FIELD OF THE INVENTION

The present invention relates to certain novel salts of the prolyl hydroxylase inhibitors of formula (la), processes for the preparation of these novel salts, use thereof and pharmaceutical composition comprising the same.

BACKGROUND OF THE INVENTION

Hypoxia-inducible factor (HIF) is a heteroduplex, with a and b subunit. The beta subunit is usually present in excess, while the alpha subunit is the limiting factor in the formation of the functional dimer. The HIF-a subunit binds with the b subunit in the nucleus and, with the cooperation of cofactors, binds to DNA sequences called hypoxia response elements, and hence induces expression of target genes. There are three isoforms of the a subunit, HIF-la, HIF-2a and HIF-3a. The activity of HIF is regulated via hydroxylation at two proline residues by an oxygen-sensitive family of prolyl hydroxylase enzymes (PHD), known as PHD1, PHD2 and PHD3. Hydroxylation at one or both of these proline residues allows binding of HIF-a first by the von Hippel— Lindau tumor suppressor protein (pVHL) and then by ubiquitin ligase which results in rapid ubiquitination and proteosomal degradation. The HIF-a subunits are also regulated by hydroxylation at a C-terminal asparagine residue by factor inhibiting HIF (FIH), an oxygen-dependent hydroxylase enzyme. Factor inhibiting HIF prevents the recruitment of transcriptional coactivators, thereby blocking the activity of HIF.

Under normoxic (oxygenated) conditions, HIF-la is rapidly degraded, while under hypoxic conditions, HIF-la is stabilized due to hypoxia mediated reduction of PHD and FIH activities and is translocated into the nucleus, where it dimerizes with the constitutively expressed HIF- 1 b, thereby inducing the expression of several genes including glucose transporters, glycolytic enzymes, angiogenic growth factors, and several molecules involved in apoptosis and cell proliferation such as erythropoietin (EPO), transferrin, endothelin- 1 , iNOS, heme oxygenase 1, VEGF, IGF and IGF-binding proteins. The oxygen sensitive PHD family is also dependent on the presence of ferrous iron, ascorbate and the citric acid cycle intermediate, 2-oxoglutarate (20G). HIF activity, therefore, depends on oxygen concentrations, accessible iron and glucose metabolism through its regulation by FIH and PHD. Inhibition of HIF prolyl hydroxylases and HIF asparagyl hydroxylases thus provides a powerful approach for oxygen-independent activation of HIF. Such HIF activation by pharmacological means results in enhanced expression of genes as described earlier which perform multiple functions to recover from hypoxic/ischemic conditions. Therefore, HIF activation can offer significant therapeutic benefits in various disease conditions such as anemia of various types and tissue injuries caused by hypoxia/ischemia in conditions like acute kidney injury, myocardial infarction, stroke, hepatic ischemia-reperfusion injury, peripheral vascular diseases and transplantation of liver and kidney.

Hb (Hemoglobin) is an iron-containing metalloprotein in red blood cells (RBCs) that delivers oxygen. Decreased Hb levels resulting from anemia can lead to hypoxia in various organs and, therefore, cause patients severe clinical complications, such as severe fatigue, dyspnea, heart problems, nerve damage, impaired mental function and even death. The cause of anemia is multifactorial: blood loss, increased RBC destruction (e.g., hemolytic anemia), and decreased or faulty RBC production (e.g., iron deficiency and sickle cell anemia). 80% of patients with chronic kidney disease (CKD) develop anemia because of decreased production of erythropoietin (EPO) in the kidney. EPO is an essential growth factor that stimulates the erythropoiesis, and maintains their viability. Patients with rheumatoid arthritis, chronic inflammatory and infectious disorders, chronic heart failure, and cancers or who are undergoing chemotherapy often become anemic due to deficiency of EPO production.

The current treatment for anemia in chronic diseases, including anemia of chronic kidney disease, is iron repletion and treatment with EPO or its analogs. In addition to the high cost of EPO and its analogs, there are several shortcomings to this approach. First, these must be injected subcutaneously or intravenously, making administration more difficult. Second, there is a significant proportion of patients resistant to therapy with EPO or its analogs. Treatment of anemia with HIF-hydroxylase inhibitors may bypass EPO resistance, through effects on iron metabolism, and avoid the increased death and cardiovascular events associated with supraphysiologic levels of EPO.

Compounds which provide a means for inhibiting HIF hydroxylases and thereby activating the HIF, leading to enhanced expression of the various genes including EPO, vascular endothelial growth factor (VEGF), adrenomodulin etc. are therefore expected to be useful in treating various disorders including anemia of different types and conditions associated with ischemia/hypoxia.

W02014102818 discloses compounds of the following general formula ro These compounds are reported to be useful for the treatment of anemia. It has surprisingly now been found that compound of formula (la) as given below: formula (la) and its pharmaceutically acceptable salts are effective in the treatment of anemia and also in further pharmaceutical development and were also efficacious. US 20190359574 discloses the process for the preparation of formula (la).

These salts can show certain superior pharmaceutical &/or chemical properties.

These new salts are produced in solid state, can have improved characteristics such as stability, flowability and therefore easy to handle in an industrial scale. This makes these new salts suitable as intermediates for preparing the compound of formula (la) in a chemically pure form though some of these salts may not be pharmaceutically useful. Some of these salts additionally can also have superior biological properties over the known compound of formula (la).

