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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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Efonidipine, エホニジピン

Efonidipine structure.svg

ChemSpider 2D Image | Efonidipine | C34H38N3O7P



  • Molecular FormulaC34H38N3O7P
  • Average mass631.655 Da
  • エホニジピン
  • CAS 111011-63-3; FREE FORM
Image result for Efonidipine
Molecular Formula: C36H45ClN3O8P
Molecular Weight: 714.193 g/mol

LD50:> 5 g/kg (R, p.o.)

  • Synonyms:NZ-105
  • ATC:C08CA
Efonidipine hydrochloride monoethanolate  111011-76-8 [RN],エホニジピン塩酸塩エタノール付加物
CAS 111011-63-3; FREE FORM
2-(N-Benzylanilino)ethyl (±)-1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-5-phosphononicotinate Cyclic 2,2-Dimethyltrimethylene Ester
2-[Benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate
2-[Benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate
3-Pyridinecarboxylic acid, 5-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 2-[phenyl(phenylmethyl)amino]ethyl ester
5-(5,5-Dimethyl-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylic Acid 2-[Phenyl(phenylmethyl)amino]ethyl Ester P-Oxide
Landel [Trade name]
2-(N-benzylanilino)ethyl 5-(5,5-dimethyl-2-oxo-1,3,2$l^{5}-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate

Efonidipine Hydrochloride Ethanolate Bulk & Tablets 10 mg/20mg/40mg, 

Indicated for the management of
• Hypertension
• Renal parenchymal hypertension
• Angina
CDSCO approved INDIA 28.08.2017 
Launched – 1994, Shionogi Zeria
Efonidipine (INN) is a dihydropyridine calcium channel blocker marketed by Shionogi & Co. of Japan. It was launched in 1995, under the brand name Landel. The drug blocks both T-type and L-type calcium channels [A7844, A32001]. It has also been studied in atherosclerosis and acute renal failure [A32001]. This drug is also known as NZ-105, and several studies have been done on its pharmacokinetics in animals [L1456].

Efonidipine (INN) is a dihydropyridine calcium channel blocker marketed by Shionogi & Co. of Japan. It was launched in 1995, under the brand name Landel (ランデル). The drug blocks both T-type and L-type calcium channels.[1] Drug Controller General of India (DCGI) granted approval to M/s. Zuventus pharma Ltd for marketing efonidipine under brand name Efnocar in India .[2]

Structure Activity Relationship

Efonidipine is a dual Calcium Channel Blocker (L & T-type). It has a unique chemical structure. The phosphonate moiety (Figure 1) at the C5 position of the dihydropyridine ring is considered to be important for the characteristic pharmacological profile of the drug. (figure-1)

Figure-1:Efonidipine: Chemical Structure

Mechanism of action

Efonidipine, a new generation dihydropyridine (DHP) calcium channel blocker, inhibits both L-type and T-type calcium channels.[1]


  • Efonidipine exhibits antihypertensive effect through vasodilatation by blocking L-type and T-type calcium channels.[1]
  • Efonidipine has a negative chronotropic effect. Working on sino atrial node cells by inhibiting T-type calcium channel activation, Efonidipine prolongs the late phase-4 depolarization of the sino atrial node action potential and suppresses an elevated HR. The negative chronotropic effect of Efonidipine decreases heart rate, myocardial oxygen demand and increases coronary blood flow.[3]
  • Efonidipine increases coronary blood flow by blocking L & T-type calcium channels and attenuates myocardial ischaemia.[4]
  • By reducing synthesis and secretion of aldosterone, Efonidipine prevents hypertrophy and remodeling of cardiac myocytes.[5]
  • Efonidipine increases glomerular filtration rate without increasing intra-glomerular pressure and filtration fraction. This prevents hypertension induced renal damage.[6]
  • Efonidipine prevents Rho-kinase and NFB induced renal parenchymal fibrosis and provides long term renal protection.[7][8]
  • Efonidipine suppresses renin secretion from the juxta glomerular apparatus in the kidneys.[9]
  • Efonidipine enhances sodium excretion from the kidneys by suppressing aldosterone synthesis and secretion from the adrenal glands. Aldosterone induced renal parenchymal fibrosis is suppressed by Efonidipine.[5]
  • Efonidipine prevents NFB induced hypertrophy and inflammation in the renal vasculature and protects the kidneys.[7]
  • Efonidipine protects against endothelial dysfunction due to its anti-oxidant activity and by restoring NO bioavailability.[10][11]
  • Efonidipine has anti-atherogenic activity and protects the blood vessels from atherosclerosis.[12]
  • Efonidipine lowers blood pressure in cerebral resistance vessels and prevents hypertension induced brain damage.[4]



Peak plasma concentration is achieved in about 1.5 to 3.67 hours after administration. Half life is approximately 4 hours. The pharmacokinetic parameters of Efonidipine are depicted in Table-1.

Table 1: PK Parameters in Adult Healthy Male Subjects

Variable Efonidipine
Mean Range
Cmax(ng/ml) 36.25 9.66-66.91
Tmax (hour) 2.59 1.50-3.67
T1/2 (hour) 4.18 2.15-6.85

*Data on file

Long Duration of Action

Efonidipine has a slow onset and a long duration of action. This unique characteristic of Efonidipine is because of the following reasons:[13]

  1. High lipophilicity of Efonidipine allows it to enter the phospholipid rich cell membrane and access the dihydropyridine binding site of the Ca2+ channels.
  2. Tight binding to the dihydropyridine receptors.
  3. The dissociation constant of Efonidipine from dihydropyridine receptors is very low (0.0042/min/nM), signifying very slow dissociation from the receptors. This explains the long duration of action of Efonidipine.


Efonidipine is primarily metabolized in the liver. The important metabolites are N-dephenylated Efonidipine (DPH), deaminated Efonidipine (AL) and N-debenzylated Efonidipine (DBZ). DBZ and DPH exhibit activity as calcium antagonists. The vasodilating properties of DBZ and DPH were about two-thirds and one-third respectively than that of the parent compound. Results suggest that the majority of the pharmacological effect after oral dosing of Efonidipine hydrochloride in man is due to unchanged compound and its metabolites make a small contribution to the pharmacological effect.[14]


Biliary route is the main pathway of excretion. No significant amount of unchanged drug was excreted in urine. In the urine collected for 24 h after an oral dosing, 1.1 % of the dose was excreted as deaminated Efonidipine, and 0.5% as a pyridine analogue of deaminated Efonidipine.


  • Essential hypertension and renal parenchymal hypertension
  • Angina

Dosage and Administration

  • Essential hypertension and renal parenchymal hypertension: 20-40 mg orally once daily. A dose of up to 80mg/day is seen to be safe and effective in clinical trials.[15][16]
  • Angina: 40 mg/day.


