociative similarly.[1] It is unknown whether its antidepressant action is superior, inferior or equal to racemic ketamine and its opposite enantiomer, arketamine, which are both being investigated for the treatment of depression.

Esketamine was introduced for medical use in 1997.[1] In 2019, it was approved for use with other antidepressants, for the treatment of depression in adults in the United States.[9]

In August 2020, it was approved by the U.S. Food and Drug Administration (FDA) with the added indication for the short-term treatment of suicidal thoughts.[10]

Medical uses


Esketamine is a general anesthetic and is used for similar indications as ketamine.[1] Such uses include induction of anesthesia in high-risk patients such as those with hemorrhagic shockanaphylactic shockseptic shock, severe bronchospasm, severe hepatic insufficiencycardiac tamponade, and constrictive pericarditis; anesthesia in caesarian section; use of multiple anesthetics in burns; and as a supplement to regional anesthesia with incomplete nerve blocks.[1]


See also: List of investigational antidepressants

Similarly to ketamine, esketamine appears to be a rapid-acting antidepressant.[8][11] It received a breakthrough designation from the FDA for treatment-resistant depression (TRD) in 2013 and major depressive disorder (MDD) with accompanying suicidal ideation in 2016.[12][11] The medication was studied for use in combination with an antidepressant in people with TRD who had been unresponsive to treatment;[12][8][11] six phase III clinical trials for this indication were conducted in 2017.[12][8][11] It is available as a nasal spray.[12][8][11]

In February 2019, an outside panel of experts recommended that the FDA approve the nasal spray version of esketamine,[13] provided that it be given in a clinical setting, with people remaining on site for at least two hours after. The reasoning for this requirement is that trial participants temporarily experienced sedation, visual disturbances, trouble speaking, confusion, numbness, and feelings of dizziness during immediately after.[14]

In January 2020, esketamine was rejected by the National Health Service of Great Britain. NHS questioned the benefits and claimed that it was too expensive. People who have been already using the medication were allowed to complete treatment if their doctors consider this necessary.[15]

Side effects

Most common side effects when used in those with treatment resistant depression include dissociation, dizziness, nausea, sleepiness, anxiety, and increased blood pressure.[16]


Esketamine is approximately twice as potent as an anesthetic as racemic ketamine.[17] It is eliminated from the human body more quickly than arketamine (R(–)-ketamine) or racemic ketamine, although arketamine slows its elimination.[18]

A number of studies have suggested that esketamine has a more medically useful pharmacological action than arketamine or racemic ketamine[citation needed] but, in mice, that the rapid antidepressant effect of arketamine was greater and lasted longer than that of esketamine.[19] The usefulness of arketamine over eskatamine has been supported by other researchers.[20][21][22]

Esketamine inhibits dopamine transporters eight times more than arketamine.[23] This increases dopamine activity in the brain. At doses causing the same intensity of effects, esketamine is generally considered to be more pleasant by patients.[24][25] Patients also generally recover mental function more quickly after being treated with pure esketamine, which may be a result of the fact that it is cleared from their system more quickly.[17][26] This is however in contradiction with R-ketamine being devoid of psychotomimetic side effects.[27]

Unlike arketamine, esketamine does not bind significantly to sigma receptors. Esketamine increases glucose metabolism in frontal cortex, while arketamine decreases glucose metabolism in the brain. This difference may be responsible for the fact that esketamine generally has a more dissociative or hallucinogenic effect while arketamine is reportedly more relaxing.[26] However, another study found no difference between racemic and (S)-ketamine on the patient’s level of vigilance.[24] Interpretation of this finding is complicated by the fact that racemic ketamine is 50% (S)-ketamine.


Esketamine was introduced for medical use as an anesthetic in Germany in 1997, and was subsequently marketed in other countries.[1][28] In addition to its anesthetic effects, the medication showed properties of being a rapid-acting antidepressant, and was subsequently investigated for use as such.[8][12] In November 2017, it completed phase III clinical trials for treatment-resistant depression in the United States.[8][12] Johnson & Johnson filed a Food and Drug Administration (FDA) New Drug Application (NDA) for approval on September 4, 2018;[29] the application was endorsed by an FDA advisory panel on February 12, 2019, and on March 5, 2019, the FDA approved esketamine, in conjunction with an oral antidepressant, for the treatment of depression in adults.[9]

In the 1980s and ’90s, closely associated ketamine was used as a club drug known as “Special K” for its trip-inducing side effects.[30][31]

Society and culture


Esketamine is the generic name of the drug and its INN and BAN, while esketamine hydrochloride is its BANM.[28] It is also known as S(+)-ketamine(S)-ketamine, or (–)-ketamine, as well as by its developmental code name JNJ-54135419.[28][12]

Esketamine is marketed under the brand name Spravato for use as an antidepressant and the brand names Ketanest, Ketanest S, Ketanest-S, Keta-S for use as an anesthetic (veterinary), among others.[28]


Esketamine is marketed as an antidepressant in the United States;[9] and as an anesthetic in the European Union.[28]

Legal status

Esketamine is a Schedule III controlled substance in the United States.[4]


  1. Jump up to:a b c d e f g h i j Himmelseher S, Pfenninger E (December 1998). “[The clinical use of S-(+)-ketamine–a determination of its place]”. Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie33 (12): 764–70. doi:10.1055/s-2007-994851PMID 9893910.
  2. ^ “Spravato 28 mg nasal spray, solution – Summary of Product Characteristics (SmPC)”(emc). Retrieved 24 November 2020.
  3. ^ “Vesierra 25 mg/ml solution for injection/infusion – Summary of Product Characteristics (SmPC)”(emc). 21 February 2020. Retrieved 24 November2020.
  4. Jump up to:a b c d e “Spravato- esketamine hydrochloride solution”DailyMed. 6 August 2020. Retrieved 26 September 2020.
  5. ^ “Spravato EPAR”European Medicines Agency (EMA). 16 October 2019. Retrieved 24 November 2020.
  6. ^ “Text search results for esketamine: Martindale: The Complete Drug Reference”MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 20 August 2017.[dead link]
  7. ^ Brayfield A, ed. (9 January 2017). “Ketamine Hydrochloride”MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 20 August2017.[dead link]
  8. Jump up to:a b c d e f g Rakesh G, Pae CU, Masand PS (August 2017). “Beyond serotonin: newer antidepressants in the future”. Expert Review of Neurotherapeutics17 (8): 777–790. doi:10.1080/14737175.2017.1341310PMID 28598698S2CID 205823807.
  9. Jump up to:a b c “FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic”U.S. Food and Drug Administration (FDA) (Press release). Retrieved 2019-03-06.
  10. ^ “FDA Approves A Nasal Spray To Treat Patients Who Are Suicidal”NPR. 4 August 2020. Retrieved 27 September 2020.
  11. Jump up to:a b c d e Lener MS, Kadriu B, Zarate CA (March 2017). “Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression”Drugs77 (4): 381–401. doi:10.1007/s40265-017-0702-8PMC 5342919PMID 28194724.
  12. Jump up to:a b c d e f g “Esketamine – Johnson & Johnson – AdisInsight”. Retrieved 7 November 2017.
  13. ^ Koons C, Edney A (February 12, 2019). “First Big Depression Advance Since Prozac Nears FDA Approval”Bloomberg News. Retrieved February 12, 2019.
  14. ^ Psychopharmacologic Drugs Advisory Committee (PDAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee (February 12, 2019). “FDA Briefing Document” (PDF). Food and Drug Administration. Retrieved February 12, 2019. Meeting, February 12, 2019. Agenda Topic: The committees will discuss the efficacy, safety, and risk-benefit profile of New Drug Application (NDA) 211243, esketamine 28 mg single-use nasal spray device, submitted by Janssen Pharmaceutica, for the treatment of treatment-resistant depression.
  15. ^ “Anti-depressant spray not recommended on NHS”BBC News. 28 January 2020.
  16. ^ “Esketamine nasal spray” (PDF). U.S. Food and Drug Administration (FDA). Retrieved 21 October 2019.
  17. Jump up to:a b Himmelseher S, Pfenninger E (December 1998). “[The clinical use of S-(+)-ketamine–a determination of its place]”. Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie (in German). 33 (12): 764–70. doi:10.1055/s-2007-994851PMID 9893910.
  18. ^ Ihmsen H, Geisslinger G, Schüttler J (November 2001). “Stereoselective pharmacokinetics of ketamine: R(–)-ketamine inhibits the elimination of S(+)-ketamine”. Clinical Pharmacology and Therapeutics70 (5): 431–8. doi:10.1067/mcp.2001.119722PMID 11719729.
  19. ^ Zhang JC, Li SX, Hashimoto K (January 2014). “R (-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine”. Pharmacology, Biochemistry, and Behavior116: 137–41. doi:10.1016/j.pbb.2013.11.033PMID 24316345S2CID 140205448.
  20. ^ Muller J, Pentyala S, Dilger J, Pentyala S (June 2016). “Ketamine enantiomers in the rapid and sustained antidepressant effects”Therapeutic Advances in Psychopharmacology6 (3): 185–92. doi:10.1177/2045125316631267PMC 4910398PMID 27354907.
  21. ^ Hashimoto K (November 2016). “Ketamine’s antidepressant action: beyond NMDA receptor inhibition”. Expert Opinion on Therapeutic Targets20 (11): 1389–1392. doi:10.1080/14728222.2016.1238899PMID 27646666S2CID 1244143.
  22. ^ Yang B, Zhang JC, Han M, Yao W, Yang C, Ren Q, Ma M, Chen QX, Hashimoto K (October 2016). “Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression”Psychopharmacology233 (19–20): 3647–57. doi:10.1007/s00213-016-4399-2PMC 5021744PMID 27488193.
  23. ^ Nishimura M, Sato K (October 1999). “Ketamine stereoselectively inhibits rat dopamine transporter”. Neuroscience Letters274 (2): 131–4. doi:10.1016/s0304-3940(99)00688-6PMID 10553955S2CID 10307361.
  24. Jump up to:a b Doenicke A, Kugler J, Mayer M, Angster R, Hoffmann P (October 1992). “[Ketamine racemate or S-(+)-ketamine and midazolam. The effect on vigilance, efficacy and subjective findings]”. Der Anaesthesist (in German). 41 (10): 610–8. PMID 1443509.
  25. ^ Pfenninger E, Baier C, Claus S, Hege G (November 1994). “[Psychometric changes as well as analgesic action and cardiovascular adverse effects of ketamine racemate versus s-(+)-ketamine in subanesthetic doses]”. Der Anaesthesist (in German). 43 Suppl 2: S68-75. PMID 7840417.
  26. Jump up to:a b Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J (February 1997). “Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET)”. European Neuropsychopharmacology7 (1): 25–38. doi:10.1016/s0924-977x(96)00042-9PMID 9088882S2CID 26861697.
  27. ^ Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, Dong C, Hashimoto K (September 2015). “R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects”Translational Psychiatry5 (9): e632. doi:10.1038/tp.2015.136PMC 5068814PMID 26327690.
  28. Jump up to:a b c d e “Esketamine”
  29. ^ “Janssen Submits Esketamine Nasal Spray New Drug Application to U.S. FDA for Treatment-Resistant Depression”. Janssen Pharmaceuticals, Inc.
  30. ^ Marsa, Linda (January 2020). “A Paradigm Shift for Depression Treatment”. DiscoverKalmbach Media.
  31. ^ Hoffer, Lee (7 March 2019). “The FDA Approved a Ketamine-Like Nasal Spray for Hard-to-Treat Depression”Vice. Retrieved 11 February 2020.

External links

Clinical data
Trade namesSpravato, Ketanest, Vesierra, others
Other namesEsketamine hydrochloride; (S)-Ketamine; S(+)-Ketamine; JNJ-54135419
License dataUS DailyMedEsketamineUS FDAEsketamine
Low–moderate[citation needed]
Routes of
IntranasalIntravenous infusion[1]
Drug classNMDA receptor antagonistsAntidepressantsGeneral anestheticsDissociative hallucinogensAnalgesics
ATC codeN01AX14 (WHON06AX27 (WHO)
Legal status
Legal statusAU: S8 (Controlled drug)UK: POM (Prescription only) [2][3]US: Schedule III [4]EU: Rx-only [5]In general: ℞ (Prescription only)
IUPAC name[show]
CAS Number33643-46-8 as HCl: 33795-24-3 
PubChem CID182137
UNII50LFG02TXDas HCl: 5F91OR6H84
KEGGD07283 as HCl: D10627 
CompTox Dashboard (EPA)DTXSID6047810 
ECHA InfoCard100.242.065 
Chemical and physical data
Molar mass237.73 g·mol−1
3D model (JSmol)Interactive image
InChI[hide]InChI=1S/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3/t13-/m0/s1 Key:YQEZLKZALYSWHR-ZDUSSCGKSA-N 

/////////////Esketamine, JNJ 54135419, phase 3



CAS 1639324-58-5

  • ALN-60212
  • ALN-PCSsc

Inclisiran was first developed by Alnylam Pharmaceuticals, Inc. (Cambridge, Massachusetts, US). Development has now been assumed by The Medicines Company (Parsippany, New Jersey, US). One phase I and two phase II trials have been completed. Topline results of two phase III trials were also recently presented while other phase III trials are still ongoing as part of the ORION clinical development program. …..

Inclisiran is a long-acting, synthetic small interfering RNA (siRNA) directed against proprotein convertase subtilisin-kexin type 9 (PCSK9), which is a serine protease that regulates plasma low-density lipoprotein cholesterol (LDL-C) levels. By binding to PCSK9 messenger RNA, inclisiran prevents protein translation of PCSK9, leading to decreased concentrations of PCSK9 and plasma concentrations of LDL cholesterol.1,2 Lowering circulating plasma LDL-C levels offers an additional benefit of reducing the risk of cardiovascular disease (CVD) and improving cardiovascular outcomes, as hypercholesterolemia is a major known risk factor for CVD.1,2

On December 11, 2020, the European Commission (EC) granted authorization for marketing inclisiran as the first and only approved siRNA for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, alone or in combination with other lipid-lowering therapies. It is marketed under the trade name Leqvio 8 and is also currently under review by the FDA.

Inclisiran, sold under the brand name Leqvio, is a medication for the treatment of people with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents and heterozygous familial hypercholesterolemia (HeFH). It is a small interfering RNA that inhibits translation of the protein PCSK9.[2][3][4] It is being developed by The Medicines Company which licensed the rights to inclisiran from Alnylam Pharmaceuticals.[5]

On 15 October 2020, 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 Leqvio, intended for the treatment for primary hypercholesterolaemia or mixed dyslipidaemia.[6] Inclisiran was approved for use in the European Union in December 2020.[1]


In 2019 The Medicines Company announced positive results from pivotal phase III study (all primary and secondary endpoints were met with efficacy consistent with Phase I and II studies). The company anticipates regulatory submissions in the U.S. in the fourth quarter of 2019, and in Europe in the first quarter of 2020.[7] The Medicines Company is being acquired by Novartis.[8]


  1. Jump up to:a b “Leqvio EPAR”European Medicines Agency. 13 October 2020. Retrieved 6 January 2021.
  2. ^ Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, et al. (January 2017). “A Highly Durable RNAi Therapeutic Inhibitor of PCSK9”The New England Journal of Medicine376 (1): 41–51. doi:10.1056/NEJMoa1609243PMC 5778873PMID 27959715.
  3. ^ Spreitzer H (11 September 2017). “Neue Wirkstoffe: Inclisiran”. Österreichische Apotheker-Zeitung (in German) (19/2017).
  4. ^ “Proposed INN: List 114” (PDF). WHO Drug InformationWHO29 (4): 531f. 2015.
  5. ^ Taylor NP (26 August 2019). “Medicines Company’s PCSK9 drug hits phase 3 efficacy goals”FierceBiotech.
  6. ^ “Leqvio: Pending EC decision”European Medicines Agency (EMA). 16 October 2020. Retrieved 16 October 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. ^ “The Medicines Company Announces Positive Topline Results from First Pivotal Phase 3 Trial of Inclisiran”The Medicines Company. Retrieved 29 August 2019.
  8. ^ “Novartis acquires medicines company”Novartis. Retrieved 15 January 2020.

