FIELD OF INVENTION

The present invention relates to compounds of formula (I), or their isotopic forms, stereoisomers, tautomers, or pharmaceutically acceptable salt (s) thereof as prodrugs of abiraterone. The present invention also describes method of making such compounds, pharmaceutical compositions comprising such compounds and the use of compounds of formula (I).

BACKGROUND OF THE INVENTION

Prostate cancer is a cancer that occurs in the prostate, a small walnut-shaped gland in men that produces the seminal fluid that nourishes and transports sperm. Prostate cancer is one of the most common types of cancer in men. Prostate cancer is the second most common cancer diagnosed in men living in the U.S. Prostate cancer develops mainly in older men and African-American men. About 6 cases in 10 are diagnosed in men aged 65 or older, and it is rare before the age of 40. The average age at the time of diagnosis is about 66. Prostate cancer is highly dependent on androgen levels. The testes secrete 95% of testosterone, and the remaining 5% is produced by the adrenal glands. The diagnosis is made by prostate-specific antigen (PSA) screening, a digital rectal examination, and genitourinary symptoms. A small percentage of men may present with symptoms of metastatic disease such as bone pain. PSA is a marker that is specific to the prostate.

Abiraterone acetate (Zytiga ^® ) is approved in the United States by the FDA in April 2011, in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. The prescribing information for Zytiga ^® tablets recommends 1,000 mg (4 x 250 mg tablets) administered orally once daily in combination with prednisone (5 mg) administered orally twice daily. Abiraterone acetate (17-[pyridin-3-yl] androsta-5,16-dien-3-yl acetate) is absorbed through the gut when administered orally and then deacetylated in the liver to the active drug abiraterone. The abiraterone acetate is a lipophilic compound that is practically insoluble in water (Zytiga ^® Full Prescribing Information, 2012, Janssen Biotech Inc., Section 11). Further, Yonsa ^® (Abiraterone acetate) was approved by USFDA in May 2018, for the treatment of patients with metastatic castration-resistant prostate cancer. The recommended dose of Yonsa ^® is 500 mg (4 xl25 mg tablets) administered orally once daily in combination with methylprednisolone 4 mg administered orally twice daily.

Structure of Abiraterone acetate:

Due to its highly lipophilic nature and low aqueous solubility in the gastrointestinal tract, the oral bioavailability of abiraterone acetate is limited. The insolubility of abiraterone acetate allows for its preparation in capsule form for oral dosing and this precludes intravenous (IV) administration which is used for other treatments for prostate cancer, such as cabazitaxel ( Sartor , O. et al. The Oncologist 2011, 16: 1487-1497). After an oral dose of abiraterone acetate, 88% of the administered drug gets excreted unchanged through feces, and another 5% is excreted in the urine ( Ryan CJ et al, J Clin Oncol. 2010;28(9): 1481-1488). Therefore, >90% of the administered drug gets excreted and is not used for its intended treatment.

The abiraterone acetate shows greater food effect and significant inter individual pharmacokinetic variability. Further, low water solubility of abiraterone acetate leads to under/over dosing. Hence strict patient compliance is required to achieve the intended dosing. Additionally, abiraterone acetate which itself is a prodrug of abiraterone is a substrate of the CYP3A4 liver enzyme which can lead to potential drug-drug interactions with other drugs which may be taken together that inhibit or induce CYP3A4 enzyme. The development of soluble abiraterone prodrugs would allow for IV dosing, which bypasses the liver and can reduce some of the above mentioned problems.

The PCT publications, WO2018/071544, CN102477061, WO2015/200837, WO2014/111815 and WO2010/091306 disclose some of the abiraterone derivatives / prodrugs, or analogs but as of now no prodrug of abiraterone is launched in the market. Due to the poor solubility and oral bioavailability of the abiraterone acetate, currently marketed products i.e.. Zytiga ^® and Yonsa ^® , need to be administered at a higher dose to reach the efficacy concentration. Therefore, there is an un-met need to discover and develop novel prodrugs of abiraterone showing improved solubility, enhanced oral bioavailability, and lesser food effect. Such prodrugs of abiraterone will have efficacy at much lower doses and also may result in reduction of food effect. The abiraterone prodrugs of the instant invention possess improved solubility, oral bioavailability, and highly reduced food effect compared to abiraterone acetate, which will make them useful compounds to further develop for the treatment of cancers.

SUMMARY OF THE INVENTION

In first aspect, the present invention relates to novel prodrugs of abiraterone having the compound of formula (I),

wherein:

R ¹ is selected from hydrogen, halogen, hydroxy, NH ₂ , -CH ₂ OH, -(C _1-6 )-alkyl, halo(C _1-6 )-alkyl, -(C _{3- 6} )-cycloalkyl, -(C _6-10 )-aryl, alkylaryl or -(C _5-10 )-heteroaryl;

R ² is selected from hydrogen, halogen, hydroxy, NH ₂ , -CH ₂ OH, -(C _1-6 )-alkyl, halo(C _1-6 )-alkyl, -(C _{3- 6} )-cycloalkyl, -(C _6-10 )-aryl, alkylaryl or -(C _5-10 )-heteroaryl;

R ³ is selected from hydrogen, -(C _1-6 )-alkyl hydroxy, -(C _1-6 )-alkyl, halo(C _1-6 )-alkyl, -(C _3-6 )-cycloalkyl, -(C _6-10 )-aryl, alkylaryl or -(C _5-10 )-heteroaryl;

R ⁴ is selected from hydrogen, halogen, hydroxy, NH ₂ , -(C _1-6 )-alkyl hydroxy, -(C _1-6 )-alkyl-oxy-(C _1-6 )- alkyl, -CO-(C _1-6 )-alkyl, -CO-(C _1-6 )-cycloalkyl, (C _1-6 )-alkyl, -COCMC^-alkyl, halo(C _1-6 )-alkyl, -(C _3-6 )-cycloalkyl, -(C _6-10 )-aryl, alkylaryl, alkylheteroaryl, or -(C _5-10 )-heteroaryl; and R ⁵ is selected from hydrogen, halogen, hydroxy, NH ₂ , -(C _1-6 )-alkyl hydroxy, -(C _1-6 )-alkyl-oxy-(C _1-6 )- alkyl, -CO-(C _1-6 )-alkyl, -CO-(C _1-6 )-cycloalkyl, -(C _1-6 )-alkyl, -COO-(C _1-6 )-alkyl, halo(C _1-6 )-alkyl, -(C _3-6 )-cycloalkyl, -(C _6-10 )-aryl, alkylaryl, alkylheteroaryl or -(C _5-10 )-heteroaryl; Optionally R ⁴ and R ⁵ combine together with nitrogen to form a 4- to 10-membered aromatic or non-aromatic, monocyclic or bicyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the said ring is unsubstituted or substituted with one or more groups selected from carbonyl, halogen, hydroxy, -(C _1-6 )-alkyl and halo(C _1-6 )-alkyl; or an isotopic form, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to the processes for preparing the compound of formula (I), or an isotopic form, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of at least one compound of formula (I), or an isotopic form, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients or carriers. In yet another aspect, the present invention relates to the compound of formula (I), or an isotopic form, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use as a selective inhibitor of 17-α-hydroxylase/C 17,20 lyase.

In yet another aspect, the present invention relates to the compound of formula (I), or an isotopic form, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancers.

In yet another aspect, the present invention relates to the compound of formula (I), or an isotopic form, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of prostate cancer.

In yet another aspect, the present invention relates to the compound of formula (I), or an isotopic form, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of metastatic castration-resistant prostate cancer.

In yet another aspect, the present invention relates to the compound of formula (I), or an isotopic form, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of breast cancer.

In yet another aspect, the present invention relates to the compound of formula (I), or an isotopic form, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovarian cancer.

In another aspect, the present invention relates to a method for the treatment of cancers related to 17-α-hydroxylase/C 17,20 lyase, comprising administering to a patient in need thereof, a therapeutically effective amount of the compound of formula (I), or an isotopic form, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention relates to use of the compound of formula (I), or an isotopic form, a stereoisomer, a tautomer, or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer related to 17-α-hydroxylase/C 17,20 lyase.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:

The term, “-(C _1-6 )-alkyl” as used herein refers to branched or straight chain aliphatic hydrocarbon containing 1 to 6 carbon atoms. Examples of -(C _1-6 )-alkyl include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert- butyl. Preferably -(C _1-6 )-alkyl is methyl, ethyl isopropyl, tert- butyl, or isobutyl.

The term, “halogen” or “halo” as used herein refers to fluorine, chlorine, bromine or iodine. Preferably, halogen is fluorine, chlorine or bromine. More preferably halogen is fluorine or chlorine. The term “halo(C _1-6 )-alkyl” as used herein refers to -(C _1-6 )-alkyl as defined above wherein one or more hydrogen of the same or different carbon atom is substituted with same or different halogens. Examples of halo(C _1-6 )-alkyl include fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, dichloromethyl, trifluoromethyl, difluoroethyl, and the like.

The term, “-(C _3-6 )-cycloalkyl” as used herein refers to saturated monocyclic hydrocarbon ring containing from three to six carbon atoms. Examples of -(C _3-6 )-cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term, “-(C _6-10 )-aryl” as used herein refers to aromatic hydrocarbon rings containing six to ten carbon atoms. Examples of-(C _6-10 )-aryl group include phenyl or naphthyl.

The term, “-(C _5-10 )-heteroaryl” as used herein refers to aromatic monocyclic or aromatic bicyclic heterocycle ring systems containing five to ten atoms. Examples of -(C _5-10 )-heteroaryl group include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, fiiryl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyrazolyl, thiazolyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzodioxolyl, benzofuranyl, benzofurazanyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepinyl, benzoxazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, and N -oxides thereof.

The term, “alkylheteroaryl” as used herein refers to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted.

The term, “alkylaryl” as used herein refers to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

The phrase, “prodrug” as used herein refers to the chemical moiety which gets converted into the active drug within the body through enzymatic or non-enzymatic reactions.

