1. Novel Bosentan derivatives represented by Formula (I), its isomer, tautomer, prodrug, polymorph, and hydrates thereof, wherein, R1 is selected from hydrogen, methyl cyclopropane, methyl cyclobutane, methyl cyclopentane, 1,2-dimethylpyrrolidine, 1,2-dimethylpiperidine, but-2-yne, 1,3-dimethylpiperidine, isopentane, 1,1-difluoroethane, (E)-hex-3-ene, but-1-ene; and R2 is selected from hydrogen, methyl, phenyl, p-methyl benzene, p-tert-butyl- benzene.

2. The novel Bosentan derivatives of a compound as claimed in claim 1, wherein R1 is isopentane and R2 is methyl group.

3. The novel Bosentan derivatives of a compound as claimed in claim 1, wherein said derivative is Bosentan monohydrate.

4. A process for preparing novel Bosentan derivatives represented by Formula (I), its isomer, prodrug, polymorph, and hydrates thereof, said process comprising treating a compound of Formula (II) Formula II with R1-OH in the presence of a metal hydride and an organic solvent at a specific temperature between -10°C to 20°C, wherein, R1 is selected from hydrogen, methyl cyclopropane, methyl cyclobutane, methyl cyclopentane, 1,2-dimethylpyrrolidine, 1,2-dimethylpiperidine, but-2-yne, 1,3-dimethylpiperidine, isopentane, 1,1-difluoroethane, (E)-hex-3-ene, but-1-ene; R2 is selected from hydrogen, methyl, phenyl, p-methyl benzene, p-tert-butyl- benzene.

5. The process as claimed in claim 3, wherein the metal hydride is selected from Aluminium hydride, Sodium hydride, Sodium aluminium hydride, Boron hydride, Lithium borohydride.

6. The process as claimed in claim 3, wherein the solvent is selected from hexane, tetrachloroethylene, toluene, acetone, 1,4 dioxane (dioxane), dichloromethane, Acetone, Benzene, tetrahydrofuran, Chloroform, Acetic Acid and mixtures thereof.

7. The process as claimed in claim 4, wherein the specific temperature is -2°C to 2 °C.

8. The process as claimed in claim 4, wherein R1 is isopentane group and R2 is methyl group.

9. A pharmaceutical composition comprising novel Bosentan derivatives of Formula (I), its isomer, prodrug, polymorph, and hydrates thereof.

10. The pharmaceutical composition as claimed in claim 9, wherein said Bosentan derivative is Bosentan monohydrate.

11. The pharmaceutical composition as claimed in claim 8, wherein said composition is in the form of a tablet, capsule, granule, syrup, suspension, suppositories, injection and patches.

12. The novel Bosentan derivatives as claimed in claim 1, wherein said derivatives exhibit endothelin receptor antagonistic activity and are capable of being used in medicaments for the treatment of hypertensive disorders which are associated with endothelin activities, especially Pulmonary artery hypertension, ischaemia, vasospasms and angina pectoris.

FIELD OF THE INVENTION
The present invention provides novel Bosentan derivatives of Formula (I),

Formula (I)
The novel Bosentan derivatives of Formula (I) exhibit considerable endothelin receptor antagonistic activity with notable therapeutic efficacy.

The present invention also provides a process of preparing the novel Bosentan derivatives of Formula (I) and intermediates thereof. The invention further provides pharmaceutical compositions comprising novel Bosentan derivatives of Formula (I).

BACKGROUND OF THE INVENTION
Pulmonary artery hypertension (PAH) first identified by E. von Romberg in 1891, is a noxious disease identified by the rise of blood pressure in the pulmonary vein/artery, or pulmonary vascular resistance resulting dizziness, fainting, shortness of breath, including other symptoms such as swelling of ankles, feet followed by decrease in functional ability ultimately the heart failure.

In order to control this disease, three different drug categories targeting distinct pathways have been used viz.PDE5 inhibitors, PGI2 derivatives and endothelin receptor antagonists. Bosentan [4-(tert-butyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- [2, 2’-bipyrimidin]-4-yl) benzene sulfonamide] is a non-peptide, nonselective dual endothelin receptor antagonist (ERAs) for both the type A (ET-A) and type B (ET-B).
A large number of synthetic endothelin receptor antagonists have been investigated preclinically, and few small molecule inhibitors have also been studied in clinical trials for chronic heart failure, hypertension, cancer, and fibrosis. Presently, the dual ET-A/ET-B receptor antagonist bosentan and the ET-A selective antagonist (S)-2-((4,6-dimethylpyrimidin-2-yl) oxy)-3-methoxy-3,3-diphenylpropanoic acid (ambrisentan) are approved treatments for pulmonary arterial hypertension.