These salts may be present either in substantially crystalline or amorphous forms or may be present as partially crystalline forms. In a preferred embodiment the salts are present in crystalline form. In another preferred embodiment, the salts are present in an amorphous form.

In another embodiment, the salts are present in non-solvated/unsolvated form or in a solvent free form. In another embodiment, the salts are present in solvated/hydrated form. EMBODIMENTS OF THE INVENTION

In an embodiment, the present invention provides for certain pharmaceutically acceptable salts of compound of formula (la), it is referred as compounds of formula (lb).

In another embodiment the present invention discloses the process for the preparation of compounds of formula (lb).

In an embodiment the present invention provides compounds of formula (lb) either in substantially crystalline or amorphous form or partially crystalline form.

In a still further embodiment present invention provides a pharmaceutical composition comprising, the therapeutically effective amount of compound of formula (lb), prepared according to the present invention, along with at least one suitable pharmaceutically acceptable carrier, diluents, vehicle or other excipients.

In an embodiment the present invention provides a compound of formula (lb) is suitable for the treatment of anemia.

SUMMARY OF THE INVENTION

The present invention provides certain the compounds of formula (lb)

Formula (lb) wherein M is a cation; ‘a’ is the valency of the cation and is selected from 1, 2, 3; n is an integer selected from 1, 2, 3; compounds of formula (lb) exist in hemi, mono, di, bis, tri valent salts of compound of formula (la). Cation is selected from metal, amine bases and amino acids.

Wherein metal is selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt , iron, manganese, lead, aluminum, cadmium , silver, zinc, ammonium and the like;

Wherein amine base is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene - methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, 2- thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, a-naphthylamine, O- phenylenediamine, 1,3-Diaminopropane, (S)-a-naphthylethylamine, (5)- 3- methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (5)-4-chlorophenylethylamine,

(S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N- diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L- adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine, metformin, hexane- 1,6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine, and N- ethylmorpholine.

Wherein amino acid is selected from alanine, lysine, arginine, histidine, threonine, proline, glutamine and glycine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a powder X-ray diffraction (XRPD) pattern of crystalline form of compound of formula (lb) wherein cation is sodium.

FIG. 2 is a powder X-ray diffraction (XRPD) pattern of amorphous form of compound of formula (lb) wherein cation is sodium.

FIG. 3 is a powder X-ray diffraction (XRPD) pattern of crystalline form of compound of formula (lb) wherein cation is lithium.

FIG. 4 is a powder X-ray diffraction (XRPD) pattern of crystalline form compound of formula (lb) wherein cation is of potassium.

FIG. 5 is a powder X-ray diffraction (XRPD) pattern of crystalline form of compound of formula (lb) wherein cation is calcium.

FIG. 6 is a powder X-ray diffraction (XRPD) pattern of amorphous form of compound of formula (lb) wherein cation is cobalt.

FIG. 7 is a powder X-ray diffraction (XRPD) pattern of crystalline form of compound of formula (lb) wherein cation is zinc.

FIG. 8 is a powder X-ray diffraction (XRPD) pattern of crystalline form of compound of formula (lb) wherein cation is copper.

FIG. 9 is a powder X-ray diffraction (XRPD) pattern of crystalline form of compound of formula (lb) wherein cation is magnesium.

FIG. 10 is a powder X-ray diffraction (XRPD) pattern of crystalline form of compound of formula (lb) wherein cation is manganese.

FIG. 11 is a powder X-ray diffraction (XRPD) pattern of crystalline form of compound of formula (lb) wherein cation is metformin.

FIG. 12 is a powder X-ray diffraction (XRPD) pattern of crystalline form of compound of formula (lb) wherein cation is L-proline. FIG. 13 is a powder X-ray diffraction (XRPD) pattern of crystalline form of compound of formula (lb) wherein cation is D-proline.

FIG. 14 is a powder X-ray diffraction (XRPD) pattern of crystalline form compound of formula (lb) wherein cation is of urea.

DESCRIPTION OF THE INVENTION

The term ‘treating’ or ‘treatment’ or condition as used herein means: preventing or delaying the appearance of clinical symtomps of the state, disorder or condition developing in a mammal.

The term ‘subject’ is intended to use for human as well as animals. The term ‘pharmaceutically acceptable’ use embraces both human and veterinary use.

The present invention provides certain new salts of compound of formula (la);

Formula (la)

For the purpose of present invention salt of formula (la) is referred as formula (lb) as given below;

Formula (lb)

20 wherein M is a cation; ‘a’ is the valency of the cation and is selected from 1, 2, 3; n is an integer selected from 1, 2, 3; compounds of formula (lb) exist in hemi, mono, di, bis, tri valent salts of compound of formula (la).

In an embodiment, cation is selected from metal, amine bases and amino acids. Wherein metal salt is selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium and the like.

Wherein amine base salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene- methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, 2- thiopheneethanamine, 2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, a-naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-a- naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-4- chlorophenylethylamine, (S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)- quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2- hydroxyethyl), N-N-diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L- adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine, metformin, hexane- 1,6-diamine, 2-(2-aminoethoxy)ethanamine, N-methylmorpholine, N- ethylmorpholine and the like.

