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Bulaquine a CDRI India Antimalarial



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CAS NO.: 79781-00-3

2(3H)-Furanone, dihydro-3-(1-((4-((6-methoxy-8-quinolinyl)amino)pentyl)amino)ethylidene)-,

 3-[l-[[4-[(6-methoxy-8-quinolinyl)amino]pentyl]amino]- ethyMene]-dihydro-2(3H)furanone

N1– (3-ethylidinotetrahydrofuran-2-one)-N4– (6-methoxy-8-quinolinyl)-1,4-pentanediamine

Aablaquine, Elubaquine, Bulaquine [INN], Compound 80/53, UNII-TSQ6U39Q3G, AC1MI1V2, CHEMBL2106578, CDRI 80/53
Molecular Formula: C21H27N3O3   Molecular Weight: 369.45738




The Central Drug Research Institute has developed an antimalarial Drug – given in house number “Compound 80/53” and allotted International Nonproprietary Name (INN) as Bulaquin – which is a primaquine derivative.

Primaquine is the only drug available for use as anti-relapse, antimalarial for prophylactic in P.vivax malaria. However, this drug causes many side effects and the most commonly cited effect is methaemoglobinaemia in patients with G6PD deficiency. Higher doses of primaquine cause methaemoglobinaemia in most subjects and leukopenia in some. However, there is a small fraction of black population with G6PD deficiency who develop anaemia due to intravascular haemolysis at daily dose levels of 15 mg (base) and above.

It is being increasingly felt that the eroding efficacy of commonly used antimalarials has contributed substantially to the resurgence of malaria during last three decades. Although new antimalarials have appeared in the market during this time, none has yet supplemented chloroquine. There are no drugs in the market or in advanced stages of development that appear to be as well tolerated as chloroquine.

Combinations of existing antimalarials especially those now available in rural clinics and market hold great potential for effective, self-administered therapies for uncomplicated malaria, particularly where relapses are frequently encountered. Applying combined therapies to the problem should demand a high standard of proof of safety and efficacy in randomised double blind, placebo controlled trials.

Bulaquin is without any side effects that have been observed with primaquine. A comparative data analysis on initial (0 day pre-drug) and final (+7 day post-drug) values of haemoglobin, methaemoglobin, prothrombin time, partial thromboplastin time and fibrinogen in healthy human subjects treated with primaquine (15 mg OD x7 days) and Bulaquin (25 mg OD x7 days) have been carried out. The study has shown that one week primaquine treatment leads to rise in methaemoglobin levels from 3.97% to 16.32%, which is highly significant in comparison to the 2.29% and 3.02% levels of methaemoglobin before and after 7 days treatment with Bulaquin respectively. Thus, it is evident that primaquine treatment produces rise in methaemoglobin contrary to Bulaquine does not produce rise in methaemoglobin levels. This result manifests a clear superiority of Bulaquin over Primaquine.

Bulaquin has been licenced to Nicholas Piramal India Ltd., Mumbai for marketing. Nicholas Piramal has introduced Bulaquin alongwith chloroquine into the market as a combination pack under the trade name Aablaquine. The objective of the combined therapy is to control P.vivax malaria more effectively by providing initial cure and thereafter preventing relapses by use of this combination pack. It is hoped that the introduction of this combination pack of Bulaquin should contribute substantially to the ongoing National Malaria action programme advocated by Government of India.

Malaria, caused by a parasitic protozoan called Plasmodium, is one of the most serious and complex tropical parasitic diseases. Generally human malaria is caused by four species of malarial parasites which are Plasmodium falciparwn, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae. Of these P. falciparum and P. vivαx are most widespread and cause most of the mortality and morbidity associated with these types of infections.

It is known that the malarial parasites undergo complex life cycle in humans, which is initiated through the bite of an infected female Anopheles mosquito. When the mosquito bites a host, some of the sporozoites are injected into the bloodstream of the host and through the circulation they reach the liver where they multiply and liberate merozoites into the bloodstream which then invade the erythrocytes. In case of infections caused by P. vivαx, most of the time the parasites remain dormant in the liver which stage is termed hypnozoites. Hypnozoites are reactivated and reinitiate blood stage parasitemias causing relapse. It has often been observed that people infected with P. vivax do not experience any symptoms for a very long period after their initial illness but become symptomatic after certain period (Korean J. Intern Med, 1999 Juk 14(2): 86-9).

A number of drugs ranging from those of natural origin to synthetic ones have been developed for the treatment of malaria. Quinine and artemisinin are the commonly known drugs of natural origin, which are mostly used for the treatment of malaria. A number of synthetic anti- malarial drugs such as chloroquine, mefloquine, primaquine, halofantrine, ainodiaquine, proguanil, maloprim are known in the literature. Of all the synthetic anti-malarial agents chloroquine has been the most widely prescribed drug for the treatment of malaria of all the types, for more than last 60 years.