Bosentan monohydrate (brand name Tracleer) is a low-cost, first FDA approved (November 2001) oral administered pulmonary artery hypertension drug (dose of 62.5 mg and 125 mg). Bosentan performs its action by blocking endothelin (ET) receptors to cause lowering of high blood pressure in lungs.It possess a high protein binding rate (98%), specifically to albumin and is expeditiously absorbed after taken orally.

Martin H. Bolli, et al,; Medicinal Chemistry 2012, 55, 7849-7861 teaches that compound 1 should not only serve as the structural starting point for our quest for novel endothelin antagonists but should also represent the benchmark against which we gauge our novel compounds.

Compound 1 (Bosentan)
According to Martin H. Bolli, et al., a candidate suitable for clinical development needs to meet the following requirements: (1) The compound has to show a significantly increased potency on the ETA receptor when compared to compound 1; (2) The compound should block the ETB receptor in vivo; (3) The compound needs to demonstrate oral efficacy superior to the one of compound 1 as assessed by measuring arterial pulmonary blood pressure in conscious hypertensive Dahl salt-sensitive rats.; (4) Pharmacokinetic properties assessed in animals must support once daily dosing in humans; (5) The compound should easily distribute into tissue in order to also reach ET receptors expressed in the tissue; (6) Because compound 1 inhibits the canalicular bile salt export pump, a candidate compound must be devoid of bile salt transport inhibition. This led to the discovery of a novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ETA with significant affinity for the ETB receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a long-term phase III clinical trial for pulmonary arterial hypertension.

Compound 17
WO2012073135A1 relates to an improved process for preparing Bosentan of formula (I).

Formula (I)
WO2010103362A2 relates to a new process for the preparation of bosentan or bosentan monohydrate and a new salt of bosentan.

WO2013186706A1 relates to a process for the preparation of Bosentan (Formula 1) or pharmaceutically acceptable salts or hydrates thereof which results the product substantially free of impurities like ethylene glycol bis-sulfonamide dimer and 6-hydroxy sulfonamide. The process according to present invention is also producing Bosentan sodium and Bosentan ammonium which gives Bosentan or pharmaceutically acceptable salts or hydrates thereof in improved yield and quality as compared to prior art processes.

WO2009095933A2 relates to an improved and novel process for the preparation of bosentan compound of Formula (1) and a crystalline form of bosentan and its intermediates.

Formula (1)
US5420129A discloses novel sulphonamides and their use as medicaments. The compounds of formula I are inhibitors of endothelin receptors. They can accordingly be used for the treatment of disorders which are associated with endothelin activities, especially circulatory disorders such as hypertension, ischaemia, vasospasms and angina pectoris.

Formula I

US6136971A provides a process for preparing 1,2-diheteroethylene sulfonamide of the formula (1): by reacting a pyrimidine mono halide of the formula (2):

Formula 1 Formula 2
with a mono-protected 1,2-diheteroethylene anion of the formula M1 XCH2 CH2 YR5 and removing the protecting group, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Z, X, Y, M, M1 and W are defined therein.

The presently available compounds are ethylene glycol sulfonamide derivatives that involves reacting an appropriately substituted pyrimidine mono halide with a mono anion ethylene glycol (e.g., sodium ethylene glycol) typically using ethylene glycol as a solvent. However, one of the disadvantages of using a monoanion of ethylene glycol is the formation of undesired ethylene glycol bis-sulfonamide in which two molecules of the pyrimidine mono halide are coupled with one molecule of ethylene glycol. The formation of this bis-sulfonamide compound requires costly and laborious separation steps to obtain a pharmaceutically suitable pure ethylene glycol sulfonamide compound. In addition, the use of ethylene glycol as a solvent, which is acceptable in a small scale reaction, is impracticable in a large industrial scale synthesis because of its toxicity and its high boiling point which requires a large amount of time and high energy consumption to remove it by distillation.