Wherein amino acid is selected from alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine and the like.

In a preferred embodiment, a cation is selected from sodium, potassium, lithium, calcium, cobalt, zinc, copper, magnesium, manganese, metformin, urea, L-proline and D-proline. In another embodiment the present invention discloses the process for the preparation of compound of formula (b).

The process comprising: (a) dissolving compound of formula (la) in one or more suitable solvents to obtain a solution;

(b) dissolving salts source in water or organic solvents or mixture thereof;

(c) mix both solution at heating or room temperature to get clear solution

(d) cool it to room temperature and filter it or distil it or lyophilize it to obtain salts of compound of formula (la)

Cation source means different counterpart taken to prepare a salt.

The inventors also have developed a process for the preparation of compound of formula (lb) by obtaining a solution of compound of formula (la) in one or more suitable solvents and obtaining a solution of salts source in one or more suitable solvents or water or mixture thereof. The mixing of both the solution may be done by mixing procedure known in the art.

In one aspect, the process may include cooling the solution obtain after step mixing the solution of compound of formula (la) and a solution of salts source in a known manner. The solution of compound of formula (la) and a solution of salts source may be obtained by heating the solvent. It may be heated from about 25°C to reflux temperature.

The term “solvent” includes one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether; water or mixture thereof.

The solvent may be removed by a technique which includes, for example, distillation, distillation under vacuum, lyophilization, evaporation, filtration, filtration under vacuum, decantation and centrifugation. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.

In an embodiment the present invention provides compounds of formula (lb) either in substantially crystalline or amorphous form or partially crystalline forms. In a further embodiment, each of the crystalline and/or amorphous forms may independently exist either in hydrated, solvated, non-solvated, anhydrous, solvent free or desolvated solvates of either the crystalline, amorphous or various mixtures of crystalline and amorphous forms.

In one embodiment of the invention is provided the compound of formula (lb) wherein cation is sodium. In an embodiment, the compound of formula (lb) wherein cation is sodium can be present in either crystalline and/or amorphous form each of which can optionally be present in anhydrous, solvent free, hydrated or solvated forms.

In a preferred embodiment, the compound of formula (lb) wherein cation is sodium present in crystalline form.

In one embodiment of the present invention is provided a crystalline form of compound of formula (lb) wherein cation is sodium, which has at least one of the following characteristics: i) a powder X-ray diffraction pattern substantially in accordance with Figure 1 ; ii) a powder X-ray diffraction pattern having peaks at about 3.46, 9.52, 15.47, 17.39, 21.66, 22.41, 24.65, 25.47, 25.98, 27.634 + 0.2 degrees 2-theta.

In another preferred embodiment, the compound of formula (lb) wherein cation is sodium present in amorphous form.

In one embodiment of the present invention is provided an amorphous form of compound of formula (lb) wherein cation is sodium which has following characteristics: i) a powder X-ray diffraction pattern substantially in accordance with Figure 2;

In one embodiment of the invention is provided the compound of formula (lb) wherein cation is lithium. In an embodiment, compound of formula (lb) wherein cation is lithium can be present in either crystalline and/or amorphous form each of which can optionally be present in anhydrous, solvent free, hydrated or solvated forms.

In a preferred embodiment, the compound of formula (lb) wherein cation is lithium present in crystalline form.

In one embodiment of the present invention is provided a crystalline form of compound of formula (lb) wherein cation is lithium which has at least one of the following characteristics: i) a powder X-ray diffraction pattern substantially in accordance with Figure 3 ; ii) a powder X-ray diffraction pattern having peaks at about 7.54, 8.06, 10.16, 20.49, 21.64, 22.37, 23.28, 24.23, 24.63, 25.90 + 0.2 degrees 2-theta.

In one embodiment of the invention is provided the compound of formula (lb) wherein cation is potassium. In an embodiment, compound of formula (lb) wherein cation is potassium can be present in either crystalline and/or amorphous form each of which can optionally be present in anhydrous, solvent free, hydrated or solvated forms.

In a preferred embodiment, the compound of formula (lb) wherein cation is potassium present in crystalline form.

In one embodiment of the present invention is provided a crystalline form of compound of formula (lb) wherein cation is potassium which has at least one of the following characteristics: i) a powder X-ray diffraction pattern substantially in accordance with Figure 4; ii) a powder X-ray diffraction pattern having peaks at about 6.62, 11.52, 13.30, 17.62, 20.66, 23.32, 24.82, 25.34, 25.95, 26.91 + 0.2 degrees 2-theta.

In one embodiment of the invention is provided the compound of formula (lb) wherein cation is calcium. In an embodiment, compound of formula (lb) wherein cation is calcium can be present in either crystalline and/or amorphous form each of which can optionally be present in anhydrous, solvent free, hydrated or solvated forms.

In a preferred embodiment, the compound of formula (lb) wherein cation is calcium present in crystalline form. In one embodiment of the present invention is provided a crystalline form of compound of formula (lb) wherein cation is calcium which has at least one of the following characteristics: i) a powder X-ray diffraction pattern substantially in accordance with Figure 5 ; ii) a powder X-ray diffraction pattern having peaks at about 4.54, 6.11, 6.40, 7.28, 10.42, 10.51, 11.49, 12.99, 13.66, 23.71 + 0.2 degrees 2-theta.

