WO2011048611A1 - Nouveaux dérivés pyridazine fusionnés - Google Patents

Nouveaux dérivés pyridazine fusionnés Download PDF

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WO2011048611A1
WO2011048611A1 PCT/IN2010/000664 IN2010000664W WO2011048611A1 WO 2011048611 A1 WO2011048611 A1 WO 2011048611A1 IN 2010000664 W IN2010000664 W IN 2010000664W WO 2011048611 A1 WO2011048611 A1 WO 2011048611A1
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oxo
hydroxy
carbonyl
glycine
dihydropyridazino
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PCT/IN2010/000664
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English (en)
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Prabhat Kumar
Sameer Ghalasasi
Ramesh Chandra Gupta
Shailesh Deshpande
Anookh Mohanan
Anita Chaudhari
Chaitanya Dutt
Vijay Chauthaiwale
Appaji Baburao Mandhare
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Torrent Pharmaceuticals Limited
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Publication of WO2011048611A1 publication Critical patent/WO2011048611A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the present invention relates to novel fused pyridazine compounds of formula (I), their pharmaceutically acceptable salts, and their isomers, steroisomers, conformers, tautomers, polymorphs, hydrates and solvates.
  • the present invention also encompasses pharmaceutically acceptable compositions of said compounds and process for preparing novel compounds.
  • the invention further relates to the use of the above-mentioned compounds for the preparation of medicament for use as pharmaceuticals.
  • HIF Hypoxia Inducible Factor
  • bHLH basic helix-loop-helix
  • PAS Per/Arnt/Sim transcriptional activator that mediates changes in gene expression in response to changes in cellular oxygen concentration.
  • HIF is a heterodimer consisting of a constitutively expressed beta subimit and one of the two alpha subunits, HIF l and HIFa2. !
  • HIFa subunits are rapidly degraded by a mechanism that involves ubiquitination by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex.
  • pVHL von Hippel-Lindau tumor suppressor
  • HIFa is not degraded, and an active FIIFa/ ⁇ complex accumulates in the nucleus and activates the expression of several genes including glycolytic enzymes, glucose transporter (GLUT)-l , erythropoietin (EPO), vascular endothelial growth factor (VEGF) and adrenomedullin.
  • GLUT glucose transporter
  • EPO erythropoietin
  • VEGF vascular endothelial growth factor
  • HIF activation is one of the prominent adaptive mechanism associated with hypoxia/ ischemia. As mentioned, HIF activation results in enhanced expression of genes which perform multiple functions to cope up with and to recover from hypoxic/ischemic conditions. 2
  • HIF prolyl-hydroxylases PBD
  • Prolyl hydroxylated HIFa interacts with pVHL and rapidly gets degraded by proteasome machinery.
  • HIF asparagyl hydroxylase FIH
  • Asparagyl hydroxylated HIFa can not interact with transcriptional co-activator CBP/p300.
  • HIFa Under hypoxic/ischemic conditions, both HIF prolyl and HIF aspargyl hydroxylase activities are drastically lowered due to limiting amount of molecular oxygen. As a result, HIFa is not destined for proteasome degradation and hence stabilized. Further, HIFa can interact with transcriptional co-activator CBP/p300. Such stabilized and transcriptionally active HIFa then forms heterodimer with HIF-beta subunit and translocates to the nucleus and bring about transactivation of HIF target genes 1 .
  • HIF prolyl hydroxylases and HIF asparagyl hydroxylases thus can be a powerful approach for oxygen- independent activation of HIF.
  • HIF activation by pharmacological means results in enhanced expression of genes which perform multiple functions to cope up with and to recover from hypoxic/ischemic conditions.
  • HIF targets include genes responsible for vasomotor regulation (e.g. Adrenomedullin, eNOS, Haem Oxygrenase), energy metabolism (e.g. Glut-1, carbonic anhydrase-9), angiogenic signaling (e.g. VEGF, VEGF receptor- 1) and erythropoiesis (e.g.
  • 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 or kidney 3 ' 4 ' 5 ' 6 ' 7 ' 8
  • Anemia is characterised by decrease in normal number of red blood cells, which is generally caused by loss of blood (hemorrhage), excessive red blood cell destruction (hemolysis) or deficient red blood cell production (ineffective hematopoiesis). Since hemoglobin normally carries oxygen from the lungs to the tissues, anemia leads to hypoxia in organs. Since all human cells depend on oxygen for survival, anemia can have a wide range of clinical consequences. Anemia occurs ofte in elderly, in cancer patients, particularly those receiving chemotherapy & undergoing radiation, patients with renal diseases and in a wide variety of conditions associated with chronic diseases. Frequently, the cause of anemia is reduced erythropoietin (EPO) production resulting in prevention of erythropoiesis.
  • EPO erythropoietin
  • EPO Erythropoietin
  • Exogeneous administration of EPO is one of the accepted modalities of treatment of anemia particularly in chronic renal failure patients, cancer patients undergoing radiation and/or chemotherapy, however its use is limited by high cost and increased risk for thrombosis and hypertension 10 .
  • Ischemia is defined as an absolute or relative shortage of oxygen to a tissue or organ and can result from disorders such as atherosclerosis, diabetes, thromboembolisms, hypotension, etc.
  • the heart, brain and kidney are especially sensitive to ischemic stress caused by low blood supply.
  • Ischemia can be an acute (sudden onset and short duration) or chronic (slow onset with long duration or frequent recurrence).
  • Acute ischemia is often associated with regional, irreversible tissue necrosis (an infarct), whereas chronic ischemia is usually associated with transient hypoxic tissue injury. If the decrease in perfusion is prolonged or severe, however, chronic ischemia can also be associated with an infarct.
  • Infarctions commonly occur in the spleen, kidney, lungs, brain, and heart, producing disorders such as intestinal infarction, pulmonary infarction, ischemic stroke, and myocardial infarction. Ischemic and hypoxic disorders are a major cause of morbidity and mortality.