Another drawback of the presently available sulfonamide derivatives is the need for isolating a pyrimidine dihalide and the use of halogenated solvent, e.g., methylene chloride, during the isolation of pyrimidine dihalide. Halogenated solvent is expensive to dispose of properly, thus leading to an added cost.

Therefore, modification of existing molecules/ known pharmacophores in order to obtain better efficacy/ reduced side effects is a routine task for researchers. The present invention provides Bosentan derivatives that exhibit enhanced efficacy.

OBJECTS OF THE INVENTION
The main object of the present invention to provide novel Bosentan derivatives of Formula (I) exhibiting considerable endothelin receptor antagonistic activity with enhanced efficacy.

Another object of the present invention is to provide an easy and cost effective process to prepare novel Bosentan derivatives of Formula (I) and intermediates thereof.

Yet another object of the present invention is to provide pharmaceutical compositions comprising novel Bosentan derivatives of Formula (I).

SUMMARY OF THE INVENTION
It will nevertheless be understood that no limitation of the scope of the invention is thereby intended by way of embodiments and examples. Such alterations and further modifications in the present invention, and such further applications of the principles of the invention as would normally occur to those skilled in the art are to be construed as being within the scope of the present invention.

It will be understood by those skilled in the art that the summary of the invention provided herein is exemplary and explanatory of the invention and are not intended to be restrictive thereof. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. The composition, process, methods, and examples provided herein are only illustrative and not intended to be limiting.

The terms "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process or method that comprises a list of steps does not include only those steps but may include other steps not expressly listed or inherent to such a process or method. Similarly, one or more steps of method or components preceded by "comprises... a" does not, without more constraints, preclude the existence of other, steps or components. Appearances of the phrase "in a preferred embodiment”, “in an embodiment", “in another embodiment” and similar language throughout this specification may, but not necessarily do, all refer to the same embodiment.

Accordingly, one of the aspects of the present invention is to provide novel Bosentan derivatives of Formula (I) exhibiting endothelin receptor antagonistic activity with enhanced efficacy.

Formula (I)
In a first aspect, the present invention provides novel Bosentan derivatives represented by Formula (I), its isomer, tautomer, prodrug, polymorph, and hydrates thereof,

Formula (I)
wherein, R1 is selected from hydrogen, methyl cyclopropane, methyl cyclobutane, methyl cyclopentane, 1,2-dimethylpyrrolidine, 1,2-dimethylpiperidine, but-2-yne, 1,3-dimethylpiperidine, isopentane, 1,1-difluoroethane, (E)-hex-3-ene, but-1-ene;
R2 is selected from hydrogen, methyl, phenyl, p-methyl benzene, p-tert-butyl- benzene.

In a second aspect, the present invention provides a process for preparing novel Bosentan derivatives represented by Formula (I), its isomer, prodrug, polymorph, and hydrates thereof,

Formula (I)

said process comprising treating a compound of Formula (II)

Formula (II)
with R1-OH in the presence of a metal hydride and an organic solvent at a temperature between -10°C to 20°C, wherein, R1 is selected from hydrogen, methyl cyclopropane, methyl cyclobutane, methyl cyclopentane, 1,2-dimethylpyrrolidine, 1,2-dimethylpiperidine, but-2-yne, 1,3-dimethylpiperidine, isopentane, 1,1-difluoroethane, (E)-hex-3-ene, but-1-ene; R2 is selected from hydrogen, methyl, phenyl, p-methyl benzene, p-tert-butyl- benzene.

In a third aspect, the present invention provides pharmaceutical compositions comprising novel Bosentan derivatives of Formula (I), its isomer, prodrug, polymorph, and hydrates thereof.

DETAILED DESCRIPTION OF THE INVENTION WITH NON-LIMITING EMBODIMENTS AND ILLUSTRATIONS
Accordingly, the present invention provides novel Bosentan derivatives represented by Formula (I), its isomer, tautomer, prodrug, polymorph, and hydrates thereof,

Formula (I)
wherein, R1 is selected from hydrogen, methyl cyclopropane, methyl cyclobutane, methyl cyclopentane, 1,2-dimethylpyrrolidine, 1,2-dimethylpiperidine, but-2-yne, 1,3-dimethylpiperidine, isopentane, 1,1-difluoroethane, (E)-hex-3-ene, but-1-ene;
R2 is selected from hydrogen, methyl, phenyl, p-methyl benzene, p-tert-butyl- benzene.

