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WO2011048611A1 - Novel fused pyridazine derivatives - Google Patents

Novel fused pyridazine derivatives Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
oxo
hydroxy
carbonyl
glycine
dihydropyridazino
Prior art date
Application number
PCT/IN2010/000664
Other languages
French (fr)
Inventor
Prabhat Kumar
Sameer Ghalasasi
Ramesh Chandra Gupta
Shailesh Deshpande
Anookh Mohanan
Anita Chaudhari
Chaitanya Dutt
Vijay Chauthaiwale
Appaji Baburao Mandhare
Original Assignee
Torrent Pharmaceuticals Limited
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Publication of WO2011048611A1 publication Critical patent/WO2011048611A1/en

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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

The present invention relates to novel fused pyridazine compounds, their pharmaceutically acceptable salts, and their isomers, stereoisomers, 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.

Description

NOVEL FUSED PYRIDAZINE DERIVATIVES
FIELD OF THE INVENTION;
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.
BACKGROUND OF THE INVENTION:
The transcription factor HIF (Hypoxia Inducible Factor) has a central role in oxygen homeostasis. An early response to tissue hypoxia is induction of Hypoxia Inducible Factor (HIF), a basic helix-loop-helix (bHLH) 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.!
In oxygenated (nor ioxic) cells, HIFa subunits are rapidly degraded by a mechanism that involves ubiquitination by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. Under hypoxic conditions, HIFa is not degraded, and an active FIIFa/β 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.1
Thus, 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
In oxygenated cells (normoxic), two conserved proline residues of HIFa subunits undergo hydroxylation. This reaction is catalysed by HIF prolyl-hydroxylases (PHD). Prolyl hydroxylated HIFa interacts with pVHL and rapidly gets degraded by proteasome machinery. In addition, in normoxic cells, one conserved asparagine of HIFa also undergoes hydroxylation. This reaction is catalysed by HIF asparagyl hydroxylase (FIH). Asparagyl hydroxylated HIFa can not interact with transcriptional co-activator CBP/p300.
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 genes1.
Inhibition of HIF prolyl hydroxylases and HIF asparagyl hydroxylases thus can be a powerful approach for oxygen- independent activation of HIF. Such 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. Erythropoietin, Transferrin, transferrin receptor)1. 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 or kidney3'4'5'6'7'8
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.
Erythropoietin (EPO), a naturally occurring hormone that is produced in response to HIFa, stimulates the production of erythrocytes. EPO is normally secreted by the kidneys, and endogenous EPO is increased under conditions of reduced oxygen (hypoxia)9.
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 hypertension10.
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.
Currently, treatment of ischemic and hypoxic disorders is focused on relief of symptoms and treatment of causative disorders but none of these therapies directly address the tissue damage produced by the ischemia and hypoxia. Exogenous administration of some of the HIF target genes such as erythropoietin, VEGF, adrenomeduUin has shown significant functional recovery in ischemia and ischemia- reperfusion injury of heart, kidney, brain and liver.11'12' 13'14
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.
EP 661269 discloses substituted heterocyclic carboxylic acid amides and their use as inhibitors of prolyl-4-hydroxylase and as inhibitors of collagen biosynthesis.
Additionally, various patent publications such as WO2003049686, WO2003053997, WO2004108121, WO2007146425, WO2007146438 disclose the compounds that stabilize HIFa and their use for the prevention and treatment of conditions associated with ischemia & hypoxia and EPO associated conditions like anemia and neurological disorders.
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.
SUMMARY OF THE INVENTION;
In one embodiment, the present invention provides novel compounds of general formula (I),
Figure imgf000006_0001
X= C, N
ΓΤΤ = Single or double bond
(I)
their pharmaceutically acceptable salts and their isomers, stereoisomers, conformers, tautomers, polymorphs, hydrates, and solvates:
Wherein:
Ri & R2 are independently selected from the group consisting of hydrogen, R7, - N(R9) (R9), -N(R9) (R7), -S02(R7), -S02(R9), - N(R9)(S02-R7), - N(R9)(S02-R9), - N(R9)(CO- R7), - N(R9)(CO-R ) and -Ci-8alkyl; wherein (C1-8alkyl) is optionally substituted with one or more substituents selected from R7, halo, cyano, nitro, -C(0)(R9), -C(0)(R7), -C(0)0- ' R9, -C(0)0-R7, -C(0)N(R9)(R9), -C(0)N(R9)(R7), -COCF3, -0(R9), -OR7, -NHOH - N(R9)(R9), -S020-R9, -S020-R7, -SR9, -SR7, -S(0)(C1-8 alkyl), -S(0)(R7), -S02(R9), -S02(R7), -S02(CI-3alkyI)-R7, -S02N(R9)(R9), -S02N(R9)(R7), -S02CF3, -N(R9)(R9), *N(R9)(R7), -N(R9)(CO- R9), -N(R9)(CO- R7), -N(R9)(C(0)-CF3) , -N(R9)(C(0)0-R9), -N(R9)(C(0)0-R7), -N(R9)(S02- C)-8 alkyl), -N(R9)(S02- R7), -N(R9)(S02-CF3), - N(R9)C(0)N(R9)(R9), -N(R9)C(0)N(R9)(R7), -N(R9)C(0)C(0)N(R9)(R9), -N(R9)C(0) C(0)N(R9)(R7), -N(R9)C(S)N(R9)(R9), -N(R9)C(S)N(R9)(R7), -N(R9)S02N(R9)(R9), - N(R9)S02fr(R9)( R7), oxo or thioxo; wherein, the above said C1-8alkyl may be straight, branched chain or cyclic, and may contain one or two double or triple bonds; or
R\ and R2 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 R8;
R7 at each occurrence is selected from:
1) opitionally substituted monocyclic or bicyclic three to ten membered cycloalkyl,
2) optionally substituted monocyclic or bicyclic five to ten membered aryl,
3) optionally substituted monocyclic or bicyclic five to ten membered heterocyclyl or
4) optionally substituted monocyclic or bicyclic five to ten membered heteroaryl, wherein heterocycle or heteroaryl contain one or more heteroatom selected from nitrogen, oxygen and sulphur;
R7 may be optionally substituted with one or more R8; wherein R8 is independently selected from the group consisting of halo, cyano, nitro, -Ci-8alkyl, -C(0)CF3, CF3, - NHOH, -S02CF3, -(C1-3alkyl)m -N(R9)(CO-R9), -(C1-3alkyl)m -N(R9)(CO- aryl),-(Ci. 3alkyl)m -N(R9)(CO- heteroaryl), -(Ci.3alkyl)m -N(R9)(CO- heterocyclyl), -(d.3alkyl)m - N(R9)(S02-R9), -(C]-3alkyl)m -N(R9)(S02- CF3), -(C1-3alkyl)m -N(R9)(S02- aryl), -( . 3alkyl)m -N(R9)(S02- heteroaryl), -(C1-3alkyl)m -N(R9)(S02- heterocyclyl),-(C1-3alkyl)m - N(R9)(C(0)0-R9), -(C1-3alkyl)m -N(R9)(C(0)0-aryl), -(C1-3alkyl)m -N(R9)(C(0)0- heteroaryl),-(C1-3alkyl)m-N(R9)(C(0)0-heterocyclyl), -(C1-3alkyl)m-N(R9)C(0)N(R9)(R9), -(C1-3alkyl)m-N(R9)C(0)N(R9)(aryl), -(C1-3alkyl)m-N(R9)C(0)N(R9)(heteroaryl), -(Q. 3aIkyl)m-(R9)C(0)N(R9)(heterocyclyl), -(C1-3alkyl)m -N(R9)C(0)C(0)N(R9)(R9), -(d. 3alkyl)m-N(R9)C(0)C(0)N(R9)(aryl), -(C1-3alkyl)m -N(R9)C(0)C(0)N(R9)(heteroaryl), - (C1-3alkyl)m-N(R9)C(0)C(0)N(R9) (heterocyclyl), -(C1-3alkyl)m -N(R9)C(S)N(R9)(R9), - (C1-3alkyl)m-N(R9)C(S)N(R9)(aryl), -(C1-3alkyl)m -N(R9)C(S)N(R9)(heteroaryl), -(d- 3alkyl)m -N(R9)C(S)N(R9)(heterocyclyl), -(C1-3alkyl)m -N(R9)S02N(R9)(R9), -(Q. 3alkyl)m-N(R9)S02N(R9)(aryl), -(C1-3alkyl)m-N(R9)S02N(R9) (heteroaryl), -(Ci-3alkyl)m - N(R9)S02N(R9)(heterocyclyl), oxo, thioxo, -NHC(NH)NH2, -(C1-3alkyl)m-0(R9), -(Cu 3alkyl)m-OC(0)(R9), -(C1-3alkyl)m-0(aryl), -(C1-3alkyl)m-0 (heteroaryl), -(C1-3alkyl)m- O(heterocyclyl), -(C1-3alkyl)m-S(R9), -(C1-3alkyl)m -S-aryl, -(C1-3alkyl)m -S -heteroaryl, - (C1-3alkyl)m -S-heterocylyl, -(C1-3alkyl)m-N((R9)(R9), -(Ci-3alkyl)m-N(R9)(aryl), -(d. 3alkyl)m-N(R9)(heteroaryl), -(C1-3alkyl)m-N(R9)(heterocyclyl), -(Ci-3alkyl)m-C(0)(R9), - (C1-3alkyl)m-C(0)(aryl),-(C1-3alkyl)m-C(0)(heteroaryl), -(C1-3alkyl)m-C(0)(heterocyclyl),- (C1-3alkyl)m-C(0)N(R9)(R9),-(C1-3alkyl)nrC(0)N(R9)(aryl),-(C1-3alkyl)m
(heteroaryl), - -(C1-3alkyl)m-C(0)N(R9) (heterocyclyl), -(Ci-3alkyl)m -C(0)0-(R9), -(Q. 3alkyl)m -C(0)0-aryl, -(C1-3alkyl)m-C(0)0-heteroaryl, -(C) -3alkyl)m -C(0)0-heterocyclyl, -(Ci.3alkyl)m -S(0)(C1-8 alkyl), -(C1 -3alkyl)m-S(0)(aryl), -(C1-3alkyl)m-S(0)(heteroaryl), - (C1-3alkyl)m -S(0)(heterocyclyl), -(Ci-3alkyl)m -S02(C1-8 alkyl), -(C,.3alkyl)m-S02(aryl), - (Ci-3alkyl)m-S02(heteroaryl), -(C1.3alkyl)m-S02(heterocyclyl),-(Ci.3alkyl)m-S02N(R9)(R9) ,-(C1-3alkyl)m-S02 N(R9)(aryl), -(Ci.3alkyl)m -S02 N(R9)(heteroaryl), -(Ci-3alkyl)m -S02 N(R9)(heterocyclyl), -(C! -3alkyl)m -S(0)20(C,.g alkyl), -(C1-3alkyl)m -S(0)20-(aryl), -(Cj. 3alkyl)m -S(0)20-(heteroaryl), -(C1 -3alkyl)m -S(0)20-(heterocyclyl), -(Ci-3alkyl)m -aryl, - (Ci-3alkyl)m -heteroaryl and -(Ci-3alkyl)m -heterocyclyl; wherein, the above said alkyl may be straight, branched chain or cyclic, and may contain one or two double or triple bonds; m is 0 or 1 ;