In one embodiment of the invention is provided the compound of formula (lb) wherein cation is cobalt. In an embodiment, compound of formula (lb) wherein cation is cobalt can be present in either crystalline and/or amorphous form each of which can optionally be present in anhydrous, solvent free, hydrated or solvated forms.

In a preferred embodiment, the compound of formula (lb) wherein cation is cobalt present in an amorphous form.

In one embodiment of the present invention is provided an amorphous form of compound of formula (lb) wherein cation is cobalt which has following characteristics: i) a powder X-ray diffraction pattern substantially in accordance with Figure 6;

In one embodiment of the invention is provided the compound of formula (lb) wherein cation is zinc. In an embodiment, compound of formula (lb) wherein cation is zinc can be present in either crystalline and/or amorphous form each of which can optionally be present in anhydrous, solvent free, hydrated or solvated forms.

In a preferred embodiment, the compound of formula (lb) wherein cation is zinc present in crystalline form.

In one embodiment of the present invention is provided a crystalline form of compound of formula (lb) wherein cation is zinc which has at least one of the following characteristics: i) a powder X-ray diffraction pattern substantially in accordance with Figure 7 ; ii) a powder X-ray diffraction pattern having peaks at about 4.63, 10.05, 18.75, 21.44, 22.28, 23.02, 24.24, 25.60, 26.79, 27.95 ± 0.2 degrees 2-theta. In one embodiment of the invention is provided the compound of formula (lb) wherein cation is copper. In an embodiment, compound of formula (lb) wherein cation is copper can be present in either crystalline and/or amorphous form each of which can optionally be present in anhydrous, solvent free, hydrated or solvated forms. In a preferred embodiment, the compound of formula (lb) wherein cation is copper present in crystalline form.

In one embodiment of the present invention is provided a crystalline form of compound of formula (lb) wherein cation is copper which has at least one of the following characteristics: i) a powder X-ray diffraction pattern substantially in accordance with Figure 8; ii) a powder X-ray diffraction pattern having peaks at about 4.09, 10.16, 10.73, 11.14, 21.03, 21.55, 24.60, 27.05, 26.93, 28.06 + 0.2 degrees 2-theta.

In one embodiment of the invention is provided the compound of formula (lb) wherein cation is magnesium. In an embodiment, compound of formula (lb) wherein cation is magnesium can be present in either crystalline and/or amorphous form each of which can optionally be present in anhydrous, solvent free, hydrated or solvated forms.

In a preferred embodiment, the compound of formula (lb) wherein cation is magnesium present in crystalline form.

In one embodiment of the present invention is provided a crystalline form of compound of formula (lb) wherein cation is magnesium which has at least one of the following characteristics: i) a powder X-ray diffraction pattern substantially in accordance with Figure 9; ii) a powder X-ray diffraction pattern having peaks at about 9.55, 10.17, 10.83, 11.12,

14.60, 18.89, 19.64, 21.56, 26.92, 28.07 + 0.2 degrees 2-theta.

In one embodiment of the invention is provided the compound of formula (lb) wherein cation is manganese. In an embodiment, compound of formula (lb) wherein cation is manganese can be present in either crystalline and/or amorphous form each of which can optionally be present in anhydrous, solvent free, hydrated or solvated forms. In a preferred embodiment, the compound of formula (lb) wherein cation is manganese present in crystalline form.

In one embodiment of the present invention is provided a crystalline form of compound of formula (lb) wherein cation is manganese which has at least one of the following characteristics: i) a powder X-ray diffraction pattern substantially in accordance with Figure 10; ii) a powder X-ray diffraction pattern having peaks at about 6.88, 7.09, 9.23, 9.29, 12.21, 13.81, 20.81, 23.65, 26.19, 26.27 + 0.2 degrees 2-theta.

In one embodiment of the invention is provided the compound of formula (lb) wherein cation is metformin. In an embodiment, compound of formula (lb) wherein cation is metformin can be present in either crystalline and/or amorphous form each of which can optionally be present in anhydrous, solvent free, hydrated or solvated forms.

In a preferred embodiment, the compound of formula (lb) wherein cation is metformin present in crystalline form. In one embodiment of the present invention is provided a crystalline form of compound of formula (lb) wherein cation is metformin which has at least one of the following characteristics: i) a powder X-ray diffraction pattern substantially in accordance with Figure 11 ; ii) a powder X-ray diffraction pattern having peaks at about 4.34, 8.53, 8.73, 12.25, 15.66, 17.58, 21.68, 21.78, 24.77, 24.91 ± 0.2 degrees 2-theta.

In one embodiment of the invention is provided the compound of formula (lb) wherein cation is L-proline. In an embodiment, compound of formula (lb) wherein cation is L-proline can be present in either crystalline and/or amorphous form each of which can optionally be present in anhydrous, solvent free, hydrated or solvated forms. In a preferred embodiment, the compound of formula (lb) wherein cation is L-proline present in crystalline form.

In one embodiment of the present invention is provided a crystalline form of compound of formula (lb) wherein cation is L-proline which has at least one of the following characteristics: i) a powder X-ray diffraction pattern substantially in accordance with Figure 12; ii) a powder X-ray diffraction pattern having peaks at about 7.44, 9.57, 10.14, 14.93, 18.23, 18.70, 19.15, 22.49, 25.22, 26.94 + 0.2 degrees 2-theta.

