1. Novel N-ethanamine-11-azaartemisinin compounds represented by formula I and its salts. R is selected from a H; -C(O)R1, where R1 is (a) 6-14-membered substituted or unsubstituted aryl moiety selected from phenyl, -naphthyl, -biphenyl; (b) 5-14-membered substituted or unsubstituted heteroaryl moiety selected from -pyridinyl, -thienyl, -indolyl, -indolinyl; (c) 3-6-membered substituted or unsubstituted cycloalkyl moiety selected from cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl; (d) substituted or unsubstituted, linear or branched, saturated or unsaturated, -C1-C6- alkyl moiety selected from -methyl, -ethyl, n -propyl, iso-propyl, -n-butyl, -iso-butyl, -n-pentyl, -iso-pentyl, -neo-pentyl, -n-hexyl; -ethenyl, -propenyl, -butenyl, -pentenyl, -hexenyl; wherein substitution is with one or more moieties selected from but not limited to halogen, amino, nitro, cyano, hydroxy, alkoxy, thio, alkylthio group.

2. The compounds as claimed in claim 1, wherein the R is H, said compound being represented by formula 1

3. The compounds as claimed in claim 1 wherein R is -C(O)R1.

4. The compounds as claimed in claim 3, wherein R1 is selected from -benzyl, 3,4-dichlorobenzyl, 2,4-dichlorobenzyl, 2,3,4,5-dichlorobenzyl, 2-bromobenzyl, 4-iodobenzyl, 3,5-dinitrobenzyl, 3,5-dimethylbenzyl, 4-cyanobenzyl, 2-methoxybenzyl, 1-naphthyl, 2-naphthyl, 2-furyl, benzo[b]thiophenyl-2, 2-pyridinyl, piperonylyl, 1-adamantanecarbonyl, cyclohexyl, cyclopentyl, hexyl, valeryl, and iso-valeryl.

5. The compounds as claimed in claim 1 wherein the compounds of formula I are selected from (3R,5aS,6R,8aS,9R,12R,12aR)-11-(2-aminoethyl)-3,6,9-trimethyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-10(3H)-one (1); N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (2); 3,4-dichloro-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (3); 2,4-dichloro-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (4); 2,3,4,5-tetrachloro-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (5); 2-bromo-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (6); 4-iodo-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (7); 3,5-dinitro-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (8); 3,5-dimethyl-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (9); 4-cyano-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (10); 2-methoxy-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (11); N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12- epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)-1-naphthamide (12); N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)-2-naphthamide (13); N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)furan-2-carboxamide (14); N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzo[b]thiophene-2-carboxamide (15); N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)picolinamide (16); N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzo[d][1,3]dioxole-5-carboxamide (17); (3R,5R,7R)-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)adamantane-1-carboxamide (18); N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)cyclohexanecarboxamide (19); N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)cyclopentanecarboxamide (20); N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)hexanamide (21); N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)pentanamide (22); 3-methyl-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12- epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)butanamide (23).

6. A process for the preparation of Novel N-ethanamine-11-azaartemisinin compounds represented by formula I and its salts, said process comprising: (i) Treating artemisinin with ethylene diamine in a suitable solvent or mixture thereof at a temperature of -5 to 5 oC for 20-80 minutes to obtain N-ethanamine-11-azaartemisinin, (ii) Extracting the said product in a suitable solvent or mixture thereof, (iii) Adding a mineral acid and silica gel in a suitable solvent and stirring for 12 h, (iv) following the usual workup steps to obtain pure N-ethanamine-11-azaartemisinin. (v) dissolving the N-ethanamine-11-azaartemisinin in a solvent at a temperature in the range of 0 °C to 5 °C. (vi) Adding a base and stirring to obtain a solution (vii) Adding acid chloride to the solution and stirring for 30 min - 200 min till the reaction completes (viii) Adding water and an organic solvent and stirring for 5-10 min, (ix) Separating the organic layer from water. (x) Adding freshly prepared sodium hydrogen carbonate solution to the organic layer (xi) Drying the organic layer to get the crude compound.