R9 is hydrogen or (Ci-8alkyl); wherein, the above said Ci-8alkyl 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-3alkyl)amino, di^. 3alkyl)amino, -S(C1-3alkyl), -C5.i0 aryl and -Ci-3 alkoxy; wherein, C1-3alkoxy may be straight or branched, may contain one or two double or triple bonds;
R3 is selected from the group consisting of R7, CF3, -C(0)CF3, -S02CF3 and -C1-8alkyl; wherein, the said Ci-8alkyl 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 R7, halo, cyano, nitro, -NHOH, CF3, -COCF3, -S02CF3, -C(0)(R9), -C(0)(R7), -C(0)(C1-3alkyl-R7), -C(0)0-R9, -C(0)0-R7, -C(0)N(R9)(R9), -C(0)N(R9)(R7), -SR9, -SR7, -S(0)(C1-8 alkyl), -S(0)(R7), -S02(R9), -S02(R7), -S02(C1-3alkyl)- R7, -S02N(R9)(R9), -S02N(R9)(R7), -S02CF3, -0R9, -OR7, -N(R9)(R9), -N(R9)(R7), -N(R9)(C(0)-R9), -N(R9)(C(0)-R7), -N(R9)(S02-C1-8alkyl), -N(R9)(S02-R7), -N(R9)(S02-CF3), -N(R9)C(0)N(R9)(R9), -N(R9)C(0)N(R9)(R7), - N(R9)C(0)C(0)N(R9)(R9), -N(R9)C(0)C(0)N(R9)(R7), -N(R9)C(S)N(R9)(R9), - N(R9)C(S)N(R9)( R7), -N(R9)S02N(R9)(R9), -N(R9)S02N(R9)( R7), oxo, thioxo, -S020- (R9) and -S020-(R7);
R4, R5 and R6 are each independently selected from the group consisting of -hydrogen, OH, SH, oxo, thioxo, halo, cyano, nitro, -NHOH, CF3, -COCF3, -S02CF3, -Ci-8alkyl, -(Ci- 8alkyl)m -N(R9)(C(0)- R9), -(C1-8alkyl)m -N(R9)(C(0)- R7), -(C1.8alkyl)m-N(R9)(S02- R9), -(CI-8alkyl)m -N(R9)(S02- R7), -(CI.8alkyl)ril-N(R9)(S02-CF3), -(C,.galky.)m-N(R9)C(0)0- R9, -(C1-8alkyl)m -N(R9)C(0)0-R7, -(d.8alkyl)m -N(R9)C(0)N(R9)(R9), -(C1-8alkyl)m- N(R9)C(0)N(R9)(R7), -(C1-8alkyl)m-N(R9)C(0)C(0)N(R9)(R9), -(C]-8alkyl)m - N(R9)C(0)C(0)N(R9)(R7), -(Ci.8alkyl)m-N(R9)C(S)N(R9)(R9), -(C1-8alkyl)ni-N(R9) C(S)N(R9)( R7), -(C1-8alkyl)m -N(R9)S02N(R9)(R9), -(C1-8alkyl)m -N(R9)S02N(R9)( R7), -(C1-8alkyl)m -R7, -(C,.8alkyl)m -0R9, -(Ci:8alkyl)m -OR7, -(C1-8alkyl)m-SR9, -(CI-8alkyl)m - SR7, -(C1-8alkyl)m -N((R9) (R9), -(C1-8alkyl)m -N(R9)(R7), -(C,.8alkyl)m -C(0)(R9), -(C 8alkyl)m -C(0)(R7), -(C1-8alkyl)m -C(0)N(R9)(R9), -(Ci.8alkyl)m -C(0)N(R9)(R7), -(d. 8alkyl)m -C(0)0-(R9), -(C,.8alkyl)m -C(0)0- R7, .-(Ci.8alkyl)m -S(O) (R9), -(Ci-8alkyl)m - S(0)(R7), -(C,.8alkyl)m -S02(R9), -(Ci-8alkyl)m -S02(R7), -(Ci^alkyl)m -S02(CU3alkyl-R7), -(C1-8alkyl)m -S02N(R9)(R9), -(C1-8alkyl)m -S02 N(R9)(R7), -(C1-8alkyl)m -S(0)20-(R9), - (C1-8alkyl)m -S(0)20-(R7) and -NHC(NH)NH2; wherein, the above said C1-8alkyl may be straight, branched chain or cyclic, and may contain one or two double or triple bonds; or R4 and R5 are joined together to form a ring R7 or
R5 and Re are joined together to form ring R7; with a proviso that when X=C, R3 is alkyl or alkyl substituted by aryl, R4, R5, ^ is independently hydrogen or chloro and
a) R[ is hydrogen then R2 is not -CH2COOH or b) R2 is hydrogen then ¾ is not -CH2COOH.
In one of the preferred embodiment, present invention provides a comound of formula (I), wherein at least one X is N (nitrogen) and Ri, R2, R3> R4, R5, ¾ & R7 are as defined above. > ■
In one of the preferred embodiment, present invention provides a comound formula (I), wherein R4 and R5 are joined together to form a ring R7 and R1} R2, R3 & Re are as defined above.
In another preferred embodiment, present invention provides a comound formula (I), wherein R5 and R^ are joined together to form a ring R7 and Ri, R , R3) & R4 are as defined above.
In another embodiment, the present invention pertains to a compound as above, however only including pharmaceutically acceptable salts thereof.
In another embodiment, 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 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.
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.
DETAILED DESCRIPTION OF THE INVENTION:
In one embodiment, the present invention provides novel compounds of general formula
Figure imgf000012_0001
C, N
= Single or double bond
(I)
their pharmaceutically acceptable salts and their isomers, stereoisomers, conformers, tautomers, polymorphs, hydrates, and solvates, wherein Ri, R2, R3,. R4, R5 and Re are as defined above.
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
[3,4]pyrrolo[l,2-b]pyridazin-3-yl)carbonyl]glycine
N-[(l-benzyl-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro-lH-cyclopenta
[3 ,4]pyrrolo [ 1 ,2-b]pyridazin-3 -yl)carbonyl] glycine
N-[(l-ethyl-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro-lH-cyclopenta[3,4] pyrrolo [l,2-b]pyridazin-3-yl)carbonyl]glycine
N-[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl)carbonyl] glycine
N-[(4-hydroxy- 1 ,9-dimethyl-2-oxo-l ,2,5,6,7,8-hexahydropyridazino[6, 1 -a] isoindol-3-yl)carbonyl]glycine sodium salt
N-[(4-hydroxy-l,5,7-trimethyl-2-oxo-l,2-dihydropyrrolo[l,2-b]pyridazin-3-yl) carbonyl] glycine
N-{ [4-hydroxy-l ,5,7-trimethyl-6-(mo holin-4-ylcarbonyl)-2-o o-l ,2- dihydropyrrolo[ 1 ,2-b]pyridazin-3-yl] carbonyl} glycine
N-{[4-hydroxy-l,5,7-trimethyl-6-(morpholin-4-yl)-2-oxo-l,2-dihydropyrrolo[l,2-b] pyridazin-3 -yljcarbonyl } glycine
N- { [4-hydroxy- 1 ,5 ,7-trimethyl-2-oxo-6-(piperidin- 1 -yl)- 1 ,2-dihydropyrrolo [ 1 ,2-b] pyridazin-3 -yljcarbonyl } glycine
N-[(7-fluoro-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl] glycine
N-[(4-hydroxy-l-methyl-2-oxo-l,2,6,7,8,9-hexahydropyridazino[l,6-a]indol-3-yl) carbonyljglycine
N- [(4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a]indoI-3 -yI)carbonyl] alanine
N-[(4-hydroxy-l ,8-dimethyl-2-oxo-2,5,6,7-tetrahydro-lH-cyclopenta[3,4]pyrrolo [ 1 ,2-b]pyridazin-3 -yl)carbonyl]alanine
N-'[ (4-hydroxy-l -methyl-2-oxo- 1,2,6, 7,8, 9-hexahydropyridazino[l,6-aJindol-3-yl) carbonyljalanine
N-[(4-hydroxy-l,5,6,7-tetramethyl-2-oxo-l,2-dihydropyrrolo[l ,2-b]pyridazin-3-yl) carbonyljglycine
N- [(4-hydroxy- 1 ,5,6,7-tetramethyl-2-oxo- 1 ,2-dihydropyrrolo [ 1 ,2-b]pyridazih-3-yl) carbonylj alanine
N-[(4-hydroxy- 1 ,6-dimethyl-2-oxo-5-phenyl- 1 ,2-dihydropyrrolo[l ,2-bJpyridazin-3- yI)carbonylJglycine
N- [(4-hydroxy- 1 -methyl-2-oxo-2,6,7,8-tetrahydro- 1 H-cyclopenta[4,5 Jpyrrolo[ 1 ,2- bJpyridazin-3 -yl)carbonylJ glycine
N- [(4-hydroxy- 1 ,6-dimethyl-2-oxo-5-phenyl- 1 ,2-dihydropyrrolo[l ,2-bJpyridazin-3- yl)carbonyl] alanine
N-[(4-hydroxy-l ,6-dimethyl-2-oxo-5-phenyl-l ,2-dihydropyrrolo [1 ,2-b]pyridazin-3- yI)carbonyI]-N-methylglycine
N- [(4-hydroxy- 1 ,9-dimethyl-2-oxo- 1 ,2,5,6,7,8-hexahydropyridazino[6, 1 -aj isoindol-3-yl)carbonylJalanine
4-{[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl)
carbonylJamino}cyclohexanecarboxylic acid
N-[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) Chemical name carbonyl] serine
2- {[(4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazmo[l ,6-a]indol-3-yl) carbonyl]amino}cyclohexanecarboxylic acid
N-[(4-hydroxy-7-methoxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl]glycine
N-,[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl)carbonyl]- N-methylglycine
N-[(4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a]indol-3- yl)carbonyl] glycine sodium salt
N-[(4-hydroxy-l,6-dimethyl-2-oxo-5-phenyl-l ,2-dihydropyrrolo[l,2-b]pyridazin-3- yl)carbonyl] glycine sodium salt
2- { [(4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] indol-3 -yl) carbonyl] amino}-l,3-thiazole-4-carboxylic acid
N-[(6-cyclohexyl-4-hydroxy- 1 ,5,7-trimethyl-2-oxo- 1 ,2-dihydropyrrolo[ 1 ,2- b]pyridazin-3-yl)carbonyl]glycine
N-[(7-chloro-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl] glycine
N-[(4,7-dihydroxy-l-methyl-2-oxo-l ,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl]glycine
1 - [(4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a] indol-3 -yl) carbonyl] piperidine-4-carboxylic acid
l-[(4-hydroxy-l,6-dimethyl-2-oxo-5-phenyl-l,2-dihydropyrrolo[l,2-b]pyridazin-3- yl)carbonyl]piperidine-4-carboxylic acid
N-[(5,7-diethyl-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyrrolo[l,2-b]pyridazin-3- yl) carbonyl] glycine
4-{[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl] amino} benzoic acid
N-[(l-benzyl-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl)
carbonyl] glycine
N-[(l-benzyl-4-hydroxy-5-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl]glycine
N-[(l-benzyl-4-hydroxy-2-oxo-l,2,6,7,8,9-hexahydropyridazino[l,6-a]indol-3- yl)carbonyl] glycine
N-{[4-hydroxy-6-(4-methoxyphenyl)-l,5,7-trimethyl-2-oxo-l,2- dihydropyrrolo [ 1 ,2-b]pyridazin-3 -yl]carbonyl } glycine
N-[(6-benzyl-4-hydroxy-l,5,7-trimethyl-2-oxo-l,2-dihydropyrrolo[l,2-b]pyridazin- 3-yl)carbonyl]glycine