The phrase, “therapeutically effective amount” is defined as an amount of a compound of the present invention that (i) treats the particular disease, condition or disorder (ii) eliminates one or more symptoms of the particular disease, condition or disorder (iii) delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The term, “isotopic form” as used herein refers to the compound of formula (I) wherein one or more atoms of compound of formula (I) are substituted by their respective isotopes. For example, isotopes of hydrogen include ² H (deuterium) and ³ H (tritium).

The term, “stereoisomers” as used herein refers to isomers of the compound of formula (I) that differ in the arrangement of their atoms in space. Compounds disclosed herein may exist as single stereoisomer, racemates and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomer, racemates and mixtures thereof are intended to be within the scope of the present invention.

The term, “pharmaceutically acceptable salt” as used herein refers to salts of the active compound i.e. the compound of formula (I), and are prepared by reaction with the appropriate acid or acid derivative, depending on the particular substituents found on the compounds described herein.

The term “proliferative disease” as used herein refers to a disease caused by excessive proliferation of cells and turnover of cellular matrix. Non-limiting examples of proliferative diseases include cancers, atherosclerosis, arthritis (e.g. rheumatoid arthritis), psoriasis, fibrosis (e.g. pulmonary fibrosis, idiopathic pulmonary fibrosis), scleroderma and cirrhosis (e.g. cirrhosis of the liver).

The term “treating” or “treatment” as used herein refers to inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) .

The term, “patient” as used herein refers to an animal. Preferably the term “patient” refers to mammal. The term mammal includes animals such as mice, rats, dogs, rabbits, pigs, monkeys, horses, pigeons, xenopus laevis, zebrafish, guinea pigs and humans. More preferably the patient is human.

EMBODIMENTS

The present invention encompasses all the compounds described by the compound of formula (I) without limitation, however, preferred aspects and elements of the invention are discussed herein in the form of the following embodiments.

In second aspect, the present invention relates to the compound of formula (I), or an isotopic form, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention relates to the compound of formula (I), wherein:

R ¹ is selected from hydrogen, halogen, hydroxy, NH ₂ , -CH ₂ OH, -(C _1-6 )-alkyl, halo(C _1-6 )-alkyl, -(C _{3- 6} )-cycloalkyl, -(C _6-10 )-aryl, alkylaryl or -(C _5-10 )-heteroaryl;

R ² is selected from hydrogen, halogen, hydroxy, NH ₂ , -CH ₂ OH, -(C _1-6 )-alkyl, halo(C _1-6 )-alkyl, -(C _{3- 6} )-cycloalkyl, -(C _6-10 )-aryl, alkylaryl or -(C _5-10 )-heteroaryl;

R ³ is selected from hydrogen, -(C _1-6 )-alkyl hydroxy, -(C _1-6 )-alkyl, halo(C _1-6 )-alkyl, (C _3-6 ) -cycloalkyl, -(C _6-10 )-aryl, alkylaryl or -(C _5-10 )-heteroaryl;

R ⁴ is selected from hydrogen, hydroxy, NH ₂ , -(C _1-6 )-alkyl hydroxy, -(C _1-6 )-alkyl-oxy-(C _1-6 )-alkyl, -(C _1-6 )-alkyl, -CO-(C _1-6 )-CYcloalkvL -COCMC^-alkyl, -(C _1-6 )-alkyl, halo(C _1-6 )-alkyl, -(C _3-6 )- cycloalkyl, -(C _6-10 )-aryl, alkylaryl, alkylheteroaryl, or -(C _5-10 )-heteroaryl; and R ⁵ is selected from hydrogen, hydroxy, NH ₂ , -(C _1-6 )-alkyl hydroxy, -(C _1-6 )-alkyl-oxy-(C _1-6 )-alkyl, -CO-(C _1-6 )-alkyl, -CO-(C _1-6 )-cycloalkyl, -(C _1-6 )-alkyl, -COO-(C _1-6 )-alkyl, halo(C _1-6 )-alkyl, -(C _3-6 )- cycloalkyl, -(C _6-10 )-aryl, alkylaryl, alkylheteroaryl or -(C _5-10 )-heteroaryl; Optionally R ⁴ and R ⁵ combine together with nitrogen to form a 4- to 10-membered aromatic or non-aromatic, monocyclic or bicyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur; wherein the said ring is unsubstituted or substituted with one or more groups selected from carbonyl, halogen, hydroxy, -(C _1-6 )-alkyl and halo(C _1-6 )-alkyl; or an isotopic form, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to the compound of formula (I), wherein: R ⁴ is independently selected from hydrogen, halogen, hydroxy, NH ₂ , -(C _1-6 )-alkyl hydroxy, -(C _1-6 )- alkyl-oxy-(C _1-6 )-alkyl, -CO-(C _1-6 )-alkyl, -CO-(C _1-6 )-cycloalkyl, -(C _1-6 )-alkyl, -COO-(C _1-6 )-alkyl, halo(C _1-6 )-alkyl, -(C _3-6 )-cycloalkyl, -(C _6-10 )-aryl, alkylaryl, alkylheteroaryl, or -(C _5-10 )-heteroaryl; and

R ⁵ is independently selected from hydrogen, halogen, hydroxy, NH ₂ , -(C _1-6 )-alkyl hydroxy, -(C _1-6 )- alkyl-oxy-(C _1-6 )-alkyl, -(C _1-6 )-alkyl, -CO-(C _1-6 )-cycloalkyl, -(C _1-6 )-alkyl, -COO-(C _1-6 )-alkyl, halo(C _1-6 )-alkyl, -(C _3-6 )-cycloalkyl, -(C _6-10 )-aryl, alkylaryl, alkylheteroaryl, or -(C _5-10 )-heteroaryl; wherein R ¹ , R ² , and R ³ are as defined as above; or an isotopic form, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to the compound of formula (I), wherein: R ⁴ and R ⁵ combine together with nitrogen to form a 4- to 10-membered aromatic or non-aromatic, monocyclic or bicyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur; wherein the said ring is unsubstituted or substituted with one or more groups selected from carbonyl, halogen, hydroxy, -(C _1-6 )-alkyl and halo(C _1-6 )-alkyl; wherein R ¹ , R ² , and R ³ are as defined as above; or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to the compound of formula (I), wherein: R ⁴ and R ⁵ combine together with nitrogen to form a 4- to 10-membered aromatic monocyclic or bicyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur; wherein the said ring is unsubstituted or substituted with one or more groups selected from carbonyl, halogen, hydroxy, -(C _1-6 )-alkyl and halo(C _1-6 )-alkyl; wherein R ¹ , R ² , and R ³ are as defined as above; or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to the compound of formula (I), wherein: R ⁴ and R ⁵ combine together with nitrogen to form a 8- to 10- membered bicyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur; wherein the said ring is unsubstituted or substituted with one or more groups selected from carbonyl, halogen, hydroxy, -(C _1-6 )-alkyl and halo(C _1-6 )-alkyl; or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to the compound of formula (I), wherein: R ⁴ and R ⁵ combine together with nitrogen to form a 4- to 10-membered non-aromatic, monocyclic or bicyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur; wherein the said ring is unsubstituted or substituted with one or more groups selected from carbonyl, halogen, hydroxy, -(C _1-6 )-alkyl and halo(C _1-6 )-alkyl; or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to the compound of formula (I), wherein: R ⁴ and R ⁵ combine together with nitrogen to form a 4- to 10- membered non-aromatic hetero cyclic ring; represents the point of attachment;

X is independently selected from -CH ₂ , O, CO, NR ⁶ , S, SO, SO ₂ , PR ^1a , PO ₂ R ^1a ;

R ⁶ is independently selected from hydrogen, -CO-alkyl, -(C _1-6 )-alkyl, and -SO ₂ -alkyl; n is 0 to 5; wherein R ^1a is selected from hydrogen, halogen, hydroxy, NH ₂ , -CH ₂ OH, -(C _1-6 )-alkyl, halo(C _1-6 )-alkyl, -(C _{3- 6} )-cycloalkyl, -(C _6-10 )-aryl, alkylaryl or -(C _5-10 )-heteroaryl;

R ¹ , R ² , and R ³ are as defined as above; or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to the process for the preparation of the compound of formula (I) or a pharmaceutically acceptable salt thereof. The process for the preparation of the compound of formula (I) is given in the general scheme-1, 2, and 3 wherein all the groups are as defined above.

In another embodiment, the preferred compound of the invention is selected from the group consisting of:

(2-Methylamino-acetylamino)-aceticacid 10,13 -dimethyl- 17 -pyridin-3 -yl- 2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]ph enanthren-3-yl ester; (2-Ethylamino-acetylamino)-aceticacid 10,13-dimethyl- 17-pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; (2-Isopropylamino-acetylamino)-aceticacid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; (2-tert-Butylamino-acetylamino)-aceticacid 10,13-dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester;

(2-Isobutyl amino -acetylamino) -aceticacid 10,13 -dimethyl - 17 -pyridin-3 -yl -

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; (2-Cyclopentylamino-acetylamino)-acetic acid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; (2-Cyclopropylamino-acetylamino)-acetic acid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester;

[2-( 1 -Phenyl -ethylamino) -acetylamino] -acetic acid 10,13 -dimethyl - 17 -pyridin-3 -yl -

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester;

(2-Piperazin- 1 -yl-acetylamino)-aceticacid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; [2-(4-Methyl-piperazin-l-yl)-acetyl amino]-acetic acid 10,13-dimethyl-17-pyridin-3-yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; (2-Morpholin-4-yl-acetylamino)-acetic acid 10,13-dimethyl-17-pyridin-3-yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; 2-(2-Ethylamino-acetylamino)-propionic acid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; 2-(2-Isopropylamino-acetylamino)-propionic acid 10,13-dimethyl-17-pyridin-3-yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; 2-(2-tert-Butylammo-acctylamino)-propionic acid 10,13-dimethyl-17-pyridin-3-yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; 2-(2-Phenylamino-acetylamino) -propionic acid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; 2-(2-Ethylamino-acetylamino)-3 -methyl -butyric acid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; 2-(2-Isopropylamino-acetylamino)-3-methyl-butyric acid 10,13-dimethyl-17-pyridin-3-yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester;