7. The process as claimed in claim 6, wherein the acid chloride is selected from benzoyl chloride, 3,4-dichlorobenzoyl chloride, 2,4-dichlorobenzoyl chloride, 2,3,4,5-dichlorobenzoyl chloride, 2-bromobenzoyl chloride, 4-iodobenzoyl chloride, 3,5-dinitrobenzoyl chloride, 3,5-dimethylbenzoyl chloride, 4-cyanobenzoyl chloride, 2-methoxybenzoyl chloride, 1-naphthoyl chloride, 2-naphthoyl chloride, 2-furoyl chloride, benzo[b]thiophene-2-carbonyl chloride, pyridine-2-carbonyl chloride, piperonyloyl chloride, 1-adamantanecarbonyl chloride, cyclohexanecarbonyl chloride, cyclopentanecarbonyl chloride, hexanoyl chloride, pentanoyl chloride (valeryl chloride), and iso-valeryl chloride.

8. The process as claimed in claim 6, wherein the solvent is selected from the suitable solvent used for the reactions is selected from methanol, ethanol, chloroform dichloromethane, benzene, dry benzene, toluene, tetrahydrofuran, 1,2-dimethoxyethane, pyridine, tetrahydrofuran (THF), toluene, ethyl acetate, dimethyl formamide or mixture thereof.

9. The process as claimed in claim 12, wherein the base is selected from triethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium hydride, lithium diisopropylamide (LDA), potassium tert-butoxide.

10. A pharmaceutical composition comprising the Novel N-ethanamine-11-azaartemisinin compounds represented by formula I and its salts.

Description:FIELD OF INVENTION
The present invention relates to novel N-ethanamine-11-azaartemisinin and its amide derivatives, their process of preparation and antimalarial compositions comprising the same.

BACKGROUND OF THE INVENTION
Malaria is still one of the world’s most deadly disease that threatens nearly 40% yield of the world’s population and infects approximately 300 to 500 million people annually mainly in tropical and subtropical areas. It is estimated that around 1 to 3 million deaths occur every year due to malaria. In Africa alone, more than 1 million children under the age of 5 die of malaria each year.
Malaria is a vector borne disease and human infection is caused by four distinct species of a protozoan Plasmodium, namely P. vivax, P. falciparum, P. ovale and P. malariae. Malaria is transmitted by the bite of a vector, the female Anopheles mosquito which is responsible for its global epidemics.
Quite a number of natural products isolated from various plants and micro-organisms have shown potent antimalarial activity, thus acting as lead for further drug development.
Natural products as lead for malaria chemotherapy dates back to the early 18th century when bark of Cinchona tree was used in the treatment of fever by the natives of South America. It was in 1820 that quinine was isolated as active principle of the bark. Quinine is active against the trophozoites present in the erythrocytes but has no effect on exo-erythrocytic stages that develop in liver. Later on, several synthetic analogues of quinine i.e., chloroquine, mefloquine, primaquine were developed as antimalarial drugs and are still being used.

The isolation of artemisinin, a sesquiterpene lactone endoperoxide, from the Chinese traditional medicinal plant Artemisia annua marked a turning point in malaria treatment. Artemisinin and its semisynthetic derivatives, such as arteether and artemether, have showed enormous promise as innovative antimalarial drugs. These drugs are effective against both chloroquine-sensitive and chloroquine-resistant forms of Plasmodium falciparum, and they are now the preferred treatments for multidrug-resistant malaria.
Artemisinin was discovered to be the active principle of Artemisia annua, a Chinese traditional malaria medication, and its conversion to therapeutically useful derivatives: artemether, arteether, and artesunic acid was a breakthrough in malaria treatment, with high efficacy against both chloroquine-sensitive and chloroquine-resistant malaria. The 1,2,4-trioxane system found in Artemisinin molecules is critical to its bioactivity. The heme-mediated breakdown of the endoperoxide bridge generates carbon-centered free radicals, which serve as the compounds' mode of action. Carbon-centered free radicals promote the formation of alkylating heme and proteins, one of which is the translationally controlled tumor protein.
The inventors planned to create artemisinin derivatives and study their qualities in order to develop novel pharmacologically active compounds that can perform better than the parent compound.