In a preferred embodiment, the present invention provides novel Bosentan derivatives of Formula (I) wherein R1 is isopentane and R2 is methyl group.

In another embodiment, the hydrate is monohydrate.

The present invention also provides a process for preparing novel Bosentan derivatives represented by Formula (I), its isomer, prodrug, polymorph, and hydrates thereof,

Formula (I)
said process comprising treating a compound of Formula (II)

Formula II
with R1-OH in the presence of a metal hydride and an organic solvent at a temperature between -10°C to 10°C, wherein, R1 is selected from hydrogen, methyl cyclopropane, methyl cyclobutane, methyl cyclopentane, 1,2-dimethylpyrrolidine, 1,2-dimethylpiperidine, but-2-yne, 1,3-dimethylpiperidine, isopentane, 1,1-difluoroethane, (E)-hex-3-ene, but-1-ene; R2 is selected from hydrogen, methyl, phenyl, p-methyl benzene, p-tert-butyl- benzene.

The metal hydride used in the present process is selected from Aluminium hydride, Sodium hydride, Sodium aluminium hydride, Boron hydride, Lithium borohydride.

The solvent used in the present process is selected from hexane, tetrachloroethylene, toluene, acetone, 1,4 dioxane (dioxane), dichloromethane, Acetone, Benzene, tetrahydrofuran, Chloroform, Acetic Acid and mixtures thereof.

The process present invention can be preferably carried out at a temperature range between -2 to 2 °C.

The key intermediate 4, 6-dichloro-5-(2-methoxyphenoxy)-2, 2’-bipyrimidine (1) has been obtained from the chlorination of 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-diol using phosphorus oxychloride at reflux temperature in 4-5 hrs. Dihydroxy has been prepared as per literature procedure starting from the diethyl 2-(2-methoxyphenoxy) malonate and pyrimidine-2-carboximidamide hydrochloride pyrimidine-2-carboximidamide hydrochloride has been prepared from 2-cyano pyrimidine as per well-known literature procedure.

4, 6-dichloro-5-(2-methoxyphenoxy)-2, 2’-bipyrimidine has been further reacted with tert-butyl benzene sulphonamide (2), benzene sulphonamide (4), methane sulphonamide (6), 4-methylbenzene sulphonamide (8) and base cesium carbonate in polar solvent DMF to afford 4-(tert-butyl)-N-(6-chloro-5-(2-methoxyphenoxy)- [2, 2’-bipyrimidin]-4-yl) benzene sulphonamide (3), N-(6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl) benzene sulphonamide (5), N-(6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl)-4-methyl benzenesulfonamide (9), N-(6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl) methane sulphonamide (7) respectively (Scheme-1).

4-(tert-butyl)-N-(6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl) benzenesulfonamide (3) has been reacted with substituted alcohol; cyclopropyl methanol, cyclobutylmethanol, cyclopentylmethanol, (1-methylpyrrolidin-2-yl) methanol, (1-methylpyrrolidin-2-yl) methanol, but-2-yn-1-ol, (1-methylpiperidin-3-yl)methanol, 3-methylbutan-1-ol, 2,2-difluoroethan-1-ol, (E)-hex-3-en-1-ol, but-3-en-1-ol in presence of NaH using THF as solvent at 0oC to room temperature to afford compounds 11 (a-k) respectively as shown in scheme-2.

N-(6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl)-4-methylbenzenesulfonamide (8) has been reacted with substituted alcohol; cyclopropyl methanol, cyclobutylmethanol, cyclopentylmethanol, (1-methylpyrrolidin-2-yl) methanol, (1-methylpyrrolidin-2-yl) methanol, but-2-yn-1-ol, (1-methylpiperidin-3-yl)methanol, 3-methylbutan-1-ol, 2,2-difluoroethan-1-ol, (E)-hex-3-en-1-ol, but-3-en-1-ol in presence of NaH using THF as solvent at 0oC to room temperature to afford compounds 13 (a-k) respectively as shown in scheme-3.