  • Contraindicated in patients hypersensitive to Efonidipine or any of the excipients
  •  It is also contraindicated in pregnancy and lactation.


  •  Should be administered with caution in patients with hepatic impairment
  • Dose adjustment may be required in elderly as hypotension can occur
  •  Efonidipine may worsen clinical condition in patients with sinus bradycardia, sinus arrest or sinus node dysfunction
  • As dizziness can occur due to hypotensive action, one should be careful while operating machines, with aerial work platforms and driving of a motor vehicle
  • Drug should not be stopped abruptly. Discontinuation should be gradual and under supervision of a qualified physician

Drug Interactions

  • Other anti-hypertensive agents: Efonidipine enhances the antihypertensive action additively and may produce hypotension and shock. Blood pressure should be monitored regularly to adjust dose of concomitant drugs.
  •  Cimetidine: Cimetidine inhibits CYP450 enzymes involved in metabolism of CCBs. Blood concentration of calcium channel antagonists increase leading to higher incidence of side effects (hot flushes).
  • Grape fruit juice: Grapefruit juice suppresses enzymes metabolizing calcium channel antagonists (cytochrome P450) and reduces the clearance. Thus, there is a possibility that blood concentration of the drug may increase and the anti-hypertensive effect is enhanced.
  • Tacrolimus: Efonidipine inhibits metabolic enzymes involved in Tacrolimus metabolism and reduces its clearance. So, increase in blood concentration of Tacrolimus can occur.

Adverse Drug Reactions

The common side effects are hot flushes, facial flushing and headache. In addition, elevation in serum total cholesterol, ALT (SGPT), AST (SGOT) and BUN may occur. Frequent urination, pedal edema, increased triglycerides occurs in less than 0.1%.[17]

Lesser incidence of pedal edema (< 0.1%)

One common adverse effect of the L-type Ca2+ channel blockers like Amlodipine is vasodilatory Pedal edema. Combined L-/T-type Ca2+ channel blockers, such as Efonidipine, display antihypertensive efficacy similar to their predecessors (Amlodipine) with much less propensity of pedal edema formation. Efonidipine equalizes the hydrostatic pressure across the capillary bed through equal arteriolar and venular dilatation, thus reducing vasodilatory edema. These incremental microcirculatory benefits of efonidipine over the conventional L-type Ca2+ channel blockers (Amlodipine) are likely attributed to their additional T-type Ca2+ channel blocking properties and the increased presence of T-type Ca2+channels in the microvasculature (e.g. arterioles, capillaries, venules etc).[18]

Among the CCBs, Efonidipine (<0.1%)[17] has lowest incidence of pedal edema compared to amlodipine ( 5-16%)[19], cilnidipine (5%)[20], benidipine (5%)[21] and azelnidipine (15.5%).[22]

Use in Special Population

Administration to Elderly

The drug should be started at low dose (20 mg/day) in elderly. Patient should be carefully observed for development of hypo-tension. Dose may be halved if there is intolerance to the 20 mg/day dosage regimen.

Pregnancy and Lactation

The drug should not be administered to pregnant women and women suspected of being pregnant. Administration to lactating women should be avoided unless benefit significantly surpasses the risk to the child. Mothers on Efonidipine treatment should avoid breast feeding.

Pediatric Use

Safety of Efonidipine in low birth weight infants, newborns, infants and children has not been established.

Efonidipine-The Best in Class

Efonidipine is unique among clinically available CCBs. Its antihypertensive efficacy is superior or at par with other CCBs. But, in terms of pleiotropic effects leading to enhanced cerebral, cardiac and renal protection, Efonidipine scores over the other CCBs.

Advantages over Amlodipine

1.      Better renoprotection by:

  • Dual channel blockade [1]
  • Prevention of Rho-kinase and NFkB induced tubulointerstitial fibrosis[23][24]
  • Reduction of synthesis and secretion of aldosterone from the adrenal cortex[25]

2.       Preferred in  angina  with hypertension due to negative chronotropic action[26]

3.       Better control of reflex tachycardia[3]

4.       Reduces cardiac remodelling, arterial stiffness and prevents atherogenesis[27]

5.       More useful in patients with diabetes & nephropathy[28]

6.       Better protection  against cardiac hypertrophy by significant reduction in LVMI[29]

7.       Less adverse effects compared to Amlodipine[30]

8.       Reduces endothelial dysfunction and oxidative stress(anti-oxidant property)[10]

Advantages over Cilnidipine

1.       Strong negative chronotropic effect (less tachycardia) compared to Cilnidipine[3]

2.       Significant improvement in exercise tolerance.[31]Better choice in hypertensive patients with angina.

3.       Better BP control by marked urinary Na+ excretion[32]

4.       Better renoprotection by:

  • a.      Suppression of plasma renin release[33]
  • b.     Prevention of Rho-kinase and NFkB induced tubulointerstitial fibrosis[34][35]
  • c.      Reduction of synthesis and secretion of aldosterone from the adrenal cortex[5]

5.       Better choice in diabetic hypertensives[36]

6.       Prevents cardiac remodelling by suppression of aldosterone secretion[5]

7.       Superior anti-oxidant activity[10]

8.       Less adverse effects compared to Cilnidipine[30]

Advantages over Benidipine

L & T-type CCBs have invoked a lot of interest in the management of hypertension because of their unique pharmacological profile. Several novel agents have been developed including Azelnidipine, Barnidipine, Benidipine, Efonidipine, Manidipine and Nilvadipine. Among all the agents, Efonidipine has emerged as the best among its peers. The advantages of Efonidipine over Benidipine are summarized below.