N- { [4-hydroxy- 1 ,5-dimethyl-2-oxo-9-(propan-2-yl)- 1 ,2-dihydropyridazino [ 1 ,6-a] indol-3 -yl] carbonyl } glycine
N- {[4-hydroxy- l,5-dimethyl-2-oxo-7-(propan-2-yl)-l,2-dihydropyridazino[ 1,6- a]indol-3 -yl] carbonyl } glycine
N-[(l-benzyl-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]benzimidazol-3- yl)carbonyl]glycine
N-[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]benzimidazol-3- yl)carbonyl] glycine IVo. Chemical name
46 N-{[l-(2-fluorobenzyl)-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]
benzimidazo 1-3 -yl] carbonyl } glycine
47 N-{[l-(3-fluorobenzyl)-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]
benzimidazol-3 -yl]carbonyl } glycine
48 N-{[l-(4-chlorobenzyl)-4-hydroxy-2-oxo-l ,2-dihydropyridazino[l,6-a]
benzimidazol-3 -yl] carbonyl } glycine
49 N-[(l-ethyl-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]benzimidazol-3-yl) carbonyljglycine
0 N-{[4-hydroxy-2-oxo-l-(propan-2-yl)-l,2-dihydropyridazino[l,6-a] benzimidazol- 3- yl]carbonyl} glycine
1 N- { [4-hydroxy- 1 -(2-methylpropyl)-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a]
benzimidazol-3 -yl] carbonyl } g!ycine
2 N-{[l-(cyclopropylmethyl)-4-hydroxy-2-oxo-l,2-dihydropyridazino[l ,6-a]
benzimidazol-3 -yl] carbonyl} glycine
3 N-[(7-fluoro-4-hydroxy- 1 -methyl-2-oxo-l ,2-dihydropyridazino[l ,6-a]
benzimidazol-3 -yl)carbonyl] glycine
4 N- { [ 1 -(4-chlorobenzyl)-7-fluoro-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] benzimidazol-3 -yl]carbony I } glycine
5 N- { [4-hydroxy- 1 -(4-methoxybenzyl)-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a]
benzimidazol-3 -yl]carbonyl} glycine
6 N-{[4-hydroxy-l-(2-methylbenzyl)-2-oxo-l ,2-dihydropyridazino[l,6-a]
benzimidazol-3 -yl] carbonyl } glycine
7 N-( {4-hydroxy-2-oxo- 1 - [4-(trifluoromethyl)benzyl] - 1 ,2-dihydropyridazino [ 1 ,6-a] benzimidazol-3 -yl } carbony])glycine
8 N-( { 7-fluoro-4-hydroxy-2-oxo- 1 - [4-(trifluoromethyl)benzyl] - 1 ,2- dihydropyridazino[l,6-a]benzimidazol-3-yl}carbonyl)glycine
9 N- { [ 1 -(cyclohexylmethyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a]
benzimidazol-3 -yljcarbonyl } glycine
0 N-({4-hydroxy-2-oxo-l-[2-(trifluoromethyl)benzy]]-l,2-dihydropyridazino[l,6-a] benzimidazol-3 -yl } carbonyl)glycine
1 N- [(4-hydroxy- 1 - { [6-(morpholin-4-yl)pyridin-2-y l]methyl } -2-oxo- 1,2- dihydropyridazino[l ,6-a]benzimidazol-3-yl)carbonyl]glycine
2 N- { [4-hydroxy-2-oxo- 1 -(pyridin-2-ylmethyl)- 1 ,2-dihydropyridazino [ 1 ,6-a]
benzimidazol-3 -yljcarbonyl } glycine
3 N- { [ 1 -(2,4-dichlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a]
benzimidazol-3-yl]carbonyl}glycine
1 -[(4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a]benzimidazol-3-yi) carbonyl]piperidine-4-carboxylic acid .
N- { [ 1 -(2-fluorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a]
benzimidazol-3 -yljcarbonyl } alanine
N-[(l-ethyl-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]benzimidazol-3-yl) carbonyl]-b-alanine
1 -[(1 -benzyl-4-hydroxy-2-oxo-l ,2-dihydropyridazino[l ,6-a]benzimidazol-3-yl) carbonyl]piperidine-4-carboxylic acid
N- { [ 1 -(4-cyanobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] jVo. Chemical name benziniidazol-3 -yl] carbonyl } glycine
69 N-{[l-(2-chloro-6-fluorobenzyl)-4-hydroxy-2-oxo-l ,2-dihydropyridazino [1 ,6-aJ benzimidazol-3-yl]carbonyl}glycine
70 N-[(4-hydroxy-2-oxo-l-propyl-l,2-dihydropyridazino[l,6-a]benzimidazol-3-yl) carbonyljglycine
71 N-[(l-cyclohexyl-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]benzimidazol-3- yl) carbonyl]glycine
72 N-{[l-(biphenyl-4-ylmethyl)-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]
benzimidazol-3 -yl] carbonyl } glycine
3 N-[(4,8-dihydroxy-l-methyl-2-oxo-l ,2-dihydropyridazino[l,6-a]indol-3-yl)
carbonyljglycine
4 N-[(6-fluoro-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyljglycine
5 N-[(8-fluoro-4-hydroxy-l,7-dimethyl-2-oxo-l,2-dihydropyridazino[l,6-aJindol-3- yl)carbonylJglycine
6 N-[(7,8-difluoro-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazin6[l,6-aJindol-3- yl)carbonyl] glycine
7 N-[(4-hydroxy-8-methoxy- 1 -methyI-2-oxo- 1 ,2-dihydropyridazino[l ,6-aJindol-3-yl) carbonyljglycine
8 N-[(4-hydroxy-l,6,8-trimethyl-2-oxo-l,2-dihydropyridazino[l,6-aJindol-3-yl) carbonyljglycine
9 N-[(8-cyano-4-hydroxy-l-methyl-2-oxo-l ,2-dihydropyridazino[l,6-aJindol-3-yl) carbonyljglycine
0 N-{[4-hydroxy-l -methyl-8-(methylsulfc)nyl)-2-oxo-l ,2-dihydropyridazino[l ,6- a] indol-3 -ylj carbonyl } glycine
1 N-[(9-fluoro-4,6-dihydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3- yl) carbonyljglycine
2 N-[(4,7,9-trihydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyljglycine
3 N-[(6-fluoro-4-hydroxy-8-methoxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a] indol-3 -yl)carbonyl] glycine
4 N- [(8-chloro-6-fluoro-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino [1,6- aj indol-3 -yl)carbonylJ glycine
5 N-[(8-tert-butyI-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-aJindol-3-yI) carbonyljglycine
N-[(4,8-dihydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l ,6-aJindol-3-yl) carbonyljalanine
N-[(4,8-dihydroxy-l,7,9-trimethyl-2-oxo-l,2-dihydropyridazino[l,6-aJindol-3-yl) carbonyljglycine
N-[(4,6-dihydroxy-8-methoxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol- 3 -yl)carbonylJ glycine
N-[(8-carbamoyl-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3- yl) carbonyljglycine
N- [(4-hydroxy-7,9-dimethoxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] indol- 3 -yl)carbonylJ glycine Chemical name N- { [6-(difluoromethoxy)-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] indol-3 -yl] carbonyl } glycine
N-{ [8-(acetyloxy)-4-hydroxy-l -methyl-2-oxo-l ,2-dihydropyridazino [1 ,6-a]indol-3- yl]carbonyl } glycine
N-{[4-hydroxy-l-methyl-2-oxo-8-(trifluorornethyl)-l,2-dihydropyridazino[l,6-a] indol-3 -yl] carbonyl } glycine
N-{[4-hydroxy-l-methyl-2-oxo-6-(trifluoromethoxy)-l,2-dihydropyridazino[l,6-a] indol-3 -yl] carbonyl } glycine
N- { [4-hydroxy- 1 -methyl-6-(morpholin-4-yl)-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] indol-3 -yl]carbonyl } glycine
N-{[4-hydroxy-l-methyl-6-(4-methylphenoxy)-2-oxo-l,2-dihydropyridazino[l,6- a] indol-3 -yl] carbonyl } glycine
N- { [4-hydroxy-2-oxo- 1 -(propan-2-yl)-8-(trifluoromethyl)- 1 ,2- dihydropyridazino[l,6-a]indol-3-yl]carbonyl}glycine
N- { [4-hydroxy-2-oxo- 1 -(propan-2-yl)-6-(trifluoromethoxy)- 1 ,2-dihydropyridazino [l,6-a]indol-3-yl]carbonyl}glycine
N-{ [4-hydroxy- 8-methoxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino [1 ,6-a] indol-3 -yl]carbonyl } glycine
N-{[6-(difluoromethoxy)-4-hydroxy-2-oxo-l-(propan-2-y])-l ,2-dihydropyridazino [ 1 ,6-a] indol-3 -yl]carbonyl } glycine
N-{[4-hydroxy-l-methyl-8-(methylsulfonyl)-2-oxo-l,2-dihydropyridazino[l ,6-a] indol-3 -yl] carbonyl } alanine
N- { [6-(difluoromethoxy)-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] indol-3 -yl] carbonyl } alanine
N- { [8-chloro-4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino [ 1 ,6-a]indol- 3-yl]carbonyl}glycine
N-[(l-cyclohexyl-4-hydroxy-8-methoxy-2-oxo-l,2-dihydropyridazino[l,6-a]indol- 3 -yl)carbonyl] glycine
N- [( 1 -cyclohexyI-4,6-dihydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] indol-3 -yl) carbonyl] glycine
N-[(l-cyclohexyl-6-fluoro-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3- yl) carbonyl] glycine
N- [( 1 -cyclopentyl-4,6-dihydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] indol-3 -yl) carbonyl] glycine
N-[(l -cyclopentyl-4-hydroxy-8-methoxy-2-oxo- 1 ,2-dihydropyridazino[l ,6-a]indol- 3 -yl)carbonyl] glycine
N-[(l-cyclopentyl-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl]glycine
N-{[l-cyclopentyl-4-hydroxy-2-oxo-8-(trifluoromethyl)-l,2-dihydropyridazino[l,6- a]indol-3-yl]carbonyl} glycine
N-[(l-cyclopentyl-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl] glycine
N-[(l-benzyl-6-fluoro-4-hydroxy-2-oxo-l ,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl]glycine
N-{[4-hydroxy-2-oxo-l-(propan-2-yl)-l,2,6,7,8,9-hexahydropyridazino[l,6- Chemical name a] indol-3 -yl] carbonyl } alanine
N-[(4-hydroxy-2-oxo-l-phenyl-l,2,6,7,8,9-hexa ydropyridazino[l,6-a]indol-3-yI) carbonyljglycine
N-[(4-hydroxy-l -methyl-2-oxo-2,6,7,8-tetrahydro- 1 H-cyclopenta[4,5]pyrrolo[l ,2- b] pyridazin-3-yl)carbonyl]alanine
N-{[4-hydroxy-2-oxo-l-(propan-2-yl)-2,6,7,8-tetrahydro-lH- cyclopenta[4,5]pyrrolo [ 1 ,2-b]pyridazin-3 -yl] carbonyl } alanine
N-{[4-hydroxy-2-oxo-l-(propan-2-yl)-2,6,7,8-tetrahydro-lH- cyclopenta[4,5]pyrrolo[l,2-b]pyridazin-3-yl]carbonyl)glycine
N- { [4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino [ 1 ,6-a]indol-3 -yl] carbonyl} glycine