Further reading

External links

  • “Inclisiran”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03399370 for “Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol (ORION-10)” at
  • Clinical trial number NCT03400800 for “Inclisiran for Subjects With ACSVD or ACSVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol (ORION-11)” at
Clinical data
Trade namesLeqvio
Other namesALN-PCSsc, ALN-60212
Routes of
Subcutaneous injection
ATC codeC10AX16 (WHO)
Legal status
Legal statusEU: Rx-only [1]
CAS Number1639324-58-5
Chemical and physical data
Molar mass16248.27 g·mol−1

General References

  1. Kosmas CE, Munoz Estrella A, Sourlas A, Silverio D, Hilario E, Montan PD, Guzman E: Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia. Diseases. 2018 Jul 13;6(3). pii: diseases6030063. doi: 10.3390/diseases6030063. [PubMed:30011788]
  2. German CA, Shapiro MD: Small Interfering RNA Therapeutic Inclisiran: A New Approach to Targeting PCSK9. BioDrugs. 2020 Feb;34(1):1-9. doi: 10.1007/s40259-019-00399-6. [PubMed:31782112]
  3. Doggrell SA: Inclisiran, the billion-dollar drug, to lower LDL cholesterol – is it worth it? Expert Opin Pharmacother. 2020 Nov;21(16):1971-1974. doi: 10.1080/14656566.2020.1799978. Epub 2020 Aug 4. [PubMed:32749892]
  4. Goldstein JL, Brown MS: Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis. Circulation. 1987 Sep;76(3):504-7. doi: 10.1161/01.cir.76.3.504. [PubMed:3621516]
  5. Pratt AJ, MacRae IJ: The RNA-induced silencing complex: a versatile gene-silencing machine. J Biol Chem. 2009 Jul 3;284(27):17897-901. doi: 10.1074/jbc.R900012200. Epub 2009 Apr 1. [PubMed:19342379]
  6. Leiter LA, Teoh H, Kallend D, Wright RS, Landmesser U, Wijngaard PLJ, Kastelein JJP, Ray KK: Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial. Diabetes Care. 2019 Jan;42(1):173-176. doi: 10.2337/dc18-1491. Epub 2018 Nov 28. [PubMed:30487231]
  7. Cupido AJ, Kastelein JJP: Inclisiran for the treatment of hypercholesterolaemia: implications and unanswered questions from the ORION trials. Cardiovasc Res. 2020 Sep 1;116(11):e136-e139. doi: 10.1093/cvr/cvaa212. [PubMed:32766688]
  8. Novartis: Novartis receives EU approval for Leqvio (inclisiran), a first-in-class siRNA to lower cholesterol with two doses a year [Link]
  9. Summary of Product Characteristics: Leqvio (inclisiran), solution for subcutaneous injection [Link]


  • Atherosclerotic cardiovascular disease (ASCVD) remains one of the leading causes of death in Canada. Cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), is a major risk factor for cardiovascular disease (CVD) and is thereby targeted to reduce the likelihood of a cardiovascular event, such as a myocardial infarction (MI) and stroke.
  • Inclisiran, first developed by Alnylam Pharmaceuticals, Inc. (Cambridge, Massachusetts, US) then by The Medicines Company (Parsippany, New Jersey, US), is a small interfering ribonucleic acid (siRNA) molecule being investigated for the treatment of hypercholesterolemia.
  • ORION-1 was a phase II, double-blind, placebo-controlled, multi-centre, randomized controlled trial of 501 patients. Patients were included in the trial if they had a history of ASCVD or were at high risk of ASCVD. The treatment arms were administered 200 mg, 300 mg, or 500 mg of inclisiran on day 1, or 100 mg, 200 mg, or 300 mg of inclisiran on days 1 and 90. The comparator was either placebo on day 1 or placebo on days 1 and 90. The primary end point was percentage change in LDL-C at day 180 from baseline.
  • The ORION-1 study demonstrated that inclisiran, administered at various doses and intervals, compared with placebo, resulted in a statistically significant reduction in LDL-C levels (P < 0.001 for all comparisons versus placebo). The greatest reduction in LDL-C levels was obtained with the 300 mg dose of inclisiran given at days 1 and 90 with a 52.6% (95% confidence interval [CI]: −57.1 to −48.1) reduction at day 180 compared with baseline, and a mean absolute reduction in LDL-C levels of 1.66 (standard deviation 0.54) mmol/L. Results from the ORION-1 trial provided the necessary data to make a decision regarding the dosing regimen to be used in subsequent phase III trials, in particular the ORION-11 phase III trial.
  • The ORION-11 study was a phase III international, multi-centre, and double-blind trial which randomized 1,617 participants (87% with established ASCVD) to inclisiran 300 mg (n = 810) or placebo (n = 807). An initial inclisiran dose of 300 mg given subcutaneously was administered at day 1, day 90, and then every six months for two doses, that is at days 270 and 450. The mean baseline LDL-C level was 2.8 mmol/L (inclisiran) and 2.7 mmol/L (placebo); 96% of participants were on high-dose statin therapy. There was a 50% time-averaged reduction in LDL-C levels from day 90 to day 540 (P < 0.00001). Pre-specified exploratory cardiovascular composite end point (cardiac death, cardiac arrest, MI, or stroke) occurred in 7.8% of inclisiran treated patients versus 10.3% of patients on placebo; this lower rate was mainly driven by a reduction in MI and stroke. With respect to adverse effects, 4.69% of patients on inclisiran reported an injection site reaction, compared with 0.5% of patients on placebo. All reactions were transient. There was no evidence of liver, kidney, muscle, or platelet toxicity.
  • Inclisiran may be an option in the future as a cholesterol-lowering medication, where it would likely be used in patients who are unable to achieve their LDL-C targets despite maximally tolerated statin therapy or who are intolerant to statin therapy. However, results from the inclisiran cardiovascular outcome trial (ORION-4), are needed to confirm its efficacy in reducing CVD and its long-term safety.
  • Inclisiran is not yet approved by any regulatory authority, but its ORION clinical development program identifies the year 2021 as the goal to reach worldwide markets.

///////////Inclisiran, LEQVIO, ALN 60212, ALN PCSsc , NOVARTIS




U-63287, ADD-3878

  • Molecular FormulaC18H23NO3S
  • Average mass333.445 Da
  • 74772-77-3 [RN]

(±)-5-[4-(1-Methylcyclohexylmethoxy)benzyl]thiazolidine-2,4-dione2,4-Thiazolidinedione, 5-[[4-[(1-methylcyclohexyl)methoxy]phenyl]methyl]-5-[4-(1-methylcyclohexylmethoxy) benzyl]-thiazolidine-2,4-dione

Ciglitazone (INN) is a thiazolidinedione. Developed by Takeda Pharmaceuticals in the early 1980s, it is considered the prototypical compound for the thiazolidinedione class.[1][2][3][4]

Ciglitazone was never used as a medication, but it sparked interest in the effects of thiazolidinediones. Several analogues were later developed, some of which—such as pioglitazone and troglitazone—made it to the market.[2]

Ciglitazone significantly decreases VEGF production by human granulosa cells in an in vitro study, and may potentially be used in ovarian hyperstimulation syndrome.[5] Ciglitazone is a potent and selective PPARγ ligand. It binds to the PPARγ ligand-binding domain with an EC50 of 3.0 μM. Ciglitazone is active in vivo as an anti-hyperglycemic agent in the ob/ob murine model.[6] Inhibits HUVEC differentiation and angiogenesis and also stimulates adipogenesis and decreases osteoblastogenesis in human mesenchymal stem cells.[7]


T. Sohda, K. Mizuno, E. Imamiya, Y. Sugiyama, T. Fujita, and Y. Kawamatsu, Chem. Pharm. Bull., 30, 3580 (1982).

File:Ciglitazone synthesis.svg


Ciglitazone (CAS NO.: ), with other name of , 5-((4-((1-methylcyclohexyl)methoxy)phenyl)methyl)-, (+-)-, could be produced through many synthetic methods.

Following is one of the reaction routes:

Synthesis of Ciglitazone

The reaction of 1-methylcyclohexylmethanol (II) with 4-chloronitrobenzene (III) by means of NaH in hot DMSO gives 4-(1-methylcyclohexylmethoxylnitrobenzene (III), which is reduced with H2 over Pd/C in methanol yielding 4-(1-methylcyclohexylmethoxylaniline (IV). Diazotation of (IV) with NaNO2 and HCl in water affords a solution of the corresponding diazonium chloride (V), which is condensed with methyl acrylate (VI) by means of Cu2O affording methyl 2-chloro-3-[4-(1-methylcyclohexylmethoxyl)phenyl]propionate (VII). The cyclization of (VII) with thiourea (VIII) by means of sodium acetate in hot 2-methoxyethanol gives 2-imino-5-[4-(1-methylcyclohexylmethoxy)benzyl]thiazolidin-4-one (IX), which is finally hydrolyzed with HCl in refluxing 2-methoxyethanol – water.


Chem Pharm Bull 1982,30(10),3580

The reaction of 1-methylcyclohexylmethanol (II) with 4-chloronitrobenzene (III) by means of NaH in hot DMSO gives 4-(1-methylcyclohexylmethoxylnitrobenzene (III), which is reduced with H2 over Pd/C in methanol yielding 4-(1-methylcyclohexylmethoxylaniline (IV). Diazotation of (IV) with NaNO2 and HCl in water affords a solution of the corresponding diazonium chloride (V), which is condensed with methyl acrylate (VI) by means of Cu2O affording methyl 2-chloro-3-[4-(1-methylcyclohexylmethoxyl)phenyl]propionate (VII). The cyclization of (VII) with thiourea (VIII) by means of sodium acetate in hot 2-methoxyethanol gives 2-imino-5-[4-(1-methylcyclohexylmethoxy)benzyl]thiazolidin-4-one (IX), which is finally hydrolyzed with HCl in refluxing 2-methoxyethanol – water.

By cyclization of (VIII) with methyl 2-(methanesulfonyloxy)-3-[4-(1-methylcyclohexylmethoxy)phenyl]propionate (X) by means of sodium acetate in hot 2-methoxyethanol, followed by hydrolysis with HCl in ethanol water.


Vijay Kumar Sharma , Anup Barde & Sunita Rattan (2020): A short review on synthetic strategies toward glitazone drugs, Synthetic Communications, DOI: 10.1080/00397911.2020.1821223

Experimental process for synthesis of ciglitazone is fairly robust, albeit pyrophorophic NaH as base is utilized for synthesis of 15.

Scheme 4. Reagents and conditions for the preparation of (R)-ciglitazone 24 (a) (S)-1-phenylethan-1- amine 19 (0.9 mol. equiv.), EtOH, RT, 4 h; (b) 1 N HCl (2 vol.), diethyl ether, RT, 10 min; (c) CH2N2 in diethyl ether (ca. 3% w/w), diethyl ether, 0 C-RT, 30 min; (d) KSCN (1.5 mol. equiv.), DMSO, 90 C, 2 h; (e) 2 N HCl (10 vol.), and EtOH, reflux 4 h.

Chiral synthesis Racemic-ciglitazone 17 was resolved with optically active a-methylbenzylamine (PEA) 19 through asymmetric transformation of optical lability at the C-5 position of TZD ring. 2-chloro-3-(4-((1-methylcyclohexyl)methoxy)phenyl)propanoic acid 18 was resolved using (S)-()-1-Phenylethylamine 19 to isolate (S)-2-chloro-3-(4-((1- methylcyclohexyl) methoxy)phenyl)propanoicacid 21. Esterification followed by substitution with KSCN provided methyl (R)-3-(4-((1-methylcyclohexyl)methoxy)phenyl)-2- thiocyanatopropan-oate 23 which was then hydrolyzed to isolate (R)-ciglitazone 24. Similarly, S-isomer was also isolated with (R)-(þ)-1-phenylethylamine (Scheme 4).

[30]Sohda, T.; Mizuno, K.; Kawamatsu, Y. Studies on Antidiabetic Agents. VI. Asymmetric Transformation of (þ/-)-5-[4-(1-Methylcyclohexylmethoxy)Benzyl]-2,4- Thiazolidinedione (Ciglitazone) with Optically Active 1-Phenylethylamines. Chem. Pharm. Bull. 1984, 32, 4460–4465. DOI: 10.1248/cpb.32.4460.


  1. ^ Pershadsingh HA, Szollosi J, Benson S, Hyun WC, Feuerstein BG, Kurtz TW (June 1993). “Effects of ciglitazone on blood pressure and intracellular calcium metabolism”Hypertension21 (6 Pt 2): 1020–3. doi:10.1161/01.hyp.21.6.1020PMID 8505086.
  2. Jump up to:a b Hulin B, McCarthy PA, Gibbs EM (1996). “The glitazone family of antidiabetic agents”Current Pharmaceutical Design2: 85–102.
  3. ^ Imoto H, Imamiya E, Momose Y, Sugiyama Y, Kimura H, Sohda T (October 2002). “Studies on non-thiazolidinedione antidiabetic agents. 1. Discovery of novel oxyiminoacetic acid derivatives”Chem. Pharm. Bull50 (10): 1349–57. doi:10.1248/cpb.50.1349PMID 12372861.
  4. ^ Sohda T, Kawamatsu Y, Fujita T, Meguro K, Ikeda H (November 2002). “[Discovery and development of a new insulin sensitizing agent, pioglitazone]”Yakugaku Zasshi (in Japanese). 122 (11): 909–18. doi:10.1248/yakushi.122.909PMID 12440149.
  5. ^ Shah DK, Menon KM, Cabrera LM, Vahratian A, Kavoussi SK, Lebovic DI (April 2010). “Thiazolidinediones decrease vascular endothelial growth factor (VEGF) production by human luteinized granulosa cells in vitro”Fertil. Steril93 (6): 2042–7. doi:10.1016/j.fertnstert.2009.02.059PMC 2847675PMID 19342033.
  6. ^ Willson, T.M.; Cobb, J.E.; Cowan, D.J.; et al. (1996). “The structure-activity relationship between peroxisome proliferator-activated receptor γ agonism and the antihyperglycemic activity of thiazolidinediones”. J Med Chem39 (3): 665–668. doi:10.1021/jm950395aPMID 8576907.
  7. ^ Xin, X.; et al. (1999). “Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo;”J. Biol. Chem274 (13): 9116–21. doi:10.1074/jbc.274.13.9116PMID 10085162.
Clinical data
ATC codenone
IUPAC name[show]
CAS Number74772-77-3 
PubChem CID2750
CompTox Dashboard (EPA)DTXSID0040757 
ECHA InfoCard100.220.474 
Chemical and physical data
Molar mass333.45 g·mol−1
3D model (JSmol)Interactive image
InChI[hide]InChI=1S/C18H23NO3S/c1-18(9-3-2-4-10-18)12-22-14-7-5-13(6-8-14)11-15-16(20)19-17(21)23-15/h5-8,15H,2-4,9-12H2,1H3,(H,19,20,21) Key:YZFWTZACSRHJQD-UHFFFAOYSA-N 

/////////ciglitazone, U 63287, ADD 3878, DIABETES

BMS 262084

2-Azetidinecarboxylic acid, 3-(3-((aminoiminomethyl)amino)propyl)-1-((4-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazinyl)carbonyl)-4-oxo-, (2S,3R)-.png
ChemSpider 2D Image | BMS-262084 | C18H31N7O5


CAS 253174-92-4

  • Molecular FormulaC18H31N7O5
  • Average mass425.483 Da



(2S,3R)-1-[4-(tert-butylcarbamoyl)piperazine-1-carbonyl]-3-[3-(diaminomethylideneamino)propyl]-4-oxoazetidine-2-carboxylic acid(2S,3R)-1-{[4-(tert-butylcarbamoyl)piperazin-1-yl]carbonyl}-3-{3-[(diaminomethylidene)amino]propyl}-4-oxoazetidine-2-carboxylic acid
(2S,3R)-3-{3-[(Diaminomethylene)amino]propyl}-1-({4-[(2-methyl-2-propanyl)carbamoyl]-1-piperazinyl}carbonyl)-4-oxo-2-azetidinecarboxylic acid253174-92-4[RN]2-Azetidinecarboxylic acid, 3-[3-[(diaminomethylene)amino]propyl]-1-[[4-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]carbonyl]-4-oxo-, (2S,3R)-

Factor XIa inhibitors (thrombosis), BMS; Factor XIa inhibitors (thrombosis), Bristol-Myers Squibb; BMS-654457; Factor XIa inhibitors (cardiovascular diseases), BMS; BMS-724296

Novel crystalline forms of BMS-262084  as Factor XIa antagonist useful for treating cardiovascular diseases.