  • HIF target genes such as erythropoietin, VEGF, adrenomeduUin have shown significant functional recovery in ischemia and ischemia- reperfusion injury of heart, kidney, brain and liver. 11 ' 12 ' 13 ' 14
  • anemia & diseases due to hypoxia and ischemia Due to deficiencies in current treatments of anemia & diseases due to hypoxia and ischemia, there remains a need for compounds that are effective in treating anemias of different types such as anemia in elderly or anemia associated with chronic diseases or renal failure or cancer or infection or dialysis or surgery or chemotherapy and in ischemic/hypoxic disorders such as acute kidney injury, myocardial infarction, stroke, hepatic ischemia-reperfusion injury and peripheral vascular diseases.
  • the compounds of this invention provide a means for inhibiting HIF hydroxylases and thereby activating the HIF, which results in enlianced expression of the wide spectrum of target genes including erythropoietin (EPO), vascular endothelial growth factor (VEGF), adrenomeduUin etc. and thus useful in treating various disorders including anemia of different types and conditions associated with ischemia/hypoxia.
  • EPO erythropoietin
  • VEGF vascular endothelial growth factor
  • adrenomeduUin adrenomeduUin
  • EP 661269 discloses substituted heterocyclic carboxylic acid amides and their use as inhibitors of prolyl-4-hydroxylase and as inhibitors of collagen biosynthesis.
  • WO 2009075822 Al discloses the heterocyclic carboxylic acid amides that inhibit the activity of hypoxia-inducible factor (HIF) prolyl hydroxylase enzyme, therby inhibiting the differetiation of the T helper cell into the Thl cell.
  • WO 2009075826 Al discloses the heterocyclic carboxylic acid amides that inhibit the activity of hypoxia-inducible factor (HIF) prolyl hydroxylase enzyme, therby increasing white blood cell levels in blood in the subject.
  • WO 2010022240 Al discloses the Pyrrolo[l,2-b]pyrdiazine derivatives, which are capable of decreasing HIF hydroxylase enzyme activity, thereby increasing the stability and/or activity of hypoxia inducible factor.
  • the present invention provides novel compounds of general formula (I),
  • Ri & R 2 are independently selected from the group consisting of hydrogen, R 7 , - N(R 9 ) (R 9 ), -N(R 9 ) (R 7 ), -S0 2 (R 7 ), -S0 2 (R 9 ), - N(R 9 )(S0 2 -R 7 ), - N(R 9 )(S0 2 -R 9 ), - N(R 9 )(CO- R 7 ), - N(R 9 )(CO-R ) and -Ci -8 alkyl; wherein (C 1-8 alkyl) is optionally substituted with one or more substituents selected from R 7 , halo, cyano, nitro, -C(0)(R 9 ), -C(0)(R 7 ), -C(0)0- ' R 9 , -C(0)0-R 7 , -C(0)N(R 9 )(R 9 ), -C(0)N(R 9 )(R 7 ), -COCF 3
  • R ⁇ and R 2 are taken together with the nitrogen atom to which they are attached form five to ten membefed heterocyclyl or heteroaryl ring, wherein said heterocycle or heteroaryl ring contain one or more heteroatom selected from nitrogen, oxygen and sulphur and optionally substituted by one or more R 8 ;
  • R 7 at each occurrence is selected from:
  • heterocycle or heteroaryl contain one or more heteroatom selected from nitrogen, oxygen and sulphur;
  • R 7 may be optionally substituted with one or more R 8; wherein R 8 is independently selected from the group consisting of halo, cyano, nitro, -Ci -8 alkyl, -C(0)CF 3 , CF 3 , - NHOH, -S0 2 CF 3 , -(C 1-3 alkyl) m -N(R 9 )(CO-R 9 ), -(C 1-3 alkyl) m -N(R 9 )(CO- aryl),-(Ci. 3alkyl) m -N(R 9 )(CO- heteroaryl), -(Ci.
  • R 9 is hydrogen or (Ci- 8 alkyl); wherein, the above said Ci -8 alkyl may be straight, branched chain or cyclic, and may contain one or two double or triple bonds.
  • the said alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of OH, SH, oxo, thioxo, halo, amino, mono(Ci -3 alkyl)amino, di ⁇ . 3 alkyl)amino, -S(C 1-3 alkyl), -C 5 .i 0 aryl and -Ci -3 alkoxy; wherein, C 1-3 alkoxy may be straight or branched, may contain one or two double or triple bonds;
  • R 3 is selected from the group consisting of R 7 , CF 3 , -C(0)CF 3 , -S0 2 CF 3 and -C 1-8 alkyl; wherein, the said Ci -8 alkyl may be straight, branched chain or cyclic, and may contain one or two double or triple bonds and which is optionally substituted by one or more substituents independently selected from the group consisting of R 7 , halo, cyano, nitro, -NHOH, CF 3 , -COCF3, -S0 2 CF 3 , -C(0)(R 9 ), -C(0)(R 7 ), -C(0)(C 1-3 alkyl-R 7 ), -C(0)0-R 9 , -C(0)0-R 7 , -C(0)0-R 7 , -C(0)N(R 9 )(R 9 ), -C(0)N(R 9 )(R 7 ), -SR 9 , -SR 7 , -SR 7 , -SR 7
  • R 4 , R 5 and R6 are each independently selected from the group consisting of -hydrogen, OH, SH, oxo, thioxo, halo, cyano, nitro, -NHOH, CF 3 , -COCF3, -S0 2 CF 3 , -Ci -8 alkyl, -(Ci- 8alkyl) m -N(R 9 )(C(0)- R 9 ), -(C 1-8 alkyl) m -N(R 9 )(C(0)- R 7 ), -(C 1 .
  • R[ is hydrogen then R 2 is not -CH 2 COOH or b) R 2 is hydrogen then 3 ⁇ 4 is not -CH 2 COOH.
  • present invention provides a comound of formula (I), wherein at least one X is N (nitrogen) and Ri, R 2 , R 3> R4, R 5 , 3 ⁇ 4 & R 7 are as defined above. > ⁇
  • present invention provides a comound formula (I), wherein R 4 and R 5 are joined together to form a ring R 7 and R 1 ⁇ R 2 , R 3 & Re are as defined above.