N- { [4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino [ 1 ,6-a] indol-3 -yl] carbonyl} alanine
N- [( 1 -cyclopentyl-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] indol-3 -yl) carbonyl] alanine
N-{[4-hydroxy-8-methyl-2-oxo-l-(propan-2-yl)-2,5,6,7-tetrahydro-lH- cyclopenta[3,4]pyirolo[l,2-b]pyridazin-3-yl]carbonyl}alanine
N-[(4-hydroxy- 1 ,9-dimethyl-2-oxo- 1 ,2,5,6,7,8-hexahydropyridazino[6, 1 -a]isoindol- 3 -yl)carbonyl] alanine
N-{[4-hydroxy-9-methyl-2-oxo-l-(propan-2-yl)-l,2,5,6,7,8-hexahydropyridazino [6, l-a]isoindol-3-yl]carbonyl} alanine
N- [(4-hydroxy- 1 ,9-dimethyl-2-oxo- 1 ,2-dihydropyridazino [6, 1 -a]i soindol-3 -yl) carbonyl]glycine
N-{[4-hydroxy-9-methyl-2-oxo-l-(propan-2-yl)-l ,2-dihydropyridazino[6,l-a] isoindol-3 -yl] carbonyl } glycine
N-[(4-hydroxy-l,9-dimethyl-2-oxo-l,2-dihydropyridazino[6,l-a]isoindol-3- yl)carbonyl] alanine
N- [(4-hydroxy- 1 ,9-dimethyl-2-oxo- 1 ,2,7, 8-tetrahy dropyridazino [6, 1 -a] isoindol-3 - yl)carbonyl]g!ycine
N-{[4-hydroxy-9-methyl-2-oxo-l-(propan-2-yl)-l,2,7,8-tetrahydropyridazino[6,l- a]isoindol-3 -yl] carbonyl } glycine
N-[(4-hydroxy-l,9-dimethyl-2-oxo-l,2,7,8-tetrahydropyridazino[6,l-a]isoindol-3- yl)carbonyl]alanine
N-{ [4-hydroxy-9-methyl-2-oxo- 1 -(propan-2-yl)- 1 ,2,7,8-tetrahydropyridazino[6, 1 - a]isoindol-3-yl]carbonyl}alanine
N-[(4-hydroxy-l,7-dimethyl-2-oxo-l,2,6,7,8,9-hexahydropyrido [3',4':4,5]pyrrolo [ 1 ,2-b]pyridazin-3 -yl) carbonyl] glycine
N-[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyrido[3',4':4,5]pyrrolo[l,2-b] pyridazin-3-yl)carbonyl]glycine
N-{[4-hydroxy-2-oxo-l-(propan-2-yl)-l,2-dihydropyrido[3',4,:4,5]pyrrolo[l,2-b] pyridazin-3 -yl] carbonyl } glycine
N- [( 1 -benzyl-4-hydroxy-2-oxo- 1 ,2-dihydropyrido [3 ',4' :4,5]pyrrolo [ 1 ,2-b] pyridazin-3-yl)carbonyl]glycine
N-[(4-hydroxy-l -methyl-2-oxo-l ,2-dihydropyrido[4',3':4,5]pynOlo[l ,2-b] pyridazin-3 -yl)carbonyl] glycine Chemical name N-{ [4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyrido[4',3':4,i5]pyrrolo[l ,2-b] pyridazin-3 -yl] carbony I } glycine
i-[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyrido[4,,3,:4,5]pyrrolo[l ,2-b]pyridazin- 3-yl)carbonyl]piperidine-4-carboxylic acid
N-tCe-hydroxy-P-methyl-S-oxo-S^-dihydro yrimidotS'^'.^^i rrolot 1 ,2-b] pyridazin-7-yl)carbonyl] glycine
N-{[6-hydroxy-8-oxo-9-(propan-2-yl)-8,9-dihydropyrimido[5,,4':4,5]pyrrolo[l,2- b]pyridazin-7-yl]carbonyl} glycine
N-[(9-benzyl-6-hydroxy-8-oxo-8,9-dihydropyrimido[5',4':4,5]pyrrolo[l ,2- b]pyridazin-7-yl)carbonyl]glycine
N- { [5-(dimethylamino)-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino[l ,6-a] indol-3 -y 1] carbonyl } glycine
N- { [5-(4-fluorophenyl)-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyrrolo [ 1 ,2-b] pyridazin-3 -yl] carbonyl } glycine
N- { [5 -(4-fluorophenyl)-4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyrrolo [ 1 ,2- b]pyridazin-3 -yl]carbonyl } glycine
N-{[4-hydroxy-5-(4-methoxyphenyl)-l -methyl-2-oxo-l ,2-dihydropyrrolo[l ,2- b]pyridazin-3 -yl] carbonyl } glycine
N-{[4-hydroxy-5-(4-methoxyphenyl)-2-oxo-l -(propan-2-yl)-l,2- dihydropyrrolo[l ,2-b]pyridazin-3-yl]carbonyl}glycine
N-{[4-hydroxy-5-(4-hydroxyphenyl)-l-methyl-2-oxo-l,2-dihydropyrrolo[l ,2- b]pyridazin-3 -yl] carbonyl } glycine
N- { [4-hydroxy-5-(4-hydroxyphenyl)-2-oxo- 1 -(propan-2-yl)- 1,2- dihydropyrrolo[l ,2-b]pyridazin-3-yl]carbony] } glycine
N-{[4-hydroxy-2-oxo-6-phenyl-l-(propan-2-yl)-l ,2-dihydropyrrolo[l ,2- b]pyridazin-3 -yl] carbonyl } glycine
N-[(4-hydroxy-l-methyl-2-oxo-6-phenyl-[, 2-b]dihydropyrrolo[l,2-b]pyridazin-3- yl)carbonyl]glycine
N- { [6-(4-fluorophenyl)-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyrrolo [1 ,2- b]pyridazin-3-yl]carbonyl} glycine
N- { [6-(4-fluorophenyl)-4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyrrolo[ 1 ,2- b] pyridazin-3 -yljcarbonyl} glycine
N- { [4-hydroxy-6-(4-hydroxyphenyl)- 1 -methyl-2-oxo- 1 ,2-dihydropyrrolo [ 1 ,2-b] pyridazin-3 -yl] carbonyl} glycine
N- { [4-hydroxy-6-(4-methoxyphenyl)- 1 -methyl-2-oxo- 1 ,2-dihydropyrrolo [ 1 ,2-b] pyridazin-3 -yl] carbonyl } glycine
N-{[4-hydroxy-6-(4-methoxyphenyl)-2-oxo-l-(propan-2-yl)-l ,2- dihydropyrrolo [ 1 ,2-b]pyridazin-3 -yl]carbonyl } glycine
N- { [4-hydroxy-6-(4-methoxyphenyl)-5 ,7-dimethyl-2-oxo- 1 -(propan-2-yl)- 1 ,2- dihydropyrrolo[l ,2-b]pyridazin-3-yl]carbonyl}glycine
N-[(8-fluoro-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]
benzimidazol-3-yl)carbonyl]glycine
N-[(4-hydroxy-8-methoxy- 1 -methyl -2-oxo- 1 ,2-dihydropyridazino[l ,6-a]
benzimidazol-3-yl)carbonyl]glycine
N- { [4-hydroxy- 1 -methyl-2-oxo-8-(trifluoromethy 1)- 1 ,2-dihydropyridazino [ 1 ,6-a] Chemical name benzimidazol-3 -yl] carbony 1 } glycine
N-[(4-hydroxy-l,8-dimethyl-2-oxo-l,2-dihydropyridazino[l,6-a]benzimidazol-3- yl)carbonyl]glycine .
N-[(8-chloro-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a]
benzimidazol-3-yl)carbonyl]glycine
N-{[4-hydroxy-l-methyl-8-(morpholin-4-yl)-2-oxo-7-(trifluoromethyl)-l,2- dihydropyridazino[l,6-a]benzimidazol-3-yl]carbonyl}glycine
N-[(4,7-dihydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]benzimidazol-3-yl) carbony 1] glycine
N- { [8-chloro-4-hydroxy- 1 -methyl-2-oxo-6-(trifluoromethyl)- 1 ,2- dihydropyridazino[l,6-a]benzimidazol-3-yl]carbonyl} glycine
N-[(7-chloro-4-hydroxy- 1 ,8-dimethyl-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a] benzimidazol-3-yl)carbonyl]glycine
N-[(8-carbamoyl-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6- a]benzimidazol-3 -yl)carbonyl] glycine
N- { [8-fluoro-4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino [ 1 ,6-a] benzimidazol-3 -yl] carbonyl } glycine
N-{[4-hydroxy-8-methoxy-2-oxo-l-(propan-2-yl)-l,2-dihydropyridazino[l ,6-a] benzimidazol-3 -yl] carbonyl } glycine
N- { [4-hydroxy-2-oxo- 1 -(propan-2-yl)-8-(trifluoromethyl)- 1 ,2- dihydropyridazino[l ,6-a]benzimidazol-3-yl]carbonyi } glycine
N- { [4-hydroxy-8-methyl-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino[ 1 ,6-a] benzimidazol-3 -yl] carbonyl } glycine
N-{[8-chloro-4-hydroxy-2-oxo-l-(propan-2-yl)-l,2-dihydropyridazino[l,6-a] benzimidazol-3-yl]carbonyl} glycine
N-{[4-hydroxy-8-(morpholin-4-yl)-2-oxo-l-(propan-2-yl)-7-(trifluoromethyl)-l,2- dihydropyridazino[l,6-a]benzimidazol-3-yl]carbonyl}glycine
N- { [4,7-dihydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino [ 1 ,6-a]
benzimidazol-3 -yl] carbonyl } glycine
N- { [8-chloro-4-hydroxy-2-oxo- 1 -(propan-2-yl)-6-(trifluoromethyl)- 1 ,2- dihydropyridazino [ 1 ,6-a]benzimidazol-3 -yl] carbonyl } glycine
N- { [7-chloro-4-hydroxy-8-methyl-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino [l,6-a]benzimidazol-3-yl]carbonyl}glycine
N-[(8-hydroxy-6-oxo-5-phenyl-5,6-dihydroimidazo[l,2-b]pyridazin-7-yl) carbonyl] glycine
N-[(8-hydroxy-5-methyl-6-oxo-5,6-dihydroimidazo[l,2-b]pyridazin-7-yl) carbonyl]glycine
N-{[8-hydroxy-6-oxo-5-(propan-2-yl)-5,6-dihydroimidazo[l ,2-b]pyridazin-7-yl] carbonyl} glycine
N-[(5-benzyl-8-hydroxy-6-oxo-5,6-dihydroimidazo[l,2-b]pyridazin-7-yl) carbonyl] glycine
l-[(8-hydroxy-5-methyl-6-oxo-5,6-dihydroimidazo[l,2-b]pyridazin-7-yl)
carbonyl]piperidine-4-carboxylic acid
N-[(8-hydroxy-5-methyl-6-oxo-2-phenyl-5,6-dihydroimidazo[l ,2-b]pyridazin-7-yl) carbonyl]glycine Chemical name N-{ [8-hydroxy-6-oxo-2-phenyl-5-(propan-2-yl)-5,6-dihydroimidazo[l ,2-b] pyridazin-7-yI]carbonyl} glycine
N-[(4-hydroxy- 1 -methyl-2-oxo- 1 ,2,5,6,7,8-hexahydropyridazino[l ,6-b]indazol-3- yl) carbonyl] glycine
N-{[4-hydroxy-2-oxo-l -(propan-2-yl)-l ,2,5,6,7,8- exahydropyridazinofl ,6-b] indazol-3-yl]carbonyl}glycine
N-[(4-hydroxy-l-methyl-2-oxo-l,2,5,6,7,8-hexahydropyridazino[l,6-b]indazol-3- yl)carbonyl]alanine
N- { [4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2,5,6,7,8-hexahydropyridazino[ 1 ,6- b]indazol-3-yl]carbonyl} alanine
N-[(4-hydroxy-7-methyl-6-oxo-6,7-dihydropyrazolo[l ,5-b]pyridazin-5-yl) carbonyl] glycine
N-{[4-hydroxy-6-oxo-7-(propan-2-yl)-6,7-dihydropyrazolo[l,5-b]pyridazin-5- yl] carbonyl } glycine
N-[(7-benzyl-4-hydroxy-6-oxo-6,7-dihydropyrazolo[l,5-b]pyridazin-5- yl)carbonyl]glycine
N-[(4-hydroxy-6-oxo-7-phenyl-6,7-dihydropyrazolo[l,5-b]pyridazin-5-yl) carbonyljglycine
l-[(4-hydroxy-7-methyl-6-oxo-6,7-dihydropyrazolo[l,5-b]pyridazin-5- yl)carbonyl]piperidine-4-carboxylic acid
N-[(4- ydroxy-7-methyl-6-oxo-2-phenyl-6,7-di ydropyrazolo[l ,5-b]pyridazin-5- yl)carbonyl] glycine
N-{[4-hydroxy-6-oxo-2-phenyl-7-(propan-2-yl)-6,7-dihydropyrazolo[l,5-b] pyridazin-5-yl] carbonyl } glycine
N-[(7-benzyl-4-hydroxy-6-oxo-2-phenyl-6,7-dihydropyrazolo[l,5-b]pyridazin-5-yl) carbonyljglycine
N-{[4-hydrOxy-7-methyl-6-oxo-2-(4-sulfamoylphenyl)-6,7-dihydropyrazolo[l,5-b] pyridazin-5-yl] carbonyl } glycine