The Artemisinin derivatives have great parenteral efficacy but are absorbed poorly when taken orally (Meshnick, S. R.; Taylor, T. E.; Kamchonwongpaisan, S. Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiol. Rev. 1996, 60, 301–315) Major research critically focused on the development of orally active new artemisinin derivatives as potent antimalarial and anticancer drugs.
The discovery by Chinese researchers that artemisinin, a component of Artemisia annua, is a potent antimalarial against safe strains of Plasmodium falciparum has prompted several organizations to begin research on this key lead molecule.
The further investigations revealed that peroxide activity is critical for the antimalarial effect of this family of chemicals. The labile peroxide and facile hydrolysis of the lactone by acid or base restricted the reactions that could be used to introduce new functional groups or modify existing ones. The majority of the subsidiaries organized thus far have been esters, ethers, carbonates, and urethanes of dihydroartemisinin loose hydroxyl group.
To increase the therapeutic value of artemisinin, a few subordinates have been developed in recent years. However, low water solubility, hepatic biodegradation, and a short half-life all undermine artemisinin's therapeutic potential.
Artemisinin subsidiaries that do not have these deficiencies will have a better chance of progressing to clinical trials. In this way, a thorough investigation is expected to improve the pharmacological characteristics of artemisinin subordinates.
Previously, Singh et al. J. Med. Chem. 2014, 57, 2489) have reported the synthesis of hydrazides from 11-amino-azaartemisinin. There has been significant study and research on artemisinin and its semisynthetic derivatives (Klayman, D. L. Science. 1985, 228, 1049; Luo, X. D.; Shen, C. C. Med. Res. Rev. 1987, 7, 29; Woerdenbag, H. J.; Moskal, T. A.; Pras, N.; Malingré, T. M.; El-Feraly, F. S.; Kampinga, H. H.; Konings, A. W. T. J. Nat. Prod. 1993, 56, 849; Wang, S.; Sasaki, T. Bioorg. Med. Chem. Lett. 2013, 23, 4424.; Leto, I.; Coronnello, M.; Righeschi, C.; Bergonzi, M. C.; Mini, E.; Rita, A. ChemMedChem. 2016, 11, 1745; Fröhlich, T.; Çapci Karagöz, C.; Reiter, C.; Tsogoeva, S. B. J. Med. Chem. 2016, 59, 7360; Zhou, Y.; Li, W.; Xiao, Y. ACS Chem. Biol. 2016, 11, 882; Liu, G.; Song, S.; Liu, X.; Zhang, A.; Miao, Z.; Ding, C. RSC Adv. 2016, 6, 98975; Frohlich, T.; Ndreshkjana, B.; Muenzner, J. K. ChemMedChem. 2017, 12, 226; Li, Z.; Li, Q.; Wu, J.; Wang, M.; Yu, J. Molecules. 2016, 21, 1331).

OBJECT OF THE INVENTION
It is an object of this invention to provide novel antimalarial compounds.

It is an object of this invention to provide novel antimalarial compounds with high efficacy towards malarial parasite and low toxicity to the human body.

It is an object of this invention to provide an efficient synthetic process for the preparation of novel antimalarial compound where the process is robust and green.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides Novel antimalarial compounds based on N-ethanamine-11-azaartemisinin.

In one embodiment, the present invention provides Novel N-ethanamine-11-azaartemisinin compounds represented by formula I and its salts,

where R is selected from a H; -C(O)R1, where R1 is (a) 6-14-membered substituted or unsubstituted aryl moiety selected from phenyl, -naphthyl, -biphenyl; (b) 5-14-membered substituted or unsubstituted heteroaryl moiety selected from -pyridinyl, -thienyl, -indolyl, -indolinyl; (c) 3-6-membered substituted or unsubstituted cycloalkyl moiety selected from cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl; (d) substituted or unsubstituted, linear or branched, saturated or unsaturated, -C1-C6- alkyl moiety selected from -methyl, -ethyl, n -propyl, iso-propyl, -n-butyl, -iso-butyl, -n-pentyl, -iso-pentyl, -neo-pentyl, -n-hexyl; -ethenyl, -propenyl, -butenyl, -pentenyl, -hexenyl; wherein substitution is with one or more moieties selected from but not limited to halogen, amino, nitro, cyano, hydroxy, alkoxy, thio, alkylthio group.