Bioorganic & Medicinal Chemistry Letters (2002), 12(21), 3229-3233.


A series of N1-activated C4-carboxy azetidinones was prepared and tested as inhibitors of human tryptase. The key stereochemical and functional features required for potency, serine protease specificity and aqueous stability were determined. From these studies compound 2, BMS-262084, was identified as a potent and selective tryptase inhibitor which, when dosed intratracheally in ovalbumin-sensitized guinea pigs, reduced allergen-induced bronchoconstriction and inflammatory cell infiltration into the lung.

BMS-262084 was identified as a potent and selective tryptase inhibitor that, when dosed intratracheally in ovalbumin-sensitized guinea pigs, reduced allergen-induced bronchoconstriction and inflammatory cell infiltration into the lung.


Journal of Organic Chemistry (2002), 67(11), 3595-3600.

A highly stereoselective synthesis of the novel tryptase inhibitor BMS-262084 was developed. Key to this synthesis was the discovery and development of a highly diastereoselective demethoxycarbonylation of diester 12 to form the trans-azetidinone 13. BMS-262084 was prepared in 10 steps from d-ornithine in 30% overall yield.

1 as a white powder (3.18 g, 99% yield). Mp:  213-215 °C dec. [α]25D = −65.9 (c 0.99, MeOH). 1H NMR (CD3OD):  δ 4.17 (d, J = 3.29 Hz, 1H), 3.61−3.11 (m, 11H), 1.94−1.75 (m, 4H), 1.32 (s, 9H). 13C NMR (CD3OD):  δ 176.6, 168.7, 159.4, 158.7, 152.3, 58.7, 53.2, 51.8, 46.5, 45.0, 41.8, 29.6, 27.4, 26.3. HRMS:  calcd for C18H32N7O5(M+ + H) 426.2465, found 426.2470. IR (KBr):  3385, 3184, 1775, 1657, 1535, 1395, 1259, 1207, 996, 763 cm1. Anal. Calcd for C18H31N7O5:  C, 50.81, H, 7.34, N, 23.04. Found:  C, 50.65, H, 7.42, N, 22.72. Chiral HPLC:  ee 99.6%; Chiralpak OD column, 250 × 4.6 mm, 10 μm; mobile phase hexane/EtOH (85:15, v/v); isocratic at ambient temperature, 1.0 mL/min, 220 nm; concentration 0.25 mg/mL, 10 μL injection; RT = 18.6 min (enantiomer, RT = 15.7 min).



claiming macrocyclic compounds.



Novel crystalline and solid forms of BMS-262084 (designates as monohydrate or 1.5 hydrate), processes for their preparation and compositions comprising them are claimed. BMS-262084 is disclosed to be Factor XIa antagonist, useful for treating cardiovascular diseases.MS-262084 (CAS number: 253174-92-4), the chemical name is (2S,3R)-1-[4-(tert-butylcarbamoyl)piperazine-1-carbonoyl]-3-[3- (Diaminomethylamino)propyl]-4-cyclopropanamide-2-carboxylic acid, also called compound (1) in the present invention, is developed by BMS (Bristol-Myers-Squibb) to treat cardiovascular diseases The drug, as an oral coagulation factor XIa inhibitor for thrombus, has the advantage of significantly reducing the risk of bleeding, and its structure is shown in formula (1): 

Patent application WO 9967215A1 discloses the BMS-262084 compound, but the specific molecular formula of the solid substance obtained by the disclosed preparation process is C 18 H 31 N 7 O 5 ·1.56H 2 O, which is similar to the crystal of BMS-262084 described in this application. Type and amorphous water have different molecular weights.

“A stereoselective synthesis of BMS-262084 an azetidinone-based tryptase inhibitor” (Source: Journal of Organic Chemistry, 2002,67(11):3595-3600; Journal of Organic Chemistry,2002,67(11):3595-3600) It is mentioned that the preparation method of BMS-262084 is that hydrogenolysis under neutral conditions eliminates the benzene and Cbz protection groups, and obtains BMS-262084 (melting point 213-215℃). The inventors conducted experiments based on part of the contents disclosed in the document, and the test results obtained crystal form A and crystal form B. The X-ray powder diffraction patterns are shown in Figure 1 and Figure 2 respectively.Example 1 
“A stereoselective synthesis of BMS-262084 an azetidinone-based tryptase inhibitor” (Source: Journal of Organic Chemistry, 2002,67(11):3595-3600; Journal of Organic Chemistry,2002,67(11):3595-3600) Only ethanol solvents are mentioned in the literature. Since no specific crystal refining process was provided, only part of the experiment was performed using ethanol solvent. 
1) Ethanol solvent volatilization at room temperature: 50mg of BMS-262084 (amorphous) was added to 1.0 mL of ethanol solvent and completely dissolved at room temperature (about 25°C). After volatilizing at room temperature for two days, the solid product was obtained and its crystal form was tested. It is crystal form A, as shown in Figure 1. It is considered that it contains a small amount of amorphous form; but it is unstable and will undergo crystal transformation at room temperature. After standing for one day, the XRPD was tested, and it was found that it was converted to a mixture containing crystal form A, other crystal forms and amorphous forms. 
2) Ethanol solvent high-temperature volatilization: 50mg BMS-262084 is added to 1.0mL ethanol solvent, completely dissolved at high temperature (about 60℃), and high-temperature volatilization is carried out in the open to obtain a solid product. The crystal form of the solid product is detected, and the crystal form is B (contains a lot of amorphous), see Figure 2.


WO 9967215

The condensation of N-(tert-butyldimethylsilyl)-4-oxoazetidine-2(S)-carboxylic acid (I) with 1-chloro-3-iodopropane (II) by means of BuLi and triisopropylamine (TIA) in THF, followed by treatment with HCl, gives the 3(R)-(3-chloropropyl) derivative (III), which is treated with tetrabutylammonium azide and tetrabutylammonium iodide in DMF to yield the 3-azidopropyl derivative (IV). The reduction of (IV) with H2 over Pd/C in DMF affords the 3-aminopropyl compound (V), which is treated with 1-[N,N’-bis(benzyloxycarbonyl)-1H-pyrazole] (VI) in the same solvent to provide the protected 3-guanidinopropyl compound (VII). The esterification of (VII) with NaHCO3, tetrabutylammonium iodide and Bn-Br in DMF gives the benzyl ester (VIII), which is condensed with N-tert-butylpiperazine-1-carboxamide (IX) and phosgene by means of TEA in toluene to yield the protected precursor (X). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in dioxane to give the target azetidine-carboxylic acid.


Ethyl nipecotate (I) was protected as the N-Boc derivative (II) and subsequently reduced to alcohol (III) by means of LiAlH4. Conversion of alcohol (III) into iodide (IV) was achieved by treatment with iodine and triphenylphosphine. The dianion of the chiral azetidinecarboxylic acid (V) was alkylated with iodide (IV) to furnish adduct (VI) as a diastereomeric mixture that was desilylated to (VII) using tetrabutylammonium fluoride. Benzyl ester (VIII) was then obtained by reaction of carboxylic acid (VII) with benzyl bromide and NaHCO3.


Coupling of 6-phenylhexanoic acid (X) with N-Boc-piperazine (IX) to give (XI), followed by acid deprotection of the Boc group of (XI), provided (6-phenylhexanoyl)piperazine (XII). This was converted to the carbamoyl chloride (XIII) upon treatment with phosgene. The condensation of carbamoyl chloride (XIII) with azetidinone (VIII) gave rise to the urea derivative (XIV). After acid cleavage of the Boc protecting group of (XIV), the resulting piperidine (XV) was condensed with N,N’-dicarbobenzoxy-S-methylisothiourea (XVI) in the presence of HgCl2, yielding the protected guanidine (XVII). This was finally deprotected by catalytic hydrogenolysis over Pd/C.

////////////////////////BMS-262084, BMS 262084,  BMS 724296, Factor XIa inhibitors, thrombosis, Bristol-Myers Squibb,  BMS 654457, PHASE 2



ChemSpider 2D Image | Idebenone | C19H30O5



  • Molecular FormulaC19H30O5
  • Average mass338.439 Da
  • 58186-27-9
  • Idebenona, Idebenonum, CV 2619


Puldysa (idebenone), for the treatment of Duchenne muscular dystrophyTitle: Idebenone
CAS Registry Number: 58186-27-9
CAS Name: 2-(10-Hydroxydecyl)-5,6-dimethoxy-3-methyl-2,5-cyclohexadiene-1,4-dione
Additional Names: 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone; 2,3-dimethoxy-5-methyl-6-(10¢-hydroxydecyl)-1,4-benzoquinone; 6-(10-hydroxydecyl)ubiquinone
Manufacturers’ Codes: CV-2619
Trademarks: Avan (Takeda); Daruma (Takeda); Lucebanol (Hormona); Mnesis (Takeda)
Molecular Formula: C19H30O5Molecular Weight: 338.44
Percent Composition: C 67.43%, H 8.93%, O 23.64%
Literature References: Ubiquinone derivative with protective effects against cerebral ischemia. Prepn: H. Morimoto et al.,DE2519730eidem,US4271083 (1975, 1981 both to Takeda); K. Okamoto et al.,Chem. Pharm. Bull.30, 2797 (1982); C.-A. Yu, L. Yu, Biochemistry21, 4096 (1982). Effect on ischemia-induced amnesia in rats: N. Yamazaki et al.,Jpn. J. Pharmacol.36, 349 (1984). Metabolism in animals: T. Kobayashi et al.,J. Pharmacobio-Dyn.8, 448 (1985). Disposition: H. Torii et al.,ibid. 457. Pharmacokinetics and tolerance in humans: M. F. Barkworth et al.,Arzneim.-Forsch.35, 1704 (1985). Series of articles on pharmacology and clinical studies: Arch. Gerontol. Geriatr.8, 193-366 (1989). Review of chemistry, toxicology and pharmacology: I. Zs-Nagy, Arch. Gerontol. Geriatr.11, 177-186 (1990).Properties: Orange needles from ligroin, mp 46-50° (Morimoto); also reported as crystals from hexane + ethyl acetate, mp 52-53° (Okamoto). Sol in organic solvents. Practically insol in water.Melting point: mp 46-50° (Morimoto); mp 52-53° (Okamoto)Therap-Cat: Nootropic.Keywords: Nootropic.

Idebenone is a member of the class of 1,4-benzoquinones which is substituted by methoxy groups at positions 2 and 3, by a methyl group at positions 5, and by a 10-hydroxydecyl group at positions 6. Initially developed for the treatment of Alzheimer’s disease, benefits were modest; it was subsequently found to be of benefit for the symptomatic treatment of Friedreich’s ataxia. It has a role as an antioxidant. It is a primary alcohol and a member of 1,4-benzoquinones.

Idebenone (pronounced eye-deb-eh-known, trade names CatenaRaxoneSovrima, among others) is a drug that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer’s disease and other cognitive defects.[1] This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of neuromuscular diseases. In 2010, early clinical trials for the treatment of Friedreich’s ataxia[2] and Duchenne muscular dystrophy[3] have been completed. As of December 2013 the drug is not approved for these indications in North America or Europe. It is approved by the European Medicines Agency (EMA) for use in Leber’s hereditary optic neuropathy (LHON) and was designated an orphan drug in 2007.[4]

Chemically, idebenone is an organic compound of the quinone family. It is also promoted commercially as a synthetic analog of coenzyme Q10 (CoQ10).


Indications that are or were approved in some territories

Nootropic effects and Alzheimer’s disease

Idebenone improved learning and memory in experiments with mice.[5] In humans, evaluation of Surrogate endpoints like electroretinographyauditory evoked potentials and visual analogue scales also suggested positive nootropic effects,[6] but larger studies with hard endpoints are missing.

Research on idebenone as a potential therapy of Alzheimer’s disease have been inconsistent, but there may be a trend for a slight benefit.[7][8] In May 1998, the approval for this indication was cancelled in Japan due to the lack of proven effects. In some European countries, the drug is available for the treatment of individual patients in special cases.[1]

Friedreich’s ataxia (Sovrima)

Preliminary testing has been done in humans and found idebenone to be a safe treatment for Friedreich’s ataxia (FA), exhibiting a positive effect on cardiac hypertrophy and neurological function.[9] The latter was only significantly improved in young patients.[10] In a different experiment, a one-year test on eight patients, idebenone reduced the rate of deterioration of cardiac function, but without halting the progression of ataxia.[11]

The drug was approved for FA in Canada in 2008 under conditions including proof of efficacy in further clinical trials.[12] However, on February 27, 2013, Health Canada announced that idebenone would be voluntarily recalled as of April 30, 2013 by its Canadian manufacturer, Santhera Pharmaceuticals, due to the failure of the drug to show efficacy in the further clinical trials that were conducted.[13] In 2008, the European Medicines Agency (EMA) refused a marketing authorisation for this indication.[1] As of 2013 the drug was not approved for FA in Europe[14] nor in the US, where there is no approved treatment.[15]

Leber’s hereditary optic neuropathy (Raxone)

Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited (mother to all offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. Santhera completed a Phase III clinical trial in this indication in Europe with positive results,[16] and submitted an application to market the drug to European regulators in July 2011.[17] It is approved by EMA for this indication and was designated an orphan drug in 2007.[4]

Indications being explored

Duchenne muscular dystrophy (Catena)

After experiments in mice[18] and preliminary studies in humans, idebenone has entered Phase II clinical trials in 2005[3] and Phase III trials in 2009.[19]

Other neuromuscular diseases

Phase I and II clinical trials for the treatment of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)[20] and primary progressive multiple sclerosis[21] are ongoing as of December 2013.

Life style

Idebenone is claimed to have properties similar to CoQ10 in its antioxidant properties, and has therefore been used in anti-aging on the basis of free-radical theory. Clinical evidence for this use is missing. It has been used in topical applications to treat wrinkles.[22]


In cellular and tissue models, idebenone acts as a transporter in the electron transport chain of mitochondria and thus increases the production of adenosine triphosphate (ATP) which is the main energy source for cells, and also inhibits lipoperoxide formation. Positive effects on the energy household of mitochondria has also been observed in animal models.[1][23] Clinical relevance of these findings has not been established.