N-{[4-hydroxy-6-oxo-7-(propan-2-yl)-2-(4-sulfamoylphenyl)-6,7- dihydropyrazolo[l,5-b]pyridazin-5-yl]carbonyl}glycine
N-({2-[4-(acetylamino)phenyl]-4-hydroxy-6-oxo-7-(propan-2-yl)-6,7- dihydropyrazolo[l,5-b]pyridazin-5-yl}carbonyl)glycine
N-({2-[4-(acetylamino)phenyl]-4-hydroxy-7-methyl-6-oxo-6,7-dihydropyrazolo [l,5-b]pyridazin-5-yI}carbonyI)gIycine
N-{[4-hydroxy-2-(4-methoxyphenyl)-7-methyl-6-oxo-6,7-dihydropyrazolo[l,5-b] pyridazin-5-yl]carbonyl}glycine
N-{[4-hydroxy-2-(4-methoxyp enyl)-6-oxo-7-(propan-2-yl)-6,7- dihydropyrazolo [1,5 -b]pyridazin-5 -yl] carbonyl } glycine
N-({2-[4-(dimethylamino)phenyl]-4-hydroxy-7-methyl-6-oxo-6,7- dihydropyrazolo[l,5-b]pyridazin-5-yl}carbonyl)glycine
N-({2-[4-(dimethylamino)phenyl]-4-hydroxy-6-oxo-7-(propan-2-yl)-6,7- dihydropyrazolo[l,5-b]pyridazin-5-yl}carbonyl)glycine
N-{[4-hydroxy-2-(3-methoxyphenyl)-7-methyl-6-oxo-6,7-dihydropyrazolo[l,5-b] pyridazin-5-yl]carbonyl} glycine
N- { [4-hydroxy-2-(3 -hydroxyphenyl)-7-methyl-6-oxo-6,7-dihydropyrazolo[ 1 ,5-b] Chemical name pyridazin-5-yl]carbonyl} glycine
N-({2-[2-(acetyloxy)phenyl]-4-hydroxy-7-methyl-6-oxo-6,7-dihydropyrazolo[ 1 ,5- b] pyridazin-5-yl}carbonyl)glycine
N-({2-[2-chloro-5-(trifluoromethyl)phenyl]-4-hydroxy-7-methyl-6-oxo-6,7- dihydropyrazolo[l,5-b]pyridazin-5-yl}carbonyl)glycine
N-({4-hydroxy-7-methyl-6-ox0-2-[4-(trifluoromethoxy)phenyl]-6,7- dihydropyrazolo[l,5-b]pyridazin-5-yl}carbonyl)glycine
N-( {4-hydroxy'-7-methyl-6-oxo-2-[4-(trifluoromethyl)phenyl]-6,7- dihydropyrazolo[l,5-b]pyridazin-5-yl}carbonyl)glycine
N-{[2-(4-fluorophenyl)-4-hydroxy-7-methyl-6-oxo-6,7-dihydropyrazolo[l,5-b] pyridazin-5-yl]carbonyl}glycine
N-{[2-(3-chlorophenyl)-4-hydroxy-7-methyl-6-oxo-6,7-dihydropyrazolo[l,5- b]pyridazin-5 -yl] carbonyl} glycine
N-({4-hydroxy-7-methyl-6-oxo-2-[2-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo [ 1 ,5 -b]pyridazin-5-yl } carbonyl)gIycine
N-[(4-hydroxy-l -methyl-2-oxo-l,2,5,6-tetrahydropyridazino[l,6-b]indazol-3-yl) carbonyl] glycine
N- { [ 1 -(4-chlorobenzyl)-8-(dimethylamino)-4-hydroxy-2-oxo- 1 ,2- dihydropyridazino [ 1 ,6-a]benzimidazol-3 -yl] carbonyl } glycine
N- { [8-(dimethylamino)-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6- ajbenzimidazoi -3 -yljcarbonyl } glycine
N- { [ 1 -(4-chlorobenzyl)-4-hydroxy-2-oxo-7-phenyl- 1 ,2-dihydropyridazino [ 1 ,6-a] benzimidazol-3 -yl] carbonyl} glycine
N-[(7-carbamoyl-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a] benzimidazol-3 -yl)carbonyl] glycine
N-{[7-carbamoyl- l-(4-chlorobenzyl)-4-hydroxy-2-oxo-l ,2-dihydropyridazino[l ,6- a] benzimidazol-3 -yl] carbonyl} glycine
N-{[7-(benzyloxy)-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a] benzimidazol-3 -yl] carbonyl } glycine
1 - { [1 -(4-chlorobenzyl)-4-hydroxy-7-methoxy-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a] benzimidazol-3-yl]carbonyl}piperidine-4-carboxylic acid
N- [( 1 -benzyl-4-hydroxy-2-oxo- 1 ,2-dihydropyrido [3 ',2' :4,5] imidazo [ 1 ,2-b] pyridazin-3 -yl)carbonyl] glycine
N-[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyrido[3',2':4,5]imidazo[l ,2- b] pyridazin-3-yl)carbonyl]glycine
N-[(l-benzyl-4-hydroxy-2-oxo-l,2-dihydropyrido[2',3':4,5]imidazo[l,2-b] pyridazin-3-yl)carbonyl]glycine
N-[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyrido[2',3':4,5]imidazo[l,2-b] pyridazin-3 -yl)carbonyl] glycine
N-[(6-hydroxy-9-methyl-8-oxo-8,9-dihydropyridazino[l,6-e]purin-7-yl) carbonyl]glycine
N-[(9-benzyl-6-hydroxy-8-oxo-8,9-dihydropyridazino[l,6-e]purin-7-yl)
carbonyl] glycine
N-[(9-hydroxy-2,4,6-trimethyl-7-oxo-6,7-dihydropyridazino[6, 1 -f]purin-8-yl) carbonyl] glycine No. Chemical name
226 N-[(6-benzyl-9-hydroxy-2,4-dimethyl-7-oxo-6,7-diliydropyridazino[6, 1 -f]purin-8- yl)carbonyl] glycine
227 N- { [ 1 -(4-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a]
benzimidazol-3-yl]carbonyl} glycine sodium salt
In one of the preferred embodiment, the present invention provides novel compounds of general formula (I),
Figure imgf000023_0001
X= C, N
mr" = Single or double bond
(I)
their pharmaceutically acceptable salts and their isomers, stereoisomers, conformers, tautomers, polymorphs, hydrates, and solvates, wherein at least one of the X is N (nitrogen) and Ri, R2, R3, R4, R5 and R6 are as defined above.
DEFINITIONS:
The following definitions apply- to the terms as used throughout this specification, unless otherwise limited in specific instances:
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. Accordingly, 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 2H, 3H, 13C, 14C, 15N, ,80, 170, 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.
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Further, it should be understood, when partial structures of the compounds are illustrated, a dash (" - ") indicate the point of attachment of the partial structure to the rest of the molecule.
The nomenclature of the compounds of the present invention as indicated herein is according to ACD Name (version 12.0) from ACD/Lab of Advanced Chemistry Development, Inc., Toronto, Canada
"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-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glucuronic acid, galactunoric acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Also included are salts of amino acids such as arginate and the like (see, for example, Berge, S.M., et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).
As used herein, the term "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.
As used herein, the term "hydrates" pertains to a compound having a number of water molecules bonded to the compound.
As used herein, the term "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.
The term "substituted", as used herein, 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, R2 ....) 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.
As used herein, the term "oxo" or "thioxo" is intended to mean that the group when bound to a saturated carbon atom may represent C=0 or C=S and when bound to unsaturated carbon atom may be represented in the tautomeric enol form.
As used herein, a "halo" or "halogen" substituent is a monovalent halogen radical chosen from chloro, bromo, iodo or fluoro.
The term "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.
The term "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. The term "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. The term "heteroatom" as used herein includes oxygen, sulfur and nitrogen.
The term "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. The term "heteroatom" as used herein includes oxygen, sulfur and nitrogen.
As used herein, "room temperature" refers to a temperature between 25 0 C and 350 C.
As used herein, the term "mammal" means a human or an animal such as monkeys, primates, dogs, cats, horses, cows, etc.
The terms "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.
The phrase "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.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
In another embodiment, present invention provides the process for preparing the compounds of formula (I).
The following reaction schemes are given to disclose the synthesis of the compounds according to the present invention.
Accordingly, the compounds of formula (I) of the present invention may be prepared as described in the schemes below.
Figure imgf000028_0001
X= C, N
^ rr = Single or double bond
(I)
The compounds of general formula (I) are obtained through the intermediate (II), (XXX) or (XXXIII) wherein the Rj R2, R3, R4, R5 and R6 are as defined earlier.
Scheme I
Figure imgf000029_0001
In one of the specific embodiment of the present invention, as shown in scheme-I, the compounds of formula (I) is prepared in the following manner: a) The compound of formula (II) wherein, the R4, R5 & 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)15. b) The compound of formula (III) is reacted with R3-carboxylic acid wherein the R3 is as defined earlier, in the presence of 1-hydroxybenzotriazole (HOBT) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) or benzotriazol-l-yl- oxytris (dimethylamino). phosphonium hexafluorophosphate (BOP) in a solvent such as tetrahydrofuran or dimethylfonriamide at a temperature from 0° C to 25° C for about 1 hour, followed by addition of N-ethyldiisopropylamine and is stirred at a room
16 17 18
temperature for 6 to 20 hours to give compound of formula (IV) ' '
In an alternate process, the compound of formula (IV) is prepared by reacting the compound of formula (III) with R3-chloroformate, R3-carbonyl chloride, R3-sulphonyl chloride, R3-anhydride or R3-halide wherein, the R3 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.