N-(6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl) benzenesulfonamide (4) has been reacted with substituted alcohol; cyclopropyl methanol, cyclobutylmethanol, cyclopentylmethanol, (1-methylpyrrolidin-2-yl) methanol, (1-methylpyrrolidin-2-yl) methanol, but-2-yn-1-ol, (1-methylpiperidin-3-yl) methanol, 3-methylbutan-1-ol, 2,2-difluoroethan-1-ol, (E)-hex-3-en-1-ol, but-3-en-1-ol in presence of NaH using THF as solvent at 0oC to room temperature to afford compounds 15 (a-k) respectively as shown in scheme-4.

N-(6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl) methane sulphonamide (6) has been reacted with substituted alcohol; cyclopropyl methanol, cyclobutylmethanol, cyclopentylmethanol, (1-methylpyrrolidin-2-yl) methanol, (1-methylpyrrolidin-2-yl) methanol, but-2-yn-1-ol, (1-methylpiperidin-3-yl) methanol, 3-methylbutan-1-ol, 2,2-difluoroethan-1-ol, (E)-hex-3-en-1-ol, but-3-en-1-ol in presence of NaH using THF as solvent at 0oC to room temperature to afford compounds 17 (a-k) respectively as shown in scheme-5.

Scheme-1

Scheme-2

Scheme-3

Scheme-4

Scheme-5

Table 1: Structure of Bosentan derivatives screened for in vitro endothelin-1 inhibitory activity

Molecular docking
Molecular docking has been performed to study the binding interactions of synthesized derivatives of Bosentan with the active sites of targeted endothelin receptor. (Bagade et al., 2019; Chaudhary et al., 2019). A dataset of the synthesized derivatives has been drawn using Chemdraw Professional 15.0. The X-ray crystal structures of the target enzyme have been retrieved from the Protein Data Bank (Berman et al., 2002). In addition, the energy of the compounds and targets has been minimized by using CHARMM Force Field (Rappé et al., 1992) in Discovery Studio software. The in silico molecular docking was accomplished using Auto Dock-virtual screening tool (Dallakyan and Olson, 2015).

It is evident that the inhibitory activity of the synthesized derivatives depends mainly on structural factors such as the type, number and position of the functional group on the phenyl ring of the synthesized derivatives. For a better understanding of the experimental results and to emphasize the effects of type, number, and relative position of substituted groups on endothelin receptor inhibition by the tilted compounds, molecular docking study has been performed to shed light on the established binding modes of forty-five selected compounds to the closest residues in the active site of endothelin receptor. Table 2 summarized (i) the calculated binding energies of the stable complex’s ligand-endothelin receptor, (ii) number of established intermolecular hydrogen bonding between endothelin and the synthesized compounds. It also showed hydrogen bond interactions and hydrophobic bond interactions with the amino acid’s residues of active sites of the receptor.

Binding energies of the all docked compounds (Table 2) within the active site endothelin receptor show negative binding energies, which indicates the ability of the docked compound to antagonise endothelin receptor, and that the inhibition is spontaneous. Notably, hydrogen (H)-bonds are of immense importance in biological systems and ubiquitous in nature, that plays an important role in protein folding, protein-ligand interactions, and catalysis.

Table 2: The binding energies and molecular interactions between the docked compounds with endothelin receptor
Compound Structures Binding energy (Kcal/mol) Amino acid residues
Bosentan
-10.034 385 S – 109CYS2.640680
385 S – 109 CYS,2.950149
385 S -109 CYS, 2.710384
By-product
-9.855 1548 N – 181GLN
2.263585
1547 O -181 GLN
2.956764
1548 N -181 GLN
2.849409
1565 N -182 LYS
2.847704
5891 N -343 ARG
2.981383
5891 N-343ARG
2.790518
11a
-8.56 3372 O – 249 THR
2.899281

11b
-8.63 3123 O – 279 SER
2.231019
11c
-8.59 1206 O-160 TYR
2.89
385 S-109 CYS
2.34
385 S-109 CYS
2.46
11d
-8.26 1565 N -182 LYS
2.528226
5890 N -343 ARG
2.759333
5891 N -343 ARG
2.120472
5058 N – 343 ARG
2.759020
11e
-6.37 3129 N – 280 PHE
2.999072
3123 O –279 SER
1.798236
11f
-5.78 3123 O – 279SER
2.872406
11g
-8.31 3039 N -273 TRP
2.946122
11h
-5.03 2710 N – 255 CYS
2.688592
1224 N -161 LYS
2.749195
184 N – 97LYS
2.390446
11l
-9.21 2710 N -255 CYS
2.999536
2713 O -255 CYS
2.640742
1224 N -161 LYS
2.737572
1224 N – 161 LYS
2.967471
11j
-5.29 1548 N – 181GLN
2.572344
1547 O – 181GLN
2.898061
1548 N -181GLN
2.528183
11k
-8.49 385 S-109 CYS
2.96