1. More selective blockade of T-type calcium channels [37][38]

2. More balanced renal arteriolar dilatation than benidipine[37][38]

3. Superior anti-proteinuric effect [15]

4. Greater reduction of serum aldosterone [39]

5. Renoprotection by reducing plasma renin unlike Benidipine [39]

6. Greater negative chronotropic effect

7. Efonidipine has anti-platelet activity[12]

8. Efonidipine reduces Insulin Resistance [40]

9. Significantly lower incidence of pedal edema & constipation compared to Benidipine

A new synthesis of efonidipine has been described: The cyclization of 2,2-dimethylbutane-1,4-diol (I) with triethyl phosphite (II) by heating at 100 C gives 2-methoxy-5,5-dimethyl-1,3,2-dioxaphosphorinan (III), which, by treatment with iodoacetone (IV) in refluxing ether, yields 2-acetonyl-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one (V). The condensation of (V) with 3-nitrobenzaldehyde (VI) by means of piperidine in acetic acid affords 3-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-buten-2-one (VII), which is finally cyclized with 3-amino-2-propenoic acid 2-(N-benzyl-N-phenylamino)ethyl ester (VIII) in refluxing toluene.ReferencesChem Pharm Bull 1992,40(9),2362

A new synthesis for (4S)-efonidipine has been described: The reaction of 5,5-dimethyl-2-(2-oxopropyl)-1,3,2-dioxaphosphorinan-2-one (I) with dimorpholino(3-nitrophenyl)methane (II) by means of trifluoroacetic acid in hot toluene gives 5,5-dimethyl-2-[1-acetyl-2-(3-nitrophenyl)vinyl]-1,3,2-dioxaphosphorina n-2-one (III), which is cyclized with 3-aminocrotonic acid 2(S)-methoxy-2-phenylethyl ester (IV) in refluxing toluene; the recrystallization of the resulting product affords 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4(S)-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 2(S)-methoxy-2-phenylethyl ester (V). The protection of the NH group of (V) with chloromethyl methyl ether and NaH in THF yields the N-methoxymethyl derivative (VI), which is transesterified with 2-(N-benzyl-N-methylamino)ethanol (VII) and NaH in DMSO, giving the protected final product (VIII). Finally, this compound is deprotected with HCl in ethanol.

An enantioselective synthesis of efonidipine has been described: The enantioselective hydrolysis of 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-n itrophenyl)-1,4-dihydropyridine-3-carboxylic acid propionyloxymethyl ester (I) with lipase AH in 2,5-dimethyltetrahydrofuran saturated with water gives the corresponding free acid of the (S)-isomer (III), while the propionyloxymethyl ester of the (R)-isomer (II) remains undisturbed. After chromatographic separation, the (R)-ester (II) is hydrolyzed with NaOH in methanol to the (R)-acid (IV). Finally, both enantiomerically pure acids (III) and (IV) are separately esterified with 2-(N-benzyl-N-phenylamino)ethanol in the usual way



Synthesis of 1,4-dihydropyridine-5-phosphonates and their calcium antagonistic and antihypertensive activities: Novel calcium-antagonist 2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate hydrochloride ethanol (NZ-105) and its crystal structure
Chem Pharm Bull 1992, 40(9): 2362


IN 201501586

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  37. Jump up to:a b Hayashi K, Wakino S, Sugano N, Ozawa Y, Homma K, Saruta T. Ca2+ Channel Subtypes and Pharmacology in the Kidney. Circ Res. 2007;100:342-353.
  38. Jump up to:a b  Hayashi K, Ozawa Y, Fujiwara K, Wakino S, Kumagai H, Saruta T. Role of actions of calcium antagonists on efferent arterioles with special references to glomerular hypertension. Am J Nephrol. 2003 Jul-Aug;23(4):229-44.
  39. Jump up to:a b Tani S, Takahashi A, Nagao K, Hirayama A. Effects of the T/L-type calcium channel blocker benidipine on albuminuria and plasma aldosterone concentration. A pilot study involving switching from L-type calcium channel blockers to benidipine. Int Heart J. 2014;55(6):519-25
  40. Jump up^  Li M.  Role of T-Type Ca2+ Channels in Basal Insulin Release. T-type Calcium Channels in Basic and Clinical Science. Springer Vienna. 2015; 137-150. 
Efonidipine structure.svg
Clinical data
Trade names Landel (ランデル)
AHFS/ International Drug Names
Routes of
ATC code
  • none
Legal status
Legal status
  • In general: ℞ (Prescription only)
CAS Number
PubChem CID
Chemical and physical data
Formula C34H38N3O7P
Molar mass 631.65 g/mol
3D model (JSmol)
Title: Efonidipine
CAS Registry Number: 111011-63-3
CAS Name: 5-(5,5-Dimethyl-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylic acid 2-[phenyl(phenylmethyl)amino]ethyl ester, P-oxide
Additional Names: 2-(N-benzylanilino)ethyl(±)-1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-5-phosphononicotinate, cyclic 2,2-dimethyltrimethylene ester
Molecular Formula: C34H38N3O7P
Molecular Weight: 631.66
Percent Composition: C 64.65%, H 6.06%, N 6.65%, O 17.73%, P 4.90%
Literature References: Dihydropyridine calcium channel blocker. Prepn: K. Seto et al., WO 8704439idem et al., US 4885284(1987, 1989 both to Nissan); and crystal structure: R. Sakoda et al., Chem. Pharm. Bull. 40, 2362 (1992). Stereoselective synthesis of enantiomers and crystal structure of (S)-form: idem et al., ibid. 2377. Pharmacology: C. Shudo et al., J. Pharm. Pharmacol. 45,525 (1993). Mechanism of action study: T. Yamashita et al., Jpn. J. Pharmacol. 57, 337 (1991). Clinical study: T. Saito et al., Curr. Ther. Res. 52, 113 (1992).
Properties: Crystals from ethyl acetate, mp 169-170° (Sakoda); also reported as mp 155-156° (Seto).
Melting point: mp 169-170° (Sakoda); mp 155-156° (Seto)
Derivative Type: Hydrochloride
CAS Registry Number: 111011-53-1
Molecular Formula: C34H38N3O7P.HCl
Molecular Weight: 668.12
Percent Composition: C 61.12%, H 5.88%, N 6.29%, O 16.76%, P 4.64%, Cl 5.31%
Properties: LD50 in mice (mg/kg): >600 orally (Seto).
Toxicity data: LD50 in mice (mg/kg): >600 orally (Seto)
Derivative Type: Hydrochloride ethanol
CAS Registry Number: 111011-76-8
Manufacturers’ Codes: NZ-105
Trademarks: Landel (Zeria)
Molecular Formula: C34H38N3O7P.C2H5OH.HCl
Molecular Weight: 714.18
Percent Composition: C 60.54%, H 6.35%, N 5.88%, O 17.92%, P 4.34%, Cl 4.96%
Properties: Yellow crystals from aq ethanol, mp 151° (dec).
Melting point: mp 151° (dec)
Derivative Type: (S)- or (R)-Form
Properties: Pale yellow crystals from ethanol, mp 190-192°. [a]D25 + or -7.0° resp (c = 0.50 in chloroform).
Melting point: mp 190-192°
Optical Rotation: [a]D25 + or -7.0° resp (c = 0.50 in chloroform)


  • Formula:C34H38N3O7P
  • MW:631.67 g/mol
  • CAS-RN:128194-13-8


  • Formula:C34H38N3O7P
  • MW:631.67 g/mol
  • CAS-RN:128194-12-7
Therap-Cat: Antihypertensive.
Keywords: Antihypertensive; Dihydropyridine Derivatives; Calcium Channel Blocker; Dihydropyridine Derivatives.