In one embodiment, the present invention provides a process for the preparation of Novel N-ethanamine-11-azaartemisinin compounds represented by formula I and its salts,

said process comprising:
(i) Treating artemisinin with ethylene diamine in a suitable solvent or mixture thereof at a temperature of -5 to 5 oC for 20-80 minutes to obtain N-ethanamine-11-azaartemisinin,
(ii) Extracting the said product in a suitable solvent or mixture thereof,
(iii) Adding a mineral acid and silica gel in a suitable solvent and stirring for 12 h,
(iv) following the usual workup steps to obtain pure N-ethanamine-11-azaartemisinin.
(v) dissolving the N-ethanamine-11-azaartemisinin in a solvent at a temperature in the range of 0 °C to 5 °C.
(vi) Adding a base and stirring to obtain a solution
(vii) Adding acid chloride to the solution and stirring for 30 min - 200 min till the reaction completes
(viii) Adding water and an organic solvent and stirring for 5-10 min,
(ix) Separating the organic layer from water.
(x) Adding freshly prepared sodium hydrogen carbonate solution to the organic layer
(xi) Drying the organic layer to get the crude compound.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides Novel antimalarial compounds based on N-ethanamine-11-azaartemisinin.
In one embodiment, the present invention provides Novel N-ethanamine-11-azaartemisinin compounds represented by formula I and its salts.

R is selected from a H; -C(O)R1, where R1 is (a) 6-14-membered substituted or unsubstituted aryl moiety selected from phenyl, -naphthyl, -biphenyl; (b) 5-14-membered substituted or unsubstituted heteroaryl moiety selected from -pyridinyl, -thienyl, -indolyl, -indolinyl; (c) 3-6-membered substituted or unsubstituted cycloalkyl moiety selected from cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl; (d) substituted or unsubstituted, linear or branched, saturated or unsaturated, -C1-C6-alkyl moiety selected from -methyl, -ethyl, n-propyl, iso-propyl, -n-butyl, -iso-butyl, -n-pentyl, -iso-pentyl, -neo-pentyl, -n-hexyl; -ethenyl, -propenyl, -butenyl, -pentenyl, -hexenyl; wherein substitution is with one or more moieties selected from but not limited to halogen, amino, nitro, cyano, hydroxy, alkoxy, thio, alkylthio group.
In one embodiment, the present invention provides Novel N-ethanamine-11-azaartemisinin compounds represented by formula I and its salts wherein R is -C(O)R1 and the said compounds are represented by formula II,

where R1 is selected from -benzyl, 3,4-dichlorobenzyl, 2,4-dichlorobenzyl, 2,3,4,5-dichlorobenzyl, 2-bromobenzyl, 4-iodobenzyl, 3,5-dinitrobenzyl, 3,5-dimethylbenzyl, 4-cyanobenzyl, 2-methoxybenzyl, 1-naphthyl, 2-naphthyl, 2-furyl, benzo[b]thiophenyl-2-, 2-pyridinyl, piperonylyl, 1-adamantanecarbonyl, cyclohexyl, cyclopentyl, hexyl, valeryl, and iso-valeryl.
In one embodiment, the novel 11-ethanamine azaartemisinin compounds of the present invention are selected from
(3R,5aS,6R,8aS,9R,12R,12aR)-11-(2-aminoethyl)-3,6,9-trimethyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-10(3H)-one (1);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (2);
3,4-dichloro-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (3);
2,4-dichloro-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (4);
2,3,4,5-tetrachloro-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (5);
2-bromo-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (6);
4-iodo-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (7);
3,5-dinitro-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (8);
3,5-dimethyl-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (9);
4-cyano-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (10);
2-methoxy-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (11);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12- epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)-1-naphthamide (12);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)-2-naphthamide (13);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)furan-2-carboxamide (14);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzo[b]thiophene-2-carboxamide (15);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)picolinamide (16);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzo[d][1,3]dioxole-5-carboxamide (17);
(3R,5R,7R)-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)adamantane-1-carboxamide (18);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)cyclohexanecarboxamide (19);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)cyclopentanecarboxamide (20);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)hexanamide (21);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)pentanamide (22);
3-methyl-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12- epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)butanamide (23).
Table 1. Novel N-ethanamine-11-azaartemisinin compounds.