  • present invention provides a comound formula (I), wherein R 5 and R ⁇ are joined together to form a ring R 7 and Ri, R , R 3) & R 4 are as defined above.
  • the present invention pertains to a compound as above, however only including pharmaceutically acceptable salts thereof.
  • the present invention includes synthetic intermediates that are useful in preparing the compounds of formula (I) and process for preparing such intermediates.
  • Another embodiment of the present invention is a method for preparation of a compound of formula (I) as herein described in Scheme I to VII.
  • Another embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Another embodiment of the present invention is a method for treating anemia by administering a therapeutically effective amount of a compound of formula (I) to a mammal in need thereof.
  • Another embodiment of the present invention is a method for treating anemia of elderly or anemia associated with conditions like chronic diseases, renal failure, cancer, infection, dialysis, surgery, and chemotherapy by administering a therapeutically effective amount of a compound of formula (I) to a mammal in need thereof.
  • Another embodiment of the present invention is a method for prevention or treatment of tissue damage caused by renal ischemia, cardiovascular , ischemia, cerebrovascular ischemia, hepatic ischemia or peripheral vascular ischemia by administering a therapeutically effective amount of a compound of formula (I) to a mammal in need thereof.
  • Another embodiment of the present invention is a method for prevention or treatment of tissue damage caused by ischemic disorders including acute kidney injury, myocardial infarction, stroke, hepatic ischemia-reperfusion injury and peripheral vascular diseases by administering a therapeutically effective amount of a compound of formula (I) to a mammal in need thereof.
  • Another embodiment of the present invention is a method for prevention or treatment of tissue damage caused by ischemia-reperfusion injury while transplantation procedures of organs like liver or kidney by administering a therapeutically effective amount of a compound of formula (I) to a mammal in need thereof.
  • Another embodiment of the present invention is the use of a compound of formula (I) for the preparation of a medicament for treating anemia.
  • Another embodiment of the present invention is the use of a compound of formula (I) for the preparation of a medicament for treating anemia of elderly or anemia associated with conditions like chronic diseases, renal failure, cancer, infection, dialysis, surgery, and chemotherapy.
  • Another embodiment of the present invention is the use of a compound of formula (I) for the preparation of a medicament for prevention or treatment of tissue damage caused by renal ischemia, cardiovascular ischemia, cerebrovascular ischemia, hepatic ischemia or peripheral vascular ischemia.
  • Another embodiment of the present invention is the use of a compound of formula (I) for the preparation of a medicament for prevention or treatment of tissue damage caused by ischemic disorders including acute kidney injury, myocardial infarction, stroke, hepatic ischemia-reperfusion injury and peripheral vascular diseases.
  • ischemic disorders including acute kidney injury, myocardial infarction, stroke, hepatic ischemia-reperfusion injury and peripheral vascular diseases.
  • Another embodiment of the present invention is the use of a compound of formula (I) for the preparation of a medicament for prevention or treatment of tissue damage caused by ischemia-reperfusion injury while transplantation procedures of organs like liver or kidney.
  • the present invention provides novel compounds of general formula
  • a family of specific compounds of particular interest within the above formula (I) consists of compound and pharmaceutically acceptable salts thereof as follows: Chemical name N-:[(4-hydroxy-l ,8-dimethyl-2-oxo-2,5,6,7-tetrahydro-lH-cyclopenta
  • the present invention provides novel compounds of general formula (I),
  • the term "compound” employed herein refers to any compound encompassed by the generic formula disclosed herein.
  • the compounds described herein may contain one or more double bonds and therefore, may exist as isomers, stereoisomers, such as geometric isomers, E and Z isomers, and may possess asymmetric carbon atoms (optical centres) and therefore may exist as enantiomers, diastereoisomers.
  • the chemical structures described herein encompasses all possible stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure) and stereoisomer ⁇ mixtures (racemates).
  • the compound described herein may exist as a conformational isomers such as chair or boat form.
  • the compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures described herein encompass all possible tautomeric forms of the illustrated compounds.
  • the compounds described also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include, but are not limited to 2 H, 3 H, 1 3 C, 14 C, 15 N, ,8 0, 17 0, etc.
  • Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, compounds may be hydrated or solvated. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, isobutyric acid, hexanoic acid, cyclopentanepropionic acid, oxalic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, suberic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, phthalic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedis
  • polymorphs pertains to compounds having the same chemical formula, the same salt type and having the same form of hydrate/solvate but having different crystallographic properties.
  • hydrates pertains to a compound having a number of water molecules bonded to the compound.
  • solvates pertains to a compound having a number of solvent molecules bonded to the compound.
  • the present invention also encompasses compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions (in vivo) to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, for example, transdermal patch reservoir with a suitable enzyme or chemical. Prodrugs are, in some situation, easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmacological composition over the parent drug. Esters, peptidyl derivatives and the like, of the compounds are the examples of prodrugs of the present invention.
  • In vivo hydrolysable (or cleavable) ester of a compound of the present invention that contains a carboxy group is, for example, a pharmaceutically acceptable ester which is hydrOlysed in the human or animal body to produce the parent acid.
  • substituted includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed and which means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is ⁇ not exceeded, and that the ' substitution results in a stable compound, for example, when a substituent is keto, then the two hydrogens on the atom are replaced. All substituents ( j, R 2 .7) and their further substituents described herein may be attached to the main structure at any heteroatom or carbon atom which results in formation of stable compound.
  • cycloalkyl refers to a saturated or an unsaturated but nonaromatic cyclic alkyl groups of 3 to 10 carbon atoms having single or multiple cyclic rings, which may be unsubstituted or substituted.
  • aryl refers to an aromatic group for example, which is a 5 to 10 membered monocyclic or bicyclic carbon-containing ring system, which may be unsubstituted or substituted.
  • heteroaryl refers to an aromatic group for example, which is a 3 to 10 membered monocyclic or bicyclic ring system, which has at least one heteroatom, which may be unsubstituted or substituted.