///////////Efonidipine, エホニジピン, IND 2017, Landel , NZ 105, Efonidipine Hydrochloride Ethanolate



Arterolane Maleate


Image result for Arterolane Maleate

Image result for Arterolane Maleate

Arteolane Maleate

Molecular Weight: 508.612

CAS  959520-73-1

664338-39-0 (free base)   959520-73-1 (maleate)   959520-79-7 (acetate)   664338-40-3 (tosylate)   959520-82-2 (tartrate)   959520-83-3 (citrate)

N-(2-amino-2-methylpropyl)-2-((1R,3R,4”S,5R,5’s,7R)-dispiro[adamantane-2,3′-[1,2,4]trioxolane-5′,1”-cyclohexan]-4”-yl)acetamide maleate

Dispiro[cyclohexane-1,3′-[1,2,4]trioxolane-5′,2”-tricyclo[,7]decane]-4-acetamide, N-(2-amino-2-methylpropyl)-, cis-, (2Z)-2-butenedioate (1:1)


Arteolane Maleate and Piperaquine phosphate Dispersible tablets (37.5 mg +187.5 mg

Indicated in children aged 6 months to 12 years for the treatment of :
– Acute uncomplicated Plasmodium falciparum malaria infection
– Acute uncomplicated Plasmodium Vivax malaria infection
 Arterolane, also known as OZ-277, is an adenosine triphosphatase inhibitor potentially for the treatment of malaria.


cas 664338-39-0 


664338-39-0, UNII-3N1TN351VB, OZ277, RBX-11160, NCGC00274173-01
Molecular Formula: C22H36N2O4
 Molecular Weight: 392.53224
 cis-adamantane-2-spiro-3’-8’-[[[(2’-amino-2’ methylpropyl) amino] carbonyl] methyl] 1’,2’,4’-trioxaspiro [4.5] decane
cis-adamantane-2-spiro-3′-8′-[[[(2′- amino-2′-methylpropyl)amino]carbonyl]-methyl]- 1 ‘,2′,4’-trioxaspiro[4.5]decane

Arterolane, also known as OZ277 or RBx 11160, is a substance that was tested for antimalarial activity[1] by Ranbaxy Laboratories.[2] It was discovered by US and European scientists who were coordinated by the Medicines for Malaria Venture (MMV).[3] Its molecular structure is uncommon for pharmacological compounds in that it has both a ozonide (trioxolane) group and an adamantanesubstituent.[4]

Initial results were disappointing, and in 2007 MMV withdrew support, after having invested $20M in the research;[5] Ranbaxy said at the time that it intended to continue developing the drug combination on its own.[2] Ranbaxy started a Phase II clinical trial of arterolane, in combination with piperaquine in 2009 that published in 2015.[6][7]

In 2012, Ranbaxy obtained approval to market the arterolane/piperaquine combination drug in India, under the brand name Synriam,[5]and in 2014 received approval to market it in Nigeria, Uganda, Senegal, Cameroon, Guinea, Kenya and Ivory Coast; it had already received approval in Uganda.[8]

Ranbaxy launched India’s first new drug, SynriamTM, treating Plasmodium falciparummalaria in adults. The drug provides quick relief from most malaria-related symptoms, including fever, and has a high cure rate of over 95 %.

Just one tablet per day is required, for three days, instead of two to four tablets, twice daily, for three or more days with other medicines. The drug is independent of dietary restrictions for fatty foods or milk.

Ranbaxy developed Synriam as a fixed-dose combination of arterolane maleate and piperaquine phosphate, where arterolane is the new chemical entity (NCE) that was developed as an alternative to artemisinin. It is the first recently developed antimalarial not based on artemisinin, one of the most effective treatments for malaria, which has shown problems with resistance in recent years. Arterolane was discovered by a collaborative drug discovery project funded by the Medicines for Malaria Venture. Since SynriamTM has a synthetic source, unlike artemisinin-based drugs, production can be scaled up whenever required and a consistent supply can be maintained at a low cost.

The new drug, has been approved by the Drug Controller General of India (DCGI) for marketing in India and conforms to the recommendations of the World Health Organization (WHO) for using combination therapy in malaria. Ranbaxy is also working to make it available in African, Asian and South American markets where Malaria is rampant. SynriamTM trials are ongoing for Plasmodium vivax malaria and a paediatric formulation.

Derek Lowe of the famous In the Pipeline blog had written about arterolane in 2009. At the time it was in Phase III trial, which I assumed were the trials that Ranbaxy was conducting. But it turned out that arterolane was developed by a collaboration between researchers in the US, the UK, Switzerland and Australia who were funded by the World Health Organization and Medicines for Malaria Venture (a Swiss non-profit). They published this work in Nature in 2004 and further SAR (Structure Activity Relationship) studies in J Med Chem in 2010. So Ranbaxy did not develop the drug from scratch? But the press release quotes Arun Sawhney, CEO and Managing Director of Ranbaxy which misleads people to think so: “It is indeed gratifying to see that Ranbaxy’s scientists have been able to gift our great nation its first new drug, to treat malaria, a disease endemic to our part of the world. This is a historic day for science and technology in India as well as for the pharmaceutical industry in the country. Today, India joins the elite and exclusive club of nations of the world that have demonstrated the capability of developing a new drug”. So Ranbaxy mixes a known active compound (piperaquine) with a new compound that someone else found to be active (arterolane) and claims that they developed a new drug? In an interview in LiveMint, Sawhney says, “Ranbaxy spent around $30 million on Synriam and the contribution from DST [India’s Department of Science & Technology] was Rs.5 crore. The drug went through several phases of development since the project began in 2003. We did not look at this as a commercial development. Instead, this is a CSR [Corporate Social Responsibility] venture for us.” That’s a give away because developing a new drug from scratch has to cost more than $30 million + Rs.50 million.

Ranbaxy  now taken over by sun


Generic Name
Arterolane Maleate and Piperaquine Phosphate Tablets
Each film coated tablet contains: Arterolane maleate equivalent to Arterolane ……………………………150 mg Piperaquinephosphate……………750 mg
Dosage Form
Inactive ingredients:
Microcrystalline cellulose, Crospovidone, Magnesium stearate, Hydroxypropyl methyl cellulose/Hypromellose, Titanium dioxide, Macrogol/ Polyethylene glycol, Talc, Ferric Oxide (Yellow), Ferric Oxide (Red)

Description SynriamTM is a fixed dose combination of two antimalarial active ingredients arterolane maleate and piperaquine phosphate.