Idebenone is well absorbed from the gut but undergoes excessive first pass metabolism in the liver, so that less than 1% reach the circulation. This rate can be improved with special formulations (suspensions) of idebenone and by administering it together with fat food; but even taking these measures bioavailability still seems to be considerably less than 14% in humans. More than 99% of the circulating drug are bound to plasma proteins. Idebenone metabolites include glucuronides and sulfates, which are mainly (~80%) excreted via the urine.[1]


Single-step synthesis of idebenone from Coenzyme Q0 via free-radical alkylation under silver catalysis - ScienceDirect
Single-step synthesis of idebenone from Coenzyme Q0 via free-radical alkylation under silver catalysis - ScienceDirect


The palladium-catalyzed olefination of a sp2 or benzylic carbon attached to a (pseudo)halogen is known as the Heck reaction.2,63 It is a powerful tool, mainly used for the synthesis of vinylarenes, and it has also been employed for the construction of conjugated double bonds. The widespread application of this reaction can be illustrated by numerous examples in both academia small-scale64 and industrial syntheses.5 As an example, in 2011, a idebenone (124) total synthesis based on a Heck reaction was described (Scheme 35).65 This compound, initially designed for the treatment of Alzheimer’s and Parkinson’s diseases, presented a plethora of other interesting activities, such as free radical scavenging and action against some muscular illnesses. The key step in the synthesis was the coupling of 2-bromo-3,4,5-trimethoxy-1-methylbenzene (125) with dec-9-en-1-ol affording products 126. Under non-optimized conditions (Pd(OAc)2, PPh3, Et3N, 120 ºC), a mixture composed of 60% linear olefins 126 and 15% of the undesired branched product 127 was obtained after three days of reaction. Therefore, the conditions were optimized, allowing the preparation of 126 in 67% yield with no detection of 127 after only 30 min of reaction employing DMF, Pd(PPh3)4iPr2NEt under microwave heating. To conclude the synthesis, the Heck adducts were submitted to hydroxyl protection/deprotection, hydrogenation, and ring oxidation. After these reactions, idebenone was obtained with 20% overall yield over 6 steps.

Scheme 35 Synthesis of idebenone (124) based on Heck reaction of 2-bromo-3,4,5-trimethoxy-1-methylbenzene with dec-9-en-1-ol under microwave irradiation. 


  1.  Duveau, Damien Y.; Bioorganic & Medicinal Chemistry 2010, V18(17), P6429-6441 
  2. Okada, Taiiti; EP 289223 A1 1988 
  3. Watanabe, Masazumi; EP 58057 A1 1982 
  4. Okamoto, Kayoko; Chemical & Pharmaceutical Bulletin 1982, V30(8), P2797-819 
  5.  “Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US) 


Tsoukala, Anna; Organic Process Research & Development 2011, V15(3), P673-680

An environmentally benign, convenient, high yielding, and cost-effective synthesis leading to idebenone is disclosed. The synthesis includes a bromination process for the preparation of 2-bromo-3,4,5-trimethoxy-1-methylbenzene, a protocol for the Heck cross-coupling reaction using either thermal or microwave heating, olefin reduction by palladium catalyzed hydrogenation, and a green oxidation protocol with hydrogen peroxide as oxidant to achieve the benzoquinone framework. The total synthesis is composed of six steps that provide an overall yield of 20% that corresponds to a step yield of 76%.

Abstract Image


Bioorganic & Medicinal Chemistry 2010, V18(17), P6429-6441

Analogues of mitoQ and idebenone were synthesized to define the structural elements that support oxygen consumption in the mitochondrial respiratory chain. Eight analogues were prepared and fully characterized, then evaluated for their ability to support oxygen consumption in the mitochondrial respiratory chain. While oxygen consumption was strongly inhibited by mitoQ analogues 2–4 in a chain length-dependent manner, modification of idebenone by replacement of the quinone methoxy groups by methyl groups (analogues 68) reduced, but did not eliminate, oxygen consumption. Idebenone analogues 68 also displayed significant cytoprotective properties toward cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate.

Idebenone (5)18 To a stirred solution containing 200 mg (0.467 mmol) of 2,3- dimethoxy-6-methyl-5-benzyloxydecyl-p-benzoquinone (38) in 5 mL of anhydrous methanol at 23 C was added 15 mg of 10 % Pd/C in one portion. The reaction mixture was stirred at 23 C under an atmosphere of hydrogen for 24 h. Air was then bubbled through the reaction mixture at 23 C for 24 h. The suspension was filtered through Celite and the filtrate was concentrated under diminished pressure to afford idebenone (5) as an orange solid: yield 130 mg (82%); mp: 46–47 C; 1 H NMR (400 MHz, CDCl3) d 1.34 (m, 14H), 1.60 (quint, 2H, J = 7.6 Hz), 2.04 (s, 3H), 2.44 (t, 2H, J = 8.0 Hz), 3.63 (t, 2H, J = 6.8 Hz), and 3.99 (s, 6H); 13C NMR (100 MHz, CDCl3) d 11.9, 25.7, 26.4, 28.7, 29.3, 29.3, 29.4, 29.5, 29.8, 32.7


  1. Jump up to:a b c d e “CHMP Assessment Report for Sovrima” (PDF). European Medicines Agency. 20 November 2008: 6, 9–11, 67f.
  2. ^ Clinical trial number NCT00229632 for “Idebenone to Treat Friedreich’s Ataxia” at
  3. Jump up to:a b Clinical trial number NCT00654784 for “Efficacy and Tolerability of Idebenone in Boys With Cardiac Dysfunction Associated With Duchenne Muscular Dystrophy (DELPHI)” at
  4. Jump up to:a b “Raxone” Retrieved 12 July 2019.
  5. ^ Liu, XJ; Wu, WT (1999). “Effects of ligustrazine, tanshinone II A, ubiquinone, and idebenone on mouse water maze performance”. Zhongguo Yao Li Xue Bao20 (11): 987–90. PMID 11270979.
  6. ^ Schaffler, K; Hadler, D; Stark, M (1998). “Dose-effect relationship of idebenone in an experimental cerebral deficit model. Pilot study in healthy young volunteers with piracetam as reference drug”. Arzneimittel-Forschung48 (7): 720–6. PMID 9706371.
  7. ^ Gutzmann, H; Kühl, KP; Hadler, D; Rapp, MA (2002). “Safety and efficacy of idebenone versus tacrine in patients with Alzheimer’s disease: results of a randomized, double-blind, parallel-group multicenter study”. Pharmacopsychiatry35 (1): 12–8. doi:10.1055/s-2002-19833PMID 11819153.
  8. ^ Parnetti, L; Senin, U; Mecocci, P (1997). “Cognitive enhancement therapy for Alzheimer’s disease. The way forward”. Drugs53 (5): 752–68. doi:10.2165/00003495-199753050-00003PMID 9129864S2CID 46987059.
  9. ^ Di Prospero NA, Baker A, Jeffries N, Fischbeck KH (October 2007). “Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial”Lancet Neurol6 (10): 878–86. doi:10.1016/S1474-4422(07)70220-XPMID 17826341S2CID 24749816.
  10. ^ Tonon C, Lodi R (September 2008). “Idebenone in Friedreich’s ataxia”. Expert Opin Pharmacother9 (13): 2327–37. doi:10.1517/14656566.9.13.2327PMID 18710357S2CID 73285881.
  11. ^ Buyse G, Mertens L, Di Salvo G, et al. (May 2003). “Idebenone treatment in Friedreich’s ataxia: neurological, cardiac, and biochemical monitoring”. Neurology60 (10): 1679–81. doi:10.1212/01.wnl.0000068549.52812.0fPMID 12771265S2CID 36556782.
  12. ^ “Heath Canada Fact Sheet – Catena”. Archived from the original on 19 June 2014.
  13. ^ Voluntary Withdrawal of Catena from the Canadian Market
  14. ^ Margaret Wahl for Quest Magazine, MAY 28, 2010. FA Research: Idebenone Strikes Out Again
  15. ^ NINDS Fact Sheet
  16. ^ Klopstock, T; et al. (2011). “A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy”Brain134 (9): 2677–86. doi:10.1093/brain/awr170PMC 3170530PMID 21788663.
  17. ^ Staff (26 July 2011). “Santhera publishes pivotal trial results of idebenone and goes for EU approval”European Biotechnology News. Archived from the original on 2013-02-17.
  18. ^ Buyse, GM; Van Der Mieren, G; Erb, M; D’hooge, J; Herijgers, P; Verbeken, E; Jara, A; Van Den Bergh, A; et al. (2009). “Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance”European Heart Journal30 (1): 116–24. doi:10.1093/eurheartj/ehn406PMC 2639086PMID 18784063.
  19. ^ Clinical trial number NCT01027884 for “Phase III Study of Idebenone in Duchenne Muscular Dystrophy (DMD) (DELOS)” at
  20. ^ Clinical trial number NCT00887562 for “Study of Idebenone in the Treatment of Mitochondrial Encephalopathy Lactic Acidosis & Stroke-like Episodes (MELAS)” at
  21. ^ Clinical trial number NCT00950248 for “Double Blind Placebo-Controlled Phase I/II Clinical Trial of Idebenone in Patients With Primary Progressive Multiple Sclerosis (IPPoMS)” at
  22. ^ McDaniel D, Neudecker B, Dinardo J, Lewis J, Maibach H (September 2005). “Clinical efficacy assessment in photodamaged skin of 0.5% and 1.0% idebenone”. J Cosmet Dermatol4 (3): 167–73. doi:10.1111/j.1473-2165.2005.00305.xPMID 17129261S2CID 2394666.
  23. ^ Suno M, Nagaoka A (May 1988). “[Effect of idebenone and various nootropic drugs on lipid peroxidation in rat brain homogenate in the presence of succinate]”Nippon Yakurigaku Zasshi (in Japanese). 91 (5): 295–9. doi:10.1254/fpj.91.295PMID 3410376.
Clinical data
Trade namesCatena, Raxone, Sovrima
AHFS/Drugs.comInternational Drug Names
License dataEU EMAby INN
ATC codeN06BX13 (WHO)
Legal status
Legal statusIn general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability<1% (high first pass effect)
Protein binding>99%
Elimination half-life18 hours
ExcretionUrine (80%) and feces
IUPAC name[show]
CAS Number58186-27-9 
PubChem CID3686
CompTox Dashboard (EPA)DTXSID0040678 
Chemical and physical data
Molar mass338.444 g·mol−1
3D model (JSmol)Interactive image
InChI[hide]InChI=1S/C19H30O5/c1-14-15(12-10-8-6-4-5-7-9-11-13-20)17(22)19(24-3)18(23-2)16(14)21/h20H,4-13H2,1-3H3 Key:JGPMMRGNQUBGND-UHFFFAOYSA-N 

////////////IDEBENONE, Puldysa, Duchenne muscular dystrophy, Idesol, KS 5193, Nemocebral, SNT MC17, идебенон, إيديبينون , 艾地苯醌 , CV 2619


PF 3635659

PF-3635659 (hydrochloride).png
2D chemical structure of 931409-24-4
PF-3635659|931409-24-4|Active Biopharma Corp


CAS 931409-24-4 FREE FORM

Molecular Formula, C28-H32-N2-O3, Molecular Weight, 444.5718

1-Azetidinepentanamide, 3-(3-hydroxyphenoxy)-delta,delta-dimethyl-alpha,alpha-diphenyl-


Molecular FormulaC28H33ClN2O3
SynonymsPF-3635659 (hydrochloride)1079781-31-95-[3-(3-Hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic acid amide hydrochloride
Molecular Weight481 g/mol › David_Price_Presentation_0945_1030 

PDFDiscovery of PF3635659. An Inhaled Once. An Inhaled Once-daily M3. A t. i t. A t. i t f A th & COPD f A th & COPD. Antagonist. Antagonist for Asthma & COPD.file:///C:/Users/Inspiron/Downloads/David_Price_Presentation_0945_1030.pdf

Pf03635659 has been used in trials studying the treatment of Chronic Obstructive Pulmonary Disease.

Inhaled long-acting muscarinic antagonists in chronic obstructive pulmonary disease | Future Medicinal Chemistry

Synthetic Route

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5-[3-(3-hydroxy… 931409-66-4~65%PF-3635659931409-24-4
Literature: PFIZER LIMITED Patent: WO2008/135819 A1, 2008 ; Location in patent: Page/Page column 14; 15 ; WO 2008/135819 A1
N/A 1374308-52-7~%PF-3635659931409-24-4
Literature: Dillon, Barry R.; Roberts, Dannielle F.; Entwistle, David A.; Glossop, Paul A.; Knight, Craig J.; Laity, Daniel A.; James, Kim; Praquin, Celine F.; Strang, Ross S.; Watson, Christine A. L. Organic Process Research and Development, 2012 , vol. 16, # 2 p. 195 – 203
N/A 521267-13-0~%PF-3635659931409-24-4
Literature: Glossop, Paul A.; Watson, Christine A. L.; Price, David A.; Bunnage, Mark E.; Middleton, Donald S.; Wood, Anthony; James, Kim; Roberts, Dannielle; Strang, Ross S.; Yeadon, Michael; Perros-Huguet, Christelle; Clarke, Nicholas P.; Trevethick, Michael A.; MacHin, Ian; Stuart, Emilio F.; Evans, Steven M.; Harrison, Anthony C.; Fairman, David A.; Agoram, Balaji; Burrows, Jane L.; Feeder, Neil; Fulton, Craig K.; Dillon, Barry R.; Entwistle, David A.; Spence, Fiona J. Journal of Medicinal Chemistry, 2011 , vol. 54, # 19 p. 6888 – 6904


Organic Process Research & Development (2012), 16(2), 195-203.

Abstract Image

An efficient and scalable process for the synthesis of muscarinic antagonist, PF-3635659 1, is described, illustrating redesign of an analogue-targeted synthesis which contained a scale-limiting rhodium-activated C–H amination step. The final route includes a reproducible modified Bouveault reaction which has not previously been reported on a substrate of this complexity, or on such a scale with over 5 kg of the requisite gem-dimethylamine prepared via this methodology.

5-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide (1).

First Discovery Route.

To a solution of 5-methyl-2,2-diphenyl-5-{3-[3-(prop-2-en-1-yloxy)phenoxy]azetidin1-yl}hexane nitrile 9 (2.8 g, 6.01 mmol) in 3-methyl-pentan-3-ol (30 mL) was added potassium hydroxide (6.7 g, 120 mmol) and the resulting solution was stirred at 120 ºC for 22 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The aqueous layer was re-extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried with MgSO4 and concentrated in vacuo to yield 5-methyl-2,2-diphenyl-5-(3-{3- (propenyl)oxy-phenoxy}-azetidin-1-yl)-hexanamide 10 as a yellow oil (3 g, 6.01 mmol, 100%) which was taken on crude to the next step. To a solution of 5-methyl-2,2-diphenyl-5-(3-{3-(propenyl)oxy-phenoxy}-azetidin-1-yl)- hexanoic acid amide 10 (3.0 g, 6.01 mmol) in methanol (100 mL) was added a 2M aqueous hydrochloric acid solution (30 mL, 15 mmol) and the resulting solution was stirred at 60 ºC for 40 minutes. The volatile solvents were removed in vacuo and the remaining aqueous residue was basified with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were dried with magnesium sulphate and concentrated in vacuo.

The crude residue was purified by flash chromatography eluting in ethyl acetate:methanol:ammonia (90:10:1) / pentane (50/50) to yield the title compound 1 as a colourless foam (1.5 g, 3.37 mmol, 54.5%).

Second Discovery Route.

To a solution of 5-[3-(3-methoxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide 19 (9.0 g, 19.6 mmol) in dichloromethane (1.25 L) at 0 ºC was dropwise added a solution of boron tribromide (1M in dichloromethane, 58.9 mL, 58.9 mmol) and the mixture stirred for 2 hours at 0 ºC to 20 oC. The mixture was cooled to 0 ºC and quenched with 1M aqueous sodium hydroxide solution (200 mL). The reaction mixture was allowed to warm to 20 oC and stirred as such for 1 hour. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried with sodium sulphate and concentrated in vacuo. The crude residue was purified by column chromatography eluting in ethyl acetate:methanol:ammonia (90:10:1) / pentane (50/50) to yield the title compound 1 as a white foam (3.4 g, 7.64 mmol, 39%)

1H NMR (MeOD): δ=0.93 (s, 6H), 1.09-1.14 (m, 2H), 2.38-2.42 (m, 2H), 3.11-3.15 (m, 2H), 3.43-3.47 (m, 2H), 4.57-4.62 (m, 1H), 6.19-6.23 (m, 2H), 6.36 (d, 1H), 7.02 (t, 1H), 7.23-7.38 (m, 10H); MS: m/z 445 [M+H]+.