S. No.
Compounds
Structure
1 1

2 2

3 3

4 4

5 5

6 6

7 7

8 8

9 9

10 10

11 11

12 12

13 13

14 14

15 15

16 16

17 17

18 18

19 19

20 20

21 21

22 22

23 23

Table 2. Physical properties of N-ethanamine-11-azaartemisinin compounds.

S.No
Compounds M.P. (°C) Yields (%)
1 1 100-103 96
2 2 75-77 88
3 3 98-100 75
4 4 80-84 92
5 5 90-93 81
6 6 104-107 73
7 7 Oil 68
8 8 94-98 72
9 9 76-78 91
10 10 92-95 86
11 11 166-169 85
12 12 95-99 87
13 13 156-158 94
14 14 88-91 93
15 15 204-206 92
16 16 154-157 79
17 17 170-173 90
18 18 90-93 95
19 19 70-72 75
20 20 Oil 71
21 21 Oil 78
22 22 Oil 86
23 23 Oil 88

In one embodiment, the present invention provides a pharmaceutical composition comprising the Novel N-ethanamine-11-azaartemisinin compounds represented by formula I and its salts.
The present invention also provides a process for the preparation of Novel N-ethanamine-11-azaartemisinin compounds represented by formula I and its salts. The general process of synthesizing compounds of the present invention is given as below:

In one embodiment, the present invention also provides a process for the preparation of Novel N-ethanamine-11-azaartemisinin compounds represented by formula I and its salts,

said process comprising:
(i) Treating artemisinin with ethylene diamine in a suitable solvent or mixture thereof at a temperature of -5 to 5 oC for 20-80 minutes to obtain N-ethanamine-11-azaartemisinin,
(ii) Extracting the said product in a suitable solvent or mixture thereof,
(iii) Adding a mineral acid and silica gel in a suitable solvent and stirring for 12 h,
(iv) following the usual workup steps to obtain pure N-ethanamine-11-azaartemisinin.
(v) dissolving the N-ethanamine-11-azaartemisinin in a solvent at a temperature in the range of 0 °C to 5 °C.
(vi) Adding a base and stirring to obtain a solution
(vii) Adding acid chloride to the solution and stirring for 30 min - 200 min till the reaction completes
(viii) Adding water and an organic solvent and stirring for 5-10 min,
(ix) Separating the organic layer from water.
(x) Adding freshly prepared sodium hydrogen carbonate solution to the organic layer
(xi) Drying the organic layer to get the crude compound