Arterolane maleate is a synthetic trioxolane compound. The chemical name of arterolane maleate is cis-adamantane-2-spiro-3’-8’-[[[(2’-amino-2’ methylpropyl) amino] carbonyl] methyl] 1’,2’,4’-trioxaspiro [4.5] decane hydrogen maleate. The molecular formula is C26H40N2O8 and molecular weight is 508.61. The structural formula is as follows:

Malaria is one of the most prevalent and deadly parasitic diseases in the world. Up to 289 million cases of malaria may have occurred in 2010, causing between 660,000 and 1.25 million deaths, mainly in Africa and mostly of children younger than 5 years.
(WHO:; Fidock, D. A. Eliminating Malaria. Science 2013, 340, 1531-1533.)

The most serious problem in malaria treatment is that the parasites causing the disease, particularly the deadly Plasmodium falciparum, have developed resistance to widely used drugs, particularly chloroquine (CQ). Currently, the most efficacious therapies are combinations of an artemisinin-type compound with a long-lasting partner drug like lumefantrine, amodiaquine or mefloquine.

Malaria, the most common parasitic disease of humans, remains a major health and economic burden in most tropical countries. Large areas of Central and South America, Hispaniola (Haiti and the Dominican Republic), Africa, the Middle East, the Indian subcontinent, Southeast Asia, and Oceania are considered as malaria-risk areas. It leads to a heavy toll of illness and death, especially amongst children and pregnant women.

According to the World Health Organization, it is estimated that the disease infects about 400 million people each year, and around two to three million people die from malaria every year. There are four kinds of malaria parasites that infect human: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.

Malaria spreads from one person to another by the bite of mosquito, Anopheles gambiae, which serves as vector. When a mosquito sucks the blood of human, sporozoites are transfused into the human body together with saliva of the mosquito. The sporozoites enter into the hepatocytes, reproduce asexually and finally enter into the blood stream. The parasites continue to multiply inside the red blood cells, until they burst and release large number of merozoites. This process continues, destroying a significant number of blood cells and causing the characteristic paroxysm (“chills and fever”) associated with the disease. In the red blood cells, some of the merozoites become male or female gametocytes. These gametocytes are ingested by the mosquito when it feeds on blood. The gametocytes fuse in the vector’s gut; sporozoites are produced and are migrated to the vector’s salivary glands.

The clinical symptoms of malaria are generally associated with the bursting of red blood cells causing an intense fever associated with chills that can leave the infected individual exhausted and bedridden. More severe symptoms associated with repeat infections and/or infection by Plasmodium falciparum include anaemia, severe headaches, convulsions, delirium and, in some instances, death.

Quinine, an antimalarial compound that is extracted from the bark of cinchona tree, is one of the oldest and most effective drugs in existence. Chloroquine and mefloquine are the synthetic analogs of quinine developed in 1940’s, which due to their effectiveness, ease of manufacture, and general lack of side effects, became the drugs of choice. The downside to quinine and its derivatives is that they are short-acting and have bitter taste. Further, they fail to prevent disease relapses and are also associated with side effects commonly known as “Chinchonism syndrome” characterized by nausea, vomiting, dizziness, vertigo and deafness. However, in recent years, with the emergence of drug- resistant strains of parasite and insecticide-resistant strains of vector, the treatment and/or control of malaria is becoming difficult with these conventional drugs.

Malarial treatment further progressed with the discovery of Artemisinin

(qinghaosu), a naturally occurring endoperoxide sesquiterpene lactone isolated from the plant Artemisia annua (Meshnick et al., Microbiol. Rev. 1996, 60, p. 301-315; Vroman et al., Curr. Pharm. Design, 1999, 5, p. 101-138; Dhingra et al., 2000, 66, p. 279-300), and a number of its precursors, metabolites and semi-synthetic derivatives which have shown to possess antimalarial properties. The antimalarial action of artemisinin is due to its reaction with iron in free heme molecules of the malaria parasite, with the generation of free radicals leading to cellular destruction. This initiated a substantial effort to elucidate its molecular mechanism of action (Jefford, dv. Drug Res. 1997, 29, p. 271-325; Cumming et al., Adv. Pharmacol. 1997, 37, p. 254-297) and to identify novel antimalarial peroxides (Dong and Vennerstrom, Expert Opin. Ther. Patents 2001, 1 1, p. 1753-1760).

Although the clinically useful artemisinin derivatives are rapid acting and potent antimalarial drugs, they have several disadvantages including recrudescence,

neurotoxicity, (Wesche et al., Antimicrob. Agents. Chemother. 1994, 38, p. 1813-1819) and metabolic instability (White, Trans. R. Soc. Trop. Med. Hyg., 1994, 88, p. 41-43). A fair number of these compounds are quite active in vitro, but most suffer from low oral activity (White, Trans. R. Soc. Trop. Med. Hyg., 1994, 88, p. 41-43 and van Agtmael et al., Trends Pharmacol. Sci., 1999, 20, p. 199-205). Further all these artemisinin derivatives are conventionally obtained from plant source and are therefore expensive. As the cultivation of the plant material is dependent on many factors including the weather conditions, the supply source thus becomes finite and there are chances of varying yield and potency. This leads to quality inconsistencies and supply constraints. As malaria is more prevalent in developing countries, a switch to cheaper and effective medicine is highly desirable.

Thus there exists a need in the art to identify new peroxide antimalarial agents, especially those which are not dependent on plant source and can be easily synthesized, are devoid of neurotoxicity, and which possess improved solubility, stability and pharmacokinetic properties.

Following that, many synthetic antimalarial 1 ,2,4-trioxanes (Jefford, Adv. Drug Res. 1997, 29, p. 271-325; Cumming et al., Adv. Pharmacol. 1997, 37, p. 254-297), 1,2,4,5-tetraoxanes (Vennerstrom et al., J. Med. Chem., 2000, 43, p. 2753-2758), and other endoperoxides have been prepared. Various patents/applications disclose means and method for treating malaria using Spiro or dispiro 1,2,4-trioxolanes for example, U.S.

Patent Application No. 2004/0186168 and U.S. Patent Nos. 6,486, 199 and 6,825,230. The present invention relates to solid dosage forms of the various spiro or dispiro 1 ,2,4- trioxolanes antimalarial compounds disclosed in these patents/applications and are incorporated herein by reference.