Journal of Medicinal Chemistry (2011), 54(19), 6888-6904.

Abstract Image

A novel tertiary amine series of potent muscarinic M3 receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M3 receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug–drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.


WO 2007034325

WO 2008135819

US 8263583



Methods and intermediates for preparing the hydrochloride salt of PF-3635659 ,

Cholinergic muscarinic receptors are members of the G-protein coupled receptor super-family and are further divided into 5 subtypes, M to Ms. Muscarinic receptor sub-types are widely and differentially expressed in the body. Genes have been cloned for all 5 sub-types and of these, Mi, M>, and Ms receptors have been extensively pharmacologically characterized in animal and human tissue. Mi receptors are expressed in the brain (cortex and hippocampus), glands and in the ganglia of sympathetic and parasympathetic nerves. M2 receptors are expressed in the heart, hindbrain, smooth muscle and in the synapses of the autonomi c nervous system. Ms receptors are expressed m the brain, glands and smooth muscle. In the airways, stimulation of Ms receptors evokes contraction of airway smooth muscle leading to bronchoeonstnction, while in the salivary-gland Ms receptor stimulation increases fluid and mucus secretion leading to increased salivation. M2 receptors expressed on smooth muscle are understood to be pro-contractile while pre-synaptic M2 receptors modulate acetylcholine release from parasympathetic nerves. Stimulation of M2 receptors expressed in the heart produces bradycardia.

[0003] Short and long-acting muscarinic antagonists are used in the management of asthma and chronic obstructive pulmonary disease (COPD); these include the short acting agents Atrovent® (ipratropium bromide) and Oxivent® (oxitropium bromide) and the long acting agent Spiriva® (tiotropium bromide). These compounds produce bronchodilation following inhaled administration. In addition to improvements in spirometric values, anti-muscarinic use in COPD is associated with improvements m health status and quality of life scores. As a consequence of the wide distribution of muscarinic receptors in the body, significant systemic exposure to muscarinic antagonists is associated with effects such as dry mouth, constipation, mydriasis, urinary retention (all predominantly mediated via blockade of M3 receptors) and tachycardia (mediated by blockade of M2 receptors).

[0004] A newer M3 receptor antagonist that is in the carboxamide family is 5-[3-(3-hydroxyphenoxy)azetidin-l-yl]-5-methyl-2,2-diphenylhexanamide hydrochloride. This carboxamide compound exhibits the following structure (formula II):

[0005] To date, it has not been appreciated that 5-[3-(3-hydroxyphenoxy)azetidin-l-yl]-5-methyl-2,2-diphenylhexanamide hydrochloride can be synthesized from the benzoate salt of 5-[3-(3-hydroxyphenoxy)azetidin~l~y!]-5-methyl-2,2-diphenylhexanenitrile Therefore, there is a need for methods and intermediates used to efficiently prepare 5-[3-(3-hydroxyphenoxy)azetidin~l~y!]-5-methyl-2,2-diphenylhexanamide hydrochloride of good quality from the benzoate salt of 5~[3~ (3~hydroxyphenoxy)azetidin-l-yl]-5-rn ethyl-2, 2-diphenylhexanenitrile.

Reaction Scheme 1 -Preparation of Crude Carboxamide Hydrochloride

formula I formula II

[0061] The coupled benzoate compound of formula 1 can be reacted with KOH, 2-methyl-2-butano!, water, then HC1 aqueous, HC1, and TBME to obtain the crude carboxamide hydrochloride of formula II. The benzoate salt of the nitrile provides for easier purification of the nitrile.

[0062] The reagents useful in the preparation of 5-[3-(3-hydroxyphenoxy)azetidin-l-yl]-5-metiiyl-2,2-diphenyl-hexanamide hydrochloride include a base and an alcohol In some embodiments, a useful base includes potassium hydroxide, while a useful alcohol includes tertiary amyl alcohol also known as 2-methyl-2-butanol. The reaction of the benzoate compound of formula II in tertiary amyl alcohol and potassium hydroxide can be carried in a temperature range from about 85 ± 5°C to about 103 ± 2°C. In a later stage, the temperature of 103 ± 2°C can be maintained in that range for from about 30 hours to about 65 hours. A cooling period to about room temperature is followed by adjusting the pH to a range from about 6.5 to about 8.0. Hydrochloric acid is added to the product of this initial reaction to form a crude carboxamide hydrochloride compound of formula II. The initially isolated crude carboxamide hydrochloride compound of formula II can be washed with an alcohol and then washed with, or slurried in an ether. In some embodiments, the alcohol can be tertiary amyl alcohol and the ether can be methyl tertiary butyl ether.

[0063] In various embodiments, the crude 5-[3-(3-hydroxyphenoxy)azetidin-l-yl]-5-methyl-2,2-diphenylhexanamide hydrochloride can be further purified by treating this carboxamide hydrochloride compound with a slurry of activated charcoal, for example, commercially available ENQPC, PF133 or PF511 SPL (A) carbon, in isopropyl alcohol and water at 85 ± 5°C and filtering as illustrated m the Reaction Scheme 2 below:

Reaction Scheme 2 – Purification of Carboxamide Hydrochloride

Reaction Scheme 3 – Preparation of the Coupled Compound Benzoate


[0065] In some embodiments, the benzyl coupled compound of formula III is prepared by reacting an azetidine mesyl HC1 1 -(5-cyano-2-methyl-5,5-diphenylpentan-2-yl)azetidin-3-yl methanes ulfonate hydrochloride with a reagent comprising benzyl resorcinol as illustrated in the Reaction Scheme 4 below:

Reaction Scheme 4 – Preparation of the Benzyl Coupled Compound

In Reaction Scheme 4, the azetidine mesyl hydrochloride of formula IV

is reacted with benzyl resorcinol of formula V

The reagent can comprise benzyl resorcinol and, in some aspects, acetonitrile, a carbonate salt of either cesium or potassium, sodium hydroxide, water, ethyl acetate, hexanes or a mixture thereof. The order of addition of reagents in this step overcomes the need for specific equipment (e.g., a bespoke/unusual agitator) and allows the step to be run in a general purpose reactor.

[0066] Benzyl resorcinol is commercially available and can be obtained commercially, for example, from Sigma Aldrich Corp. In various embodiments, benzyl resorcinol of formula V can be prepared by reacting resorcinol with benzyl chloride to form benzyl resorcinol according to the Reaction Scheme 5 below:

Reaction Scheme 5 — Preparation of Benzyl Resorcinol

Resorcinol DMF/Hexane

Toluene Benzyl Resorcinol


3-{benzyioxy) phenol


[0067] In certain aspects, the benzyl resorcinol is prepared by reacting resorcinol with benzyl chloride m a reagent which can include potassium carbonate, dimethylformamide, water, sodium hydroxide, toluene, hydrochloric acid, hexanes or a combination thereof. In some instances, benzyl resorcinol seeding material may also be added. For the conversion of the resorcinol to the benzyl resorcinol (V), the developed chemistry’- allows effective removal of remaining resorcinol starting material and dibenzyl impurity to give the benzyl resorcinol product in good yield and quality.

Reaction Scheme 6 – Preparation of Azetidine Mesyl Hydrochloride

Azetidine alcohol Azetidine mesyl

VI hydrochloride

Reaction Scheme 7 – Preparation of Azetidine Alcohol

Scheme 8 – Preparation of Diphenyl Amine

Reaction Scheme 9 Preparation of Diphenyl Chloro Amide

Reaction Scheme 10 – Preparation of Diphenyl Alkene

3-methyl-3-buien-t-ol Mesyi Alkene Diphenyl Alkene



The compound was originally claimed without an action as example 108 in WO2007034325 , for the treatment of chronic obstructive pulmonary disease, and this is the first filing from Pfizer relating to the compound since the program was presumed discontinued in 2011.

Example 108 5-r3-(3-Hvdroxyphenoxy)azetidin-1-vπ-5-methyl-2,2-diphenylhexanamide

Figure imgf000130_0001

Boron tribromide (1M in dichloromethane, 1.75mL, 1.75mmol) was added to an ice-cooled solution of the product of example 100 (200mg, 0.44mmol) in dichloromethane (5mL) and the mixture was stirred at O0C for 1 hour. Further boron tribromide (1M in dichloromethane, 0.5mL, O.δmmol) was added and the mixture was stirred at O0C for 30 minutes. The reaction was then quenched with 1M sodium hydroxide solution (5mL), diluted with dichloromethane (2OmL) and stirred at room temperature for 40 minutes. The aqueous layer was separated, extracted with ethyl acetate (2x25mL) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate/methanol/0.88 ammonia (90/10/1), 75:25 to 50:50, afforded the title compound as a colourless foam in 91% yield, 176mg.

1HNMR(400MHz, CDCI3) δ: 1.10(s, 6H), 1.22-1.34(m, 2H), 2.42-2.55(m, 2H), 3.28-3.40(m, 2H), 3.65-3.88(m, 2H), 4.70-4.80(m, 1H), 5.55-5.70(brs, 2H), 6.23-6.36(m, 2H), 6.45-6.53(m, 1H), 7.03-7.12(m, 1H), 7.19-7.39(m, 10H); LRMS ESI m/z 445 [M+H]+ E



It does however, follow on from WO2018167804 , assigned solely to Mylan , claiming amorphous and crystalline forms designated as Forms I-XI, for treating allergy, and this seems to confirm the potential of the candidate is being revisited, and possibly licensed.

(5-[3-(3-Hydroxyphenoxy)azetidin-l-yl]-5-methyl-2,2-diphenylhexanamide hydrochloride has a structure depicted below as Compound-A.


Compound-A is a muscarinic antagonist useful for treating allergy or respiratory chronic obstructive pulmonary disease.

Compound-A and pharmaceutically acceptable salts are claimed in U.S. Pat. No. 7,772,223 B2 and one of its non-solvated crystalline forms is claimed in U.S. Pat. No. 8,263,583 B2.


Example 1: Processes for the preparation of amorphous form of Compound-A.

Compound-A (5 g) was dissolved in methanol (150 ml) at 60-65°C. The solution was filtered at 60-65°C to remove undissolved particulate and then cooled to 25-30°C. The clear solution of Compound-A was subjected to spray drying in a laboratory Spray Dryer (Model Buchi-290) with a 5 ml/min feed rate of the solution and inlet temperature at 75°C with 100% aspiration to yield an amorphous form of Compound-A.

///////////// PF-3635659,  PF 3635659



ChemSpider 2D Image | bindarit | C19H20N2O3
Bindarit Chemical Structure


  • Molecular FormulaC19H20N2O3
  • Average mass324.374 Da

CAS 130641-38-2

2-[(1-benzylindazol-3-yl)methoxy]-2-methylpropanoic acid

2-[(1 -benzyl-1 H-indazol-3-yl)methoxy]-2-methylpropanoic acid

2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropanoic acidJQ11LH711MPropanoic acid, 2-methyl-2-[[1-(phenylmethyl)-1H-indazol-3-yl]methoxy]- [ACD/Index Name]биндарит [Russian] [INN]بينداريت [Arabic] [INN]宾达利 [Chinese] [INN]PHASE 2Bindarit has been used in trials studying the prevention and treatment of Coronary Restenosis and Diabetic Nephropathy.

Bindarit, an inhibitor of monocyte chemotactic protein synthesis, protects against bone loss induced by chikungunya virus infection

Bindarit (AF2838) is a selective inhibitor of the monocyte chemotactic proteins MCP-1/CCL2MCP-3/CCL7, and MCP-2/CCL8, and no effect on other CC and CXC chemokines such as MIP-1α/CCL3, MIP-1β/CCL4, MIP-3/CCL23. Bindarit also has anti-inflammatory activity.

As is known, MCP-1 (Monocyte Chemotactic Protein-1 ) is a protein belonging to the β subfamily of chemokines. MCP-1 has powerful chemotactic action on monocytes and exerts its action also on T lymphocytes, mastocytes and basophils (Rollins BJ. , Chemokines, Blood 1997; 90: 909-928; M.

Baggiolini, Chemokines and leukocyte traffic, Nature 1998; 392: 565-568).

Other chemokines belonging to the β subfamily are, for example, MCP-2 (Monocyte Chemotactic Protein-2), MCP-3, MCP-4, MIP-1 α and MIP-1 β, RANTES.

The β subfamily differs from the α subfamily in that, in the structure, the first two cysteines are adjacent for the β subfamily, whereas they are separated by an intervening amino acid for the α subfamily. MCP-1 is produced by various types of cells (leukocytes, platelets, fibroblasts, endothelial cells and smooth muscle cells).

Among all the known chemokines, MCP-1 shows the highest specificity for monocytes and macrophages, for which it constitutes not only a chemotactic factor but also an activation stimulus, consequently inducing processes for producing numerous inflammatory factors (superoxides, arachidonic acid and derivatives, cytokines/chemokines) and amplifying the phagocytic activity.

The secretion of chemokines in general, and of MCP-1 in particular, is typically induced by various pro-inflammatory factors, for instance interleukin-1 (IL-1 ), interleukin-2 (IL-2), TNFα (Tumour Necrosis Factor α), interferon-γ and bacterial lipopolysaccharide (LPS).

Prevention of the inflammatory response by blocking the chemokine/chemokine receptor system represents one of the main targets of pharmacological intervention (Gerard C. and Rollins B. J., Chemokines and disease. Nature Immunol. 2001 ; 2:108-1 15).

There is much evidence to suggest that MCP-1 plays a key role during inflammatory processes and has been indicated as a new and validated target in various pathologies.

Evidence of a considerable physiopathological contribution of MCP-1 has been obtained in the case of patients with articular and renal inflammatory diseases (rheumatoid arthritis, lupus nephritis, diabetic nephropathy and rejection following transplant).

However, more recently, MCP-1 has been indicated among the factors involved in inflammatory pathologies of the CNS (multiple sclerosis, Alzheimer’s disease, HIV-associated dementia) and other pathologies and conditions, with and without an obvious inflammatory component, including atopic dermatitis, colitis, interstitial lung pathologies, restenosis, atherosclerosis, complications following a surgical intervention (for instance angioplasty, arterectomy, transplant, organ and/or tissue replacement, prosthesis implant), cancer (adenomas, carcinomas and metastases) and even metabolic diseases such as insulin resistance and obesity.

In addition, despite the fact that the chemokine system is involved in controlling and overcoming viral infections, recent studies have demonstrated that the response of certain chemokines, and in particular of MCP-1 , may have a harmful role in the case of host-pathogen interactions. In particular, MCP-1 has been indicated among the chemokines that contribute towards organ and tissue damage in pathologies mediated by alpha viruses characterized by monocyte/macrophage infiltration in the joints and muscles (Mahalingam S. et al. Chemokines and viruses: friend or foes? Trends in Microbiology 2003; 1 1 : 383-391 ; RuIIi N. et al. Ross River Virus: molecular and cellular aspects of disease pathogenesis. 2005; 107: 329-342).

Monocytes are the main precursors of macrophages and dendritic cells, and play a critical role as mediators of inflammatory processes. CX3CR1 , with its ligand CX3CL1 (fractalkine), represents a key factor in regulating the migration and adhesiveness of monocytes. CX3CR1 is expressed in monocytes, whereas CX3CL1 is a transmembrane chemokine in endothelial cells. Genetic studies in man and in animal models have demonstrated an important role in the physiopathology of inflammatory diseases of CX3CR1 and CX3CL1. There is in fact much evidence to suggest a key contribution of CX3CR1 and of its ligand in the pathogenesis and progression of articular, renal, gastrointestinal and vascular inflammatory diseases (e.g. rheumatoid arthritis, lupus nephritis, diabetic nephropathy, Crohn’s disease, ulcerative colitis, restenosis and atherosclerosis). The expression of CX3CR1 is over-regulated in T cells, which are believed to accumulate in the synovium of patients suffering from rheumatoid arthritis. In addition, the expression of CX3CL1 is over-regulated in endothelial cells and fibroblasts present in the synovium of these patients. Consequently, the CX3CR1/CX3CL1 system plays an important role in controlling the type of cell and the mode of infiltration of the synovium and contributes towards the pathogenesis of rheumatoid arthritis (Nanki T. et al., “Migration of CX3CR1-positive T cells producing type 1 cytokines and cytotoxic molecules into the synovium of patients with rheumatoid arthritis”, Arthritis & Rheumatism (2002), vol. 46, No. 1 1 , pp. 2878-2883). In patients suffering form renal damage, the majority of the inflammatory leukocytes that infiltrate the kidneys express CX3CR1 , and in particular it is expressed on two of the main cell types involved in the most common inflammatory renal pathologies and in kidney transplant rejection, T cells and monocytes (Segerer S. et al., Expression of the fractalkine receptor (CX3CR1 ) in human kidney diseases, Kidney International (2002) 62, pp. 488-495).