  • heteroatom as used herein includes oxygen, sulfur and nitrogen.
  • heterocyclyl refers to a fully saturated or unsaturated nonaromatic cyclic group, for example, which is a 3 to 10 membered monocyclic or bicyclic ring system, which has at least one heteroatom, which may be unsubstituted or substituted.
  • heteroatom as used herein includes oxygen, sulfur and nitrogen.
  • room temperature refers to a temperature between 25 0 C and 35 0 C.
  • mammal means a human or an animal such as monkeys, primates, dogs, cats, horses, cows, etc.
  • treating or “treatment” of any disease or disorder as used herein to mean administering a compound to a mammal in need thereof.
  • the compound may be administered thereby providing a prophylactic effect in terms of completely or partially preventing or delaying the onset of a disease or disorder or sign or symptom thereof; and/or the compound may be, administered thereby providing a partial or complete cure for a disease or disorder and/or adverse effect attributable to the disorder.
  • a therapeutically effective amount means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, mode of administration, the disease and its severity and the age, weight, etc., of the patient to be treated.
  • present invention provides the process for preparing the compounds of formula (I).
  • the compounds of formula (I) is prepared in the following manner: a) The compound of formula (II) wherein, the R4, R 5 & R6 are as defined earlier, is reacted with monochloramine, hydroxylamine-O-sulphonic acid, O- (mesitylenesulphonyl)-hydroxylamine, 0-(diphenylphosphinyl)-hydroxylamine or O- (2,4-dinitrophenyl)-hydroxylamine in the presence of base such as sodium hydride, potassium carbonate, potassium tert- butoxide or sodium ethoxide and in the solvent like acetonitrile, N, N-dimethylformamide, toluene, methyl tert-butyl ether, diethyl ether or tetrahydrofuran, under inert atmosphere at the temperature in the range of -50° to 60° C for 1 to 12 h to give the compound of formula (III)
  • BOP phosphonium hexafluorophosphate
  • the compound of formula (IV) is prepared by reacting the compound of formula (III) with R 3 -chloroformate, R 3 -carbonyl chloride, R 3 -sulphonyl chloride, R 3 -anhydride or R 3 -halide wherein, the R 3 is as defined earlier, in the presence of base such as triethylamine, N-ethyldiisopropylamine, potassium or sodium carbonate in a solvent such as tetrahydrofuran, acetonitrile, toluene at a temperature in the range of - 30° C to 60° C for 10 minutes to 8 hours.
  • base such as triethylamine, N-ethyldiisopropylamine, potassium or sodium carbonate
  • a solvent such as tetrahydrofuran, acetonitrile, toluene at a temperature in the range of - 30° C to 60° C for 10 minutes to 8 hours.
  • the compound of formula (IV) is prepared by treating the compound of formula (III) with R 3 -CHO wherein, R 3 is as defined earlier in the presence of reducing reagents such as sodium borohydride, sodium cyanobororhydride (NaCNBH 3 ) or formic acid; or in the presence of acid like acetic acid, p-toluene sulphonic acid, dilute hydrochloric acid forms a schiff base and reduction with metal catalyst such as palladium charcoal, platinium oxide in a solvent such as ethanol, methanol, isopropanol or toluene, xylene, mesitylene at a temperature in the range of 0° C - 165° C for 30 min to 12 hours 19 .
  • reducing reagents such as sodium borohydride, sodium cyanobororhydride (NaCNBH 3 ) or formic acid
  • the compound of formula (VI) is treated with diethyl malonate, di-tert-butyl malonate or dibenzyl malonate in the presence of base such as sodium hydride, potassium carbonate, sodium ethoxide, potassium tert-butoxide or lithium bis(trimethylsilyl)amide in the solvent like toluene, xylene, N, N-dimethylacetamide, l-methyl-2-pyrrolidinone, tetrahydrofuran, acetonitrile or N, N-dimethylformamide at a temperature from 0° to 130° C for 1 to 16 hours to give compound of formula (VII).
  • base such as sodium hydride, potassium carbonate, sodium ethoxide, potassium tert-butoxide or lithium bis(trimethylsilyl)amide in the solvent like toluene, xylene, N, N-dimethylacetamide, l-methyl-2-pyrrolidinone, tetrahydrofuran
  • the compound of formula (IV) is treated with alkyl or benzyl malonyl chloride in the presence of base such as triethylamine, potassium carbonate or sodium carbonate in a solvent like tetrahydrofuran, acetonitrile, toluene or pyridine at room temperature for 1 to 6 hours to give the amide of formula (IV), which is further treated with a base such as sodium ethoxide, potassium tert-butoxide or lithium bis(trimethylsilyl)amide in a solvent such as tetrahydrofuran, acetonitrile, ethanol, butanol or toluene at a temperature in the range of -20° to 100°C to give the compound of formula (VII).
  • base such as triethylamine, potassium carbonate or sodium carbonate in a solvent like tetrahydrofuran, acetonitrile, toluene or pyridine at room temperature for 1 to 6 hours
  • a base such as sodium
  • the compound of formula (I) can be prepared from the compound of formula (VII) by the following methods: g) The Compound of formula (VII) is reacted with HN(Ri)(R 2 ) wherein the Ri & R 2 are as defined earlier, in the presence of base such as triethylamine, potassium carbonate, sodium ethoxide, potassium tert-butoxide or l,8-Diazabicyclo[5.4.0]undec-7-ene in the solvent like toluene, xylene, ethanol, acetonitrile or N, N-dimethylformamide at a temperature from 80° C to 130° C for 1 to 16 hours to obtain the compound of formula (I).
  • base such as triethylamine, potassium carbonate, sodium ethoxide, potassium tert-butoxide or l,8-Diazabicyclo[5.4.0]undec-7-ene
  • base such as triethylamine, potassium carbonate, sodium ethoxid
  • the carboxylic acid of formula (VII) is treated with carbonyl diimidazole (CDI) or benzotriazol-l-yl-oxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) in the presence of base such as N-ethyldiisopropylamine, triethylamine or potassium carbonate in a solvent like tetrahydrofuran, acetonitrile or toluene at a temperature in the range of 25° C to 60° C for 1 to 6 hours to give the compound of formula (I).