Active compounds representing various Spiro and dispiro 1 ,2,4-trioxolane derivatives possess excellent potency, efficacy against Plasmodium parasites, and a lower degree of neurotoxicity, in addition to their structural simplicity and ease of synthesis. Furthermore, these compounds have half-lives which are believed to permit short-term treatment regimens comparing favorably to other artemisinin-like drugs. In general, the therapeutic dose of trioxolane derivative may range between about 0.1-1000 mg/kg/day, in particular between about 1-100 mg/kg/day. The foregoing dose may be administered as a single dose or may be divided into multiple doses. For malaria prevention, a typical dosing schedule could be, for example, 2.0-1000 mg/kg weekly beginning 1-2 weeks prior to malaria exposure, continued up to 1-2 weeks post-exposure.

Monotherapy with artemisinin (natural or synthetic) class of drugs might cure the patients within 3 days, however perceiving the potential threat of the malarial parasite developing resistance towards otherwise very potent artemisinin class of drugs, WHO had strictly called for an immediate halt to the provision of single-drug artemisinin malaria pills. Combination therapy in case of malaria retards the development of resistance, improve efficacy by lowering recrudescence rate, provides synergistic effect, and increase exposure of the parasite to the drugs.

Artemsinin based combinations are available in the market for a long time.

Artemether-lumafentrine (Co-artem®) was the first fixed dose antimalarial combination containing an artemisinin derivative and has been known since 1999. This combination has passed extensive safety and efficacy trials and has been approved by more than 70 regulatory agencies. Co-artem® is recommended by WHO as the first line treatment for uncomplicated malaria.

Other artemisinin based combinations include artesunate and amodiaquine (Coarsucam®), and dihydroartemisin and piperaquine (Eurartesim®). Unfortunately, all the available artemisinin based combinations have complicated dosage regimens making it difficult and inconvenient for a patient to comply completely with the total prescribed duration. For example, the dosage regimen of Co-artem® for an adult having body weight of more than 35 kg includes 6 doses over three days. The first dose comprises four tablets initially, the second dose comprises four tablets after eight hours, the third to sixth doses comprise four tablets twice for another two days; making it a total of 24 tablets. The dosage regimen of Coarsucam® for an adult having body weight of more than 36 kg or age above 14 years includes three doses over three days; each dose comprises two tablets; making it a total of six tablets. The dosage regimen of Eurartesim® for an adult having body weight between 36 kg – 75 kg includes 3 doses over three days, each dose comprises of three tablets, making it a total of nine tablets.

It is evident that the available artemisinin-based combinations have a high pill burden on patients as they need to consume too many tablets. As noted above, this may increase the possibility of missing a few doses, and, consequently, could result in reduced efficacy due to non-compliance and may even lead to development of resistance for the drug. Therefore, there is an urgent and unmet need for anti-malarial combinations with a simplified daily dosing regimen that reduces the pill burden and would increase patient compliance.

Apart from simplifying the regimen, there are certain limitations for formulators developing formulations with trioxolones, the first being their susceptibility to degradation in presence of moisture that results in reduced shelf lives. Another is their bitter taste, which can result in poor compliance of the regimen or selection of another, possibly less effective, therapeutic agent.


Figure US06906205-20050614-C00051


structural Formula II.

Figure imgf000013_0001

Formula II

Active compound includes one or more of the various spiro and dispiro trioxolane derivatives disclosed in U.S. Application No. 2004/0186168 and U.S. Patent Nos.

6,486,199 and 6,825,230, which are incorporated herein by reference. These trioxolanes are relatively sterically hindered on at least one side of the trioxolane heterocycle which provides better in vivo activity, especially with respect to oral administration. Particularly, spiro and dispiro 1,2,4-trioxolanes derivatives possess excellent potency and efficacy against Plasmodium parasites, and a lower degree of neurotoxicity.

The term “Active compound I” herein means cis-adamantane-2-spiro-3′-8′-[[[(2′- amino-2′-methylpropyl)amino]carbonyl]-methyl]- 1 ‘,2′,4’-trioxaspiro[4.5]decane hydrogen maleate. The Active compound I may be present in an amount of from about 5% to about 25%, w/w based on the total dosage form.


A synthetic procedure for preparing compounds of Formula I, salts of the free base c«-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methyl propyl) amino] carbonyl] methyl]- 1 ‘, 2′, 4’-trioxaspiro [4.5] decane has been disclosed in U.S. 6,906,205.

Figure imgf000002_0001

The process for the preparation of compounds of Formula I wherein a compound of Formula II (wherein R is lower alkyl) is reacted with a compound of Formula III (wherein R is lower alkyl) to obtain compound of Formula IV;

Figure imgf000005_0001
Figure imgf000005_0002

Formula Formula IV

followed by hydrolysis of the compounds of Formula IV to give a compound of Formula V;

Figure imgf000005_0003

Formula V followed by the reaction of the compound of Formula V with an activating agent, for example, methyl chloroformate, ethyl chloroformate, propyl chloro formate, n-butyl chloro formate, isobutyl chloroformate or pivaloyl chloride leads to the formation of mixed anhydride, which is reacted in situ reaction with 1 ,2-diamino-2-methyl propane to give a compound of Formula VI; and

Figure imgf000005_0004

Formula Vl reacting the compound of Formula VI with an acid of Formula HX (wherein X can be the same as defined earlier) to give compounds of Formula I.

Example 1 : Preparation of O-methyl-2-adamantanone oxime

To a solution of 2-adamantanone (50 g, 0.3328 mol, 1 equiv.) in methanol (0.25 lit), sodium hydroxide solution (15 g, 0.3761mol, 1.13 equiv, in 50 mL water) was added followed by methoxylamine hydrochloride (37.5 g x 81.59% Purity= 30.596 g, 0.366 mol, 1.1 equiv) at room temperature under stirring. The reaction mixture was stirred at room temperature for 1 to 2 h. The reaction was monitored by HPLC. The reaction mixture was concentrated at 40- 45°C under vacuum to get a thick residue. Water (250 mL) was added at room temperature and the reaction mixture was stirred for half an hour. The white solid was filtered, washed with water (50 mL), and dried at 40 to 45°C under reduced pressure. O-methyl 2- adamantanone oxime (57 g, 95 % yield) was obtained as a white solid.

(M++l) 180, 1HNMR (400 MHz, CDCl3 ): δ 1.98 – 1.79 (m, 12H), 2.53 (s, IH), 3.46 ( s, IH), 3.81 (s, 3H).

Example 2: Preparation of 4-(methoxycarbonvmethvPcvclohexanone A high pressure autoclave was charged with a mixture of methyl (4- hydroxyphenyl)acetate (50 g, 0.30 mol), palladium ( 5g) (10 %) on carbon (50 % wet) and O- xylene (250 mL). The reaction mixture was stirred under 110 to 115 psi of hydrogen pressure for 7 to 8 h at 1400C. The reaction was monitored by HPLC. The reaction mixture was then cooled to room temperature, and the catalyst was filtered off. Filtrate was concentrated under reduced pressure to get 4-(methoxycarbonylmethyl)cyclohexanone as light yellow to colorless oily liquid (48.7 g, 97.4 %).