Participation of the CX3CR1/CX3CL1 system has been suggested also in inflammatory bowel diseases (IBD). In point of fact, in the case of patients suffering from IBD (e.g. Crohn’s disease, ulcerative colitis), a significant increase in the production of CX3CL1 by the intestinal capillary system and a – A – significant increase in CX3CR1 -positive cells have been demonstrated, both at the circulatory level and in the mucosa (Sans M. et al., “Enhanced recruitment of CX3CR1 + T cells by mucosal endothelial cell-derived fractalkine in inflammatory bowel diseases”, Gastroenterology 2007, vol. 132, No. 1 , pp. 139-153).

Even more interesting is the demonstration of the key role played by the CX3CR1/CX3CL1 system in vascular damage and in particular under pathological conditions, for instance atherosclerosis and restenosis. CX3CR1 is indicated as a critical factor in the process of infiltration and accumulation of monocytes in the vascular wall, and CX3CR1 polymorphism in man is associated with a reduced prevalence of atherosclerosis, coronary disorders and restenosis (Liu P. et al., “Cross-talk among Smad, MAPK and integrin signalling pathways enhances adventitial fibroblast functions activated by transforming growth factor-1 and inhibited by Gax” Arterioscler. Thromb. Vase. Biol. 2008; McDermott D. H. et al., “Chemokine receptor mutant CX3CR1 -M280 has impaired adhesive function and correlates with protection from cardiovascular diseases in humans”, J. Clin. Invest. 2003; Niessner A. et al., Thrombosis and Haemostasis 2005).

IL-12 and IL-23 are members of a small family of proinflammatory heterodimeric cytokines. Both cytokines share a common subunit, p40, which is covalently bonded either to the p35 subunit to produce the mature form of IL-12, or to the p19 subunit to produce the mature form of IL-23. The receptor for IL-12 is constituted by the subunits IL-12Rβ1 and IL-12Rβ2, while the receptor for IL-23 is constituted by the subunits IL-12Rβ1 and IL-23R. IL-12 and IL-23 are mainly expressed by activated dendritic cells and by phagocytes. The receptors for the two cytokines are expressed on the T and NK cells, and NK T cells, but low levels of complexes of the receptor for IL-23 are also present in monocytes, macrophages and dendritic cells.

Despite these similarities, there is much evidence to suggest that IL-12 and IL-23 control different immunological circuits. In point of fact, whereas IL-12 controls the development of Th1 cells, which are capable of producing gamma-interferon (IFN-γ), and increases the cytotoxic, antimicrobial and antitumoral response, IL-23 regulates a circuit that leads to the generation of CD4+ cells, which are capable of producing IL-17. The induction of IL-23- dependent processes leads to the mobilization of various types of inflammatory cell, for instance TH-17, and it has been demonstrated as being crucial for the pathogenesis of numerous inflammatory pathologies mediated by immonological responses. Typical examples of pathologies associated with the expression of p40 are chronic inflammatory diseases of the articular apparatus (e.g. rheumatoid arthritis), of the dermatological apparatus (e.g. psoriasis) and of the gastrointestinal apparatus (e.g. Crohn’s disease). However, IL-23 also exerts a role in promoting tumour incidence and growth. In point of fact, IL-23 regulates a series of circuits in the tumoral microenvironment, stimulating angiogenesis and the production of inflammation mediators.

Psoriasis is a chronic inflammatory skin disease that affects 3% of the world’s population (Koo J. Dermatol. Clin. 1996; 14:485-96; Schon M. P. et al., N. Engl. J. Med. 2005; 352: 1899-912). A type-1 aberrant immune response has been correlated with the pathogenesis of psoriasis, and the cytokines that induce this response, such as IL-12 and IL-23, may represent suitable therapeutic objects. The expression of IL-12 and IL-23, which share the subunit p40, is significantly increased in psoriasis plaques, and preclinical studies have demonstrated a role of these cytokines in the pathogenesis of psoriasis. More recently, the treatment of anti- IL-12 and IL-23 monoclonal antibodies of patients suffering from psoriasis proved to be effective in improving the signs of progression and seriousness of the disease and has subsequently reinforced the role of IL-12 and IL-23 in the physiopathology of psoriasis. Crohn’s disease is a chronic inflammatory pathology of the digestive apparatus and may affect any region thereof – from the mouth to the anus. It typically afflicts the terminal tract of the ileum and well-defined areas of the large intestine. It is often associated with systemic autoimmune disorders, such as mouth ulcers and rheumatic arthritis. Crohn’s disease affects over 500 000 people in Europe and 600 000 people in the United States.

Crohn’s disease is a pathology associated with a Th1 cell-mediated excessive activity of cytokines. IL-12 is a key cytokine in the initiation of the inflammatory response mediated by Th1 cells. Crohn’s disease is characterized by increased production of IL-12 by cells presenting the antigen in intestinal tissue, and of gamma-interferon (IFN-γ) and TNFα by lymphocytes and intestinal macrophages. These cytokines induce and support the inflammatory process and thickening of the intestinal wall, which are characteristic signs of the pathology. Preclinical and clinical evidence has demonstrated that inhibition of IL-12 is effective in controlling the inflammatory response in models of intestinal inflammation and/or in patients suffering from Crohn’s disease.

The relationship between cancer and inflammation is now an established fact. Many forms of tumours originate from sites of inflammation, and inflammation mediators are often produced in tumours.

IL-23 has been identified as a cytokine associated with cancer and, in particular, the expression of IL-23 is significantly high in samples of human carcinomas when compared with normal adjacent tissues. In addition, the absence of a significant expression of IL-23 in the normal adjacent tissues suggests an over-regulation of IL-23 in tumours, reinforcing its role in tumour genesis.

European patent EP-B-O 382 276 describes a number of 1-benzyl-3-hydroxymethylindazole derivatives endowed with analgesic activity. In turn, European patent EP-B-O 510 748 describes, on the other hand, the use of these derivatives for preparing a pharmaceutical composition that is active in the treatment of autoimmune diseases. Finally, European patent EP-B-1 005 332 describes the use of these derivatives for preparing a pharmaceutical composition that is active in treating diseases derived from the production of MCP-1. 2-Methyl-2-{[1-(phenylmethyl)-1 H-indazol-3-yl]methoxy}propanoic acid is thought to be capable of inhibiting, in a dose-dependent manner, the production of MCP-1 and TNF-α induced in vitro in monocytes from LPS and Candida albicans, whereas the same compound showed no effects in the production of cytokines IL-1 and IL-6, and of chemokines IL-8, MIP-1 α, and RANTES (Sironi M. et al., “A small synthetic molecule capable of preferentially inhibiting the production of the CC chemokine monocyte chemotactic protein-1 “, European Cytokine Network. Vol. 10, No. 3, 437-41 , September 1999).

European patent application EP-A-1 185 528 relates to the use of triazine derivatives for inhibiting the production of IL-12. European patent application EP-A-1 188 438 and EP-A-1 199 074 relate to the use of inhibitors of the enzyme PDE4, for instance Rolipram, Ariflo and diazepine-indole derivatives, in the treatment and prevention of diseases associated with excessive production of IL-12. European patent application EP-A-1 369 1 19 relates to the use of hyaluronane with a molecular weight of between 600 000 and 3 000 000 daltons for controlling and inhibiting the expression of IL-12. European patent application EP-A-1 458 687 relates to the use of pyrimidine derivatives for treating diseases related to an overproduction of IL-12. European patent application EP-A-1 819 341 relates to the use of nitrogenous heterocyclic compounds, for instance pyridine, pyrimidine and triazine derivatives, for inhibiting the production of IL-12 (or of other cytokines, such as IL-23 and IL-27 which stimulate the production of IL-12). European patent application EP-A-1 827 447 relates to the use of pyrimidine derivatives for treating diseases related to an overproduction of IL-12, IL-23 and IL-27.

European patent applications EP-A-1 869 055, EP-A-1 869 056 and EP-A-1 675 862 describe 1 ,3-thiazolo-4,5-pyrimidine derivatives that are capable of acting as CX3CR1 receptor antagonists.

Despite the activity developed thus far, there is still felt to be a need for novel pharmaceutical compositions and compounds that are effective in the treatment of diseases based on the expression of MCP-1 , CX3CR1 and p40. The Applicant has found, surprisingly, novel 1-benzyl-3-hydroxymethylindazole derivatives with pharmacological activity.

The Applicant has found, surprisingly, that the novel 1-benzyl-3-hydroxymethylindazole derivatives according to formula (I) of the present invention are capable of reducing the production of the chemokine MCP-1. More surprisingly, the Applicant has found that the novel 1-benzyl-3-hydroxymethylindazole derivatives according to formula (I) of the present invention are capable of reducing the expression of the chemokine MCP-1.

Even more surprisingly, the Applicant has found that the 1-benzyl-3-hydroxymethylindazole derivatives according to formula (I) of the present invention are capable of reducing the expression of the subunit p40 involved in the production of the cytokines IL-12 and IL-23, and the expression of the receptor CX3CR1.



EP 0382276


WO 2009109613

Preparation of compound 29

2-[(1 -benzyl-1 H-indazol-3-yl)methoxy]-2-methylpropanoic acid The preparation of product 29 was performed as described in patent application EP 382 276.


WO 2011015502

Example 5

Preparation of 2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid

Ethyl-2-hydroxyisobutyrate (18.5 g, 140 mmol, 1.2 eq.), toluene (100 ml_) and DMF (20 ml_) were placed in a three-necked flask fitted with a mechanical stirrer and a reflux condenser under an inert atmosphere. A dispersion of 60% NaH (5.6 g, 140 mmol, 1.2 eq.) was added to the mixture in portions over a period of approximately 1.5 hours. A solution of i -benzyl-3-chloromethyl-I H-indazole (30 g,

117 mmol, 1 eq.) in toluene (90 ml_) and DMF (60 ml_) was then added dropwise. The reaction mixture was heated to approximately 90°C and kept at that temperature until the reaction was complete (checked by TLC, approximately 10 hours). After cooling to room temperature the mixture was washed with acidified water and water. The organic phase was concentrated under reduced pressure and the oily residue obtained was treated with 10 M NaOH (36 ml_) at reflux temperature for at least 3 hours. The product, which was precipitated out by the addition of concentrated HCI, was filtered and dried. Yield: 32.3 g of white solid (85%).

mp: 133-134°C.

Elemental analysis:Calculated: C (70.35), H (6.21 ), N (8.64), Found: C (70.15), H (6.17), N (8.63).

1H NMR (300 MHz, DMSO-d6) δ (ppm) 1.44 (s, 6H), 4.76 (s, 2H), 5.60 (s, 2H), 7.14 (t, 1 H, J = 7.6 Hz), 7.20-7.34 (m, 5H), 7.37 (ddd, 1 H, J = 8.3 Hz, 7.0 Hz, 1.1 Hz), 7.66 (d, 1 H, J = 8.4 Hz), 7.94 (d, 1 H, J = 8.1 Hz), 12.77 (s, 1 H).

13C NMR (300 MHz, DMSO-d6) δ (ppm) 24.48, 24.48, 51.63, 59.65,76.93, 109.69, 120.22, 121.06, 122.62, 126.28, 127.36, 127.36, 127.44, 128.46, 128.46, 137.49, 140.31 , 141.97, 175.46.


WO 2011015501


US 8350052

US 8354544

US 8835481

//////////////BINDARIT, JQ11LH711M, биндарит , بينداريت , 宾达利 , AF2838, AF 2838, PHASE 2



Roluperidone | C22H23FN2O2 | ChemSpider

  • Molecular FormulaC22H23FN2O2
  • Average mass366.429 Da


CAS 359625-79-9

1937215-88-7 hcl

ролуперидон [Russian] [INN]

رولوبيريدون [Arabic] [INN]

罗鲁哌酮 [Chinese] [INN]

1H-Isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-2-({1-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl}methyl)-1-isoindolinone

2-[[1- [2–fluorophenyl) -2-oxotyl] piperidine –4-yl] methyl] isoindrin-hydrochloride





Roluperidone (former developmental code names MIN-101CYR-101MT-210) is a 5-HT2A and σ2 receptor antagonist that is under development by Minerva Neurosciences for the treatment of schizophrenia.[1][2][3][4] One of its metabolites also has some affinity for the H1 receptor.[2] As of May 2018, the drug is in phase III clinical trials.[5]

Minerva Neurosciences (following the merger of Cyrenaic and Sonkei Pharmaceuticals ), under license from Mitsubishi Tanabe Pharma , is developing roluperidone (MIN-101, CYR-101, MT-210), a dual 5-HT2A /sigma 2 antagonist, as a modified-release formulation, for the potential oral treatment of schizophrenia. In December 2017, a phase III trial was initiated in patients with negative symptoms of schizophrenia. By March 2020, Minerva had filed an IND for apathy in dementia.

Schizophrenia is a complex, challenging, and heterogeneous psychiatric condition, affecting up to 0.7% of the world population according to the World Health Organization (WHO, 2006). Patients suffering with schizophrenia present with a range of symptoms, including: positive symptoms, such as delusions, hallucinations, thought disorders, and agitation; negative symptoms, such as mood flatness and lack of pleasure in daily life; cognitive symptoms, such as the decreased ability to understand information and make decisions, difficulty focusing, and decreased working memory function; and sleep disorders.

The etiology of schizophrenia is not fully understood. A major explanatory hypothesis for the pathophysiology of schizophrenia is the Dopamine (DA) hypothesis, which proposes that hyperactivity of DA transmission is responsible for expressed symptoms of the disorder. This hypothesis is based on the observation that drugs effective in treating schizophrenia share the common feature of blocking DA D2 receptors. However, these so-called typical antipsychotics are associated with a very high incidence of extrapyramidal symptoms (EPS). Furthermore, negative symptoms and cognitive impairment are considered relatively unresponsive to typical antipsychotics.

Most currently approved therapies for schizophrenia show efficacy primarily in the management of positive symptoms. An estimated 4.2 million people suffered from schizophrenia in 2012 in the United States and the five major European Union markets. Of those, an estimated 48% experienced predominantly negative symptoms and 80% suffered from cognitive impairment. In addition, about 50% of patients with schizophrenia experience sleep disorders, which can further exacerbate both positive and negative symptoms.

The introduction of the so-called atypical antipsychotics in the last decade represented a significant advance in the treatment of schizophrenia. Although these atypical antipsychotics differ widely in chemical structure and receptor-binding profiles, they share a characteristic of potent antagonism of the Serotonin (5-hydroxytryptamine) type 2 receptor (5-HT2A). A high 5-HT2A:D2 affinity ratio is thought to substantially reduce the liability for inducing EPS, compared with typical antipsychotics.

However, many patients are still treatment-noncompliant despite the advantage of atypical antipsychotics of tolerability. Although the risk of EPS is clearly lower with the atypical antipsychotics, the high doses required with some atypical antipsychotics are likely to result in an increased incidence of EPS and require concomitant medications such as antiparkinson drugs.