In one embodiment of the invention is provided the compound of formula (lb) wherein cation is D-proline. In an embodiment, compound of formula (lb) wherein cation is D-proline can be present in either crystalline and/or amorphous form each of which can optionally be present in anhydrous, solvent free, hydrated or solvated forms.

In a preferred embodiment, the compound of formula (lb) wherein cation is D-proline present in crystalline form. In one embodiment of the present invention is provided a crystalline form of compound of formula (lb) wherein cation is D-proline which has at least one of the following characteristics: i) a powder X-ray diffraction pattern substantially in accordance with Figure 13; ii) a powder X-ray diffraction pattern having peaks at about 3.68, 7.41, 11.15, 14.90, 18.67, 20.84, 22.47, 24.39, 25.54, 26.79 + 0.2 degrees 2-theta.

In one embodiment of the invention is provided the compound of formula (lb) wherein cation is urea. In an embodiment, compound of formula (lb) wherein cation is urea can be present in either crystalline and/or amorphous form each of which can optionally be present in anhydrous, solvent free, hydrated or solvated forms. In a preferred embodiment, the compound of formula (lb) wherein cation is urea present in crystalline form.

In one embodiment of the present invention is provided a crystalline form of compound of formula (lb) wherein cation is urea which has at least one of the following characteristics: i) a powder X-ray diffraction pattern substantially in accordance with Figure 14; ii) a powder X-ray diffraction pattern having peaks at about 5.46, 6.26, 9.20, 10.98, 12.56, 12.73, 15.17, 16.54, 21.52, 22.87 ± 0.2 degrees 2-theta.

In one embodiment present invention provides a process for the obtaining pure compound of formula (la) from compounds of formula (lb). Process comprising following steps:

(i) dissolving compound of formula (lb) in one or more suitable solvents to obtain a solution;

(ii) drop-wise addition of suitable dilute acid solution to the solution of step (i) at suitable temperature and with continuous stirring; (iii) solid material, thus precipitate out then filtered, washed and dried to obtain compound of formula (la).

The term “solvent” includes one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether; water or mixture thereof.

Suitable acid includes dilute solution of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, p-toluene sulfonic acid (PTSA), methane sulfonic acid, trifluoroacetic acid, and the like.

The solvent may be removed by a technique which includes, for example, distillation, distillation under vacuum, lyophilization, evaporation, filtration, filtration under vacuum, decantation and centrifugation.

The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier. In another embodiment of the present invention the dose of the effective amount of the compound of formula (lb) to be administered to the subject is selected from 1.0 to 500 mg with respect to compound of formula (la).

The dose of the effective amount of the compound of formula (lb) to be administered to the subject is selected from 25 mg to 250 mg preferably 50 mg to 150 mg with respect to compound of formula (la).

In an embodiment the present invention provides a compound of formula (lb) is administrated orally, intravenously or parentally in the subject who is in need of treatment. In an embodiment the present invention also provides a suitable pharmaceutical composition of compounds of formula (lb). The pharmaceutical composition of the present invention essentially comprises of: the pharmaceutically active substance of formula (lb); - optionally with one or more pharmaceutically acceptable excipients.

The pharmaceutically acceptable excipients are selected at least one from diluent, binders, disintegrating agents, lubricating agents, glidant agent, coating redimix and the like.

Diluents include, but are not limited to lactose monohydrate, lactose, microcrystalline cellulose, polymethacrylates selected from Eudragit, potassium chloride, sulfobutylether b -cyclodextrin, sodium chloride, spray dried lactose, and preferably sulfobutyl ether b -cyclodextrin combinations thereof and other such materials known to those of ordinary skill in the art.

Binders include, but are not limited to Hypromellose 3 Cps, carbomers selected from carbopol, gellan, gum Arabic, hydrogenated vegetable oil, polymethacrylates selected from Eudragit, xanthan, lactose and Zein combinations thereof and other such materials known to those of ordinary skill in the art.

Disintegrating agents include, but are not limited to, Croscarmellose Sodium, bicarbonate salt, chitin, gellan gum, polacrillin potassium and Docusate Sodium combinations thereof and other such materials known to those of ordinary skill in the art.

Glidant agents include, but are not limited to, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art. Lubricant agents include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, Glycerin behenate, hydrogenated vegetable oil, sodium stearyl fumarate and Myristic Acid suitable combinations thereof and other such materials known to those of ordinary skill in the art. Coating redimix is selected from Opadry Pink all such materials known to those of ordinary skill in the art.

In an embodiment present invention is provided compound of formula (lb) or its pharmaceutical composition is suitable for treatment of anemia.

The compound of formula (la), is known as Desidustat. The compound of formula (la), may be prepared by any of the methods known in the art including those processes disclosed in the prior art such as those mentioned elsewhere in the specification.

The efficacy of the compound in hematopoietic activity nay be evaluated in vivo as described in the examples.