The suitable solvent used for the reactions is selected from methanol, ethanol, chloroform dichloromethane, benzene, dry benzene, toluene, tetrahydrofuran, 1,2-dimethoxyethane. Pyridine, tetrahydrofuran (THF), toluene, ethyl acetate, dimethyl formamide or mixture thereof.
In one embodiment the solvent at step (i) is a mixture of chloroform and methanol.
In one embodiment the solvent at step (ii) is chloroform.
The mineral acid for used in the present invention is selected from sulphuric acid, hydrochloric acid, nitric acid, phosphoric acid and mixture thereof.
In one embodiment the mineral acid at step (iii) is sulphuric acid.
In one embodiment the solvent at step (iv) is chloroform.
The base used in the reaction at step (vi) is selected from triethylamine, pyridine, 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU), sodium hydride, Lithium diisopropylamide (LDA), Potassium tert-butoxide.
In one embodiment the base at step (vi) triethylamine is used.
The acid chlorides used in the reaction are compounds R1COCl wherein R1 is selected from (a) 6-14-membered substituted or unsubstituted aryl moiety selected from phenyl, -naphthyl, -biphenyl; (b) 5-14-membered substituted or unsubstituted heteroaryl moiety selected from -pyridinyl, -thienyl, -indolyl, -indolinyl; (c) 3-6-membered substituted or unsubstituted cycloalkyl moiety selected from cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl; (d) substituted or unsubstituted, linear or branched, saturated or unsaturated, -C1-C6- alkyl moiety selected from -methyl, -ethyl, n -propyl, iso-propyl, -n-butyl, -iso-butyl, -n-pentyl, -iso-pentyl, -neo-pentyl, -n-hexyl; -ethenyl, -propenyl, -butenyl, -pentenyl, -hexenyl; wherein substitution is with one or more moieties selected from but not limited to halogen, amino, nitro, cyano, hydroxy, alkoxy, thio, alkylthio group.
In one embodiment, the acid chloride (R1COCl) used in the reaction at step (vii) are compounds wherein R1 is selected from -benzyl, 3,4-dichlorobenzyl, 2,4-dichlorobenzyl, 2,3,4,5-dichlorobenzyl, 2-bromobenzyl, 4-iodobenzyl, 3,5-dinitrobenzyl, 3,5-dimethylbenzyl, 4-cyanobenzyl, 2-methoxybenzyl, 1-naphthyl, 2-naphthyl, 2-furyl, benzo[b]thiophenyl-2, 2-pyridinyl, piperonylyl, 1-adamantanecarbonyl, cyclohexyl, cyclopentyl, hexyl, valeryl, and iso-valeryl.
The products are purified by conventional processes known in the art such as crystallisation, distillation, sublimation, differential extraction, chromatography and the like.

Examples:
Example 1: Synthesis of N-ethanamine-11-azaartemisinin (1): (3R,5aS,6R,8aS,9R,12R,12aR)-11-(2-aminoethyl)-3,6,9-trimethyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-10(3H)-one.
To a stirred solution of ethylene diamine (35.51 mL, 531.29 mmol, 25 equiv) in a mixture of chloroform and methanol at 0 oC, was added artemisinin (6.0 g, 21.28 mmol) dissolved in chloroform gradually over five min. and the reaction mixture was allowed to stir for 1 h at the same temperature. The reaction mixture was diluted with water (300 mL) and extracted with chloroform. To the combined organic layer, 20% H2SO4 (40 mL) and silica gel (20 g) was added and stirred for 12 h at rt. The reaction mixture was filtered, and silica gel was washed with CHCl3 (2 × 100 mL). The combined organic layer was washed with water (2 × 100 mL), dried over anhyd. Na2SO4, concentrated under reduced pressure at rt and without using column chromatography, pure N-ethanamine-11-azaartemisinin 2 (5.7 g, 96% yield) as a brown solid, m.p. 100-103 oC was obtained.

Example 2: Synthesis of N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (2).
To the cooled stirred slurry, benzoyl chloride (85.94 µL, 0.73 mmol, 1.2 equiv) was dissolved in 3 mL dry benzene was added and the whole reaction mixture was granted to agitate for 2 h at the same temperature. After observing the TLC, the reaction was ceased with distilled water and diethyl ether. To the reaction mixture 10 mL distilled water was added and the solution was allowed it to stir for 10 minutes. The desired compound was removed with diethyl ether (3 x 5 mL). The organic solution so derived was treated with freshly prepared sodium hydrogen carbonate solution (2 x 5 mL). The mixed organic layers were dried over sodium sulphate and distilled over rotatory evaporator to get the crude product. The required compound was derived after column chromatography using silica gel (60-120 mesh size) as Ethyl acetate/Hexane (10:90) as mobile phase. The suitable compound 2 was obtained in (88%) yield as a white solid.
Following the above procedure, the following 11-ethanamine azaartemisinin amides, as shown in Table-1 and Table-2, were prepared.