2 -( 2 -tert- B uty 1 am i n o -acc ty 1 am i n o ) -3 -methyl -butyric acid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; [(2-tert-Butylamino-acetyl)-methyl-amino] -acetic acid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; (2-amino-acetylamino)-acetic acid 10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,10,11,12,13,14,15 - dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ester;

(2-Amino-3-hydroxy-propionyl-amino)-acetic acid 10,13-dimethyl-17-pyridin-3-yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; (2-amino-propionylamino)-acetic acid 10,13-dimethyl-17-pyridin-3-yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; 2-(2-amino-acetylamino)-propionic acid 10,13-dimethyl-17-pyridin-3-yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; 2-(2-amino-acetylamino)-3-methyl-butyric acid 10,13-dimethyl-17-pyridin-3-yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; 2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-prop ionic acid 10,13-dimethyl-17- pyridin-3-yl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cy clopenta[a]phenanthren-3-yl ester; [2-(2,2-Dimethyl-propionylamino)-3-hydroxy-propionyl]-methyl -amino-acetic acid 10,13- dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,10,11,12,13,14,15-dodec ahydro-1H- cyclopenta[a]phenanthren-3-yl ester;

[2-(tert-Butoxy carbonyl -isopropyl-amino)-acetylamino] -acetic acid 10,13 -dimethyl- 17 -pyridin-3 - yl-2,3,4,7,8,9, 10,11,12, 13,14, 15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ester; and [2-( Acetyl -isopropyl-amino)-acetylamino] -acetic acid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester; or an isotopic form, a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

In another embodiment, the preferred compound of the invention is selected from the group consisting of: (2-tert-Butylamino-acetylamino)-acetic acid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12, 13,14, 15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ester oxalate;

[(2-tert-Butylamino-acctyl)-mcthyl -amino I -acetic acid 10,13-dimethyl-17-pyridin-3-yl-

2.3.4.7.8.9.10.11.12.13.14.15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester oxalate;

[(2-tert-Butylamino-acctyl)-mcthyl -amino I -acetic acid 10,13-dimethyl-17-pyridin-3-yl-

2.3.4.7.8.9.10.11.12.13.14.15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester tartarate;

[(2-tert-Butylamino-acetyl)-methyl-amino| -acetic acid 10,13-dimethyl-17-pyridin-3-yl-

2.3.4.7.8.9.10.11.12.13.14.15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester fumarate; and

[(2-tert-Butylamino-acetyl)-methyl-amino] -acetic acid 10,13 -dimethyl- 17 -pyridin-3 -yl- 2,3,4,7,8,9,10,11,12, 13,14, 15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ester fumarate.

Experimental Procedures:

General Schemes 1, 2 and 3 depicts processes for the preparation of compound of formula (I), wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above and ‘P’ is protecting group and ‘X’ is leaving group. Scheme-1: Preparation of the Compound of formula (I) from intermediates of formula 4 and 5:

Step-1: Preparation of intermediate of formula-2:

The compound, abiraterone is reacted with intermediate of formula-1 in presence of coupling reagents such as DIC, DCC, TBTU, EDC.HC1, DMAP in solvents such as DCM, DMF, acetonitrile, acetone, THF, 1,4-dioxan, under nitrogen atmosphere, at a temperature of -5°C to 30°C for 8-24 h to obtain the intermediate of formula-2.

Step-2: Preparation of intermediate of formula-3:

The intermediate of formula-2 obtained in step-1 is reacted with dry HC1 in IPA, dry HC1 in diethylether, dry HC1 in ethyl acetate or trifluoro acetic acid in presence of solvents selected from dichloromethane, chloroform, isopropyl alcohol, diethyl ether, ethyl alcohol and like, under nitrogen atmosphere, at the temperature range of 0 to 30°C for 2-6 h to obtain a hydrochloride or trifluoroacetate salt to obtain intermediate of formula-3.

Step-3: Preparation of intermediate of formula-4: The intermediate of formula-3 obtained in step-2 is reacted with the compound of formula-A in presence of a coupling agent selected from TBTU, HATU, DCC or EDC.HC1, a base such as triethylamine, DIPEA, or DABCO, solvents such as DCM, DMF, under nitrogen atmosphere, at the temperature range of 0 to 30°C for 8-24 h to obtain the intermediate of formula-4.

Step-4: Preparation of the compound of formula (I):

The intermediate of formula-4 obtained in step-3 is reacted with nucleophiles of formula-B selected from alkyl amine, dialkyl amine, heterocycle group, or alkyl heterocycle in presence of a base selected from potassium carbonate, sodium carbonate, sodium hydroxide, alkali metal hydrides such as sodium hydride or potassium hydride, sodium tertiary butoxide, potassium tertiary butoxide and solvents such as THF, DCM, DMF, DMSO or acetonitrile, under nitrogen atmosphere, at the temperature range of 30°C to 100°C for 8-24 h to obtain the compound of formula (I).

Step-3a: Preparation of intermediate of formula-5:

The intermediate of formula-3 obtained in step-2 is reacted with the compound of formula-C in presence of a coupling reagents selected from TBTU, HATU, DCC, DIC or EDC.HC1, a base such as DIPEA, triethylamine or DABCO and a solvent(s) selected from DCM, DMF, under nitrogen atmosphere, at the temperature range of 0 to 30°C for 8-24 h to obtain the intermediate of formula-5. Step-4a: Preparation of the compound of formula (I) from intermediate of formula-5:

The intermediate of formula-5 obtained in step-3a is reacted with dry HC1 in IPA, dry HC1 in diethylether, dry HC1 in ethyl acetate or trifluoro acetic acid in presence of solvents selected from dichloromethane, chloroform, isopropyl alcohol, diethyl ether, ethyl alcohol and like, under nitrogen atmosphere, at the temperature range of 0°C to 30°C for 2-6 h to obtain a hydrochloride or trifluoroacetate salt which was basified with aqueous NaHCO ₃ , NaOH and like bases to obtain the compound of formula (I).

Scheme-2: Preparation of the compound of formula (I) from intermediate of formula-7: Step-1: Preparation of intermediate of formula-6:

The compound of formula-D is reacted with formula-E in presence of bases such as K ₂ CO ₃ , NaHCO ₃ , Na ₂ CO ₃ , triethylamine, DBU, DABCO in solvents such as DCM, DMF, acetonitrile, acetone, THF, 1,4-dioxan, or the compound of formula-D is reacted with compound of formula-A (obtained in scheme-1) in presence of bases such as triethylamine, DBU, DABCO in solvents such as DCM, DMF, acetonitrile, acetone, THF, 1,4-dioxan, under nitrogen atmosphere, at a temperature of - 5°C to 30°C for 8-24 h to obtain the intermediate of formula-6.

Step-2: Preparation of intermediate of formula-7:

The intermediate of formula-6 obtained in step-1 is reacted with bases such as FiOH, NaOH, KOH, in solvents such as H ₂ O, methanol, ethanol, acetone, THF, 1,4-dioxan, under nitrogen atmosphere, at a temperature of -5°C to 30°C for 8-24 h to obtain the intermediate of formula-7. Step-3: Preparation of intermediate of formula-4:

The abiraterone is reacted with the compound of intermediate of formula-7 obtained in step-2 in presence of a base such as DIPEA, triethylamine, DABCO or DBU and a coupling agent selected from DIC, DCC, TBTU, EDC.HC1 like, under nitrogen atmosphere, at the temperature range of 0 to 30°C for 8-24 h to obtain the intermediate of formula-4.

Step-4: Preparation of the compound of formula (I):

The amino derivative R ⁴ NHR ⁵ (Formula-B of scheme- 1) selected from alkyl amine, dialkyl amine, heterocycle group, or alkyl heterocycle is reacted with the compound of intermediate of formula-4 (obtained in step-3) in presence of a base selected from potassium carbonate, sodium carbonate, sodium hydroxide, alkali metal hydrides such as sodium hydride or potassium hydride, sodium tertiary butoxide, potassium tertiary butoxide and solvents such as THF, DCM, DMF, DMSO or acetonitrile, under nitrogen atmosphere at the temperature range of 30°C to 100°C for 8-24 h to obtain the compound of formula (I).

Scheme-3: Preparation of the compound of formula (I) from intermediates of formula-10:

Step-1: Preparation of intermediate of formula-8:

The compound of formula NH2R ⁴ is reacted with intermediate of formula-6 (obtained in scheme-2) in presence of bases such as K ₂ CO ₃ , NaHCO ₃ , Na ₂ CO ₃ , triethylamine, DBU, DABCO in solvents such as DCM, DMF, acetonitrile, acetone, THF, 1,4-dioxan, under nitrogen atmosphere, at a temperature of -5°C to 30°C for 8-24 h to obtain the intermediate of formula-8.

Step-2: Preparation of intermediate of formula-9:

The intermediate of formula-8 obtained in step-1 is reacted with amine protecting groups such as BOC anhydride, pivaloyl chloride, Fmoc, etc. in presence of bases such as K ₂ CO ₃ , NaHCO ₃ , Na ₂ CO ₃ , triethylamine, DBU, DABCO in solvents such as DCM, DMF, acetonitrile, acetone, THF, 1,4-dioxan, under nitrogen atmosphere, at a temperature of -5°C to 30°C for 8-24 h to obtain the intermediate of formula-9.

Step-3: Preparation of intermediate of formula-10:

The intermediate of formula-9 obtained in step-2 is reacted with bases such as LiOH, NaOH, KOH, in solvents such as H ₂ O, methanol, ethanol, acetone, THF, 1,4-dioxan or combination of two or more solvents, under nitrogen atmosphere, at a temperature of -5°C to 30°C for 8-24 h to obtain the intermediate of formula-10.