In addition to EPS, antipsychotic medications cause a broad spectrum of side effects including sedation, anticholinergic effects, prolactin elevation, orthostatic hypotension, weight gain, altered glucose metabolism, and QTc prolongation. These side effects can affect patients’ compliance with their treatment regimen. It should be noted that noncompliance with treatment regimen is a primary reason for relapse of the disease.

Although atypical antipsychotics offer advantages over typical antipsychotics in terms of symptom alleviation and side effect profile, these differences are generally modest. A certain population of patients still remains refractory to all currently available antipsychotics. Newer agents to address these issues continue to be sought.

Product Ingredients

Roluperidone hydrochlorideWFL7TF8DTP1937215-88-7NZKANSJXJCILHS-UHFFFAOYSA-N


Example 1: 2-[[1- [2–fluorophenyl) -2-oxotyl] piperidine –4-yl] methyl] isoindrin-hydrochloride (Compound 1 in Table 1)

a) tert-Butyl 4-aminomethylpiperidine-carpoxylate hydrochloride’salt

4-Aminomethylpiperidin 5. 71g as a starting material

Tert-Butyl 4-aminomethylbiperidine-power reportage was synthesized according to the method described in Synthetic Commun., 22 (16), 2357-2360 (1992). This compound was dissolved in 80 ml of ethyl acetate, 4N ethyl monoacetate hydrochloride was added, and the mixture was stirred. Precipitated solid

Was collected to obtain 10.27 g (yield 82%) of the indicated compound. At melting point 236-240.

Ή-NMR (DMS0-d 6 ): 8.00 (3H, s), 3. 92 (2H, br d, J = 12.6), 2.68 H, m), 1.77- 1. 65 (3H, m), 1.39 (9H, s), 1.02 (2H, m) b) 2-Bromomethylbenzoic acid etyl ester

2-Methylbenzoic acid etyl ester (2.00 g, 11.9 mmol) is dissolved in carbon tetrachloride (60 ml), and N-promosucciimide (2.56 g, 14.4 mmo 1) and a catalytic amount of benzoyl peroxide are added to the solution. In addition, heat reflux. After 1 hour, the reaction mixture was cooled to room temperature, hexan (40 m was added, the insoluble material was filtered off, and the filtrate was distilled off under reduced pressure to obtain 3.16 g of the indicated compound as a yellow oil. It was used for the next reaction without purification as it was.

c) tert-Butyl 4- (1-oxoisoindrin-2 -ylmethyl) piperidine-1 -carpoxylate

Add 3.15 g of the compound obtained in Example lb and the compound (3.00 g, 12. Ommol) obtained in Example la to dimethylformamide (30πΠ), and stir at room temperature with trietylamine (3.5 ml, 25 mmol). ) Is added and stirred at the same temperature for 17 hours. Water is added to the reaction mixture, and the mixture is extracted with a mixed solvent of etyl hexane vinegar. The organic layer is washed with 10% aqueous quenic acid solution, water, sodium bicarbonate solution, and saturated brine, and dried with magnesium sulfate. The insoluble material was filtered, the filtrate was distilled off under reduced pressure, and the obtained oil was purified by silicon gel column chromatography (etyl-hexan acetate). I got it as a thing.

Ή-NMR (CDC1 3 ): 7.85 (1H, d, J = 7.5), 7.4-7.6 (3Η, m),

4.41 (2H, s), 4.0-4.2 (2H, m), 3.4-3.6 (2H, m), 2.6-2.8 (2H, m), 1.8-2.0 (1H, m), 1.5 -1.7 (4H, m), to 45 (9H, s)

d) 2- (Piperidine -4 -Ilmethyl) Isondrin -1 -On Hydrochloride

The compound (1.6 lg, 4.87 mmol) obtained in Example 1c is dissolved in methylene chloride (5 ml) and ethanol (lm mixed solvent, and at room temperature, 4 standard ethyl acetate solvent (5 ml, 20 mmol) is added. Stir at warm temperature for 1 hour and filter the precipitated solid. The obtained solid was washed with ethanol acetate and then dried under reduced pressure to give the indicated compound 7260 ^ (yield 56%) as a colorless solid. ..

Ή-NMR (DMS0-d 6 ): 8. 83 (1H, brs), 8. 53 (1H, brs), 7. 4-7. 7 (4 Η, m), 4. 50 (2H, s), 3. 44 (2H, d, J = 7.2), 3. 2-3. 3 (2H, i), 2. 7-2.9 (2H, m), 1. 9-2.1 (1H) , m), 1. 6-1. 8 (2H, m), 1. 3-1. 5 (2H, m)

e) 2- [Π_ [2- (4-Fluo-mouth phenyl) -2-oxotil] Piperidin –4-yl] Methyl] Isoindrin-卜 on

Add the compounds obtained in Example Id (518 mg, 1. 94 mmo and 2-cloucet -4, -fluoroacetophenone (358 mg, 2.07 mmol) to dimethylform amamide (12 ml) with stirring at room temperature. Add trietylamine (575 1, 4. 13 mmol). After stirring at the same temperature for 4 hours, add water to the reaction solution and extract with ethyl acetate. The organic layer is washed with water and saturated saline and sodium sulfate. Dry with thorium. Filter the insoluble material and concentrate the filtrate under reduced pressure to obtain 0.70 g of orange oil. Add hexane to the obtained oil to solidify. Filter this. By drying under reduced pressure, 551 mg (yield 77%) of the notation compound was obtained as a pale yellow solid.

! H-NMR (CDC1 3 ): 8.0-8 . 1 (2H, m), 7. 85 (1H, d = 7.2), 7.4-7. 55 (3 Η, m), 7.1 2 ( 2H, t), 4. 41 (2H, s), 3. 73 (2H, s), 3.51 (2H, d, J = 7.5), 2. 9-3. 0 (2H, m) , 2. 1-2. 2 (2H, m), 1. 4-19.9 (5H, m)

f) 2- [Π- [2- (4 -Fluolophenyl) -2 -Oxoetyl] Piperidin –4-yl] Methyl] Isoindoline-Piol hydrochloride

The compound (550 mg, 1.5 Ommo 1) obtained in Example le was used as an etano.

Dissolve in (2 ml) and add 4 specified ethyl hydrochloride solvent (2 ml, 8 imol) at room temperature and stir at the same temperature for 15 minutes. Ethyl acetate (10 ml) is added to the reaction solution, and the precipitated solid is filtered. The obtained solid is washed with ethyl acetate and then dried under reduced pressure to obtain 364 mg of white powder. This was recrystallized from ethanol monoacetate to give 246 mg (yield 41%) of the notation compound as a colorless solid. At melting point 182-188.

Ή-NMR (DMS0-d 6 ): 9.93 (1H, brs), 8.0-8. 2 (2H, m), 7.4-7.7 (6 Η, m), 4. 9-5.1 (2H, m), 4.53 (2H, s), 2.9-3.6 (6H, m), 1.6-2.2 (5H, m)


Example 12-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]piperidin-4-yl]methyl]isoindolin-1-one hydrochloride (Compound 1 in Table 1)a) tert-Butyl 4-aminomethylpiperidine-1-carboxylate hydrochloride

By using 4-aminomethylpiperidine 5.71 g as a starting material, tert-butyl 4-aminomethylpiperidine-1-carboxylate was prepared according to the method described in Synthetic Commun., 22(16), 2357–2360 (1992). The resulting compound was dissolved in 80 ml of ethyl acetate, and the solution was added with 4N hydrogen chloride-ethyl acetate and stirred. The precipitated solids were collected by filtration to obtain the title compound (10.27 g, yield: 82%).

Melting point: 236–240° C. 1H-NMR(DMSO-d6): 8.00(3H,s), 3.92(2H, br d, J=12.6), 2.68(4H, m), 1.77–1.65(3H, m), 1.39(9H, s), 1.02(2H, m)

b) 2-Bromomethylbenzoic acid ethyl ester

2-Methylbenzoic acid ethyl ester (2.00 g, 11.9 mmol) was dissolved in carbon tetrachloride (60 ml), and the solution was added with N-bromosuccinimide (2.56 g, 14.4 mmol) and a catalytic amount of benzoylperoxide and then heated under reflux. After one hour, the reaction mixture was cooled to room temperature and added with hexane (40 ml) to remove insoluble solids by filtration. The filtrate was evaporated under reduced pressure to obtain the title compound 3.16 g as yellow oil. the product was used in the next reaction without purification.

c) tert-Butyl 4-(1-oxoisoindolin-2-yl-methyl)piperidine-1-carboxylate

The compound obtained in Example 1b (3.15 g), and the compound obtained in Example 1a (3.00 g, 12.0 mmol) were added in dimethylformamide (30 ml). The mixture was added with triethylamine (3.5 ml, 25 mmol) with stirring at room temperature, and then stirring was continued for 17 hours at the same temperature. Water was added to the reaction mixture and extracted with a mixed solvent of ethyl acetate-hexane. The organic layer was washed with 10% aqueous citric acid solution, water, aqueous sodium bicarbonate solution, and then with saturated brine and the dried over magnesium sulfate. Insoluble solids were removed by filtration, and the filtrate was evaporated under reduced pressure. The resulting oil was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound as yellow oil (yield: 41%)

1H-NMR(CDCl3): 7.85(1H,d,J=7.5), 7.4–7.6(3H,m), 4.41(2H,s), 4.0–4.2(2H,m), 3.4–3.6(2H,m), 2.6–2.8(2H,m), 1.8–2.0(1H,m), 1.5–1.7(4H,m), 1.45(9H,s)

d) 2-(Piperidin-4-yl-methyl)isoindolin-1-one hydrochloride

The compound obtained in Example 1c (1.61 g, 4.87 mmol) was dissolved in a mixed solvent of methylene chloride (5 ml) and ethanol (1 ml) and the solution was added with 4N hydrochloric acid in ethyl acetate (5 ml, 20 mmol) at room temperature. The mixture was stirred at the same temperature for 1 hour, and the precipitated solids were collected by filtration. The resulting solids were washed with ethyl acetate and then dried under reduced pressure to obtain the title compound as colorless solid (726 mg, yield: 56%).

1H-NMR(DMSO-d6): 8.83(1H,brs), 8.53(1H,brs), 7.4–7.7(4H,m), 4.50(2H,s), 3.44(2H,d,J=7.2), 3.2–3.3(2H,m), 2.7–2.9(2H,m), 1.9–2.1(1H,m), 1.6–1.8(2H,m), 1.3–1.5(2H,m)

e) 2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]piperidin-4-yl]methyl]isoindolin-1-one

The compound obtained in Example 1d (518 mg, 1.94 mmol) and 2-chloro-4′-fluoroacetophenone (358 mg, 2.07 mmol) was added to dimethylformamide (12 ml), and the solution was added with triethylamine (575 μl, 4.13 mmol) with stirring at room temperature. Stirring was continued at the same temperature for 4 hours, and then the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and then dried over sodium sulfate. Insoluble solids were removed by filtration and the filtrate was evaporated under reduced pressure to obtain orange oil (0.70 g). The resulting oil was solidified by adding hexane, and the solids were collected by filtration and dried under reduced pressure to obtain the title compound as pale yellow solid (551 mg, yield: 77%).

1H-NMR(CDCl3): 8.0–8.1(2H,m), 7.85(1H,d=7.2), 7.4–7.55(3H,m), 7.12(2H,t), 4.41(2H,s), 3.73(2H,s), 3.51(2H,d,J=7.5), 2.9–3.0(2H,m), 2.1–2.2(2H,m), 1.4–1.9(5H,m)

f) 2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]piperidin-4-yl]methyl]isoindolin-1-one hydrochloride

The compound obtained in Example 1e (550 mg, 1.50 mmol) was dissolved in ethanol (2 ml), and the solution was added with 4N hydrochloric acid in ethyl acetate (2 ml, 8 mmol) at room temperature, and stirring was continued at the same temperature for 15 minutes. The reaction mixture was added with ethyl acetate (10 ml) and the precipitated solids were collected by filtration. The resulting solids were washed with ethyl acetate and then dried under reduced pressure to obtain white powder (364 mg). The product was recrystallized from ethanol-ethyl acetate to obtain the title compound as colorless solid (246 mg, yield: 41%)

Melting point: 182–188° C. 1H-NMR(DMSO-d6): 9.93(1H,brs), 8.0–8.2(2H,m), 7.4–7.7(6H,m), 4.9–5.1(2H,m), 4.53(2H,s), 2.9–3.6(6H,m), 1.6–2.2(5H, m)




Novel crystalline form of roluperidone HCL (designated as form 4) as 5-HT 2a receptor antagonist useful for treating schizophrenia.

Roluperidone has the chemical name 2-({ l-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl}methyl)-l-isoindolinone. Roluperidone has the following chemical structure:

[0003] Roluperidone is reported to be a drug candidate with equipotent affinities for 5-hydroxytryptamine-2A (5-HT2A) and sigma2 and, at lower affinity levels, al -adrenergic receptors. A pivotal Phase 3 clinical trial is ongoing with roluperidone as a monotherapy for negative symptoms in patients diagnosed with schizophrenia.

[0004] Roluperidone is known from U.S. Patent No. 7,166,617.

[0005] Solid state form of 2-((l-(2-(4-Fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-l-o-ne monohydrochloride dihydrate is known from U.S. Patent No.9,458,130.


[00113] Roluperidone can be prepared according to the procedure described in U.S. Patent No. 7,166,617.

Example 1: Preparation of Roluperidone HC1

[00114] 2.02 grams of Roluperidone was dissolved in acetone (80 mL). 2.76 mL of HC1 (2M) was added to the solution. The obtained suspension was stirred for 21 hours at 10°C and then filtered over black ribbon filter paper under vacuum. Obtained solid was analyzed by PXRD.


  1. ^ Mestre TA, Zurowski M, Fox SH (April 2013). “5-Hydroxytryptamine 2A receptor antagonists as potential treatment for psychiatric disorders”. Expert Opinion on Investigational Drugs22 (4): 411–21. doi:10.1517/13543784.2013.769957PMID 23409724.
  2. Jump up to:a b Ebdrup BH, Rasmussen H, Arnt J, Glenthøj B (September 2011). “Serotonin 2A receptor antagonists for treatment of schizophrenia”. Expert Opinion on Investigational Drugs20 (9): 1211–23. doi:10.1517/13543784.2011.601738PMID 21740279.
  3. ^ Köster LS, Carbon M, Correll CU (December 2014). “Emerging drugs for schizophrenia: an update”. Expert Opinion on Emerging Drugs19 (4): 511–31. doi:10.1517/14728214.2014.958148PMID 25234340.
  4. ^ “Drug Development in Schizophrenia: Summary and Table”. Pharmaceutical Medicine28 (5): 265–271. 2014. doi:10.1007/s40290-014-0070-6ISSN 1178-2595.
  5. ^ “Roluperidone – Minerva Neurosciences”Adis Insight. Springer Nature Switzerland AG.
Clinical data
Other namesMIN-101; CYR-101; MT-210
Routes of
By mouth
IUPAC name[show]
CAS Number359625-79-9
CompTox Dashboard (EPA)DTXSID10189512 
Chemical and physical data
Molar mass385.435 g·mol−1
3D model (JSmol)Interactive image

/////////////////Roluperidone, PHASE 3, ролуперидон , رولوبيريدون , 罗鲁哌酮 , CYR 101, UNII-4P31I0M3BF , MIN 101,




EMA……Ogluo (glucagon), a hybrid medicine for the treatment of severe hypoglycaemia in diabetes mellitus. Hybrid applications rely in part on the results of pre-clinical tests and clinical trials of an already authorised reference product and in part on new data.

On 10 December 2020, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Ogluo, intended for the treatment of severe hypoglycaemia in diabetes mellitus. The applicant for this medicinal product is Xeris Pharmaceuticals Ireland Limited.

Ogluo will be available as 0.5 and 1 mg solution for injection. The active substance of Ogluo is glucagon, a pancreatic hormone (ATC code: H04AA01); glucagon increases blood glucose concentration by stimulating glycogen breakdown and release of glucose from the liver.