Example 3: In vitro screening of the novel compounds:
(a) Plasmodium falciparum culture: Plasmodium falciparum 3D7 culture was maintained regularly in human O+ RBCs supplemented with RPMI-1640 (Invitrogen, USA) media containing 0.5% Alumax I (Invitrogen, USA), 25mM Na2CO3 (SIGMA, USA), 25mM HEPES (SRL Pvt. Ltd.), 0.1mM Hypoxanthine (Invitrogen, USA), 10ug/ml Gentamicin (Invitrogen, USA) in a mixed gas environment (5% O2, 5% CO2, and 90% N2) at 37 oC. The culture was regularly monitored by preparing thin smears and staining with GIEMSA.

(b) In vitro screening of the compounds: The half-maximal inhibitory concentration (IC50) of compounds was analyzed on the 3D7 strain of Plasmodium falciparum. The assay was performed using tightly synchronized ring-stage parasites at 1% parasitemia. Synchronization was achieved by treating the culture with five pellet volumes of 5% sorbitol for 10 minutes at 37 °C. The sorbitol was removed by pelleting the culture at 1500 rpm for 5 minutes, followed by two washes with incomplete RPMI-1640 to ensure complete removal of sorbitol. The pellet was then resuspended in complete RPMI-1640. When the parasites reached the 10–12-hour ring stage, at 1% parasitemia and 2% hematocrit, 100 µL of culture along with varying concentrations of the compounds were seeded per well. The concentration range of the compounds used was from 10 nM to 0.31 nM (10 nM, 5 nM, 2.5 nM, 1.25 nM, 0.625 nM, 0.3125 nM). Wells not incubated with the compound served as untreated controls, and parasites treated with 8 nM artemisinin were used as positive controls. After 72 hours, thin smears from one well of each concentration were prepared and stained with Giemsa. The relative inhibitory effect of the compounds was determined by counting the number of infected erythrocytes among 2000 uninfected erythrocytes in the Giemsa-stained smears.

Percent growth inhibition was determined using the formula:
%Growth Inhibition = [1-(Treated Control)] ×100
The values were plotted on a non-linear regression curve using GraphPad Prism 8.0 to determine the IC50 value. The result are tabulated below in Table 3:

S.No. Code Structure IC50 (nM)
1. 1
1.182
2. 13
2.505
3. 14 2.067
4. 18 1.933

The foregoing description and examples are not intended to limit the scope of the invention and have been set forth merely to illustrate the invention. Modifications of the embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, and the invention should be construed broadly as including all variations within the scope of the description and claims.
, Claims:WE CLAIM:
1. Novel N-ethanamine-11-azaartemisinin compounds represented by formula I and its salts.

R is selected from a H; -C(O)R1, where R1 is (a) 6-14-membered substituted or unsubstituted aryl moiety selected from phenyl, -naphthyl, -biphenyl; (b) 5-14-membered substituted or unsubstituted heteroaryl moiety selected from -pyridinyl, -thienyl, -indolyl, -indolinyl; (c) 3-6-membered substituted or unsubstituted cycloalkyl moiety selected from cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl; (d) substituted or unsubstituted, linear or branched, saturated or unsaturated, -C1-C6- alkyl moiety selected from -methyl, -ethyl, n -propyl, iso-propyl, -n-butyl, -iso-butyl, -n-pentyl, -iso-pentyl, -neo-pentyl, -n-hexyl; -ethenyl, -propenyl, -butenyl, -pentenyl, -hexenyl; wherein substitution is with one or more moieties selected from but not limited to halogen, amino, nitro, cyano, hydroxy, alkoxy, thio, alkylthio group.