Step-4: Preparation of the compound of formula (I):

The abiraterone is reacted with the compound of intermediate of formula-10 in presence of a base such as DIPEA, triethylamine, DABCO or DBU and a coupling agent selected from DIC, DCC, TBTU, EDC.HC1 like, under nitrogen atmosphere, at the temperature range of 0 to 30°C for 8-24 h to obtain the compound of formula (I).

Preparation of pharmaceutically acceptable salt of the compound of formula (I): The compound of formula (I) can optionally be converted into its pharmaceutically acceptable salt by reaction with the appropriate acid or acid derivative in suitable solvents such as methanol, ethanol, isopropanol, acetonitrile, DCM and like. The reaction temperature can be from 0°C to room temperature. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. The salts are formed with inorganic acids e.g., hydrochloric, hydrobromic, sulfuric, perchloric & phosphoric acid or organic acids e.g., oxalic, succinic, maleic, acetic, fumaric, citric, malic, tartaric, benzoic, tolueic, toluenesulfonic acid, benzenesulfonic acid, methanesulfonic or naphthalene sulfonic acid.

Preparation of stereoisomers of the compound of formula (I):

The stereoisomers of the compounds of formula (I) may be prepared by one or more conventional ways presented below: a. One or more of the reagents may be used in their optically active form. b. Optically pure catalyst or chiral ligands along with metal catalyst may be employed in the reduction process. The metal catalyst may be rhodium, ruthenium, indium and the like. The chiral ligands may preferably be chiral phosphines. c. The mixture of stereoisomers may be resolved by conventional methods such as forming diastereomeric salts with chiral acids or chiral amines or chiral amino alcohols, or chiral amino acids. The resulting mixture of diastereomers may then be separated by methods such as fractional crystallization, chromatography and the like, which is followed by an additional step of isolating the optically active product from the resolved material/salt. d. The mixture of stereoisomers may be resolved by conventional methods such as microbial resolution, resolving the diastereomeric salts formed with chiral acids or chiral bases. Chiral acids that can be employed may be tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, chiral amino acids and the like. Chiral bases that can be employed may be cinchona alkaloids, brucine or a basic amino acid such as lysine, arginine and the like.

In yet another aspect, the present invention relates to the pharmaceutical composition of the compound of formula (I). In order to use the compound of formula (I), or their stereoisomers and pharmaceutically acceptable salts thereof in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.

The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients are diluents, disintegrants, binders, lubricants, glidants, polymers, coating agents, solvents, cosolvents, preservatives, wetting agents, thickening agents, antifoaming agents, sweetening agents, flavouring agents, antioxidants, colorants, solubilizers, plasticizer, dispersing agents and the like. Excipients are selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch, sodium starch glycolate, com starch or derivatives thereof, povidone, crospovidone, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, talc, colloidal silicone dioxide, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid or hydrogenated vegetable oil, gum arabica, magnesia, glucose, fats, waxes, natural or hardened oils, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions and the like or a mixture of the various excipients.

In yet another aspect, the active compounds of the invention may be formulated in the form of pills, tablets, coated tablets, capsules, powder, granules, pellets, patches, implants, films, liquids, semi solids, gels, aerosols, emulsions, elixirs and the like. Such pharmaceutical compositions and processes for preparing same are well known in the art.

In yet another aspect, the pharmaceutical composition of the instant invention contains 1 to 90 %, 5 to 75 % and 10 to 60 % by weight of the compounds of the instant invention or pharmaceutically acceptable salt thereof. The amount of the active compounds or its pharmaceutically acceptable salt in the pharmaceutical composition(s) can range from about 1 mg to about 500 mg or from about 5 mg to about 400 mg or from about 5 mg to about 250 mg or from about 7 mg to about 150 mg or in any range falling within the broader range of 1 mg to 500 mg.

The dose of the active compounds can vary depending on factors such as age and weight of patient, nature and severity of the disease to be treated and such other factors. Therefore, any reference regarding the pharmacologically effective amount of the compounds of general formula (I), stereoisomers and pharmaceutically acceptable salts thereof refer to the aforementioned factors.

The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipient is carrier or diluent. Thus, the active compounds of the invention may be formulated for oral dosing. Such pharmaceutical compositions and processes for preparing same are well known in the art.

In another aspect of the present invention, the compound of formula (I) are selective inhibitors of 17-α-hydroxylase/C 17,20 lyase (CYP17A1).

In embodiments, the present invention relates to a method of treating proliferative disease comprising administering to a patient in need thereof, a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

In embodiments, the present invention relates to a method of treating cancer comprising administering to the patient in need thereof, a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

In embodiments, the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In embodiments, the present invention relates to use of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

In embodiments, said cancer can be prostate cancer, breast cancer, or ovarian cancer.

In embodiments, the prostate cancer can be metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, or non-metastatic castration-sensitive prostate cancer.

In embodiments, the compounds of formula (I), or a pharmaceutically acceptable salt thereof, possess improved solubility, and oral bioavailability when administered to the patient.

ABBREVIATIONS:

The following abbreviations are used herein:

AUC Area under the curve

ACN Acetonitrile

BOC anhydride Ditertiarybutyldicarbonate

CDCI ₃ Deuterated chloroform

C _max Maximum concentration

DCM Dichloromethane

DCC N,N'-Dicyclohexylcarbodiimide

DIPEA N’N’Diisopropylethylamine

DIC N,N'-Diisopropylcarbodiimide

DMAP N,N' -dimethylaminopyridine

DMF Dimethyl fumarate

DAB CO 1 ,4-Diazabicyclo [2.2.2] octane

DMSO Dimethyl sulfoxide

DBU 1,8 -Diazabicyclo [5.4.0] undec-7 -ene

EDC Ethylene dichloride

EDC.HC1 N-Ethyl-N'-(3-dimethylami nopropyl )carbodii mi de- hydrochloride

EtOAc : Ethylacetate Fmoc : Fluorenylmethyloxycarbonyl g (or) gm gram(s) HATU ( 1 -[Bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 - b]pyridinium 3 -oxide hexafluorophosphate

HC1 Hydrochloric acid

HPLC High-performance liquid chromatography H ₂ O Water h (or) hr hour(s) IPA Isopropyl alcohol kg Kilogram kP Kilopond

LC-MS/MS Liquid chromatography/ Tandem mass spectrometry

M Molarlity mg Milligram min minute (s) mL Milliliter mmol Millimolar mm Millimetre

N Normality

NADPH Nicotinamide adenine dinucleotide phosphate

NaHCO ₃ Sodium bicarbonate

NaOH Sodium hydroxide

Na ₂ SO ₄ Sodium sulphate ng : Nanogram nm : Nanometre

Rpm Rotation per minute

RT Room temperature (25 to 30°C)

T Temperature

TBTU 2-( 1 H-Benzotriazole - 1 -yl) - 1 , 1 , 3 ,3 -tetramethylaminium

Tetrafluoroborate

THF Tetrahydrofuran T _max Time of maximum plasma concentration T _1/2 Half-life time °C Degree Celsius v/v volume/volume

% w/w : Percent weight/weight μL Microlitre μM Micromolar μm Micrometer

Examples: The compounds of the present invention were prepared according to the following experimental procedures, using appropriate materials and conditions. The following examples are provided by way of illustration only but not to limit the scope of the present invention.

Preparation of intermediates of formula-1:

Synthesis of tert-Butoxycarbonylamino-acetic acid (la):

To a stirred solution of glycine (5 gm, 66.6 mmol) in IN NaOH solution (138 mL) at 0°C, under nitrogen atmosphere, BOC anhydride (18.4 mL, 79.92 mmol) in 1,4 dioxane (66 mL) was added slowly. The reaction temperature was gradually raised to RT and stirred for 12 h. After completion of the reaction, the reaction mass was concentrated and aqueous layer was acidified with IN sodium bisulphate solution, extracted with ethyl acetate and dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum to afford the tert-Butoxycarbonylamino-acetic acid.

Yield (9.87 g, 84.7 %). ¹ H - NMR (400 MHz, DMSO-D ₆ ): δ 12.24 (bs, 1H), 7.05 (t, J = 5.6 Hz, 1H),

3.57 (d, J = 4.0 Hz, 2H), 1.37 (s, 9H); Mass (m/z); 176.2 (M+H) ⁺ . Synthesis of (tert-Butoxycarbonyl-methyl-amino)-acetic acid (lb):

Commercially procured from Combi-Blocks; CAS No. [13734-36-6]

Synthesis of 2-tert-Butoxycarbonylamino-propionic acid (lc): To a stirred solution of alanine (3.00 gm, 33.70 mmol) in IN NaOH solution (70.2 mL, 0.48

M) at 0°C, under nitrogen atmosphere, BOC anhydride (9.3 mL, 40.44 mmol) in 1,4 dioxane (33.7 mL, 1M) was added slowly. The reaction temperature was gradually raised to RT and stirred for overnight. After completion of the reaction, the reaction mass was concentrated and aqueous layer was acidified with IN sodium bisulphate solution, extracted with ethyl acetate and dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum to afford the 2-tert-Biitoxycarbonylamino-propionic acid.

Yield (5.8 g, 91.2 %). ¹ H - NMR (400 MHz, DMSO-D ₆ ): δ 12.37 (bs, 1H), 7.10 - 7.05 (t, J = 5.6 Hz, 1H), 3.87 - 3.83 (m, 1H), 1.37 (s, 9H), 1.20 (s, 3H); Mass (m/z); 188.1 (M+H)-.

Synthesis of 2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid (Id):

To a stirred solution of L-serine (3.17 gm, 30.2 mmol) in IN NaOH solution (63 mL, 0.58 M) at 0°C, under nitrogen atmosphere, BOC anhydride (8.3 mL, 36.24 mmol) in 1,4 dioxane (32.2 mL, 1M) was added slowly. The reaction temperature was gradually raised to RT and stirred for overnight. After completion of the reaction, the reaction mass was concentrated and aqueous layer was acidified with IN sodium bisulphate solution extracted with ethyl acetate and dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum to afford the 2-tert-Butoxycarbonylamino-3 -hydroxy-propionic acid.