  • base such as N-ethyldiisopropylamine, triethylamine or potassium carbonate
  • solvent like tetrahydrofuran, acetonitrile or toluene at a temperature in the range of 25° C to 60° C for 1 to 6 hours to give the compound of formula (I).
  • the compound of formula (II) is prepared by the following methods: a,b) The compound of formula (VIII) wherein, R 5 & R 6 are as defined earlier, is reacted with dialkyl oxalate such as diethyl oxalate or dimethyl oxalate in the presence of base such as potassium ethoxide, sodium ethoxide or potassium tert-butoxide in a solvent such as tetrahydrofuran, ethanol, butanol or diethyl ether at a temperature in the range of 0° C to 60° C for 10 minutes to 2 hours to give the compound of formula (IX).
  • dialkyl oxalate such as diethyl oxalate or dimethyl oxalate
  • base such as potassium ethoxide, sodium ethoxide or potassium tert-butoxide
  • solvent such as tetrahydrofuran, ethanol, butanol or diethyl ether
  • metal catalyst such as palladium charcoal or platinium oxide under hydrogen (H 2 ) atmosphere in the presence of acid like acetic acid, dilute hydrochloric acid in an alcoholic solvent such as ethanol, methanol, isopropanol or acetic acid at a temperature in the range of 20° C to 110° C for of 1 to 12 hours to give compound of formula (II) 21 .
  • dialkyl carbonate such as diethyl carbonate or dimethyl carbonate
  • base such as sodium hydride, potassium carbonate, sodium carbonate or lithium bis (triamethylsilyl) amide in a solvent like tetrahydrofuran, dimethyl formamide, toluene or 1 -methyl 2-pyroIidinone at a temperature in the range of 0° C to 150 0 C for 1 to 20 hours to give the product of formula (II) 22 .
  • the compound of formula (II) is prepared by the following methods: a,b) The compound of formula (XXI) wherein, the R4, R5 & 3 ⁇ 4 are as defined earlier, is reacted with 2-amino dialkylmalonate in the presence of acid such as acetic acid, hydrochloric acid or p-toluene sulphonic acid in the solvent like toluene, tetrahydrofuran, ethanol or butanol at the temperature in the range of -40° to 110° C for 1 to 12 hours to give the compound of formula (XXII), which is further refluxed in solvent like 2-alkyl imidazole, 2,4-dialkyl imidazole, l-methyl-2-pyrrolidinone or diphenyl ether at a temperature in the range of 100° C to 240° C for 1 to 12 hours to give the compound of formula (II).
  • acid such as acetic acid, hydrochloric acid or p-toluene s
  • the compound of formula (I) can be prepared from the compound of formula (II) by the Scheme I as described above.
  • the compound of formula (XXX) is prepared by the following methods: a,b,c) The solution of compound of formula (XXVII) wherein, the R 5 or are as defined earlier, is reduced with stannous chloride, zinc or iron in the presence of acid like hydrochloric acid, acetic acid; or with palladium charcoal under hydrogen atmosphere in a alcoholic solvent like ethanol, methanol, isopropanol or acetic acid at a temperature in the range of 30° C to 100° C for a period of 1 to 12 hours to give the compound of formula (XXVIIA), which is reacted with glycolic acid in the presence of acid such as hydrochloric acid, acetic acid or p-toluene sulphonic acid in the solvent like toluene, ethanol or butanol at the temperature in the range of 30° to 100° C for 1 to 10 hours to give the compound of formula (XXVIII), which is oxid
  • the compound of formula (XXXIII) is prepared by the following methods: a,b) The compound of formula (XXXI) wherein, the R 5 or are as defined earlier, is reacted with methoxyamine hydrochloride in the presence of acid such as hydrochloric acid, acetic acid or p-toluene sulphonic acid in the solvent like toluene, ethanol or butanol at the temperature in the range of 30° to 100° C for 1 to 6 hours to give the methoxy imidate intermediate, which is further treated with tert-butyl carbazate in the presence of acid such as acetic acid or propionic acid in a solvent like toluene, xylene, mesitylene or 1-methyl-pyrrolidinone at a temperature in the range of 30° C to 150° C fori to 10 hours to give the compound of formula (XXXIII).
  • acid such as hydrochloric acid, acetic acid or p-toluene sulphonic
  • the compound of formula (III) is prepared by the following methods: a,b) The compound of formula (XXXIV) wherein, the R 5 or R are as defined earlier, is reacted with N-amino phthalimide ir the presence of acid such as hydrochloric acid, acetic acid or p-toluene sulphonic acid in the solvent like toluene, ethanol or butanol at the temperature in the range of 30° to 100° C for 1 to 6 hours to give the N-amino phthalimde derivative, which is further reacted with alkyl bromoacetate such as ethyl bromoacetate or benzyl bromoacetate in the presence of base such as triethylamine, potassium carbonate or cesium carbonate in a solvent like tetrahydrofuran, acetonitrile or toluene at a temperature in the range of 30° C to 100° C
  • the phthalimide group is deprotected with the solution of hydrazine hydrate in the solvent like methanol, ethanol, 1,4-dioxane or toluene at a temperature in the range of 30°C to 110° C for 1 to 10 hours to give the compound of formula (III A).
  • the compound of formula (XXXVIIA) is reduced with palladium charcoal under hydrogen atmosphere or stannous chloride, zinc or iron in the presence of acid such as hydrochloric acid, acetic acid in a solvent like methanol, ethanol or acetic acid at a temperature in the range of 30° C to 100° C for 1 to 12 hours to give its amino derivative, which is cyclised in the presence of acid such as acetic acid or hydrochloric acid to give N-pyrrole phthalimide derivative.
  • acid such as hydrochloric acid, acetic acid in a solvent like methanol, ethanol or acetic acid at a temperature in the range of 30° C to 100° C for 1 to 12 hours
  • the phthalimide group is deprotected with the solution of hydrazine hydrate in the solvent like methanol, ethanol, 1,4-dioxane or toluene at a temperature in the range of 30°C to 1 10° C for 1 to 10 hours to give the compound of formula (III B).