13a
-8.42 1547 O -181GLN
2.912674
1548 N -181GLN
2.325399
1548 N -181GLN
2.613007
13b
-5.97 3287 O -289THR
2.901768
13c
-8.21 1206 O-160 TYR
2.88
385 S-109 CYS
2.51
385 S-109 CYS
2.30

13d
-5.89 1206 O-160 TYR
2.89
385 S-109 CYS
2.91
385 S-109 CYS
2.47

13e
-8.61 385 S -109CYS
2.886191
1206 O -160TYR
2.669503
1206 O -160TYR
2.951628
13f
-6.01 1565 N -182LYS
2.578078
1565 N -182 LYS
2.792342
5891 N -343 ARG
2.761141
5891 N- 343 ARG
2.298931
13g
-6.38 3005 N -273 LYS
2.686061
2739 N -257 LEU
2.362822
2421 O -236 GLU
2.948287
1565 N -182LYS
2.394998
1565 N – 182 LYS
2.424750
1565 N -182LYS
2.472127
13h
-8.34 1206 O-160 TYR
2.90
385 S-109 CYS
2.98
385 S-109 CYS
2.45
13i
-5.10 184 N -97 LYS
2.731999
184 N -97 LYS
2.855364
184 N – 97 LYS
2.389265
6331 O -369 TYR
2.640699
6331 O -369 TYR
2.534702
1224 N -161 LYS
2.589578
1224 N -161 LYS
2.892444
13j
-5.45 1565 N – 182 LYS
2.944964
1565 N – 182 LYS
2.808683
1547 N -181 GLN
2.537187
1548 N – 181 GLN
2.063184
13k
-5.12 184 N – 97 LYS
2.825997
184 N –97 LYS
2.927894
184 N - 97 LYS
2.594242
6331 O – 369 TYR
2.172748
1224 N -161 LYS
2.640043

17a
-6.90 1558 N – 181 GLN
2.185485
5891 N -343 ARG
2.939563
5891 N 343 ARG
2.251545
5891 N- 343 ARG
2.913134
17b
-8.18 1548 N -181 GLN
2.459884
1548 N – 181 GLN
2.535580
1565 N – 182 LYS
2.639339
5091 N – 343 ARG
2.922316
17c
-7.83 1548 N -181 GLN
2.920417
1548 N – 181 GLN
2.940882
1548 N – 181 GLN
2.135170
1565 N – 182 LYS
2.837028
1565 N – 182 LYS
2.96993
5891 N – 343 ARG
2.452284
17d
-6.99 3422 O – 297 THR
2.884963
3372 O – 294 THR
2.530372
3372 O – 294 THR
2.349476
17e
-7.66 1548 N – 181 GLN
2.975087
1548 N – 181 GLN
2.958143
1548 N – 181 GLN
2.648957
1565 N 182 LYS
2.829867
1565 N -182 LYS
2.481806
17f
-7.97 1224 N – 161 LYS
2.915798
5890 N – 343 ARG
2.956370
17g
-7.99 1548 N – 181 GLN
2.490170
1548 N – 181 GLN
2.648724
1565 N – 182 LYS
2.781939
1565 N – 182 LYS
2.517707
3005 N – 273 LYS
2.675072
5891 N – 343 ARG
2.999655
17h
-10.73 6331 O – 369 TYR
2.092078
184 N – 97 LYS
2.951350
184 N – 97 LYS
2.087115
6331 O – 369 TYR
2.572354
184 N -97 LYS
2.728040
6331 O – 369 TYR
2.999740
5890 N 343 ARG
2.944508
316 N – 104 ASN
2.744595
17i
-9.45 1224 N – 161 LYS
2.672256
1224 N – 161 LYS
2.289838
6331 O – 369 TYR
2.816078
184 N -97 LYS
2.167023
184 N – 97 LYS
2.784608
17j
-9.85 6331 O – 369 TYR
2.498347
184 N – 97 LYS
2.886424
184 N – 97 LYS
2.531994
184 N – 97 LYS
2.895474
1224 N – 161 LYS
2.832032
1224 N – 161 LYS
2.278684
17k
-6.84 6331 O – 369 TYR
2.673272
184 N – 97 LYS
2.896114
184 N – 97 LYS
2.897437
184 N – 97 LYS
2.116613
1224 N – 161 LYS
2.695780