Yield (6.0 gm, 97.0 %). ¹ H - NMR (400 MHz, DMSO-D ₆ ): δ 11.0 (bs, 1H), 5.63 (bs, 1H), 4.36 (bs,

1H), 4.15 (t, J = 7.2Hz, 1H), 4.09(d, J = 12.8 Hz, 2H), 1.46 (s, 9H); Mass ( m/z); 206.2 (M+H) ⁺ .

Synthesis of 2-tert-Butoxycarbonylamino-3-methyl-butyric acid (le):

To a stirred solution of valine (10.0 gm, 85.36 mmol) in IN NaOH solution (178.0 mL, 0.48 M) at 0°C, under nitrogen atmosphere, BOC anhydride (23.5 mL, 102.43 mmol) in 1,4 dioxane (85.0 mL, 1M) was added slowly. The reaction temperature was gradually raised to RT and stirred for overnight. After completion of the reaction, the reaction mass was concentrated and aqueous layer was acidified with IN sodium bisulphate solution extracted with ethyl acetate and dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum to afford the 2-tert-Butoxycarbonylamino-3-methyl-butyric acid. Yield (17.3 gm, 93.52 %). ¹ H - NMR (400 MHz, CDC1 ₃ ): δ 5.04 - 5.02 (d, J = 8.0 Hz, 1H), 4.26 - 4.25 (d, J = 4Hz, 1H), 1.45 (s, 9H), 1.09 - 0.99 (d, J = 6.8 Hz, 6H); Mass (m/z); 218.1 (M+H) ⁺ .

Preparation of abiraterone from abiraterone acetate:

To a stirred solution of abiraterone acetate (10 gm, 25.54 mmol) in H ₂ O:THF 1: 1 (102 mL) at 0°C, under nitrogen atmosphere, lithium hydroxide monohydrate was added (3.2 gm, 76.62 mmol). The reaction temperature was gradually raised to RT and stirred for two days. After completion of the reaction the reaction mass was concentrated under vacuum, diluted with water (51 mL), and solids were filtered and dried under high vacuum to obtained the 10,13-dimethyl-17-pyridin-3-yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-ol.

Yield (8.91 gm, 99 %). ¹ H - NMR (400 MHz, DMSO-D ₆ ): δ 8.43 (d, J = 4.0 Hz, 1H), 7.76 - 7.74 (d, J = 7.6 Hz, 1H), 7.34 - 7.31 (t, J = 4.8 Hz, 1H), 6.11 (s, 1H), 5.30 (s, 1H), 4.60 (s, 1H), 3.31 (bs, 1H), 2.19 - 1.98 (m, 6H), 1.78 - 1.50 (m, 7H), 1.41 - 1.35 (m, 2H), 1.01 - 0.96 (m, 8H); Mass (m/z); 350.1 (M+H) ⁺ .

Preparation of intermediates of formula-2:

Synthesis of tert-Butoxycarbonylamino-aceticacid10,13-dimethyl-17-pyridin -3-yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester (2a):

To a stirred solution of abiraterone (4.8 gm, 13.73 mmol) in DCM (55 mL) at 0°C, under nitrogen atmosphere, tert-Butoxycarbonylamino-acetic acid (la) (3.6 gm, 20.61 mmol) and EDC.HC1 (7.9 gm, 41.19 mmol) were added and followed DMAP (335.0 mg, 2.75 mmol). The reaction temperature was gradually raised to RT and stirred for overnight, after completion of the reaction, the reaction mass was diluted with DCM and water. Two layers were separated, the organic layer was washed with brine solution and dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum to obtain the tert-Butoxycarbonylamino-aceticacid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester.

Yield (6.81 gm, 98 %). ¹ H - NMR (400 MHz, CDC1 ₃ ): δ 8.61 (s, 1H), 8.46 (d, J = 4.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 4.8 Hz, 1H), 5.99 (s, 1H), 5.42 (d, J = 4.4 Hz. 1H), 5.29 (s, 1H), 4.99 (bs, 1H), 4.80 - 4.65 (m, 1H), 3.88 (d, J = 4.8 Hz, 2H), 2.37 (d, J = 7.6 Hz. 2H), 2.29 - 2.28 (m, 2H), 2.27 - 2.22 (m, 2H), 1.62 1.53 (m, 8H), 1.456 (s, 9H), 1.08 (d, J = 14.4 Hz, 8H); Mass (m/z); 507.2 (M+H) ⁺ . Synthesis of intermediates of formula 2b to 2d was carried out using the procedure described above and with some non-critical variations.

Preparation of intermediates of formula-3:

Synthesis of Amino-aceticacidl0,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,1 0,11,12,13,14,15- dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ester hydrochloride (3a):

To a stirred solution of tert-Butoxycarbonylamino-aceticacid 10,13-dimethyl- 17-pyridin-3-yl-

2.3.4.7.8.9.10.11.12.13.14.15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester (2a) (6.8 gm, 13.44 mmol) in isopropyl alcohol (55 mL) at 0°C, under nitrogen atmosphere, dry HC1 in IPA (27 mL, 0.5M) was added slowly. The reaction temperature was gradually raised to RT and stirred for 3 h. After completion of the reaction, the reaction mass was concentrated and titrated until solids were obtained, dried under high vacuum to afford the Amino-aceticacidl0,13-dimethyl-17-pyridin-3-yl-

2.3.4.7.8.9.10.11.12.13.14.15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester hydrochloride. Yield (5.72 gm, 96.2 %). ¹ H - NMR (400 MHz, DMSO-D ₆ ): δ 8.89 (s, 1H), 8.75 (t, J = 5.6 Hz, 1H), 8.57 (d, J = 6.8 Hz, 1H), 8.01 - 7.98 (m, 1H), 6.50 (s, 1H), 5.44 (s, 2H), 4.62 (bs, 1H), 2.76 (s, 1H), 2.38 (d, J = 7.2 Hz, 3H), 2.16 - 2.04 (m, 3H), 1.90 - 1.84 (m, 2H), 1.63 - 1.55 (m, 6H), 1.43 (s, 3H), 1.08 (d, J = 14.8 Hz, 8H); Mass (m/z); 407.2 (M+H) ⁺ .

Synthesis of intermediates of formula 3b to 3d was carried out using the procedure described above and with some non-critical variations. Preparation of intermediates of formula-4:

Synthesis of (2-Chloro-acetylamino)-acetic acid 10,13-dimethyl-17-pyridin-3-yl- 2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]ph enanthren-3-yl ester (4a):

To a stirred solution of Amino-aceticacid 10,13-dimethyl-17-pyridin-3-yl- 2,3,4,7,8,9,10,11,12, 13,14, 15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ester hydrochloride (3a) (9.0 gm, 20.4 mmol) in DCM (81 mL) at 0°C, under nitrogen atmosphere, chloroacetic acid (1.92 gm, 20.40 mmol) and DIPEA (8.8 mL, 50.85 mmol) were added and followed TBTU (7.18 gm, 22.37 mmol). The reaction temperature was gradually raised to RT and stirred for overnight. After completion of the reaction, the reaction mass was diluted with DCM and water, and the two layers were separated; the organic layer was washed with brine solution and dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum to afford the (2-Chloro-acetylamino)-acetic acid 10,13 -dimethyl- 17- pyridin-3-yl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cy clopenta[a]phenanthren-3-yl ester.

Yield (9.78 gm, 99.8 %). ¹ H - NMR (400 MHz, CDC1 ₃ ): δ 8.62 (s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 7.23 - 7.20 (t, J = 4.8 Hz, 1H), 7.05 (bs, 1H), 5.99 (s, 1H), 5.44 (d, J = 4.4 Hz, 1H), 4.75 - 4.68 (m, 1H), 4.09 (s, 2H), 4.07 (d, J = 4.8 Hz, 2H), 2.39 (d, J = 8.0 Hz, 2H), 2.28 - 2.24 (m, 1H), 2.10 - 2.03 (m, 3H), 1.91 - 1.87 (m, 2H), 1.79 - 1.62 (m, 6H), 1.52 - 1.49 (m, 1H), 1.21 - 1.17 (m, 1H), 1.11 - 1.04 (m, 8H); Mass (m/z); 483.2 (M+H) ⁺ .

Synthesis of intermediates of formula 4b to 4c was carried out using the procedure described above and with some non-critical variations.

Preparation of intermediates of formula-5: Synthesis of (2-tert-Butoxycarbonylamino-acetylamino)-acetic acid 10,13-dimethyl-17-pyridin-3- yl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester (5a):

To a stirred solution of amino-acetic acid 10,13-dimethyl-17-pyridin-3-yl-

2.3.4.7.8.9.10.11.12.13.14.15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester hydrochloride (3a) (500.0 mg, 1.13 mmol) in DCM (11.3 mL) at 0°C, under nitrogen atmosphere, tert- butoxycarbonylamino acetic acid (la) (296.6 mg, 1.695 mmol) and DIPEA (0.6 mL, 3.429 mmol) were added and followed TBTU (403.6 mg, 1.257 mmol). The reaction temperature was gradually raised to RT and stirred for overnight. After completion of the reaction, the reaction mass was diluted with DCM and water, and the two layers were separated; the organic layer was washed with brine solution and dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum to afford the (2-tert- Butoxycarbonylamino-acetylamino)-acetic acid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2.3.4.7.8.9.10.11.12.13.14.15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester.