  • the compound of formula (XXXVIIB) is reduced with palladium charcoal under hydrogen atmosphere or stannous chloride, zinc or iron in the presence of acid such as hydrochloric acid, acetic acid in a solvent like methanol, ethanol or acetic acid at a temperature in the range of 30° C to 100° C for 1 to 12 hours to give its amino derivative, which is reacted with alkyl glyoxalate in the presence of iodine in the solvent like methanol, ethanol, 1,4-dioxane or toluene at a temperature in the range of 30°C to 110° C for 1 to 10 hours to give alkyl carbamate compound of formula (IIIB) which is deprotected in the presence of acid such as hydrochloric acid, trifluoroacetic acid or hypochlorous acid in a solvent like ethanol, methanol, dichloromethane, dioxane, water at a temperature ranges from 0° C to 100° C for
  • the compound of formula (I) can be prepared from the compound of formula (III A) & (III B) by the Scheme I as described above.
  • the compounds of formula (I) is prepared by the following methods: a,b) The compound of formula (XXXVIII) wherein, the R4, R5 & 3 ⁇ 4 are as defined earlier, is treated with monochloramine, hydroxylamine-O-sulphonic acid, O- (mesitylenesulphonyl)-hydroxylamine, 0-(diphenylphosphinyl)-hydroxylamine or O- (2,4-dinitrophenyl)-hydroxylamine in the presence of base such as sodium hydride, potassium carbonate, potassium tert- butoxide or sodium ethoxide and in the solvent like acetonitrile, N, N-dimethylformamide, toluene, methyl tert-butyl ether, diethyl ether (Et 2 0) or tetrahydrofuran, under inert atmosphere at the temperature in the range of -50° to 60° C for 1 to 12 hours
  • the compound of formula (XXXIX) is prepared by reacting the N- amino derivative of compound of formula (XXXVIII) with R 3 -carbonyl chloride, R 3 - anhydride, R 3 -chloroformate, R 3 -sulphonyl chloride or R 3 -halide wherein, the R 3 is as defined earlier, in the presence of base such as triethylamine, N-ethyldiisopropylamine, potassium or sodium carbonate in a solvent such as tetrahydrofuran, acetonitrile, toluene at a temperature in the range of -30° C to 60° C for 10 minutes to 8 hours.
  • base such as triethylamine, N-ethyldiisopropylamine, potassium or sodium carbonate
  • a solvent such as tetrahydrofuran, acetonitrile, toluene at a temperature in the range of -30° C to 60° C for 10 minutes to
  • the compound of formula (XXXIX) is prepared by treating the N-amino derivative of compound of formula (XXXVIII) with R3-CHO wherein, R 3 is as defined earlier in the presence of reducing reagents such as sodium borohydride, sodium cyanoborohydride (NaCNBH 3 ) or formic acid ; or in the presence of acid like acetic acid, p-toluene sulphonic acid, dilute hydrochloric acid forms a schiff base and reduction with metal catalyst such as palladium charcoal, platinium oxide in a solvent such as ethanol, methanol, isopropanol or toluene, xylene, mesitylene at a temperature in the range of 0° C to 165° C for 30 min to 12 hours.
  • reducing reagents such as sodium borohydride, sodium cyanoborohydride (NaCNBH 3 ) or formic acid ; or in the presence of acid like acetic acid, p-tol
  • the compound of formula (I) can be prepared from the compound of formula (VII) by the SchemeT, as described above.
  • the compound of formula (I) can be prepared by reacting the solution of the compound of formula (XL) with Ri-NCO, wherein, 3 ⁇ 4 is as defined earlier, such as ethyl isocyanatoacetate or methyl isocyanatoacetate in the presence of base such as 1, 8- Diazabicyclo [5.4.0]undec-7-ene (DBU), potassium carbonate or sodium hydride in a solvent like tetrahydrofuran, acetonitrile or toluene at atemperature from 30° C to 110° C for 1 to 16 hours.
  • base such as 1, 8- Diazabicyclo [5.4.0]undec-7-ene (DBU)
  • a general synthetic method is provided for each of the disclosed groups of chemical compounds.
  • One of ordinary skill will recognize to substitute appropriately modified starting material containing the various substituents.
  • One of ordinary skill will readily synthesize the disclosed compounds according to the present invention using conventional synthetic organic techniques and microwave techniques from starting material which are either purchased or may be readily prepared using prior art methods.
  • the compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers or enantiomers with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers.
  • novel compounds of the present invention are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus.
  • novel compounds of the present invention were prepared according to the procedure of the schemes as described herein above, using appropriate materials and are further exemplified by the following specific examples. The examples are not to be considered nor construed as limiting the scope of the invention.