Alternatively, the compound of formula (IV) is prepared by treating the compound of formula (III) with R3-CHO wherein, R3 is as defined earlier in the presence of reducing reagents such as sodium borohydride, sodium cyanobororhydride (NaCNBH3) 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 hours19. c) The compound of formula (IV) is treated with base such as sodium hydroxide or potassium hydroxide in a solvent like ethanol, methanol, isopropanol or toluene at a temperature in the range of 0° C to 110° C for 30 min to 12 hours to give compound of formula (V). d) The compound of formula (V) is reacted with triphosgene, trichloro ethyl chloroformate or phosgene in the presence of base such as triethylamine, N-ethyl diisopropylamine, potassium carbonate or sodium carbonate in a solvent like tetrahydrofuran, acetonitrile, toluene, I, 4-dioxane or pyridine at a temperature in the range of -30° C to 1 10° C for 1 to 16 hours to give compound of formula (VI) 20. e) 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). f) Alternately, 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).
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)(R2) wherein the Ri & R2 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). h) The compound of formula (VII) is treated with base such as sodium hydroxide or potassium hydroxide in a solvent like ethanol, methanol, isopropanol or toluene at a temperature in the range of 0° C to 110° C for 30 min to 12 hours to obtain the carboxylic acid of formula (VII), which is further treated with 1-hydroxybenzotriazole and l-(3- dimethylaminopropyl)-3-ethyIcarbodiimide hydrochloride (EDCI) or benzotriazol-l-yl- oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) in a solvent such as tetrahydrofuran or dimethylformamide at a temperature from 0° C to 25° C for about 1 hour, further the addition of N-ethyldiisopropylamine and HN(R (R2) at a room temperature for 6 to 20 hours to obtain the compound of formula (I).
Alternately, 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). i) The carboxylic acid of formula (VII) as obtained in method (b) is reacted with alkyl chloroformate or benzyl chloroformate in the presence of base such as triethylamine, N- ethyl diisopropylamine, potassium carbonate or sodium carbonate in a solvent like tetrahydrofuran, acetonitrile, toluene or pyridine at room temperature for a period of 1 to 6 hours to obtain the mixed anhydride of formula (VII) which was further reacted with HN(Ri)(R2) at a temperature in the range of 0° C to 1 10° C for 1 to 6 hours to obtain the compound of formula (I). j) The carboxylic acid of formula (VII) as obtained in method (b) is reacted with thionyl chloride or oxalyl chloride in the presence of catalytic amount of dimethylformamide in a solvent like toluene, dichloromethane or dichloroethane at a temperature in the range of 0° C to 1 10° C for a period of 1 to 6 hours to obtain the carbonyl chloride of formula (VII), which is further treated with HN(Rj)(R2) in presence of base such as triethylamine, N-ethyl diisopropylamine or potassium carbonate in a solvent like tetrahydrofuran, acetonitrile or toluene at a temperature in the range of 0° C to 110° C for 1 to 6 hours to obtain the compound of formula (I).
Compound of formula (I) can also be prepared fom compound of formula (XXX) or formula (XXXIII) by analogus method as described above. Scheme II
Figure imgf000033_0001
In a further embodiment of the present invention, as shown in scheme-II, the compound of formula (II) is prepared by the following methods: a,b) The compound of formula (VIII) wherein, R5 & R6 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). This is further reduced with metal catalyst such as palladium charcoal or platinium oxide under hydrogen (H2) 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. c) The compound of formula (X) in a solvent like ethanol, methanol or isopropanol is reacted with the solution of sodium nitrite in dilute hydrochloric acid in an alcoholic solvent like ethanol, methanol or isopropanol at a temperature in the range of 0° C to 10° C for 30 min to 4 hours to give the diazonium salt of formula (X), which is further reduced with stannous chloride at room temperature for 1 to 10 hours to give the compound of formula of (XI). d,e) The compound of formula (XI) so obtained, is treated with benzophenone in the presence of acid such as p-toluene sulphonic acid or acetic acid in the solvent like toluene or xylene at a temperature- in the range of 60° C to 110° C for 1 to 8 hours to give the hydrazone of formula (XI), which is further treated with I^-acetaldehyde wherein, R4 is as defined earlier, in the presence of anhydrous zinc chloride or p-toluene sulphonic acid in solvent like tetrahydrofuran, dichloroethane, ethanol or isopropanol at a temperature in the range of 60° C to 90° C for 1 to 16 hours to give the compound of formula (XII). Further, this is reacted with dialkyl carbonate such as diethyl carbonate or dimethyl carbonate in the presence of 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. f,g) The compound of formula (XIII) wherein, the R5 & are as defined earlier, is reacted with alkyl azidoacetate 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, tetrahydrofuran, ethanol or butanol under inert atmosphere at the temperature in the range of -50° to 40° C for 1 to 12 h to give the compound of formula (XIV),which is refluxed in a solvent like toluene, xylene, mesitylene, diphenyl ether or dowtherm at a temperature in the range of 1 10° C to 220° C for 1 to 10 hours to give compound of formula (II)23. h) The compound of formula (XV) is treated with tert-butyl pyrrocarbonate (Boc- anhydride) in the presence of base such as sodium hydroxide, potassium carbonate, triethylamine, in the solvent tike 1,4-dioxane, dichloromethane, tetrahydrofuran, acetonitrile or dimethylformamide at room temperature for 1 to 8 hours, which is further treated with alkyl propiolate such as ethyl propiolate or methyl propiolate in the presence of metal catalysts like palladiumbis(triphenylphosphine)dichloride [Pd(PPh3)2Cl2], tetrakis(triphenylphosphine) palladium, Tris(dibenzylideneacetone)dipalladium(0), palladium acetate or palladium dichloride and copper iodide(CuI) with a base such as triethylamine, N-ethyl diisopropylethylamine (DIEA), potassium carbonate or sodium carbonate in a solvents like N, N dimethylformamide, 1,4-dioxane, 1 -methyl -2- pyrrolidinone, ethanol, tetrahydrofuran or acetonitrile at a temperature in the range of 30° C to 150° C for 1 to 16 hours to obtain the compound of formula (XVI). i) The compound of formula (XVI) is treated with tetrabutyl ammonium fluoride at a temperature from 40° to 110° C for 1 to 8 hours to give the compound of formula (II). j,k) The compound of formula (XVII) is treated with (ethoxycarbonylm ethylene) triphenylphosphorane in the solvent like dichloromeihane, dichloroethane or toluene under inert atmosphere at a temperature in the range of 25° C to 110° C for 2 to 12 hours to obtain the compound of formula (XVIII). This is treated with sodium azide in the solvent like N, N-dimethylformamide, dimethyl sulphoxide (DMSO) or 1,4-dioxane at a temperature 25° C to 100° C for 1 to 16 hours to give the product of formula (II). l,m) The compound of formula (XIX) is treated with alkyl haloacetate such as ethyl bromoacetate, tert-butyl bromoacetate in the presence of base such as sodium hydride, potassium carbonate, triethylamine, in the solvent like dichloromethane, tetrahydrofuran, acetonitrile or N, N-dimethylformamide at a temperature from 0° to 90° C for 1 to 16 hours to obtain the compound of formula (XX). This is treated with base such as sodium hydride, sodium ethoxide, sodium methoxide, potassium tert-butoxide or lithium bis(trimethylsilyl)amide in the solvent like ethanol, tetrahydrofuran, butanol or toluene under inert atmosphere, at a temperature in the range of 0° C to 1 10° C for 1 to 12 hours to give the compound of formula (II). The compound of formula (I) can be prepared from the compound of formula (II) by the Scheme I as described above.
Scheme III
Figure imgf000036_0001
In a further embodiment of the present invention, as shown in scheme-Ill, the compound of formula (II) is prepared by the following methods: a,b) The compound of formula (XXI) wherein, the R4, R5 & ¾ 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). c,d) The compound of formula (XXIII) wherein, the R5 & ¾ are as defined earlier, is reacted with alkyl glycinate or benzyl glycinate 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 30° to 110° C for 1 to 12 hours to give the compound of formula (XXIV), which is further treated with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or lithium bis(trimethylsilyl)amide in a solvent like ethanol, methanol, butanol or tetrahydrofuran at a temperature in the range of -20° C to 80° C for 1 to 10 hours to give the compound of formula (II)24. e,f) The solution of compound of formula (XXV) wherein, the R4 & R5 are as defined earlier in the solvent like toluene, tetrahydrofuran, methanol, ethanol, or isopropanol , is reduced with Raney nickel or palladium under hydrogen atmosphere; or cobaltous chloride and sodium borohydride at the temperature in the range of 30° to 1 10° C for 1 to 12 h to give the compound of formula (XXVI), which is further refluxed in the presence of acid such as acetic acid, hydrochloric acid or p-toluene sulphonic acid in a solvent like toluene, xylene or 1 -methyl-2-pyrro]idinone at a temperature in the range of 60° C to 140° C for 1 to 10 hours to give the compound of the formula (II).
The compound of formula (I) can be prepared from the compound of formula (II) by the Scheme I as described above.
Scheme IV
Figure imgf000038_0001
(XXX)
k
g
Figure imgf000038_0002
(XXVII) (XXVI IB)
In a further embodiment of the present invention, as shown in scheme-IV, the compound of formula (XXX) is prepared by the following methods: a,b,c) The solution of compound of formula (XXVII) wherein, the R5 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 oxidized with reagent like potassium permanganate, potassium dicliromate, selenium dioxide or eerie ammonium nitrate in the presence of base such as sodium hydroxide or potassium hydroxide in a solvent like ethanol, methanol or dioxane at a temperature in the range of 30° C to 80° C for 1 to 10 hours to give the compound of formula (XXIX). d) The compound of formula (XXIX) is treated with sulphuric acid or thionyl chloride in a solvent such as ethanol, methanol, butanol or benzyl alcohol at the temperature in the range of 0° to 100° C in the presence of base such as triethylamine for 1 to 6 hours to give the compound of formula (XXX) . e) The solution of compound of formula (XXVIIA) wherein, the R5 or R6 are as defined earlier, is reacted with alkyl glyoxalate such as ethyl glyoxalate 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 compound of formula (XXX)25. f) The solution of compound of formula (XXVII) is reacted with alkyl oxalyl chloride such as ethyl oxalyl chloride, methyl oxalyl chloride or benzyl oxalyl chloride in the presence of base such as potassium carbonate, sodium carbonate, triethylamine or N-ethyl diisopropylamine in the solvent like tetrahydrofuran, acetonitrile or toluene at room temperature for 1 to 8 hours to give the compound of formula (XXVIIB). g) The compound of formula (XXVIIB) is reduced with stannous chloride, zinc or iron in the presence of acid such as hydrochloric acid, acetic acid; or with palladium charcoal under hydrogen atmosphere in a solvent like ethanol, methanol, isopropanol or acetic acid at a temperature in the range of 30° C to 100° C for 1 to 12 hours to give the compound of formula (XXX) 26.
The compound of formula (I) can be prepared from the compound of formula (XXX) by the Scheme I as described above. Scheme V
Figure imgf000040_0001
In a further embodiment of the present invention, as shown in scheme- V, the compound of formula (XXXIII) is prepared by the following methods: a,b) The compound of formula (XXXI) wherein, the R5 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). c) The solution of compound of formula (XXXII) wherein, the R5 or ¾ are as defined earlier, is reacted with hydrazine 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 compound of formula (XXXIII)27.