Yield (577.0 mg, 90 %). ¹ H - NMR (400 MHz, CDC1 ₃ ): δ 8.61 (s, 1H), 8.46 (d, J = 4.4 Hz, 1H), 7.65

(d, J = 7.6 Hz, 1H), 7.23 (dd, J = 4.8 Hz, 1H), 6.59 ( bs, 1H), 5.99 (S, 1H), 5.43 (d, J = 4.0 Hz, 1H), 4.72 - 4.66 (m, 1H), 4.04 ( d, J =5.2 Hz , 2H), 3.86 (d, J = 5.6 Hz, 2H) 2.36 (d, J = 7.6 Hz, 2H), 2.29 -

2.26 (m, 2H), 2.05 - 2.03 (m, 4H), 1.87 (d, J = 11.2 Hz ,2H), 1.67- 1.59 (m, 6H), 1.45 (s, 9H), 1.08 (d, J = 15.2 Hz, 8H); Mass (m/z); 564.3 (M+H) ⁺ .

Synthesis of intermediates of formula 5b to 5e was carried out using the procedure described above with some non-critical variations.

Preparation of intermediates of formula-6 and formula-7:

Synthesis of (2-Chloro-acetylamino)-acetic acid methyl ester (6a): To a stirred solution of glycine methyl ester hydrochloride salt (5.00 gm, 39.84 mmol) in

DCM (160 mL, 0.25M) at 0°C, under nitrogen atmosphere, chloroacetic acid (3.76 gm, 39.84 mmol) and N’N’-diisopropylethylamine (17.3 mL, 99.7 mmol) were added and followed TBTU (14.0 gm, 43.87 mmol). The reaction temperature was gradually raised to RT and stirred for overnight, after completion of the reaction, the reaction mass was diluted with DCM and water. Two layers were separated; organic layer was washed with brine solution and dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum gave solid (2-Chloro-acetylamino)-acetic acid methyl ester.

Yield (4.0 gm, 61 %). ¹ H - NMR (400 MHz, CDCft): δ 7.01 (bs, 1H), 4.10 (s, 4H), 3.79 (s, 3H); Mass (m/z); 166.5 (M+H) ⁺ .

Synthesis of (2-Chloro-acetylamino)-acetic acid (7a) To the stirred solution of intermediate-6a (2.5 g, 15.2 mmol) in THF (30.4 mL) cooled at 0°C, a IN aqueous solution of LiOH (30.4 mL) was added. The reaction mixture temperature was gradually raised to RT and it was stirred for 2 h at this temperature upon which the TLC revealed absence of starting material-6. The reaction mixture was diluted with ether and the two layers were separated. The aqueous layer was acidified and was extracted with EtOAc to obtain intermediate-7a (2.31 g) in quantitative yield. ¹ H - NMR (400 MHz, DMSO-d ₆ ): δ 8.37 (bs, 1H), 4.13 (s, 2H), 3.71 (s, 2H); Mass (m/z); 150.1, 152.0 (M-H) ⁺ .

Preparation of intermediates of formula-8: Synthesis of (2-Ethylamino-acetylamino)-acetic acid methyl ester (8a):

To a stirred solution of (2-chloro-acetylamino)-acetic acid methyl ester (6a) (2.0 gm, 12.08 mmol) in acetonitrile (48 mL, 0.25M) at RT, under nitrogen atmosphere, ethylamine (1.28 gm, 25.6 mmol) and potassium carbonate (2.5 gm, 18.13 mmol) were added and followed sodium iodide (1.81 gm, 12.08 mmol), it was heated and refluxed for 3 hr, After completion of the reaction, the reaction mass was diluted with ethyl acetate and water. Two layers were separated; organic layer was washed with brine solution and dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum to obtain (2- Ethylamino-acetylamino)-acetic acid methyl ester.

Yield (710 mg, 34 %). ¹ H - NMR (400 MHz, DMSO-d ₆ ): δ 9.0 (bs, 1H), 3.96 - 3.95 (d, J = 6.0 Hz, 2H), 3.78 - 3.75 (d, J = 5.6 Hz, 2H), 3.65 (s, 3H), 2.97 - 2.92 (m, 2H), 1.20 - 1.18 (t, J = 7.2 Hz,

3H); Mass (m/z); 175.1 (M+H) ⁺ .

Synthesis of intermediates of formula 8b and 8c were carried out using the procedure described above and with some non-critical variations.

Preparation of intermediates of formula-9:

Synthesis of [2-(tert-Butoxycarbonyl-isopropyl-amino)-acetylamino]-acetic acid methyl ester (9a):

To a stirred solution of (2-Isopropylamino-acetylamino)-acetic acid methyl ester (8b) (1.0 gm, 5.31 mmol) in DCM (20 mL, 0.25M) at 0°C, under nitrogen atmosphere, BOC anhydride (1.2 mL, 5.31 mmol) and triethylamine (1.1 mL, 7.96 mmol) were added. The reaction temperature was raised to RT and stirred for overnight, after completion of the reaction, the reaction mass was diluted with DCM and water. Two layers were separated; organic layer was washed with brine solution and dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum to get [2-(tert-Butoxycarbonyl-isopropyl- amino)-acetylamino] -acetic acid methyl ester.

Yield (1.20 gm, 78 %). ¹ H - NMR (400 MHz, CDC1 ₃ ): δ 7.9 (bs, 1H), 4.12(d, J = 5.6Hz, 2H), 3.88- 3.80 (m, 1H), 3.78 (s, 2H), 3.75 (s, 3H), 1.48 (s, 9H), 1.15 (d, J = 6.8 Hz, 6H); Mass (m/z); 289.2 (M+H) ⁺ .

Synthesis of intermediates of formula 9b to 9d were carried out using the procedure described above with some non-critical variations

Preparation of intermediates of formula-10:

Synthesis of [2-(tert-Butoxycarbonyl-ethyl-amino)-acetylamino] -acetic acid (10a):

To a stirred solution of [2-(tert-Butoxycarbonyl -ethyl -amino)-acetylamino] -acetic acid methyl ester (9b) (1.0 gm, 3.64 mmol) in 1: 1 ratio of H ₂ O:THF (15 mL) at 0°C, lithium hydroxide monohydrate was added (230.0 mg, 5.46 mmol). The reaction temperature was gradually raised to RT and stirred for 4 hr, after completion of the reaction, the reaction mass was diluted with ethyl acetate and water. Two layers were separated; and the aqueous layer was acidified with IN NaHCO ₃ solution, extracted with DCM dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum to afford the [2- (tert-Butoxycarbonyl-cthyl-amino)-acctylamino| -acetic acid.

Yield (450.0 mg, 48 %). ¹ H - NMR (400 MHz, CDC1 ₃ ): δ 7.90 (bs, 1H), 4.15- 4.13 (d, J = 6.4 Hz,

2H), 3.87 -3.85 (m, 2H), 3.34 (s, 2H), 1.44 (s, 9H), 1.12-1.11 (t, J = 6.8 Hz, 3H); Mass ( m/z); 261.2 (M+H) ⁺ . Synthesis of intermediates of formula 10b to lOd was carried out using the procedure described above with some non-critical variations

Example-1: Synthesis of (2-Methylamino-acetylamino)-aceticacidlO,13-dimethyl-17-pyri din-3- yl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester: To a stirred solution of intermediate of formula-4a (300.0 mg, 0.62 mmol) in acetonitrile (6.2 mL) at RT, under nitrogen atmosphere, methyl amine hydrochloride (84.0 mg, 1.24 mmol) and potassium carbonate (128.50 mg, 50.85 mmol) were added and followed sodium iodide (93.0 mg, 0.62 mmol). The reaction mixture was stirred for overnight. After completion of the reaction, the reaction mass was diluted with ethyl acetate and water, two layers were separated and the organic layer was washed with brine solution and dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum to afford the (2-Methylamino-acetylamino)-aceticacid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester.

Yield (112.4 mg, 38 %). ¹ H - NMR (400 MHz, CDC1 ₃ ): δ 8.61 (s, 1H), 8.46 (d, J = 4.4Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.21 (t, J = 2.8 Hz, 1H), 5.99 (s, 1H), 5.43 (d, J = 4.4 Hz, 1H), 4.70 - 4.67 (m, 1H), 4.06 (d, J = 5.6 Hz, 2H), 3.30 (s, 2H), 2.47 (s, 3H), 2.38 (d, J = 7.2 Hz, 2H), 2.29 - 2.26 (m, 1H),

2.09 - 2.03 (m, 3H), 1.89 - 1.86 (m, 2H), 1.79 - 1.72 (m, 2H), 1.62 - 1.48 (m, 6H), 1.19 - 1.04 (m, 8H); Mass (m/z); 478.3 (M+H) ⁺ . The Examples 2 to 18 were prepared by following the experimental procedures as described in the Example- 1, with some non-critical variations.

Example-19: Synthesis of [(2-tert-Butylamino-acetyl)-methyl-amino]-acetic acid 10,13-dimethyl-

17-pyridin-3-yl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro -1H-cyclopenta[a]phenanthren-3-yl ester:

To a stirred solution of intermediate of formula-3b (6.0 gm, 13.14 mmol) in DCM (52.0 mL) at 0°C, under nitrogen atmosphere, N-tert-butylglycine hydrochloride (2.20 gm, 13.14 mmol) and DIPEA (8.0 mL, 46.01 mmol) were added and followed TBTU (4.66 gm, 14.45 mmol). The reaction temperature was gradually raised to RT and stirred for overnight. After completion of the reaction, the reaction mass was diluted with DCM and water, the two layers were separated and the organic layer was washed with brine solution and dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum. Purification on a silica gel column (3-5% methanol in DCM) gave (2-tert-Butylamino-acetyl methyl- amino)-acetic acid 10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,10,11,12,13,14,15 -dodecahydro-1H- cyclopenta[a]phenanthren-3-yl ester.