EXAMPLES The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

Example 1 Synthesis of Sodium salt of compound of formula (la)

In 50 ml round bottom flask, compound of formula (la) (0.5 g, 0.0015 mole) was charged at room temperature. A solution of Sodium hydroxide (0.06 g, 0.0015 mole) in water (10 ml) was added at room temperature. After addition of sodium hydroxide solution, reaction mixture turned to clear solution. Reaction mixture was stirred for 30 minutes at room temperature. Reaction mixture filtered off through hyflow supercel bed. Collect filtrate and lyophilize it for 18 h to get Sodium salt of compound of formula (la) with 99% yield. HPLC purity: 99.16%, Sodium content by IC: 6.56% w/w, Polymorphic data (XRPD): Amorphous. Example 2

Synthesis of Sodium salt of compound of formula (la)

In 50 ml round bottom flask, Methanol (7 ml) was charged at room temperature. Compound of formula (la) (1.0 g, 0.0030 mole) was charged at room temperature. A solution of Sodium hydroxide (0.12 g, 0.0030 mole) in water (7 ml) was charged at room temperature. After addition of sodium hydroxide solution, reaction mixture turned to clear solution. Reaction mixture was stirred for 30 minutes at room temperature. Reaction mixture filtered off through hyflow supercel bed. Collect filtrate and concentrated solvents in vacuo to get solid material. Charge Diisopropyl ether (20 ml) and stirred the reaction mass for 30 minutes at room temperature. Solid was filtered off and washed with twice Diisopropyl ether (5 ml X 2). Suck dry for 30 minutes. Dry the product in fan dryer for 3 to 4 h at 50 to 60°C to get Sodium salt of compound of formula (la) with 99% yield. HPLC purity: 99.48%, Sodium content by IC: 7.30% w/w, Polymorphic data (XRPD): Crystalline. Example 3

Synthesis of Lithium salt of compound of formula (la)

In 50 ml round bottom flask, Water (5 ml) was charged at room temperature. Compound of formula (la) (1.0 g, 0.0030 mole) was charged at room temperature. A solution of Lithium hydroxide H2O (0.13 g, 0.0030 mole) in water (5 ml) was charged at room temperature. After addition of Lithium hydroxide solution, reaction mixture turned to clear solution. Reaction mixture was stirred for 30 minutes at room temperature. Reaction mixture filtered off through hyflow supercel bed. Concentrated solvents in vacuo to get solid material. Charge Diisopropyl ether (20 ml) and stirred the reaction mass for 30 minutes at room temperature. Solid was filtered off and washed with twice Diisopropyl ether (5 ml X 2). Suck dry for 30 minutes. Dry the product in fan dryer for 3 to 4 h at 50 to 60°C to get Lithium salt of compound of formula (la) with 91% yield. HPLC purity: 99.46%, Lithium content by IC: 1.89% w/w, Polymorphic data (XRPD): Crystalline. Example 4

Synthesis of Potassium salt of compound of formula (la)

In 50 ml round bottom flask, Methanol (7 ml) was charged at room temperature. Compound of formula (la) (1.0 g, 0.0030 mole) was charged at room temperature. A solution of Potassium hydroxide (0.17 g, 0.0030 mole) in water (7 ml) was charged at room temperature. After addition of potassium hydroxide solution, reaction mixture turned to clear solution. Reaction mixture was stirred for 30 minutes at room temperature. Reaction mixture filtered off through hyflow supercel bed. Collect filtrate and concentrated solvents in vacuo to get solid material. Charge Diisopropyl ether (20 ml) and stirred the reaction mass for 30 minutes at room temperature. Solid was filtered off and washed with twice Diisopropyl ether (5 ml X 2). Suck dry for 30 minutes. Dry the product in fan dryer for 3 to 4 h at 50 to 60°C to get Potassium salt of compound of formula (la) with 99% yield. HPLC purity: 99.05%, Potassium content by IC: 10.64% w/w, Polymorphic data (XRPD): Crystalline. Example 5

Synthesis of Calcium salt of compound of formula (la)

In 100 ml round bottom flask, Methanol (75 ml) was charged at room temperature. Compound of formula (la) (0.5 g, 0.0015 mole) was charged at room temperature. Reaction mixture was stirred for 30 minutes at room temperature. Reaction mixture was heated at 50 to 55°C. Reaction mixture was stirred for 30 minutes at 50 to 55°C. Added clear solution of Calcium (II) acetate (0.24 g, 0.0015 mole) in Water (5 ml) at 50 to 55°C. Reaction mixture was stirred for 1 h at room temperature. Solid material was filtered off and washed with twice methanol (5 ml X 2). Suck dry for 30 minutes. Dry the product in fan dryer for 3 to 4 h at 50 to 60°C to get Calcium salt of compound of formula (la) with 42% yield. HPLC purity: 99.60%, Calcium content by IC: 6.72% w/w, Polymorphic data (XRPD): Crystalline. Example 6

Synthesis of Cobalt salt of compound of formula (la)