Chloroquine has been the effective treatment so far for the P. vivax malarial infections, however, some strains of P. vivax have shown resistance to this well known drug {Ann. Trop. Med. ParasitoL, 1999 Apr; 93(3): 225-230). In recent years drug resistant malaria has become one of the most serious problems in malaria control. Drug resistance necessitates the use of drugs which are more expensive and may have dangerous side effects. To overcome the problems associated with drug resistance, treatments comprising combinations of anti-malarial agents are on the rise. A number of anti-malarial combinations are already known in the malarial chemotherapy. For example, a combination of amodiaquine and tetracycline, a combination of sulfadoxine and pyrimethamine known as fansidar, are known therapies for the treatment of P. falάparum. Also fansimef, a combination of mefloquine with sulfadoxine and pyrimetha min e is used against multidrug resistant strains of P. faldparum.

United States Patent No. 5 998 449 describes a method for the treatment of malaria wherein combination of atovaquone and proguanil is used for the treatment of malaria. In US Patent No. 5 834 505, combination of fenozan with another anti-malarial agent selected from artemisinin, sodium artesunate, chloroquine, mefloquine is described for the prophylactic and curative treatment of malaria.

All the aforementioned anti-malarial combinations reported heretofore are generally used for the treatment of P. faldparum. None of the standard anti-malarial combination treatment regimens have been found to be favourable for the treatment of P. vivax malaria which is the most relapsing type of malaria. For a very long time chloroquine was used for the treatment of infections caused by P. vivax, however, chloroquine eradicates only the asexual erythrocytic stages of P. vivax and does not eliminate the hypnozoites. Until recently primaquine has been the drug of choice for the treatment of malarial relapse. Generally the standard therapy for the P. vivax malarial infection comprises of a sequential chloroquine-primaquine combination treatment regimen wherein primaquine is administered for 14 days following the 3 days course of chloroquine. WHO (World Health Organisation) also recommends a 14 days primaquine treatment for P. vivax malarial infection. A shorter duration of cMoroquine-primaquine treatment regimen was also tried out wherein primaquine was administered only for 5 days following the chloroquine course. However, the outcome of the treatment was not encouraging, since the percentage relapse was more than the standard 14 days primaquine treatment regimen (Trans. R. Soc. Trop. Med. Hyg., 93(6), 641-643). Also primaquine is known to cause hemolytic anemia in persons deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD) (Pharmacol Rev. 21: 73-103 (1969); Rev. Cubana Med trop, 1997; 49 (2): 136-8 ). Moreover, methemoglobin toxicity is another predictable dose-related adverse effect associated with primaquine. Needless to say that in the case of sequential combination therapy the patient may not complete the course once the symptoms of malaria are diminished, hence this may increase the chances of relapse. Thus, the chloroquine- primaquine treatment regimen is not safe with respect to toxicity of primaquine and has a further limitation from the standpoint of patient compliance due to longer duration of treatment.

Another anti-relapse agent namely tafenoquine is disclosed in United States Patent 4 617 394. Though more effective than primaquine, the drug was found to cause methemoglobin toxicity almost three times more than that of primaqu ie (Fundam. Appl. Toxicol. 1988, 10(2), 270-275), hence has drawbacks in terms of safety.

The compound, 3-[l-[[4-[(6-nιethoxy-8-quinolinyl)aιnino]pentyl)am.ino]- ethylidene]-dihydro-2(3H)furanone is a derivative of primaquine. It was described in Indian Patent Specification No. 158111 as 6-methoxy-8-(4-

N-(3′-aceto-4^5′-dihydro-2-furanylamino)- l-methylbutylamino)quinoline , the structure of which was revised to that represented by the following formula I. As per the revised structure, the compound is named 3-[l-[[4-

[(6-metJhoxy-8-quinolmyl)amino]pentyl]amino]ethylidene]-dihydro-2(3H)- furanone (hereinafter referred to as compound I). The revised structure is described in WHO Drug Information Vol. 13, No. 4, pg. 268 (1999).

Figure imgf000005_0001

The compound of formula (I) has been found to be safer and less toxic than the parent compound primaquine (Am. J. Trop. Med. Hyg, 1989 Dec; 41(6): 635-637). Its anti-relapse activity has been found to be comparable to primaquine.