The compound of formula (I) can be prepared from the compound of formula (XXXIII) by the Scheme I as described above. Scheme VI
Figure imgf000041_0001
Figure imgf000041_0002
In a further embodiment of the present invention, as shown in scheme- VI, the compound of formula (III) is prepared by the following methods: a,b) The compound of formula (XXXIV) wherein, the R5 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 for 1 to 6 hours to give the compound of formula (XXXV). c,d) The compound of formula (XXXV) is treated with a base such as sodium ethoxide, sodium hydrfde, potassium tert-butoxide or lithium bis(trimethylsilyl)amide in a solvent like tetrahydrofuran, acetonitrile, ethanol or toluene at a temperature in the range of -20° C to 100° C for 1 to 12 hours to give N-pyrrole phthalimide derivative. 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). e) The solution of compound of formula (XXXVI) wherein, the R5 or Re are as defined earlier, is reacted with N-amino phthalimide in the presence of base such as triethylamine, potassium carbonate or cesium carbonate in the solvent like toluene, tetrahydrofuran, N, N-dimethylformamide or acetonitrile at the temperature in the range of 0° to 100° C for 1 to 24 hours to give the N-amino phthalimde which is further reacted with alkyl oxalyl chloride such as ethyl oxalyl chloride 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 0° C to 100° C for 1 to 6 hours to give the compound of formula (XXXVIIA). f) The solution of compound of formula (XXXVI) wherein, the R5 or R are as defined earlier, is reacted with alkyl carbazate such as tert-butyl carbazate or methyl carbazate in the solvent like toluene, tetrahydrofuran, N, N-dimethylformamide or acetonitrile at the temperature in the range of 0° to 100° C for 1 to 24 hours to give the compound of formula (XXXVIIB). g) Further, 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. 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). h) Further, 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 1 to 12 hours to give the the compound of formula (III B).
The compound of formula (I) can be prepared from the compound of formula (III A) & (III B) by the Scheme I as described above.
Scheme VII
Figure imgf000043_0001
Figure imgf000043_0002
In an alternate embodiment of the present invention, as shown in scheme-VII, the compounds of formula (I) is prepared by the following methods: a,b) The compound of formula (XXXVIII) wherein, the R4, R5 & ¾ 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 (Et20) or tetrahydrofuran, under inert atmosphere at the temperature in the range of -50° to 60° C for 1 to 12 hours to give the N-amino derivative15, which is further "treated with R3 carboxylic acid wherein the R3 is as defined earlier, and 1 -hydro xybenzotriazole (HOBT), l-(3-dimethyIaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) or benzotriazol-l-yl-oxytris(dimethylamino) phosphonium hexafluorophosphate (BOP) in a solvent such as tetrahydrofuran or N, N-dimethylformamide at a temperature from 0° C to 25° C for about 1 hour, followed by addition of N-ethyldiisopropylamine (DIEA), and is stirred at a room temperature for 6 to 20 hours to give the compound of formula (XXXIX).
In an alternate process, the compound of formula (XXXIX) is prepared by reacting the N- amino derivative of compound of formula (XXXVIII) with R3-carbonyl chloride, R3- anhydride, R3-chloroformate, R3-sulphonyl chloride or R3-halide wherein, the R3 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.
Alternatively, the compound of formula (XXXIX) is prepared by treating the N-amino derivative of compound of formula (XXXVIII) with R3-CHO wherein, R3 is as defined earlier in the presence of reducing reagents such as sodium borohydride, sodium cyanoborohydride (NaCNBH3) 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. c) The compound of formula (XXXIX) is reacted with triethyl methanetricarboxylate in the presence of base such as triethylamine, N-ethyl diisopropylamine, potassium carbonate or sodium carbonate in a solvent like toluene, xylene, mesitylene, l-methyl-2- pyrrolidone or diphenyl ether at a temperature in the range of 60° C to 190° C for 1 to 16 hours to give the compound of formula (VII). d) The solution of compound of formula (XXXIX) is reacted with alkyl malonyl chloride such as ethyl malonyl chloride or methyl malonyl chloride in the presence of base such as triethylamine, N-ethyl diisopropylamine, potassium carbonate or sodium carbonate in a solvent like toluene, xylene, mesitylene or diphenyl ether at a temperature in the range of 60° C to 190° C for 1 to 16 hours to give the compound of formula (XL). e) The solution of compound of formula (XL) is reacted with alkyl chloroformate such ethyl chloroformate or benzyl chloroformate in the presence of base such as triethylamine, N-ethyl diisopropylamine, potassium carbonate or sodium carbonate in a solvent like tetrahydrofuran, acetonitrile, dichloromethane or toluene at a temperature in the range of 30° C to 100° C for 1 to 16 hours, which is further treated with aluminium chloride in a solvent like dichloroethane or toluene at a temperature in the range of 30° C to 100° C for 1 to 12 hours to give the compound of formula (VII).
The compound of formula (I) can be prepared from the compound of formula (VII) by the SchemeT, as described above. i) The compound of formula (I) can be prepared by reacting the solution of the compound of formula (XL) with Ri-NCO, wherein, ¾ 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. 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.
The 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.
The 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.
Example 1:
N-f(4-hvdroxy-l-methyl-2-oxo-l,2-dihvdropyridazino[l,6-alindol-3-yl)carbonyll alanine (Compound no. 12)
Figure imgf000046_0001
Step A: Preparation of Ethyl 1 -amino- lH-indole-2-carboxylate
To the solution of Ethyl- lH-Indole-2-carboxylate (36 g, 190.4 mmol) in N, N- dimethylformamide (500 ml), sodium hydride (15.2 g, 380.8 mmol) was added under inert atmosphere at room temperature and stirred for 1 h. The solution of monochlorar ine in diethyl ether (3%, 3 lit.) [prepared by reacting the aqueous solution of sodium hypochlorite (12%, 1.08 1, 1.73 mol) with the solution of ammonium chloride (108 g, 2 mol) & ammonium hydroxide (35%, 180 ml, 1.8 mol) in diethyl ether (4 lit) at -10° - 0° C for 30 min], (3%, 3 lit.) was added dropwise to the reaction mixture and stirred for 1 h ..Then it was treated with solution of sodium thiosulphate (472g, 1.9 mol) in water (1 lit.). The reaction mixture was partitioned between water and diethyl ether (4 x 500 ml). The combined organic layer was washed with water (200 ml x 2) and dried over, anhydrous sodium sulphate, evaporated under vacuo to afford the titled compound (42 g) as yellow oil. The crude product was used in the next step without purification.
Ή NMR (400 MHz, CDC13) δ :1.32 -1.35 (3H, t), 4.25 - 4.35 (2H, q), 5.26 (2H, s), 7.00 - 7.07 (1H, dd), 7.09 (1H, s), 7.11 - 7.17 (1H, dd), 7.22 - 7.29 (1H, m), 7.53 -7.56 (1H, dd). m/z = 205 (M+H)+
Step B: Preparation of Ethyl l-["(trifluoroacetyl) aminol-lH-indole-2-carboxylate
To the solution of 41 g (201 mmol) of the product of Step A in dichloromethane (400 ml), the triethylamine (87 ml, 603 mmol) was added at 0° - 10° C and stirred for 30 min. Then the solution of trifluoroacetic anhydride (42.2 ml, 301.5 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 10 h. After completion of reaction, the mixture was diluted with water (100 ml) and pH was neutralized using sodium bicarbonate solution and partitioned between water and dichloromethane (3 x 500 ml). The combined organic layers was dried over anliydrous sodium sulphate and evaporated under vacuo to afford the titled compound (42 g) as yellow oil. The crude product was used in the next step without purification. lH NMR (400 MHz, DMSOd6) δ : 1.1 1 -1.18 (3H, t), 4.25 - 4.28 (2H, q), 7.06 - 7.15 (lH, m), 7.16 - 7.17 (lH, d) 7.29 - 7.3 (1H, m), 7.4 - 7.6 (1H, m).
m/z = 299 (M -H)+1
Step C: Preparation of Ethyl 1- ["methyl (trifluoroacetyl) amino]- lH-indole-2-carboxylate
To the solution of 41 g (136.6 mmol) of the product of Step B in acetonitrile (200 ml), the potassium carbonate (56.6g, 409.5 mmol) was added at 0° -10° C and stirred for 30 min. Then the solution of iodomethane (25.5 ml, 410 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 10 h. After completion of reaction, the mixture was diluted with water (200 ml) and partitioned between water and ethyl acetate (3 x 300 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (37.2 g) as brown oil. The crude product was used in the next step without purification.
]H NMR (400 MHz, DMSOd6) δ: 1.28 - 1.33 (3H, t), 3.25 (3H, s), 4.30 - 4.36 (2H, q), 7.29 - 7.33 (1H, t), 7.49 - 7.54 (2H, t), 7.55 (1H, s), 7.65 - 7.67 (1H, d), 7.79 -7.81 (1H, d).
m/z = 315 (M-H)+
Step D: Preparation of Ethyl l-(methylamino)-lH-indo]e-2-carboxylate
To the solution of 36 g (1 14.6 rnmol) of the product of Step C in ethanol (150 ml), the sodium ethoxide (11.7 g, 171.9 mmol) was added at 10° C - 20° C and stirred for 5 h. After completion of reaction, the mixture was diluted with water (100 ml) and concentrated under vacuo. Then it was partitioned between water and ethyl acetate (3 x 300 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column cliromatography on silica gel using 5% ethyl acetate in hexane as the eluent to provide the titled compound (22.8 g) as yellow solid. !H NMR (400 MHz, DMSOd6) δ : 1.31 - 1.35 (3H, t), 2.71 - 2.72 (3H, d), 4.29 -4.38 (2H, q), 6.38 - 6.42 (1H, q), 7.10 - 7.16 (1H, t), 7.21 (1H, s), 7.32 - 7.36 (1H, t), 7.53 -7.56 (1H, d), 7.65 - 7.69 (1H, d).
m/z = 219 (M-H)+
Step E; Preparation of l-(MethylaminoVlH-indole-2-carboxylic acid
To the solution of 22 g (100.9 mmol) of the product of Step D in ethanol (200 ml), the solution of potassium hydroxide (56 g, lmol) was added in water (200 ml) and refluxed for 8 h. After completion of reaction, the mixture volume was reduced under vacuo and pH was adjusted to 6 using dilute hydrochloric acid. The solid thus obtained was filtered, washed with water (50 ml x 2) and dried under vacuo at 60° C for 4 h to provide the titled compound (16.4 g) as a white solid.
Ή NMR (400 MHz, DMSOd6) δ : 2.72 (3H, s), 7.13 - 7.14 (lH, t), 7.16 (lH, s), 7.35 - 7.38 (1H, t), 7.52 - 7.54 (1H, d), 7.64 - 7.66 (2H, d), 11.76 (1H, s).
m/z = 191 (M-H)+
Step F: Preparation of l-Methyl-4H-[1.3.41oxadiazinor4.5-a|indole-2.4(l H)-dione
To the solution of 16 g (84.2 mmol) of the product of Step E in 1, 4-dioxane (100 ml), the triphosgene (24.9 g, 84.1 mmol) was added at room temperature and stirred for 10 h. After completion of reaction, the mixture was diluted with water (50 ml) and pH was neutralized using sodium bicarbonate solution and partitioned between water and ethyl acetate (3 x 200 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (14.6 g) as brown oil. The crude product was used in the next step without purification.