The benefits with Ogluo are its ability to restore blood glucose levels in hypoglycaemic subjects. The most common side effects are nausea and vomiting.

Ogluo is a hybrid medicine1 of GlucaGen/GlucaGen Hypokit; GlucaGen has been authorised in the EU since October 1962. Ogluo contains the same active substance as GlucaGen but is available as a ready-to-use formulation intended for subcutaneous injection.

The full indication is:

Ogluo is indicated for the treatment of severe hypoglycaemia in adults, adolescents, and children aged 2 years and over with diabetes mellitus.

Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.

1 Hybrid applications rely in part on the results of pre-clinical tests and clinical trials for a reference product and in part on new data.

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It works to raise the concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body.[3] It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose.[4] It is produced from proglucagon, encoded by the GCG gene.

The pancreas releases glucagon when the amount of glucose in the bloodstream is too low. Glucagon causes the liver to engage in glycogenolysis: converting stored glycogen into glucose, which is released into the bloodstream.[5] High blood-glucose levels, on the other hand, stimulate the release of insulin. Insulin allows glucose to be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels stable. Glucagon increases energy expenditure and is elevated under conditions of stress.[6] Glucagon belongs to the secretin family of hormones.


Glucagon generally elevates the concentration of glucose in the blood by promoting gluconeogenesis and glycogenolysis.[7] Glucagon also decreases fatty acid synthesis in adipose tissue and the liver, as well as promoting lipolysis in these tissues, which causes them to release fatty acids into circulation where they can be catabolised to generate energy in tissues such as skeletal muscle when required.[8]

Glucose is stored in the liver in the form of the polysaccharide glycogen, which is a glucan (a polymer made up of glucose molecules). Liver cells (hepatocytes) have glucagon receptors. When glucagon binds to the glucagon receptors, the liver cells convert the glycogen into individual glucose molecules and release them into the bloodstream, in a process known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver and kidney to synthesize additional glucose by gluconeogenesis. Glucagon turns off glycolysis in the liver, causing glycolytic intermediates to be shuttled to gluconeogenesis.

Glucagon also regulates the rate of glucose production through lipolysis. Glucagon induces lipolysis in humans under conditions of insulin suppression (such as diabetes mellitus type 1).[9]

Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined. In invertebrate animals, eyestalk removal has been reported to affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia.[10]

Mechanism of action

 Metabolic regulation of glycogen by glucagon.

Glucagon binds to the glucagon receptor, a G protein-coupled receptor, located in the plasma membrane of the cell. The conformation change in the receptor activates G proteins, a heterotrimeric protein with α, β, and γ subunits. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule that was bound to the α subunit with a GTP molecule. This substitution results in the releasing of the α subunit from the β and γ subunits. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.

Adenylate cyclase manufactures cyclic adenosine monophosphate (cyclic AMP or cAMP), which activates protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase b (PYG b), converting it into the active form called phosphorylase a (PYG a). Phosphorylase a is the enzyme responsible for the release of glucose 1-phosphate from glycogen polymers. An example of the pathway would be when glucagon binds to a transmembrane protein. The transmembrane proteins interacts with Gɑβ𝛾. Gɑ separates from Gβ𝛾 and interacts with the transmembrane protein adenylyl cyclase. Adenylyl cyclase catalyzes the conversion of ATP to cAMP. cAMP binds to protein kinase A, and the complex phosphorylates phosphorylase kinase.[11] Phosphorylated phosphorylase kinase phosphorylates phosphorylase. Phosphorylated phosphorylase clips glucose units from glycogen as glucose 1-phosphate. Additionally, the coordinated control of glycolysis and gluconeogenesis in the liver is adjusted by the phosphorylation state of the enzymes that catalyze the formation of a potent activator of glycolysis called fructose 2,6-bisphosphate.[12] The enzyme protein kinase A (PKA) that was stimulated by the cascade initiated by glucagon will also phosphorylate a single serine residue of the bifunctional polypeptide chain containing both the enzymes fructose 2,6-bisphosphatase and phosphofructokinase-2. This covalent phosphorylation initiated by glucagon activates the former and inhibits the latter. This regulates the reaction catalyzing fructose 2,6-bisphosphate (a potent activator of phosphofructokinase-1, the enzyme that is the primary regulatory step of glycolysis)[13] by slowing the rate of its formation, thereby inhibiting the flux of the glycolysis pathway and allowing gluconeogenesis to predominate. This process is reversible in the absence of glucagon (and thus, the presence of insulin).

Glucagon stimulation of PKA also inactivates the glycolytic enzyme pyruvate kinase in hepatocytes.[14]



 A microscopic image stained for glucagon

The hormone is synthesized and secreted from alpha cells (α-cells) of the islets of Langerhans, which are located in the endocrine portion of the pancreas. Production, which is otherwise freerunning, is suppressed/regulated by amylin, a peptide hormone co-secreted with insulin from the pancreatic β cells.[15] As plasma glucose levels recede, the subsequent reduction in amylin secretion alleviates its suppression of the α cells, allowing for glucagon secretion.

In rodents, the alpha cells are located in the outer rim of the islet. Human islet structure is much less segregated, and alpha cells are distributed throughout the islet in close proximity to beta cells. Glucagon is also produced by alpha cells in the stomach.[16]

Recent research has demonstrated that glucagon production may also take place outside the pancreas, with the gut being the most likely site of extrapancreatic glucagon synthesis.[17]


Secretion of glucagon is stimulated by:

Secretion of glucagon is inhibited by:


Glucagon is a 29-amino acid polypeptide. Its primary structure in humans is: NH2HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGlnTrpLeuMetAsnThrCOOH.

The polypeptide has a molecular mass of 3485 daltons.[25] Glucagon is a peptide (nonsteroid) hormone.

Glucagon is generated from the cleavage of proglucagon by proprotein convertase 2 in pancreatic islet α cells. In intestinal L cellsproglucagon is cleaved to the alternate products glicentin, GLP-1 (an incretin), IP-2, and GLP-2 (promotes intestinal growth).[26]


Abnormally elevated levels of glucagon may be caused by pancreatic tumors, such as glucagonoma, symptoms of which include necrolytic migratory erythema,[27] reduced amino acids, and hyperglycemia. It may occur alone or in the context of multiple endocrine neoplasia type 1[28]

Elevated glucagon is the main contributor to hyperglycemic ketoacidosis in undiagnosed or poorly treated type 1 diabetes. As the beta cells cease to function, insulin and pancreatic GABA are no longer present to suppress the freerunning output of glucagon. As a result, glucagon is released from the alpha cells at a maximum, causing rapid breakdown of glycogen to glucose and fast ketogenesis.[29] It was found that a subset of adults with type 1 diabetes took 4 times longer on average to approach ketoacidosis when given somatostatin (inhibits glucagon production) with no insulin. Inhibiting glucagon has been a popular idea of diabetes treatment, however some have warned that doing so will give rise to brittle diabetes in patients with adequately stable blood glucose.[citation needed]

The absence of alpha cells (and hence glucagon) is thought to be one of the main influences in the extreme volatility of blood glucose in the setting of a total pancreatectomy.


In the 1920s, Kimball and Murlin studied pancreatic extracts, and found an additional substance with hyperglycemic properties. They described glucagon in 1923.[30] The amino acid sequence of glucagon was described in the late 1950s.[31] A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific radioimmunoassay was developed.[citation needed]


Kimball and Murlin coined the term glucagon in 1923 when they initially named the substance the glucose agonist.[32]


  1. Jump up to:a b c GRCh38: Ensembl release 89: ENSG00000115263 – Ensembl, May 2017
  2. ^ “Human PubMed Reference:”National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ Voet D, Voet JG (2011). Biochemistry (4th ed.). New York: Wiley.
  4. ^ Reece J, Campbell N (2002). Biology. San Francisco: Benjamin Cummings. ISBN 978-0-8053-6624-2.
  5. ^ Orsay J (2014). Biology 1: Molecules. Examkrackers Inc. p. 77. ISBN 978-1-893858-70-1.
  6. ^ Jones BJ, Tan T, Bloom SR (March 2012). “Minireview: Glucagon in stress and energy homeostasis”Endocrinology153 (3): 1049–54. doi:10.1210/en.2011-1979PMC 3281544PMID 22294753.
  7. ^ Voet D, Voet JG (2011). Biochemistry (4th ed.). New York: Wiley.
  8. ^ HABEGGER, K. M., HEPPNER, K. M., GEARY, N., BARTNESS, T. J., DIMARCHI, R. & TSCHÖP, M. H. (2010). “The metabolic actions of glucagon revisited”Nature Reviews. Endocrinology6 (12): 689–697. doi:10.1038/nrendo.2010.187PMC 3563428PMID 20957001.
  9. ^ Liljenquist JE, Bomboy JD, Lewis SB, Sinclair-Smith BC, Felts PW, Lacy WW, Crofford OB, Liddle GW (January 1974). “Effects of glucagon on lipolysis and ketogenesis in normal and diabetic men”The Journal of Clinical Investigation53 (1): 190–7. doi:10.1172/JCI107537PMC 301453PMID 4808635.
  10. ^ Leinen RL, Giannini AJ (1983). “Effect of eyestalk removal on glucagon induced hyperglycemia in crayfish”. Society for Neuroscience Abstracts9: 604.
  11. ^ Yu Q, Shuai H, Ahooghalandari P, Gylfe E, Tengholm A (July 2019). “Glucose controls glucagon secretion by directly modulating cAMP in alpha cells”Diabetologia62 (7): 1212–1224. doi:10.1007/s00125-019-4857-6PMC 6560012PMID 30953108.
  12. ^ Hue L, Rider MH (July 1987). “Role of fructose 2,6-bisphosphate in the control of glycolysis in mammalian tissues”The Biochemical Journal245 (2): 313–24. doi:10.1042/bj2450313PMC 1148124PMID 2822019.
  13. ^ Claus TH, El-Maghrabi MR, Regen DM, Stewart HB, McGrane M, Kountz PD, Nyfeler F, Pilkis J, Pilkis SJ (1984). “The role of fructose 2,6-bisphosphate in the regulation of carbohydrate metabolism”. Current Topics in Cellular Regulation23: 57–86. doi:10.1016/b978-0-12-152823-2.50006-4ISBN 9780121528232PMID 6327193.
  14. ^ Feliú JE, Hue L, Hers HG (August 1976). “Hormonal control of pyruvate kinase activity and of gluconeogenesis in isolated hepatocytes”Proceedings of the National Academy of Sciences of the United States of America73 (8): 2762–6. Bibcode:1976PNAS…73.2762Fdoi:10.1073/pnas.73.8.2762PMC 430732PMID 183209.
  15. ^ Zhang, Xiao-Xi (2016). “Neuroendocrine Hormone Amylin in Diabetes”World J Diabetes7 (9): 189–197. doi:10.4239/wjd.v7.i9.189PMC 4856891PMID 27162583.
  16. ^ Unger RH, Cherrington AD (January 2012). “Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover”The Journal of Clinical Investigation122(1): 4–12. doi:10.1172/JCI60016PMC 3248306PMID 22214853.
  17. ^ Holst JJ, Holland W, Gromada J, Lee Y, Unger RH, Yan H, Sloop KW, Kieffer TJ, Damond N, Herrera PL (April 2017). “Insulin and Glucagon: Partners for Life”Endocrinology158(4): 696–701. doi:10.1210/en.2016-1748PMC 6061217PMID 28323959.
  18. ^ Layden BT, Durai V, Lowe WL (2010). “G-Protein-Coupled Receptors, Pancreatic Islets, and Diabetes”Nature Education3 (9): 13.
  19. ^ Skoglund G, Lundquist I, Ahrén B (November 1987). “Alpha 1- and alpha 2-adrenoceptor activation increases plasma glucagon levels in the mouse”. European Journal of Pharmacology143 (1): 83–8. doi:10.1016/0014-2999(87)90737-0PMID 2891547.
  20. ^ Honey RN, Weir GC (October 1980). “Acetylcholine stimulates insulin, glucagon, and somatostatin release in the perfused chicken pancreas”. Endocrinology107 (4): 1065–8. doi:10.1210/endo-107-4-1065PMID 6105951.
  21. ^ Zhang, Xiao-Xi (2016). “Neuroendocrine Hormone Amylin in Diabetes”World J Diabetes7 (9): 189–197. doi:10.4239/wjd.v7.i9.189PMC 4856891PMID 27162583.
  22. ^ Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, Liu S, Wendt A, Deng S, Ebina Y, Wheeler MB, Braun M, Wang Q (January 2006). “Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system”. Cell Metabolism3 (1): 47–58. doi:10.1016/j.cmet.2005.11.015PMID 16399504.
  23. ^ Krätzner R, Fröhlich F, Lepler K, Schröder M, Röher K, Dickel C, Tzvetkov MV, Quentin T, Oetjen E, Knepel W (February 2008). “A peroxisome proliferator-activated receptor gamma-retinoid X receptor heterodimer physically interacts with the transcriptional activator PAX6 to inhibit glucagon gene transcription”. Molecular Pharmacology73 (2): 509–17. doi:10.1124/mol.107.035568PMID 17962386S2CID 10108970.
  24. ^ Johnson LR (2003). Essential Medical Physiology. Academic Press. pp. 643–. ISBN 978-0-12-387584-6.
  25. ^ Unger RH, Orci L (June 1981). “Glucagon and the A cell: physiology and pathophysiology (first two parts)”. The New England Journal of Medicine304 (25): 1518–24. doi:10.1056/NEJM198106183042504PMID 7015132.
  26. ^ Orskov C, Holst JJ, Poulsen SS, Kirkegaard P (November 1987). “Pancreatic and intestinal processing of proglucagon in man”. Diabetologia30 (11): 874–81. doi:10.1007/BF00274797 (inactive 2020-10-11). PMID 3446554.
  27. ^ John AM, Schwartz RA (December 2016). “Glucagonoma syndrome: a review and update on treatment”. Journal of the European Academy of Dermatology and Venereology30 (12): 2016–2022. doi:10.1111/jdv.13752PMID 27422767S2CID 1228654.
  28. ^ Oberg K (December 2010). “Pancreatic endocrine tumors”. Seminars in Oncology37 (6): 594–618. doi:10.1053/j.seminoncol.2010.10.014PMID 21167379.
  29. ^ Fasanmade OA, Odeniyi IA, Ogbera AO (June 2008). “Diabetic ketoacidosis: diagnosis and management”. African Journal of Medicine and Medical Sciences37 (2): 99–105. PMID 18939392.
  30. ^ Kimball C, Murlin J (1923). “Aqueous extracts of pancreas III. Some precipitation reactions of insulin”J. Biol. Chem58 (1): 337–348.
  31. ^ Bromer W, Winn L, Behrens O (1957). “The amino acid sequence of glucagon V. Location of amide groups, acid degradation studies and summary of sequential evidence”. J. Am. Chem. Soc79 (11): 2807–2810. doi:10.1021/ja01568a038.
  32. ^ “History of glucagon – Metabolism, insulin and other hormones – Diapedia, The Living Textbook of Diabetes” Archived from the original on 2017-03-27. Retrieved 2017-03-26.

External links

  • PDBe-KB provides an overview of all the structure information available in the PDB for Human Glucagon
Available structuresPDBHuman UniProt search: PDBe RCSBshowList of PDB id codes
AliasesGCG, GLP1, glucagon, GRPP, GLP-1, GLP2
External IDsOMIM: 138030 HomoloGene: 136497 GeneCards: GCG
hideGene location (Human)Chr.Chromosome 2 (human)[1]Band2q24.2Start162,142,882 bp[1]End162,152,404 bp[1]
hideRNA expression patternMore reference expression data
showGene ontology
Entrez 2641 n/a
Ensembl ENSG00000115263 n/a
UniProt P01275 n/a
RefSeq (mRNA) NM_002054 n/a
RefSeq (protein) NP_002045 n/a
Location (UCSC)Chr 2: 162.14 – 162.15 Mbn/a
PubMed search[2]n/a
View/Edit Human


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