15a
-6.71 1206 O – 160 TYR
2.445251

15b
-8.06 1565 N – 182 LYS
2.983156
1548 N - 181 GLN
2.165287
1548 N -181 GLN
2.543918
15c
-6.21 1565 N – 182 LYS
2.434105
1565 N – 182 LYS
2.527960
1565 N – 182 LYS
2.513959
3005 N – 273 LYS
2.712433
5891 N – 343 ARG
2.967151
2739 N – 257 LEU
2.190667
15d
-10.09 385 S – 109 CYS
2.769009
15e
-8.04 5890 N – 343 ARG
2.363964
5890 N – 343 ARG
2.741329
3005 N – 273 LYS
2.996949
1565 N – 182 LYS
2.824884
1565 N – 182 LYS
2.154285
15f
-5.23 1224 N – 161 LYS
2.433656
1224 N – 161 LYS
2.820416
184 N – 97 LYS
2.183099
15g
-5.91 1565 N – 182 LYS
2.313988
1565 N – 182 LYS
2.204154
1565 N – 182 LYS
2.565178
5891 N – 343 ARG
2.673006
2739 N -257 LEU
2.144964
15h
-8.13 1548 N – 181 GLN
2.8927
1548 N -181 GLN
2.476667
1547 O – 181 GLN
2.535979
1565 N – 182 LYS
2.984357
1565 N – 182 LYS
2.792633
5891 N – 343 ARG
2.936498
15i
-8.97 1565 N – 182 LYS
2.974935
5890 N – 343 ARG
2.666646
5891 N – 343 ARG
2.548486
15j
-8.74 1224 N – 161 LYS
2.778025
1224 N – 161 LYS
2.552686
184 N – 97 LYS
2.647836
184 N – 97 LYS
2.708097
6331 O – 369 TYR
2.139564
184 N – 97 LYS
2.529627
6331 O – 369 TYR
2.952508
15k
-5.67 1565 N – 182 LYS
2.998532
5891 N – 343 ARG
2.965292

In Vitro Studies:
Synthesized compounds were tested for in vitro endothelin-1 inhibitory activity using commercially available endothelin-1 human ELISA assay kit (Thermo Fischer Scientifics # EIAET1). Results of the in vitro study reveals that the synthesized derivatives exhibit mild to excellent endothelin receptor antagonistic activity. Compound 17h found to be most efficacious derivative with IC50 of 0.18nM against endothelin receptor when compared with reference standard bosentan bearing IC50 of 4.7 nM (nano Mole).

The results of molecular docking and in vitro endothelin inhibitory activities of different compounds are presented in Table 3.

Table 3: Molecular docking scores and in vitro endothelin Inhibitory activities of different bosentan derivatives

Compound Code Binding Energy H-bonding IC50
17h -10.73 Y 0.18
15d -10.09 Y 0.22
17j -9.85 Y 0.26
17i -9.45 Y 0.47
11l -9.21 Y 0.77
15i -8.97 Y 0.88
15j -8.74 Y 0.97
11b -8.63 Y 1.05
13e -8.61 N 1.14
11c -8.59 Y 1.15
11a -8.56 Y 1.22
11k -8.49 N 1.24
13a -8.42 N 1.21
13h -8.34 Y 1.39
11g -8.31 Y 1.43
11d -8.26 Y 1.46
13c -8.21 Y 1.62
17b -8.18 Y 1.69
15h -8.13 Y 1.73
15b -8.06 Y 1.84
15e -8.04 Y 1.91
17g -7.99 Y 2.01
17f -7.97 Y 2.13
17c -7.83 Y 2.19
17e -7.66 Y 2.21
17d -6.99 Y 2.33
17a -6.90 Y 2.38
17k -6.84 Y 2.41
15a -6.71 N 2.44
13g -6.38 N 2.46
11e -6.37 N 2.59
15c -6.21 N 2.78
13f -6.01 N 2.99
13b -5.97 N 3.22
15g -5.91 N 3.38
13d -5.89 N 3.53
11f -5.78 N 3.67
15k -5.67 N 3.78
13j -5.45 N 3.92
11j -5.29 N 3.99
15f -5.23 N 4.33
13k -5.12 N 4.56
13i -5.10 N 4.76
11h -5.03 N 4.78
Y: Yes; N: No