In 100 ml round bottom flask, Methanol (50 ml) was charged at room temperature. Compound of formula (la) (0.5 g, 0.0015 mole) was charged at room temperature. Reaction mixture was stirred for 30 minutes at room temperature. Reaction mixture was heated at 50 to 55°C. Reaction mixture was stirred for 30 minutes at 50 to 55°C. Added clear solution of Cobalt (II) acetate 4 H2O (0.37 g, 0.0015 mole) in Water (10 ml) at 50 to 55°C. Reaction mixture was stirred for 1 h at room temperature. Concentrated solvents in vacuo to get solid material. Charge Diisopropyl ether (20 ml) and stirred the reaction mass for 30 minutes at room temperature. Solid was filtered off and washed with twice Diisopropyl ether (5 ml X 2). Suck dry for 30 minutes. Dry the product in fan dryer for 3 to 4 h at 50 to 60°C to get Cobalt salt of compound of formula (la) with 53% yield. HPLC purity: 99.29%, Cobalt content by titration: 8.25% w/w, Polymorphic data (XRPD): Amorphous. Example 7

Synthesis of Zinc salt of compound of formula (la)

In 100 ml round bottom flask, Methanol (25 ml) was charged at room temperature. Compound of formula (la) (0.5 g, 0.0015 mole) was charged at room temperature. Reaction mixture was stirred for 30 minutes at room temperature. Reaction mixture was heated at 50 to 55°C. Reaction mixture was stirred for 30 minutes at 50 to 55°C. Added clear solution of Zinc (II) acetate 2 H2O (0.19 g, 9.0 mmole) in Water (5 ml) at 50 to 55°C. Reaction mixture was stirred for 1 h at room temperature. Solid material was filtered off and washed with twice methanol (5 ml X 2). Suck dry the product for 30 minutes. Dry the product in fan dryer for 3 to 4 h at 50 to 60°C to get Zinc salt of compound of formula (la) with 50% yield. HPLC purity: 98.97%, Zinc content by titration: 8.04% w/w, Polymorphic data (XRPD): Crystalline. Example 8

Synthesis of Copper salt of compound of formula (la)

In 100 ml round bottom flask, Methanol (50 ml) was charged at room temperature. Compound of formula (la) (1.0 g, 0.0030 mole) was charged at room temperature. Reaction mixture was stirred for 30 minutes at room temperature. Reaction mixture was heated at 50 to 55°C. Reaction mixture was stirred for 30 minutes at 50 to 55°C. Added clear solution of Copper (II) acetate H2O (0.36 g, 0.0018 mole) in Water (10 ml) at 50 to 55°C. Reaction mixture was stirred for 1 h at room temperature. Solid material was filtered off and washed with twice methanol (10 ml X 2). Suck dry the product for 30 minutes. Dry the product in fan dryer for 3 to 4 h at 50 to 60°C to get Zinc salt of compound of formula (la) with 46% yield. HPLC purity: 98.39%, Copper content by titration: 9.26% w/w, Polymorphic data (XRPD): Crystalline.

Example 9

Synthesis of Magnesium salt of compound of formula (la) In 100 ml round bottom flask, Methanol (50 ml) was charged at room temperature. Compound of formula (la) (1.0 g, 0.0030 mole) was charged at room temperature. Reaction mixture was stirred for 30 minutes at room temperature. Reaction mixture was heated at 50 to 55°C. Reaction mixture was stirred for 30 minutes at 50 to 55°C. Added clear solution of Magnesium (II) acetate 4 H2O (0.38 g, 0.0018 mole) in Water (5 ml) at 50 to 55°C. Reaction mixture was stirred for 1 h at room temperature. Concentrated solvents in vacuo to get solid material. Charge Diisopropyl ether (20 ml) and stirred the reaction mass for 30 minutes at room temperature. Solid was filtered off and washed with twice Diisopropyl ether (5 ml X 2). Suck dry for 30 minutes. Dry the product in fan dryer for 3 to 4 h at 50 to 60°C to get Magnesium salt of compound of formula (la) with 62% yield. HPLC purity: 99.34%, Magnesium content by titration: 3.87% w/w, Polymorphic data (XRPD): Crystalline. Example 10

Synthesis of Manganese salt of compound of formula (la)

In 100 ml round bottom flask, Methanol (50 ml) was charged at room temperature. Compound of formula (la) (1.0 g, 0.0030 mole) was charged at room temperature. Reaction mixture was stirred for 30 minutes at room temperature. Reaction mixture was heated at 50 to 55°C. Reaction mixture was stirred for 30 minutes at 50 to 55°C. Added clear solution of Manganese (II) acetate (0.44 g, 0.0018 mole) in Water (5 ml) at 50 to 55°C. Reaction mixture was stirred for 1 h at room temperature. Solid material was filtered off and washed with twice methanol (5 ml X 2). Suck dry for 30 minutes. Dry the product in fan dryer for 3 to 4 h at 50 to 60°C to get Manganese salt of compound of formula (la) with 50% yield. HPLC purity: 99.58%, Manganese content by titration: 7.34% w/w, Polymorphic data (XRPD): Crystalline.