Over the years primaquine was the only drug used for the radical cure of malaria caused by P. vivax. Primaquine is associated with a number of severe adverse effects, therefore there is a need to develop agents which are more effective and/ or less toxic than primaquine. The compound I has been found to exhibit anti-relapse activity comparable to Primaquine (Am. J. Trop. Med. Hyg., 41(6): 633-637 (1989)). However, this compound has been shown to cause less methemoglobin formation (Am. J. Trop Hyg., 41(6): 638-642 (1989) ) and also has less effect on anti-oxidant defence enzymes than primaquine (Biochem Pharmacol. 46(10): 1859- 1860 (1993) ). Thus, this primaquine derivative (I) is found to be less toxic as compared to the parent drug, primaquine.

Therefore, there is a longfelt need for a more practical, effective, patient compliant and safe remedy for the radical cure of P. vivax malarial infection.

The inventors have found that the longfelt need may be fulfilled by providing a treatment regimen consisting of regulated use of chloroquine and 3-[l-[[4-[(6-methoxy-8-quinolinyl)aιnino]pentyl]amino]ethylidene]- dihydro-2(3H)furanone of formula I over a period of between 5 to 8 days.

It has also been found that the treatment regimen may be executed most effectively and in a user friendly manner by providing a combination kit which comprises two anti-malarial agents, namely chloroquine and 3-[l- [[4-[(6-meth.oxy-8-qumolmyl)am^


The title enamine derivative is prepared by condensation of primaquine (I) with acetyl butyrolactone (II) by means of piperidine.


  • manufacture fo a medicament for the treatment of malaria of primaquine derivative N1-(3-ethylidinotetrahydrofuran-2-one)-N4-(6-methoxy-8-quinolinyl)-1,4-pentanediamine as a gametocytocidal agent. More particularly, this invention relates to the use of primaquine derivative N1– (3-ethylidinotetrahydrofuran-2-one)-N4– (6-methoxy-8-quinolinyl)-1,4-pentanediamine of formula 1 shown below useful for controlling the spread of malaria by virtue of its high therapeutic value as a gametocytocidal agent.
Figure 00010001
    • The primaquine derivative of the present invention does not damage either normal or G-6PD deficient erythrocytes to the extent it is observed with the use of primaquine.
      • scheme:

        Figure 00150001

The following example illustrates the details of the process of this invention:

N1– (3-ethylidinotetrahydrofuran-2-one)-N4– (6-methoxy-8-quinolinyl)-1,4-pentanediamine

  • A mixture of primaquine base (0.97g, 3.7 mmole) freshly distilled 3-acetyl-r-butyrolactone (1.0g, 7.8 mmole) and a base like piperidine (2-3 drops) were stirred under magnetic stirrer at room temperature. In an hour or so the reaction mixture solidified. The product was titrated in ether and filtered to get the product. It was crystallised from alcoholic solvent like propanol. Yield 0.89g, m.p. 118-120°C.


BELL A.: “Recent developments in the chemotherapy of malaria.” CURRENT OPINION IN ANTI-INFECTIVE INVESTIGATIONAL DRUGS, (2000) 2/1 (63-70). , XP001038054
2 * DUTTA, G. P. ET AL: “Radical curative activity of a new 8-aminoquinoline derivative ( CDRI 80/53) against Plasmodium cynomolgi B in monkeys” AM. J. TROP. MED. HYG. (1989), 41(6), 635-7 , 1989, XP001037488 cited in the application
3 * KAR, K. ET AL: “Pharmacology of compound CDRI 80/53;a potential new antirelapse antimalarial agent” INDIAN J. PARASITOL. (1988), 12, 259-62 , 1988, XP001034143
4 * NEWTON P. ET AL: “Malaria: New developments in treatment and prevention.” ANNUAL REVIEW OF MEDICINE, (1999) 50/- (179-192). , XP001036946
5 * PALIWAL, JYOTI KUMAR ET AL: “Simultaneous determination of a new antimalarial agent, CDRI compound 80/53, and its metabolite primaquine in serum by high-performance liquid chromatography” J. CHROMATOGR., BIOMED. APPL. (1993), 616(1), 155-60 , 1993, XP000955186
6 * PURI, S. K. ET AL: “Methemoglobin toxicity and hematological studies on malaria anti-relapse compound CDRI 80/53 in dogs” AM. J. TROP. MED. HYG. (1989), 41(6), 638-42 , 1989, XP001037486 cited in the application
7 * SETHI, N. ET AL: “Long term toxicity studies with a synthetic anti-relapse antimalarial compound 80/53 in rats and monkeys” INDIAN J. PARASITOL. (1993), 17(1), 15-26 , 1993, XP001034142
8 * VALECHA, NEENA ET AL: “Comparative antirelapse efficacy of CDRI compound 80/53 (Bulaquine) vs. primaquine in double blind clinical trial” CURR. SCI. (2001), 80(4), 561-563 , 2001, XP001037095

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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 LIFE SCIENCES 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 PLUS year tenure till date June 2021, 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, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, 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 33 lakh plus views on New Drug Approvals Blog in 233 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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