Yield (4.0 gm, 57.1 %). ¹ H - NMR (400 MHz, CDC1 ₃ ): δ 8.61 (s, 1H), 8.46 (d, J = 4.4 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 4.8 Hz, 1H), 5.99 (S, 1H), 5.42 (d, J = 4.8 Hz, 1H), 4.68 - 4.65 (m, 1H), 4.12 (s, 2H), 3.15 (s, 2H), 3.06 (s, 3H), 2.36 (d, J = 3.32 Hz, 2H), 2.25 - 2.24 (m, 1H), 2.09 - 2.03 (m, 3H), 1.72 - 1.65 (m, 4H), 1.62 - 1.57 (m, 5H), 1.51 - 1.48 (m, 1H), 1.15 (d, J = 6.8 Hz, 9H), 1.07 (d, J = 13.6 Hz, 8H); Mass (m/z); 534.3 (M+H) ⁺ .

Example-20: Synthesis of (2-Amino-acetylamino)-acetic acid 10,13-dimethyl-17-pyridin-3-yl- 2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]ph enanthren-3-yl ester:

To a stirred solution of intermediate of formula-5a (300.0 mg, 0.53 mmol) in diethyl ether (5 mL) at 0°C, under nitrogen atmosphere, dry HC1 in ether (1.0 mL, 0.5M) was added slowly. The reaction temperature was gradually raised to RT and stirred for 3 hr. After completion of the reaction, the reaction mass was concentrated under vacuum, diluted with water quenched with 2N NaOH solution, extracted with DCM and the organic layer was concentrated under reduced pressure to afford (2- Amino-acetylamino)-acetic acid 10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,10,11,12,13,14,15 - dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ester. Yield (157.7 mg, 62.8 %). ¹ H - NMR (400 MHz, CDC1 ₃ ): δ 8.61 (s, 1H), 8.46 (d, J = 4.0 Hz, 1H), 7.68 (bs, 1H), 7.65 (d, J = 8.0 Hz, 1H), .23 (t, J = 4.8 Hz, 1H), 5.99 (s, 1H), 5.43 (d, J = 4.0 Hz, 1H), 4.73 - 4.65 (m, 1H), 4.06 (d, J = 5.6 Hz, 2H), 3.41 (s, 2H), 2.38 (d, J = 7.2 Hz, 2H), 2.26 - 2.23 (m, 1H), 2.10 - 2.03 (m, 3H), 1.90 - 1.86 (m, 2H), 1.79 - 1.58 (m, 9H), 1.20 - 1.04 (m, 8H); Mass (m/z); 464.3 (M+H) ⁺ .

The Examples 21 to 24 were prepared by following the experimental procedures as described in the

Example-20, with some non-critical variations.

Example-25: Synthesis of 2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-prop ionic acid 10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,10,11,12,13,14,15 -dodecahydro-1H- cyclopenta[a]phenanthren-3-yl ester: To a stirred solution of compound of example-23 (52.0 mg, 0.11 mmol) in toluene (1.1 mL, 0.1M), under nitrogen atmosphere, phtahalic anhydride (16.3 mg, 0.11 mmol) was added. The reaction temperature was gradually raised to reflux for 4 h. After completion of the reaction, the reaction mass was concentrated under vacuum to afford [2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]- aceticacidl0,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,10,11,1 2,13,14,15-dodecahydro-1H- cyclopenta[a]phenanthren-3-yl ester.

Yield (64.0, 96 %) . ¹ H - NMR (400 MHz, CDC1 ₃ ): δ 8.68 (d, J =6.8, 1H), 8.59 (s, 1H), 8.46 - 8.45 (d, J = 4.0 Hz, 1H), 7.898 - 7.89 (d, J = 3.2 Hz, 2H), 7.77 - 7.75 (d, J = 8.0 Hz, 2H), 7.23 - 7.20 (t, J = 4.8 Hz, 1H), 6.11 (s, 1H), 5.38 - 5.37 (d, J = 4.4 Hz, 1H), 4.47 - 4.49 (m, 1H), 4.24 (s, 2H), 4.20 - 4.18 (m, 1H), 2.29 - 2.19 (m, 4H), 2.08 - 2.02 (m, 4H), 1.73 - 1.69 (m, 7H), 1.28 (s, 3H), 1.05 - 1.02 (m, 8H); Mass (m/z); 608.5 (M+H) ⁺ .

Example-26: Synthesis of [2-(2,2-Dimethyl-propionylamino)-3-hydroxy-propionyl]-methyl - amino-acetic acid 10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,10,11,12,13,14,15 -dodecahydro-1H- cyclopenta[a]phenanthren-3-yl ester:

To a stirred solution of intermediate of formula-3b (1.6 gm, 3.5 mmol) in DCM (14.0 mL) at 0°C, under nitrogen atmosphere, 2-(2,2-dimethyl-propionylamino)-3-hydroxy-propionic acid (6.61 mg, 3.5 mmol) and DIPEA (1.8 mL, 10.5 mmol) were added and followed TBTU (1.23 gm, 3.85 mmol). The reaction temperature was gradually raised to RT and stirred for overnight. After completion of the reaction, the reaction mass was diluted with DCM and water. Two layers were separated, the organic layer was washed with brine solution and dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum. Purification on a silica gel column (3-5% methanol in DCM) gave [2- (2, 2-Dimethyl -propionylamino)-3 -hydroxy-propionylamino] -acetic acid 10,13 -dimethyl- 17 -pyridin-3 - yl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester.

Yield (301.0 mg, 15.1 %). ¹ H - NMR (400 MHz, CDC1 ₃ ): δ 8.61 (s, 1H), 8.46 (d, J = 4.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 4.8 Hz, 1H), 6.86 (d, J = 6.4 Hz, 1H), 5.99 (s, 1H), 5.42 (s, 1H), 5.02 (d, J = 3.2 Hz, 1H), 4.70 - 4.67 (m, 1H), 4.42 (d, J = 17.2 Hz, 1H), 3.88 - 3.79 (m, 2H), 3.19 (s, 3H), 2.37 (bs, 2H), 2.26 - 2.24 (m, 1H), 2.09 - 2.03 (m, 4H), 1.89 (d, J = 10 Hz, 2H), 1.72 - 1.64 (m, 4H), 1.57 - 1.54 (m, 4H), 1.22 (d, J = 5.2 H, 9H), 1.07 (d, J = 13.6 Hz, 8H); Mass (m/z); 592.3 (M+H) ⁺ . Example-27: Synthesis of [2-tert -Butoxycarbonyl-isopropyl-amino)-acetylamino]-acetic acid 10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,10,11,12,13,14,15 -dodecahydro-1H- cyclopenta[a]phenanthren-3-yl ester:

To a stirred solution of abiraterone (200.0 mg, 0.57 mmol) in DCM (5.7 mL, 0.1M) at 0°C, under nitrogen atmosphere, intermediate of formula-10b (156.0 mg, 0.57 mmol) and DCC (352.0 mg, 1.77 mmol) were added and followed DMAP (14.0 mg, 0.114 mmol). The reaction temperature was gradually raised to RT and stirred for overnight, after completion of the reaction, the reaction mass was diluted with DCM and water. Two layers were separated; organic layer was washed with brine solution and dried over Na ₂ SO ₄ . The solvent was concentrated under vacuum to afford the solid [2- (tert-Butoxycarbonyl -isopropyl -amino)-acetylamino] -acetic acid 10,13 -dimethyl- 17 -pyridin-3 -yl-

2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a ]phenanthren-3-yl ester.

Yield (300.0 mg, 84 %). ¹ H - NMR (400 MHz, CDC1 ₃ ): δ 8.61 (s, 1H), 8.46 - 8.45 (d, J = 4.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.23 - 7.20 (t, J = 7.6 Hz, 1H), 5.99 (s, 1H), 5.42 (d, J = 3.6 Hz, 1H), 4.70 - 4.68 (m, 1H), 4.30 - 4.22 (m, 1H), 4.03 (d, J = 4.8 Hz, 1H), 4.03 (d, J = 4.8 Hz, 1H), 3.78 (s,2H), 2.36 (d, J = 8.0 Hz, 2H), 2.26 - 2.23 (m, 1H), 2.10 - 2.03 (m, 3H), 1.89 - 1.86 (m, 2H), 1.75 - 1.72 (m, 2H), 1.62 - 1.52 (m, 5H), 1.47 (s, 9H), 1.15 - 1.13 (d, J = 6.8 Hz, 6H), 1.08 - 1.04 (m, 8H); Mass (m/z); 606.6 (M+H) ⁺ .

Example-28: Synthesis of [2-(Acetyl-isopropyl-amino)-acetylamino]-acetic acid 10,13-dimethyl-

17-pyridin-3-yl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro -1H-cyclopenta[a]phenanthren-3-yl ester: Abiraterone and intermediate of formula- lOd were coupled using the reaction procedure as mentioned in example-26 with non-critical modifications to obtain above titled compound.

Yield (80 %). ¹ H - NMR (400 MHz, CDC1 ₃ ): δ 8.61 (s, 1H), 8.46 - 8.45 (d, J = 4.0 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.23 - 7.20 (t, J = 10.8 Hz, 1H), 6.99 (s, 1H), 5.45 (S,1H), 4.68- 4.64 (m, 1H), 4.12 - 4.06 (m, 1H), 3.97 - 3.89 (m, 4H), 2.36 - 2.33 (d, J = 8.0 Hz, 2H), 2.24 - 2.19 (m, 3H), 2.05 (S, 3H),

1.88 - 1.72 (m, 6H), 1.25 -1.24(d, J = 6.4 Hz, 4H), 1.18 -1.13(d, J = 6.8 Hz, 6H), 1.08 - 1.04 (m, 8H); Mass (m/z); 548.5 (M+H) ⁺ .

Salt formation:

General procedure: To the stirred solution of intended free amine (1.0 mmol) in solvent IPA (4.0 mL) cooled at 0°C, oxalic acid/fumaric acid/tartaric acid or any other organic acid (1.05 mmol) was added. The reaction mixture was gradually warmed to RT and after stirring for 1 h at this temperature, the precipitated salt was filtered and the filter bed was washed several times with solvent ether to obtain the intended salt.

Using the above general procedure with non-critical variations, Examples 29 to 33 were prepared.