Among synthesized compounds screened for in vitro endothelin receptor inhibitory activity, compound N-(6-(isopentyloxy)-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl) methanesulfonamide (17h) is found as the most active derivative of Bosentan.

Compound 17h

The present invention also provides pharmaceutical compositions comprising Bosentan derivatives of Formula (I), its isomer, prodrug, polymorph, and hydrates thereof.

The pharmaceutical composition can be in the form of a tablet, capsule, granule, syrup, suspension, suppositories, injection and patches.

The novel Bosentan derivatives of the present invention exhibit endothelin receptor antagonistic activity and are capable of being used in medicaments for the treatment of hypertensive disorders which are associated with endothelin activities, especially Pulmonary artery hypertension, ischaemia, vasospasms and angina pectoris.

We claim:

1. Novel Bosentan derivatives represented by Formula (I), its isomer, tautomer, prodrug, polymorph, and hydrates thereof,

wherein, R1 is selected from hydrogen, methyl cyclopropane, methyl cyclobutane, methyl cyclopentane, 1,2-dimethylpyrrolidine, 1,2-dimethylpiperidine, but-2-yne, 1,3-dimethylpiperidine, isopentane, 1,1-difluoroethane, (E)-hex-3-ene, but-1-ene; and
R2 is selected from hydrogen, methyl, phenyl, p-methyl benzene, p-tert-butyl- benzene.
2. The novel Bosentan derivatives of a compound as claimed in claim 1, wherein R1 is isopentane and R2 is methyl group.
3. The novel Bosentan derivatives of a compound as claimed in claim 1, wherein said derivative is Bosentan monohydrate.
4. A process for preparing novel Bosentan derivatives represented by Formula (I), its isomer, prodrug, polymorph, and hydrates thereof,

said process comprising treating a compound of Formula (II)

Formula II
with R1-OH in the presence of a metal hydride and an organic solvent at a specific temperature between -10°C to 20°C, wherein, R1 is selected from hydrogen, methyl cyclopropane, methyl cyclobutane, methyl cyclopentane, 1,2-dimethylpyrrolidine, 1,2-dimethylpiperidine, but-2-yne, 1,3-dimethylpiperidine, isopentane, 1,1-difluoroethane, (E)-hex-3-ene, but-1-ene; R2 is selected from hydrogen, methyl, phenyl, p-methyl benzene, p-tert-butyl- benzene.
5. The process as claimed in claim 3, wherein the metal hydride is selected from Aluminium hydride, Sodium hydride, Sodium aluminium hydride, Boron hydride, Lithium borohydride.
6. The process as claimed in claim 3, wherein the solvent is selected from hexane, tetrachloroethylene, toluene, acetone, 1,4 dioxane (dioxane), dichloromethane, Acetone, Benzene, tetrahydrofuran, Chloroform, Acetic Acid and mixtures thereof.
7. The process as claimed in claim 4, wherein the specific temperature is -2°C to 2 °C.
8. The process as claimed in claim 4, wherein R1 is isopentane group and R2 is methyl group.
9. A pharmaceutical composition comprising novel Bosentan derivatives of Formula (I), its isomer, prodrug, polymorph, and hydrates thereof.
10. The pharmaceutical composition as claimed in claim 9, wherein said Bosentan derivative is Bosentan monohydrate.
11. The pharmaceutical composition as claimed in claim 8, wherein said composition is in the form of a tablet, capsule, granule, syrup, suspension, suppositories, injection and patches.
12. The novel Bosentan derivatives as claimed in claim 1, wherein said derivatives exhibit endothelin receptor antagonistic activity and are capable of being used in medicaments for the treatment of hypertensive disorders which are associated with endothelin activities, especially Pulmonary artery hypertension, ischaemia, vasospasms and angina pectoris.