  • Step A Preparation of Ethyl 1 -amino- lH-indole-2-carboxylate
  • Step B Preparation of Ethyl l-[ " (trifluoroacetyl) aminol-lH-indole-2-carboxylate
  • Step C Preparation of Ethyl 1- [ " methyl (trifluoroacetyl) amino]- lH-indole-2-carboxylate
  • Step D Preparation of Ethyl l-(methylamino)-lH-indo]e-2-carboxylate
  • Step E Preparation of l-(MethylaminoVlH-indole-2-carboxylic acid
  • Step F Preparation of l-Methyl-4H-[1.3.41oxadiazinor4.5-a
  • Step H Preparation of Ethyl - N-r(4-hvdroxy-l-methyl-2-oxo-l, 2-dihydropyridazino fl . 6-a] indol-3-yl carbonyI1alaninate
  • Step I Preparation of N-r(4-hvdroxy-l-methyl-2-oxo-l,2-dihydropyridazino[1.6-a]mdol- 3-yl)carbonvnalanine
  • Step B Preparation of l-r(4-Hydroxy-l-methyl-2-oxo-1.2-dihydropyridaziriori .6- a]indol-3-yl)carbonyl]piperidine-4-carboxylic acid
  • Step A Preparation of Ethyl 4- ⁇ r(4-hydroxy-l-methyl-2-oxo-1.2-dihydropyridazino l,6-a]indol-3-yl)carbonyllamino
  • Step B Preparation of 4- ⁇ r(4-Hydroxy-l-methyl-2-oxo-1.2-dihydropyridazino 1.6- fl]indol-3-yl)carbonvnamino)cyclohexanecarboxylic acid
  • Step A Preparation of Methyl N-[Y4-hydroxy-l-methyI-2-oxo-1.2-dihydropyridazino ri,6-alindol-3-yl)carbonynserinate
  • Step 8 Preparation of N-[(4-hvdroxy-l-methyl-2-oxo-l ,2-dihvdropyridazinofL6- Q indol-3-yl)carbonyllserine
  • Step A Ethyl-3-methyl-2.4.5.6-tetrahvdrocvclopentarc1pyrrole-l-carboxylate
  • Step B Preparation of Ethyl 2-amino-3-rnethyl-2, 4, 5, 6-tetrahydrocyclopenta
  • Step C Preparation of Ethyl 3-methyl-2-r(trifiuoroacetyl) aminol-2, 4. 5, 6- tetrahvdrocvclopenta[ ⁇ c
  • Step D Preparation of Ethyl 3 -methyl-2- [methyl (trifluoroacetyl amino]-2, 4, 5, 6- tetrahydrocyclopentafclpyrrole- 1 -carboxylate
  • Step E Preparation of Ethyl 3-methyl-2-(methylamino)-2, 4, 5, 6-tetrahvdrocyclopertta [clpyrrole- 1 -carboxylate
  • Step F Preparation of 3-Methyl-2-(methylamino)-2, 4, 5. 6-tetrahvdro cyclopenta ⁇ c] pyrrole- 1-carboxylic acid
  • Step G Preparation of 1.8-Dimethyl-6J-dihvdrocvclopentar3.41pyrrolori.2-d1 ⁇ 13.41 oxadiazine-2,4( 1 H, 5H)-dione
  • Step H Preparation of Ethyl l,8-dimethyl-2.4-dioxo-2, 3.4.5.6, 7-hexahvdro-lH- cyclopentaf3,4]pyrrolori,2-b]pyridazine-3-carboxylate.
  • Step I Preparation of Ethyl [(1.8-dimethyl-2.4-dioxo-2,3.4.5.6.7-hexahydro-lH- cvclopentar3.41pyrrolo[1.2-b1pyridazin-3-yl)carbonyl1glycinate
  • Step J Preparation of N-r( , 4-hydroxy-l,8-dimethyl-2-oxo-2.5.6.7-tetrahydro-lH- cvclopentar3,41pyrrolon.2-b1pyridazin-3-yl)carbonyl1glycine
  • Step B Preparation of Ethyl-3, 5-dimethyl-4-(morpholin-4-vn-lH-pyrrole-2-carboxylate
  • Step D Preparation of Ethyl 3, 5-dimethyl-4-( ' mo ⁇ holin-4-yl -l -
  • Step E Preparation of Ethyl 3, 5-dimethyl-l -[methyl (trifluoroacetyl) aminol- 4- (morpholin-4-yl)- 1 H-pyrroIe-2-carboxylate
  • Step F Preparation of Ethyl 3. 5-dimethyl-l-fmethylamino)- 4-fmorpholin-4-yl)-lH- pyrrole-2-carboxylate
  • Step G Preparation of 3, 5 -Dimethyl- l-(methylamino) - 4-fmorpholin-4-ylVlH-pyrrole- 2-carboxylic acid
  • Step H Preparation of 1.5,7- ⁇ 1 ⁇ 1-6- ⁇ -4- ⁇ 1)-4 ⁇ - ⁇ ] ⁇ 1.2- ⁇ 1 fl .3,4] oxadiazine-2,4(l HVdione
  • Step J Preparation of Ethyl ⁇ - ⁇ ⁇ , ⁇ - ⁇ - ⁇ - ⁇ - ⁇ - ⁇ . ⁇ - tetrahydropyrrolo[l,2-b1pyridazin-3-yl)carbonyl]glycinate
  • Step K Preparation of N- ⁇ r4-hvdroxy-L5.7-trimethyl-6-(morpholin-4-yl -2-oxo-l,2- dihydropyrrolo ⁇ 1 ,2-b1pyridazin-3 -yll carbonyl) glycine
  • Step B Preparation of 4-tert-Butyl 2-ethyl l-amino-3, 5-dimethyl-lH-pyrrol-2.4- dicarboxylate
  • Step D Preparation of 4-tert-Butyl-2 -ethyl 3. 5-dimethyl-l -rmethyl (trifluoroacetyl) amino]- 1 H-pyrrole-2, 4-dicarboxylate
  • Step F Preparation of Ethyl 3. 5-dimethyl-l -[methyl (trifluoroacetyl) aminol-4- (morpholin-4-ylcarbonyl)- 1 H-pyrrole-2-carboxylate
  • Step H Preparation of 3, 5-Diroethyl-l -fmethylamino) - 4-fmorpholin-4-ylcarbonyl)- lH-pyrrole-2-carboxylic acid
  • Step I Preparation of .1.5,7-Trimethyl-6-imorpholin-4-ylcarbonvn-4 H- p yrroloiL2- d] ⁇ l .3,41oxadiazine-2.4( 1 HVdione
  • Step J Preparation of Ethyl 4-hydroxy-l, 5, 7-trimethyl-6-(morpholin-4-ylcarbonyl)-2- oxo-1, 2-dihydropyrrolo ⁇ , 2-b] pyridazine-3-carboxylate
  • Step L Preparation of N- ⁇ r4-hydroxy-1.5,7-trimethyl-6-(morpholin-4-ylcarbonyl)-2-
  • Step E Preparation of Ethyl 4-methyl-3-phenyl-l -[ " ftrifluoroacetyl) aminol-lH-pyrrole- 2-carboxylate
  • Step G Preparation of Ethyl 4-methyl-l-(methylamino -3-phenyl-lH-pyrrole-2- carboxylate
  • Step I Preparation of l ,6-Dimethyl-5-phenyl-4H-pyrrolo[T,2-d]
  • Step K Preparation of Ethyl N-rf4-hydroxy-l ,6-dimethyl-2-oxo-phenyl-1.2- dihydropyrrolo ri.2-b1pyridazin-3-yncarbonyl1glycinate
  • Step A Preparation of tert-butyl 2-(2-nitrophenyl)hydrazinecarboxylate
  • Step B Preparation of tert-butyl 2-(2-aminophenyl)hvdrazinecarboxylate
  • Step C Preparation of ethyl l-ritert-butoxycarbonyl)amino1-lH-benzimidazole-2- carboxylate
  • Step E Synthesis of ethyl l-(benzylamino)-lH-benzimidazole-2-carboxylate
  • Step F Preparation of ethyl 1 benzyl(3-ethoxy-3-oxopropanovDarnino1-lH- benzimidazole-2-carboxylate
  • Step G Synthesis of ethyl l-benzyl-4-hydroxy-2-oxo-l,2-dihydropyridazinon .6- albenzimidazole-3-carboxylate
  • Step H Synthesis of N-,rd-benzyl-4-hvdroxy-2-oxo-l,2-dihydropyridazinori,6- a] benzimidazol-3 - vDcarbonyll glycine :
  • Compounds of the present invention may be administered in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula (I) are useful.