(M++!) 171, ‘ HNMR (400 MHz, CDCl 3): δ 1.48 – 1.51 ( m, 2H), 2.1 1-2.07 (m, 2H), 2.4- 2.23 (m, 7H), 3.7 (s, 3H).

Example 3: Preparation of methyl (Is, 4s)-dispiro [cyclohexane-l, 3′-f 1,2,4] trioxolane-5′, 2″-tricvclor3.3.1.1371decan1-4-ylacetate

A solution of O-methyl-2-adamantanone oxime (example 1) (11.06 g, 61.7 mmol, 1.5 equiv.) and 4-(methoxycarbonymethyl)cyclohexanone (example 2) (7.0 g, 41.1 mmol, 1 equiv.) in cyclohexane ( 200ml) and dichloromethane (40 mL) was treated with ozone (ozone was produced with an OREC ozone generator [0.6 L/min. O2, 60 V] passed through an empty gas washing bottle that was cooled to -780C). The solvent was removed after the reaction was complete. After removal of solvents, the crude product was purified by crystallization from 80% aqueous ethanol (200 mL) to afford the title compound as a colorless solid. Yield: 10.83 g, 78%, mp: 96-980C; 1HNMR (500 Hz3CDCl3): δ 1.20-1.33 (m, 2H), 1.61-2.09 (m, 5 21H), 2.22 (d, J = 6.8Hz, 2H), 3.67(s,3H).

Example 4: Preparation of (Is, 4s)-dispiro [cyclohexane-1, 3′-[l,2,4] trioxolane-5′, 2″- tricvclo [] decanl-4-ylacetic acid

Sodium hydroxide (3.86 g, 96.57 mmol, 3 equiv.) in water (80 mL) was added to a solution of methyl (\s, 4s)-dispiro [cyclohexane-1, 3′-[l,2,4] trioxolane-5′, 2″-tricyclo

10 [3.3.1.I37] decan]-4-ylacetate (example 3) (10.83 g, 32.19 mmol, 1 equiv.) in 95% ethanol (150 mL). The mixture was stirred at 500C for about 4 h, cooled to O0C, and treated with IM hydrochloric acid (129ml, 4 equiv). The precipitate was collected by filtration, washed with 50 % aqueous ethanol (150 mL) and dried in vacuum at 40 0C to give the title compound as colorless solid. Yield: 9.952 g, 96%, mp: 146-1480C ( 95% ethanol), 1HNMR (500 Hz,

15 CDCl3): δ 1.19-1.41 (m,2H), 1.60-2.05 (m,21H), 2.27 (d, J=6.8 Hz,2H).

Example 5: Preparation of c?s-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methyl propyl) amino] carbonyl] methyl]-! ‘, T , 4’-trioxaspiro [4.5] decane

Method A:

(Is, 4s)-dispiro[cyclohexane- 1 ,3 ‘-[ 1 ,2,4]trioxolane-5 ‘,2 ‘ ‘-tricyclo[]decan]-4-

.0 ylacetic acid (example 4) (5 g ,15.5mmol, 1 equiv) was mixed with triethylamine (2.5 g , 24.8 mmol, 1.6 equiv) in 100ml of dichloromethane. The reaction mixture was cooled to – 1O0C to 00C. Ethyl chloro formate (1.68 g, 17 mmol, 1.0 equiv) in 15 mL dichloromethane was charged to the above reaction mixture at – 100C to 00C. The reaction mixture was stirred at the same temperature for 10 to 30 minutes. The resulting mixed anhydride reaction mixture

15 was added dropwise to a previously prepared solution of l,2-diamino-2-methylpropane (1.64 g, 18.6 mmol, 1.2 equiv), in 100 mL dichloromethane at -100C to O0C. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the same temperature till the reaction was complete. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. The reaction was complete

>0 within 2 h. Nitrogen atmosphere was maintained throughout the reaction. Water (50 mL) was charged, organic layer was separated and washed with 10% sodium bicarbonate solution (50 mL) and water (50 mL) at room temperature. The organic layer was dried over sodium sulphate and the solvent was removed at 25 to 4O0C under reduced pressure. Hexane (50ml) was added to obtain residue under stirring at room temperature. The mixture was filtered and washed with 5 mL of chilled hexane. The solid was dried under reduced pressure at room 5 temperature.

Yield: 5.2 g (85.4 %), (M++l) 393, 1HNMR (400 MHz, DMSO-J6 ): δ 0.929 ( s, 6H), 1.105 – 1.079 (m, 2H), 1.887-1.641 (m, 21H), 2.030-2.017 (d, 2H), 2.928 (d, 2H).

Method B:

(Is, 4s)-dispiro [cyclohexane-1, 3′-[l,2,4] trioxolane-5′, 2″-tricyclo [3.3.1.I37]

10 decan]-4-ylacetic acid (example 4) (10 g, 31mmol, 1 equiv) was treated with isobutyl chloroformate (4.5 g, 33mmol, 1.1 equiv) in presence of organic base like triethyl amine (5 g, 49.6mmol, 1.6 equiv) at 00C to 7°C in 250ml of dichloromethane. The solution was stirred at O0C to 7°C for aboutlO to 30 minutes. To the above reaction mixture, previously prepared solution of l,2-diamino-2-methylpropane (3.27 g, 37 mmol, 1.2 equiv), in 50 mL of

15 dichloromethane was added at O0C to 7°C in one lot. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the room temperature till reaction was over. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. Reaction was complete within 2 h. The reaction nitrogen atmosphere was maintained throughout the reaction. Water (250 mL) was charged, organic

20 layer was separated and washed with 10% sodium bicarbonate solution (200 mL) and water (100 mL) at room temperature and the solvent was removed at 25 to 4O0C under reduced pressure. Hexane (100ml) was added to the residue, under stirring, at room temperature. The mixture was filtered and washed with chilled hexane (10 mL). The resultant solid was dried under reduced pressure at room temperature. Yield: 10.63 g (87%), (M++l) 393, 1HNMR

>5 (400 MHz, DMSO-J6 ) :δ 0.928 ( s, 6H), 1.102 – 1.074 (m, 2H), 1.859-1.616 (m, 21H), 2.031- 2.013 (d, 2H), 2.94-2.925 (d, 2H). Method C:

(\s, 4s)-dispiro[cyclohexane-l,3′-[l,2,4]trioxolane-5′,2″-tricyclo[>7]decan]-4- ylacetic acid (example 4) (5 g, 15.5mmol, 1 equiv) was treated with pivaloyl chloride (1.87 g, 15.5 mmol, 1 equiv) and triethylamine (2.5gm, 24.8mmol, 1.6 equiv) at -15°C to -100C in dichloromethane (125 mL). The solution was stirred at -150C to -100C for aboutlO to 30 minutes. It resulted in the formation of mixed anydride. To the above reaction mixture, previously prepared solution of 1 ,2-diamino-2-methylpropane (1.64 g, 18.6 mmol, 1.2 equiv) in 25 mL dichloromethane was added at -15°C to -100C. The temperature of reaction mixture was raised to room temperature. The reaction mixture was stirred at the room temperature till reaction was over. Reaction monitoring was done by thin layer chromatography using 5 to 10% methanol in dichloromethane. The reaction was complete within 2 h. Nitrogen atmosphere was maintained throughout the reaction. Water (125 mL) was charged, organic layer was separated and washed with 50 mL of 10% sodium bicarbonate solution and 125 mL of water, respectively at room temperature. Finally solvent was removed at 25 to 4O0C under reduced pressure. 50 mL of 5% Ethyl acetate – hexane solvent mixture was added to the residue under stirring at room temperature. The mixture was filtered and washed with 5 mL of chilled hexane. Solid was dried under reduced pressure at room temperature. Yield: 5.03 g (83 %), (M++l) 393, 1JINMR (400 MHz, OMSO-d6 ):δ 0.93 ( s, 6H), 1.113 – 1.069 (m, 2H), 1.861-1.644 (m, 21H), 2.033-2.015 (d, 2H), 2.948-2.933 (d, 2H).

Example 6: Preparation of c/s-adamantane-2-spiro-3′ -8 ‘-πT(2′-amino-2’ -methyl propyl) amino! carbonyl] methyli-l ‘, 2\ 4′-U-JoXaSpJrQ [4.51 decane maleate To a solution of c/s-adamantane-2-spiro-3′-8′-[[[(2′-amino-2’-methyl propyl) amino] carbonyl] methyl]-! ‘, 2′, 4’-trioxaspiro [4.5] decane (example 5) (60 g, 0.153 moles) in ethanol (150 mL) was added a solution of maleic acid (17.3 g, 0.15 moles, 0.98 equiv. in ethanol 90 mL) and the reaction mixture was stirred for about 1 h. To this clear solution, n- heptane (720 mL) was added at room temperature in 1 h and the reaction mixture was stirred for 3 h. It was then cooled to 0 to 100C and filtered. The cake was washed with n-heptane (60 mL) and dried under vacuum at 40-450C.

Yield: 67 g, 77.4%, mp: 1490C (decomp), (M++l) 393.5, 1HNMR (300 MHz, DMSO-^ ): δ 1.05-1.11 (2H,m), 1.18 (6H,s), 1.64-1.89 (21H,m), 2.07(2H,d), 3.21 (2H,d), 6.06 (2H,d), 7.797 (2H, bs), 8.07 (IH, t).


  1.  Dong, Yuxiang; Wittlin, Sergio; Sriraghavan, Kamaraj; Chollet, Jacques; Charman, Susan A.; Charman, William N.; Scheurer, Christian; Urwyler, Heinrich et al. (2010). “The Structure−Activity Relationship of the Antimalarial Ozonide Arterolane (OZ277)”. Journal of Medicinal Chemistry 53 (1): 481–91. doi:10.1021/jm901473sPMID 19924861.
  2.  Blow to Ranbaxy drug research plans at, Sep 21 2007
  3.  Vennerstrom, Jonathan L.; Arbe-Barnes, Sarah; Brun, Reto; Charman, Susan A.; Chiu, Francis C. K.; Chollet, Jacques; Dong, Yuxiang; Dorn, Arnulf et al. (2004). “Identification of an antimalarial synthetic trioxolane drug development candidate”. Nature 430 (7002): 900–4.doi:10.1038/nature02779PMID 15318224.
  4.  In the Pipeline: “Ozonides As Drugs: What Will They Think Of Next?”, by Derek Lowe, November 23, 2009, at
  5.  Indian company starts Phase III trials of synthetic artemisinin, May 4 2009, at the WorldWide Antimalarial Resistance Network
Spiro and dispiro 1,2,4-trioxolane antimalarials
Spiro and dispiro 1,2,4-trixolane antimalarials


Antimalarial drugsSpeeding to a new lead

Structure of NITD609; the 1R,3Sconfiguration is fundamental for its antimalarial activity


  1. Jump up^ Dong, Yuxiang; Wittlin, Sergio; Sriraghavan, Kamaraj; Chollet, Jacques; Charman, Susan A.; Charman, William N.; Scheurer, Christian; Urwyler, Heinrich; et al. (2010). “The Structure−Activity Relationship of the Antimalarial Ozonide Arterolane (OZ277)”. Journal of Medicinal Chemistry53 (1): 481–91. doi:10.1021/jm901473sPMID 19924861.
  2. Jump up to:a b Blow to Ranbaxy drug research plans at, Sep 21 2007
  3. Jump up^ Vennerstrom, Jonathan L.; Arbe-Barnes, Sarah; Brun, Reto; Charman, Susan A.; Chiu, Francis C. K.; Chollet, Jacques; Dong, Yuxiang; Dorn, Arnulf; et al. (2004). “Identification of an antimalarial synthetic trioxolane drug development candidate”. Nature430 (7002): 900–4. doi:10.1038/nature02779PMID 15318224.
  4. Jump up^ In the Pipeline: “Ozonides As Drugs: What Will They Think Of Next?”, by Derek Lowe; published November 23, 2009; retrieved November 17, 2015; at
  5. Jump up to:a b Akshat Rathi for Chemistry World. 3 May 2012 Ranbaxy launches new anti-malarial Synriam
  6. Jump up^ India Clinical trials registry CTRI/2009/091/000531
  7. Jump up^ Toure OA et al. Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate dispersible tablets in paediatric patients with acute uncomplicated Plasmodium falciparum malaria: a phase II, multicentric, open-label study. Malar J. 2015 Nov 25;14(1):469. Clinical Trial Registry India: CTRI/2009/091/000531. PMID 26608469 PMC4660726
  8. Jump up^ Staff, Business Standard. December 16, 2014 Ranbaxy receives approval for malaria drug Synriam from 7 African countries


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Clinical data
Routes of
ATC code
CAS Number
PubChem CID
Chemical and physical data
Formula C22H36N2O4
Molar mass 392.531 g/mol
3D model (JSmol)

////////////Arteolane Maleate, OZ-277, RBx-11160, OZ 277, RBx 11160, OZ277, RBx11160, IND 2017


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