Example 11

Synthesis of Metformin salt of compound of formula (la) In 250 ml round bottom flask, THF (70 ml) was charged at room temperature. Compound of formula (la) (3.5 g, 0.010 mole) was charged at room temperature. Methanol (35 ml) was charged at room temperature. Reaction mixture was stirred for 30 minutes at room temperature. After 30 minutes, reaction mixture turned to clear solution. Added clear solution of Metformin (1.36 g, 0.010 mole) in methanol (35 ml) at room temperature. Reaction mixture was stirred for 10 minutes at room temperature. After 10 minutes white precipitation obtained. Diisopropyl ether (70 ml) was charged at room temperature. Reaction mixture was stirred for 2 h at room temperature. Solid material was filtered off and washed with twice Diisopropyl ether (10 ml X 2). Suck dry for 30 minutes. Dry the product in fan dryer for 3 to 4 h at 60 to 70°C to get Metformin salt of compound of formula (la) with 82% yield. HPLC purity: 79.82%, Polymorphic data (XRPD): Crystalline Example 12

Synthesis of L-Proline salt of compound of formula (la)

In 500 ml round bottom flask, THF (80 ml) was charged at room temperature. Compound of formula (la) (4.0 g, 0.012 mole) was charged at room temperature. Methanol (40 ml) was charged at room temperature. Reaction mixture was stirred for 30 minutes at room temperature. After 30 minutes, reaction mixture turned to clear solution. Added clear solution of L-Proline (1.45 g, 0.0126 mole) in methanol (40 ml) at room temperature. Reaction mixture was stirred for 10 minutes at room temperature. After 10 minutes white precipitation obtained. Diisopropyl ether (80 ml) was charged at room temperature. Reaction mixture was stirred for 2 h at room temperature. Solid material was filtered off and washed with twice Diisopropyl ether (10 ml X 2). Suck dry for 30 minutes. Dry the product in fan dryer for 3 to 4 h at 60 to 70°C to get L- Proline salt of compound of formula (la) with 52% yield. HPLC purity: 100%, Polymorphic data (XRPD): Crystalline Example 13

Synthesis of D-Proline salt of compound of formula (la)

In 250 ml round bottom flask, THF (40 ml) was charged at room temperature. Compound of formula (la) (2.0 g, 0.0060 mole) was charged at room temperature. Methanol (20 ml) was charged at room temperature. Reaction mixture was stirred for 30 minutes at room temperature. After 30 minutes, reaction mixture turned to clear solution. Added clear solution of D-Proline (0.69 g, 0.0060 mole) in methanol (20 ml) at room temperature. Reaction mixture was stirred for 10 minutes at room temperature. After 10 minutes white precipitation obtained. Diisopropyl ether (40 ml) was charged at room temperature. Reaction mixture was stirred for 2 h at room temperature. Solid material was filtered off and washed with twice Diisopropyl ether (5 ml X 2). Suck dry for 30 minutes. Dry the product in fan dryer for 3 to 4 h at 60 to 70°C to get D-

Proline salt of compound of formula (la) with 50% yield. HPLC purity: 99.80%, Polymorphic data (XRPD): Crystalline Example 14

Synthesis of Urea salt of compound of formula (la)

In 100 ml round bottom flask, THF (20 ml) was charged at room temperature. Compound of formula (la) (1.0 g, 0.0030 mole) was charged at room temperature. Methanol (10 ml) was charged at room temperature. Reaction mixture was stirred for 30 minutes at room temperature. After 30 minutes, reaction mixture turned to clear solution. Added clear solution of Urea (0.18 g, 0.0030 mole) in methanol (10 ml) at room temperature. Reaction mixture was stirred for 10 minutes at room temperature. After 10 minutes white precipitation obtained. Diisopropyl ether (40 ml) was charged at room temperature. Reaction mixture was stirred for 18 h at room temperature. Solid material was filtered off and washed with twice Diisopropyl ether (5 ml X 2). Suck dry for 30 minutes. Dry the product in fan dryer for 3 to 4 h at 60 to 70°C to get Urea salt of compound of formula (la) with 53% yield. HPLC purity: 99.76%, Polymorphic data (XRPD): Crystalline. Example 15

Synthesis of compound of formula (la) from compound of formula (lb)

In a 50 mL fixed glass assembly, Water (2.5 mL) was charged at room temperature. Sodium salt of formula (la) (0.25 g, 7.52 mol) was charged at room temperature. Dilute hydrochloric acid solution (2 mL) in water (2 mL) was added carefully at 25 to 35 °C. Upon completion of addition of hydrochloric acid solution, the reaction mass turned to off white colored thick slurry. Reaction mixture was stirred for 1 h at room temperature. Solid material was filtered off and washed with water (4 x 5 mL). The compound was dried under fan dryer at temperature 25 to 35°C for 6 hours and then dried for 4 hours at 50 to 60 °C to get formula (la) 80% yield, as a solid.

Example 16

Stability analysis:

Following table 1 depicts HPLC purity of all the synthesized novel salts of formula (la) that were stored at room temperature for twelve months. Form the HPLC analysis it has been found that all the compounds are stable and within the purity limits till twelve months. Table 1

Example 17

Evaluation of hematopoietic activity of Compound of formula (la) and its salts after daily once dose administration for a week in male C57 mice

Animals: 7-9 weeks old male C57 mice Compounds:

Example 1 Example 14 Example 12

Example 11

Compound of formula (la) All the doses were administered to deliver Compound of formula (la) 15 mg/kg dose, adjusted as per Compound of formula (la) percentage in every compound. The animals were dosed once a day for a week, and after 24 h of the last dose, the blood samples were collected by retro- orbital puncture and hemoglobin and red blood cell count (RBC count) were estimated. Result:

Table 2:

Table 3: All the salts showed significant improvement in hemoglobin, when compared to vehicle control. Among those, Sodium salt is most effective, followed by Metformin salt of compound of formula (la).