  • Such other drugs may be administered contemporaneously or sequentially with a compound of Formula ( ⁇ ).
  • a pharmaceutical composition containing such other drugs in addition to the compound of Formula (I) is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula (I).
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more of a compound of formula (I). While it is possible to administer therapeutically effective quantity of compounds of formula (I) either individually or in combination, directly without any formulation, it is common practice to administer the compounds in the form of pharmaceutical dosage forms comprising pharmaceutically acceptable excipient(s) and at least one active ingredient. These dosage forms may be administered by a variety of routes including oral, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal, pulmonary etc. Oral compositions may be in the form of solid or liquid dosage form.
  • Solid dosage form may comprise pellets, pouches, sachets or discrete units such as tablets, multi-particulate units, capsules (soft & hard gelatin) etc.
  • Liquid dosage forms may be in the form of elixirs, suspensions, emulsions, solutions, syrups etc.
  • Composition intended for oral use may be prepared according to any method known in the art for the manufacture of the 4
  • composition and such pharmaceutical compositions may contain in addition to active ingredients, excipients such as diluents, disintegrating agents, binders, solubilizers, lubricants, glidants, surfactants, suspending agents, emulsifiers, chelating agents, stabilizers, flavours, sweeteners, colours etc.
  • excipients such as diluents, disintegrating agents, binders, solubilizers, lubricants, glidants, surfactants, suspending agents, emulsifiers, chelating agents, stabilizers, flavours, sweeteners, colours etc.
  • excipients include lactose, cellulose and its derivatives such as microcrystalline cellulose, methylcellulose, hydroxy propyl methyl cellulose & ethylcellylose, dicalcium phosphate, mannitol, starch, gelatin, polyvinyl pyrolidone, various gums like acacia, tragacanth, xanthan, alginates & its derivatives, sorbitol, dextrose, xylitol, magnesium Stearate, talc, colloidal silicon dioxide, mineral oil, glyceryl mono stearate, glyceryl behenate, sodium starch glycolate, cross povidone, crosslinked carboxymethylcellulose, various emulsifiers such as polyethylene glycol, sorbitol, fatty acid esters, polyethylene glycol alkylethers, sugar esters, polyoxyethylene polyoxypropyl block copolymers, polyethoxyJated fatty acid monoesters, diesters and mixtures
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, N -Methyl-2-Pyrrolidone, propylene glycol and other glycols, alcohols, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cotton sead oil or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, antioxidants, preservatives, complexing agents like cellulose derivatives, peptides, polypeptides and cyclodextrins and the like can be incorporated as required.
  • a vehicle such as water for injection, N -Methyl-2-Pyrrolidone, propylene glycol and other glycols, alcohols, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cotton sead oil or a synthetic fatty vehicle like ethyl oleate or the like.
  • the dosage form can have a slow, delayed or controlled release of active ingredients in addition to immediate release dosage forms.
  • the amount of active ingredient which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, and the particular disorder or disease being treated.
  • the compounds of the invention may be administered orally or parenteraly at a dose ranging from 0.001 to 1500 mg/kg per day, preferably from 0.01 to 1500 mg/kg per day, more preferably from 0.1 to 1500 mg/kg per day, most preferably from 0.1 to 500 mg/kg per day.
  • the dose range for adult humans is generally from 5 mg to 35 g per day and preferably 5 mg to 2 g per day. Tablets or other dosage forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for example units containing 5 mg to 500 mg.
  • Hep3B cell line (ATCC HB8064) was employed. Induction of erythropoietin was carried out for the indicated dose of compounds for 16 hours duration. At the end of 16 hours, cell culture medium was collected and centrifuged to remove any debris. Supernatant obtained was analyzed for erythropoietin by ELISA (R&D systems, USA). The results were expressed as fold induction as compared to vehicle control.

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Abstract

L'invention concerne de nouveaux composés pyridazine fusionnés, leurs sels pharmaceutiquement acceptables, ainsi que leurs isomères, stéréoisomères, conformères, tautomères, polymorphes, hydrates et solvates. Elle concerne aussi des compositions pharmaceutiquement acceptables de ces composés et un procédé d'élaboration de nouveaux composés. L'invention concerne en outre l'utilisation des composés susmentionnés pour la préparation de médicaments destinés à être utilisés comme produits pharmaceutiques.
PCT/IN2010/000664 2009-10-07 2010-10-06 Nouveaux dérivés pyridazine fusionnés WO2011048611A1 (fr)

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US9499553B2 (en) 2013-03-13 2016-11-22 Chugai Seiyaku Kabushiki Kaisha Dihydropyridazine-3,5-dione derivative and pharmaceuticals containing the same
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