2. The compounds as claimed in claim 1, wherein the R is H, said compound being represented by formula 1

3. The compounds as claimed in claim 1 wherein R is -C(O)R1.
4. The compounds as claimed in claim 3, wherein R1 is selected from -benzyl, 3,4-dichlorobenzyl, 2,4-dichlorobenzyl, 2,3,4,5-dichlorobenzyl, 2-bromobenzyl, 4-iodobenzyl, 3,5-dinitrobenzyl, 3,5-dimethylbenzyl, 4-cyanobenzyl, 2-methoxybenzyl, 1-naphthyl, 2-naphthyl, 2-furyl, benzo[b]thiophenyl-2, 2-pyridinyl, piperonylyl, 1-adamantanecarbonyl, cyclohexyl, cyclopentyl, hexyl, valeryl, and iso-valeryl.
5. The compounds as claimed in claim 1 wherein the compounds of formula I are selected from
(3R,5aS,6R,8aS,9R,12R,12aR)-11-(2-aminoethyl)-3,6,9-trimethyldecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-10(3H)-one (1);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (2);
3,4-dichloro-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (3);
2,4-dichloro-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (4);
2,3,4,5-tetrachloro-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (5);
2-bromo-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (6);
4-iodo-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (7);
3,5-dinitro-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (8);
3,5-dimethyl-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (9);
4-cyano-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (10);
2-methoxy-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzamide (11);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12- epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)-1-naphthamide (12);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)-2-naphthamide (13);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)furan-2-carboxamide (14);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzo[b]thiophene-2-carboxamide (15);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)picolinamide (16);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)benzo[d][1,3]dioxole-5-carboxamide (17);
(3R,5R,7R)-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)adamantane-1-carboxamide (18);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)cyclohexanecarboxamide (19);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)cyclopentanecarboxamide (20);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)hexanamide (21);
N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)pentanamide (22);
3-methyl-N-(2-((3R,5aS,6R,8aS,9R,12aR)-3,6,9-trimethyl-10-oxodecahydro-3,12- epoxy[1,2]dioxepino[4,3-i]isoquinolin-11(12H)-yl)ethyl)butanamide (23).
6. A process for the preparation of Novel N-ethanamine-11-azaartemisinin compounds represented by formula I and its salts,

said process comprising:

(i) Treating artemisinin with ethylene diamine in a suitable solvent or mixture thereof at a temperature of -5 to 5 oC for 20-80 minutes to obtain N-ethanamine-11-azaartemisinin,
(ii) Extracting the said product in a suitable solvent or mixture thereof,
(iii) Adding a mineral acid and silica gel in a suitable solvent and stirring for 12 h,
(iv) following the usual workup steps to obtain pure N-ethanamine-11-azaartemisinin.
(v) dissolving the N-ethanamine-11-azaartemisinin in a solvent at a temperature in the range of 0 °C to 5 °C.
(vi) Adding a base and stirring to obtain a solution
(vii) Adding acid chloride to the solution and stirring for 30 min - 200 min till the reaction completes
(viii) Adding water and an organic solvent and stirring for 5-10 min,
(ix) Separating the organic layer from water.
(x) Adding freshly prepared sodium hydrogen carbonate solution to the organic layer
(xi) Drying the organic layer to get the crude compound.

7. The process as claimed in claim 6, wherein the acid chloride is selected from benzoyl chloride, 3,4-dichlorobenzoyl chloride, 2,4-dichlorobenzoyl chloride, 2,3,4,5-dichlorobenzoyl chloride, 2-bromobenzoyl chloride, 4-iodobenzoyl chloride, 3,5-dinitrobenzoyl chloride, 3,5-dimethylbenzoyl chloride, 4-cyanobenzoyl chloride, 2-methoxybenzoyl chloride, 1-naphthoyl chloride, 2-naphthoyl chloride, 2-furoyl chloride, benzo[b]thiophene-2-carbonyl chloride, pyridine-2-carbonyl chloride, piperonyloyl chloride, 1-adamantanecarbonyl chloride, cyclohexanecarbonyl chloride, cyclopentanecarbonyl chloride, hexanoyl chloride, pentanoyl chloride (valeryl chloride), and iso-valeryl chloride.
8. The process as claimed in claim 6, wherein the solvent is selected from the suitable solvent used for the reactions is selected from methanol, ethanol, chloroform dichloromethane, benzene, dry benzene, toluene, tetrahydrofuran, 1,2-dimethoxyethane, pyridine, tetrahydrofuran (THF), toluene, ethyl acetate, dimethyl formamide or mixture thereof.
9. The process as claimed in claim 12, wherein the base is selected from triethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium hydride, lithium diisopropylamide (LDA), potassium tert-butoxide.
10. A pharmaceutical composition comprising the Novel N-ethanamine-11-azaartemisinin compounds represented by formula I and its salts.