Example-34: Solubility of the compounds of formula (I) and abiraterone acetate in water and 0.1 N HC1 solutions (Aqueous solubility method):

Preparation of test sample in aqueous solution: To the test sample (5.0 mg) taken in a 1.5 mL eppendorf tube, milli-Q water (1.0 mL) was added and swirled to form homogenous solution. The sample tube was then installed on rugged rotator with 30 rounds per minute (rpm) at ambient temperature for 24 h. The sample tube was then centrifuged with 3000 rpm for 10 min. After completion of centrifugation, the clear supernatant solution was collected into HPLC vial for analysis. If the supernatant solution was not clear, then the supernatant solution (500 μL) was transferred into another eppendorf tube and centrifuged at 3000 rpm for 10 min to have a clear test solution.

Preparation of test sample in 0.1 N HC1 solution:

To the test sample (10.0 mg) taken in a 1.5 mL eppendorf tube, 0.1 N HC1 (0.5 mL) was added and swirled to form homogenous solution. The sample tube was then installed on rugged rotator for rotation with 30 rpm at ambient temperature for 24 h. The sample tube was then centrifuged with 3000 rpm for 10 min. After completion of centrifugation, the supernatant solution was collected into HPLC vial for analysis. If the supernatant solution was not clear, then the supernatant solution (500 μL) was transferred into another eppendorf tube and centrifuged at 3000 rpm for 10 min to have a clear test solution. Preparation of Standard Solution:

The test sample (10.0 mg) was taken in a 10 mL volumetric flask and dissolved it by adding acetonitrile and make up to mark with it so as to have test solution concentration 1.0 mg/mL. Transferred test solution (1.0 mL) into another 10 mL volumetric flask to make up the solution with acetonitrile to have the test solution with 0.1 mg/mL concentration.

Method of analysis by HPLC:

Buffer : 10 mmol ammonium acetate in milli-Q water, adjusted to pH: 6.0 with dilute orthophosphoric acid

Mobile phase : Buffer: ACN (5 : 95)

Column : Unison UK; C18; 50 x 4.6 mm ID, S-3 μm

Column Oven Temp : 30°C

Flow Rate : 1 mL /min Injecting Volume : 10 μL

Run time : 10 min

Wavelength : 254 nm

Calculations:

Sample concentration = sample average area x standard dilution standard average area

Table-1: Solubility of the compounds of formula (I) and abiraterone acetate in water and 0.1 N HC1.

Example-35: General procedure for the preparation of immediate release composition (tablets) comprising the compounds of formula (I):

1. Dispensed quantity of compounds of formula (I) was taken and sifted through # 40 ASTM sieve.

2. Dispensed quantity of microcrystalline cellulose NF (A vied PH-102) was taken and sifted through # 40 ASTM sieve.

3. Step-1 and step-2 materials were mixed in polybag for 5 min.

4. Dispensed quantity of colloidal silicon dioxide NF (Aerosil 200) and magnesium stearate was sifted through # 40 ASTM sieve.

5. Step-4 material was added to step-3 material containing polybag.

6. Step-5 blend was mixed properly in polybag for 2 min.

7. Finally step-6 material was manually compressed into tablet at target weight of 250.00 mg using 9.0 mm standard concave punch set in rotary compression machine.

Table-2: Tablets compression parameters

Example-36: Conversion of the compounds of formula (I) to abiraterone in rat, dog, and human liver microsomes, intestinal microsomes, blood and plasma.

The following procedure is employed to determine the formation of abiraterone, the active pharmaceutical ingredient from the abiraterone prodrugs. For measuring the formation of abiraterone in microsomal preparations, rat, dog, and human liver and intestinal microsomes were prepared at a concentration of 0.58 mg/mL in phosphate buffer. The microsomal suspension (172 μL) was added to a 96 well plate in triplicates followed by addition of 20 μL of 10 mmol NADPH and 20 μL of buffer to the samples designated to be tested without NADPH. The incubation mixtures were pre-incubated for 10 min at 37°C. The reactions were initiated by the addition of 8 μL of the 25 mM solution (prepared in mixture of water and acetonitrile: 80:20 v/v) of the prodrug. At 0, 7.5, 15, 30, 45 and 60 min 50 μL of the sample was withdrawn and added to 96-well plates containing ice-cold stop solution (acetonitrile containing internal standard).

The plates were centrifuged at 4000 rpm for 20 min and the supernatants were transferred to a new plate. The supernatants were analyzed by LC-MS/MS for the prodrug and abiraterone, and the results were used to calculate the percentage formation of abiraterone from each prodrug at the end of 60 min. The blood and plasma stability was conducted as follows. Rat, dog and human blood or plasma (192 μL) was added to 96-well plate in triplicates followed by 10 min pre-warming at 37°C. The reactions were initiated by the addition of 8 μL of 25 μM solution of the prodrug. At 0, 7.5, 15, 30, 45 and 60 min, 50 μL of the sample was withdrawn and added to 96-well plates containing ice- cold stop solution (acetonitrile containing internal standard). The plates were centrifuged at 4000 rpm for 20 min and the supernatants were transferred to a new plate. The supernatants were analyzed by LC-MS/MS for the prodrug of abiraterone and abiraterone. The results were used to calculate the percentage formation of abiraterone from each prodrug at the end of 60 min. Data are shown in table below

Table-3: Stability of the compounds of formula (I).

* Percentage formation of abiraterone calculated relative to the 0 min concentrations of the prodrug. Values in parenthesis are the maximum percentage formation of abiraterone observed at time less than 60 min.

Conclusion: The results indicate that the abiraterone prodrugs of the instant invention would be converted into abiraterone in the systemic circulation after being administered to rat/dog/human.

Example-37: Pharmacokinetic evaluation of the compounds of formula (I) in male Beagle dogs.

To evaluate the in vivo performance of the immediate release (IR) tablet formulations of the abiraterone prodrugs of the instant invention, the tablets (dose equivalent to 50 mg abiraterone) were orally administered to male beagle dogs along with Zytiga (250 mg abiraterone acetate) and Yonsa ^® (125 mg abiraterone acetate tablet) in a two-way crossover study design.

Examples 2, 3 and 4 as immediate release (IR) tablet formulations (dose equivalent to 50 mg abiraterone) under fasted and fed condition were administered to male Beagle dogs. The reference listed drugs (RLD), Zytiga ^® (250 mg abiraterone acetate tablet) and Yonsa ^® (125 mg abiraterone acetate tablet) were also evaluated for comparison purpose. A minimum of 15 days of washout period was given between each period. Each Beagle dog was dosed as a single oral administration, the tablet was placed on back of the tongue and the throat was massaged for swallowing of tablet. Immediately 50 mL of drinking water was administered via syringe to ensure the tablet was washed down into stomach.

Fasted conditions: Animals were fasted overnight before dosing with ad libitum access to drinking water. Post-dose animals were fasted for another 4 h. Animals were deprived of water for 1 h pre and post dose.

Fed conditions (Food effect study): Approximately 55 g of in-house prepared high fat diet (based on US FDA guidelines) was given at 10 min prior to dosing a tablet. Regular feed was offered at 4 h post dose. Animals were deprived of water for 1 h pre and post dose.

At pre-determined point, blood samples were collected through cephalic/ saphenous vein. Blood samples were collected at following time points: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 h post dose. The collected blood was transferred into a labeled micro centrifuge tubes containing 10 μL of heparin sodium as an anticoagulant and centrifuged at 4000 rpm for 10 min. Plasma was separated and stored frozen at -80°C until analysis. The concentrations of the abiraterone prodrugs of the instant invention were quantified in plasma by qualified LC-MS/MS method.

The PK parameters such as C _max - AUC _last , AUC _0-infinity , AUC _0-8 , T _1/2 , clearance and bioavailability (F) were calculated by non-compartmental model using standard non-compartmental model by using Phoenix WinNonlin 8.1 version Software package. Results are represented in Tables 4 and 5.

Table-4: The PK analysis of abiraterone prodrugs as IR tablets to Zytiga ^® and Yonsa ^® estimated geometric mean ratios of dose-normalized AUC _0-8 and C _ma are far higher than both Zytiga ^® and Yonsa ^® .

Table-5:

Conclusion: Rate and extent of abiraterone mean plasma exposures were increased to 1.5 to 2.2-fold higher in presence of food compared to fasted state following a single oral administration of Example- 2 and Example-3 in male Beagle dogs. Whereas, for Example-4, the rate and extent of plasma exposures were increased 12 to 13 fold higher in presence of food compared to fasted state following a single oral administration in male Beagle dogs.

Example-38: Toxicity evaluation in male Wistar rats.

To evaluate the toxicity profile of Example-3, twenty nine young healthy male Wistar rats were dosed orally by gavage at 50, 150, and 400 mg/kg/day for 7 days. All animals survived and no mortality or clinical signs were observed throughout the treatment period. Significant reduction in mean body weight (2-8%) and decreased mean body weight gain (21-34%) compared to control was observed at 400 mg/kg/day. No significant treatment related effects were observed in feed consumption, hematology and urinalysis at any dose of Example-3. In clinical chemistry, significant decreased level of globulin, cholesterol and triglycerides and increased albumin/globulin ratio was observed at 400 mg/kg/day.

Significant decrease in weights of prostate (24-58%) and seminal vesicles (62-68%) at ≥ 5, and epididymides (39%) at ≥400 mg/kg/day was observed. At necropsy, decreased size of epididymides, prostate, seminal vesicles was noted at ≥ 50mg/kg/kg. Microscopic examination revealed atrophy of prostrate and seminal vesicle at ≥ 50 mg/kg/day. At ≥ 150 mg/kg/day, basophilic cells hypertrophy in pituitary; leydig cells hyperplasia, seminiferous tubules degeneration, and reduced spermatogenesis in testes; and atrophy in epididymides was also observed. The decreased size of secondary sex organs viz. prostate, seminal vesicles, and epididymides, and microscopic changes in reproductive organs were considered secondary to decreased levels of testosterone which is a class effect of Example-3.