1H NMR (400 MHz, DMSOd6) 5 : 2.72 (3H, s), 7.13 - 7.14 (1H, t), 7.16 (1H, s), 7.35 - 7.38 (1H, t), 7.52 - 7.54 (1H, d), 7.64 - 7.66 (1H, d), 11.76 (1H, s).
m/z = 217 (M+H)+ Step G; Preparation of Ethyl 4-hvdroxy-l-methyl-2-oxo-l. 2-dihyro-pyridazino IT, 6-al indole-3-carboxylate
To the solution of diethyl malonate (103.6 g, 647.5 mmol) in N, N-dimethylaeetamide (50 ml), the sodium hydride (5.2 g, 129.6 mmol) was added portionwise under inert atmosphere at room temperature and stirred for 30 min. Then the solution of 14 g (64.8 mmol) of the product of Step F in N,N-dimethylacetamide (50 ml) was added dropwise to the reaction mixture and was heated to 120° C for 12 h. After completion of reaction, the mixture was diluted with water (50 ml) and pH was neutralized using dilute hydrochloric acid and partitioned between water and ethyl acetate (3 x 300 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo The residue was purified by column chromatography on silica gel using 2 -5% ethyl acetate in hexane as the eluent to provide the titled compound (6.6 g) as brown solid.
Ή NMR (400 MHz, DMSOd6) δ : 1.17 - 1.21 (3H, t), 3.59 (3H, s), 4.02 - 4.07 (2H, q), 6.67 (1H, s), 7.05 - 7.09 (1H, t), 7.16 - 7.19 (1H, t), 7.63 - 7.65 (1H, d), 7.68 - 7.70 (2H, d).
m/z = 285 (M-H)+
Step H : Preparation of Ethyl - N-r(4-hvdroxy-l-methyl-2-oxo-l, 2-dihydropyridazino fl . 6-a] indol-3-yl carbonyI1alaninate
To the solution of 1 g (3.5 mmol) of the product of Step G in toluene (40 ml) and triethylamine (1.5 ml, 10.5 mmol), alanine ethyl ester.HCl (0.9 g, 7 mmol) was added and refluxed for 3 h. After completion of reaction, the mixture was diluted with water (20 ml) and partitioned between water and ethyl acetate (3 x 50 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 2-5% ethyl ' acetate in dichloromethane as the eluent to provide the titled compound (0.8 g) as colourless solid. ]H NMR (400 MHz, DMSOd6) δ : 1.45 - 1.47 (3H, d), 3.71 (3H, s), 4.12 (3H, s), 4.59 - 4.66 (1H, m), 7.24 - 7.28 (2H, m), 7.36 - 7.39 (1H, t), 7.83- 7.85 (1H, d), 8.14 (1H, d), 10.29 (lH, bs).
rn/z = 344 (M+H)+
Step I: Preparation of N-r(4-hvdroxy-l-methyl-2-oxo-l,2-dihydropyridazino[1.6-a]mdol- 3-yl)carbonvnalanine
To the solution of 0.2 g (0.5 mmol) of product of Step H, in ethanol (10 ml), the solution of sodium hydroxide (0.04 g, 1 mmol) in water was added at room temperature and stirred for 4 h. After completion of reaction, the mixture was diluted with water (30 ml) and pH was adjusted to 2 using dilute hydrochloric acid and the reaction volume was reduced under vacuo. The solid thus obtained was filtered, washed with water (2 x 20 ml) and dried under vacuo at 60° C for 5 h to afford the titled compound (0.07g) as colourless solid. lH NMR (400 MHz, DMSOd6) δ : 1.45 - 1.47 (3H, d), 4.13 (3H, s), 4.51 - 4.54 (1H, d), 7.25 - 7.29 (2H, m), 7.36 - 7.38 (1H, t), 7.84 - 7.86 (1H, d), 8.15 - 8.17 (1H, d), 10.30 (111, bs).
m/z = 330 (M+H)+ Example 2: l-|(4-Hvdroxy-l-methyl-2-oxo-l,2-dihvdropyridazino[l ,6-fllindol-3-yl)carbonyl1 piperidine-4-carboxyIic acid (Compound no. 33)
Figure imgf000051_0001
Figure imgf000052_0001
a]indol-3-yl)carbonynpiperidine-4-carboxylate
To the solution of 0.2 g (0.69 mmol) of the product of Step G of example 1, in toluene (10 ml) containing triethylamine (0.3 ml, 2.09 mmol), the ethyl isonipecotate (0.3 g, 1.33 mmol) was added and refluxed for 3 h. After completion of reaction, the mixture was diluted with water (20 ml) and partitioned between water and ethyl acetate (2 x 50 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 80% ethyl acetate in hexane as the eluent to provide the titled compound (0.15 g) as yellow solid.
1H NMR (400 MHz, DMSOd6) δ : 1.18 - 1.20 (3H, t), 1.66 - 1.70 (2H, m), 1.91 - 1.92 (2H, m), 2.51 (3H, s), 2.85 - 2.88 (1H, m), 3.09 - 3.10 (2H, m), 3.12 - 3.17 (2H, m), 4.05 - 4.07 (2H, q), 7.0 - 7.1 (1H, t), 7.15 - 7.16 (2H, m), 7.23 - 7.27 (2H, m).
m/z = 396 (M-H)+
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
To the solution of 0.15 g (0.37 mmol) of the product of Step A of example 2, in ethanol (10 ml), the solution of sodium hydroxide (0.1 g, 1 mmol) in water was added at room temperature and stirred for 1 h. After completion of reaction, the mixture was diluted with water (30 ml) and pH was adjusted to 2 using dilute hydrochloric acid and the reaction volume was reduced under vacuo. The solid thus obtained was filtered, washed with water (2 x 25 ml) and dried under vacuo at 60° C for 5 h to afford the titled compound (0.1 g) as brown solid.
1H NMR (400 MHz, DMSOd6) δ : 1.49 - 1.54 (2H, m), 1.82 - 1.85 (2H, m), 2.98 - 3.1 (4H, m), 4.02 (4H, s), 7.16 (lH, s), 7.19 - 7.23 (1H, t), 7.28 - 7.31 (1H, t), 7.78 - 7.80 (1H, d), 8.05 - 8.07 (1H, d), 12.30 (1H, s).
m/z = 368 (M-H)+ Example 3:
4-ir 4-hvdroxy-l-methvI-2-oxo-l,2-dihydropyridazinofl,6-fl1indol-3-yl)carbonyll amino} cyclohexanecarboxylic acid (Compound no. 22)
Figure imgf000053_0001
Step A : Preparation of Ethyl 4- { r(4-hydroxy-l-methyl-2-oxo-1.2-dihydropyridazino l,6-a]indol-3-yl)carbonyllamino|cyclohexanecarboxylate . ■
To the solution of 0.4 g (1.39 mmol) of the product of Step G of example 1 in toluene (10 ml) containing triethylamine (0.8 ml, 2.79 mmol), the ethyl-4-amino cyclohexyl carboxylate (0.3 g, 1.7 mmol) was added and refluxed for 3 h. After completion of reaction, the mixture was diluted with water (20 ml) and partitioned between water and ethyl acetate (2 x 50 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 70% ethyl acetate in hexane as the eluent to provide the titled compound (0.15 g) as yellow solid.
Ή NMR (400 MHz, DMSOd6) δ : 1.18 - 1.22 (3H, t), 1.7 - 1.74 (8H, m), 4.0 - 4.12 (5H, m), 7.24 - 7.31 (2H, m), 7.34 - 7.38 (1H, t), 7.83 - 7.85 (1H, d), 8.13 - 8.15 (lH, d), 10.19 (lH, s).
m/z = 412 (M+H)+ - '
Step B : Preparation of 4-{ r(4-Hydroxy-l-methyl-2-oxo-1.2-dihydropyridazino 1.6- fl]indol-3-yl)carbonvnamino)cyclohexanecarboxylic acid
To the solution of 0.15 g (0.36 mmol) of the product of Step A of example 3 in ethanol (10 ml), the solution of sodium hydroxide (0.03 g, 0.72 mmol) in water was added at room temperature and stirred for 10 h. After completion of reaction, the mixture was diluted with water (20 ml) and pH was adjusted to 2 using dilute hydrochloric acid and the reaction volume was reduced under vacuo. The solid thus obtained was filtered, washed with water (2 x 25 ml) and dried under vacuo at 60° C for 5 h to afford the titled compound (0.07 g) as yellow solid.
1H NMR (400 MHz, DMSOd6) 8 : 1.72 (8H, m), 2.43 (1H, m), 4.12 (4H, m), 7.26 - 7.36 (3H, m), 7.83 (1H, m), 8.13 (1H, m), 10.2 (1H, s), 12.23 (1H, s).
m/z = 382 (M-H)+
Example 4:
N-f(4-hvdroxy-l-methyl-2-oxo-l,2-dihvdropyridazinofl,6-fllindoI-3-yl)carbonyll serine (Compound no. 23)
Figure imgf000054_0001
Step A : Preparation of Methyl N-[Y4-hydroxy-l-methyI-2-oxo-1.2-dihydropyridazino ri,6-alindol-3-yl)carbonynserinate
To the solution of 0.4 g (1.39 mmol) of the product of Step G of example 1 in toluene (10 ml) containing triethylamine (0.8 ml, 2.79 mmol), the L-serine methylester (0.4 g, 2.79 mmol) was added and refluxed for 3 h. After completion of reaction, the mixture was diluted with water (20 ml) and partitioned between water and ethyl acetate (2 x 50 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 70% ethyl acetate in hexane as the eluent to provide the titled compound (0. 07g) as brown solid. *H NM (400 MHz, DMSOd6) δ : 3.71 (3H, s), 3.73 - 3.76 (1H, m), 3.86 - 3.93 (1H, m), 4.13 (3H, s), 4.66 - 4.68 (1H, m), 5.40 (1H, m), 7.15 - 7.27 (2H, m), 7.36 - 7.40 (1H, t), 7.80 - 7.82 (1H, d), 8.1 1 - 8.13 (1H, d), 10.48 (1H, bs).
m/z = 358 (M-H)+
Step 8 : Preparation of N-[(4-hvdroxy-l-methyl-2-oxo-l ,2-dihvdropyridazinofL6- Q indol-3-yl)carbonyllserine
To the solution of 0.07 g (0.19 mmol) of the product of Step A of example 4 in ethanol (10 ml), the solution of sodium hydroxide (0.02 g, 0.38 mmol) in water was added at room temperature and stirred for 10 h. After completion of reaction, the mixture was diluted with water (20 ml) and pH was adjusted to 2 using dilute hydrochloric acid and the reaction volume was reduced under vacuo. The solid thus obtained was filtered, washed with water (2 x 25 ml) and dried under vacuo at 60° C for 5 h to afford the titled compound (0.05 g) as colourless solid.
Ή NMR (400 MHz, DMSOd6) δ : 3.69 - 3.72 (1H, m), 3.85 - 3.87 (1H, m), 4.04 (3H, s)5 4.45 _ 4.65 (1H, m), 7.18 (2H, m), 7.32 - 7.36 (1H, t), 7.74 - 7.82 (1H, d), 8.0 - 8.13 (2H, d), 10.48 (lH, bs).
m/z = 344 (M+H)+
Example 5:
N-i(4- vdroxy-l,8-dimethyI-2-oxo-2,5,6,7-tetrahydro-lH-cvcIopentaf3,4]pyrrolo
[l,2-blpyridazin-3-yl carbonyllgIycine (Compound no. 1)
Figure imgf000055_0001
Step A : Ethyl-3-methyl-2.4.5.6-tetrahvdrocvclopentarc1pyrrole-l-carboxylate
To the solution 2-acetyl cyclopentanone (25 g, 198 mmol) in ethanol (400 ml) containing triethylamine (28 ml, 198 mmol), the ethyl glycinate hydrochloride (28 g, 198 mmol) was added at room temperature and stirred for 14 h. After completion of reaction, the reaction volume was reduced under vacuo and then diluted with water (100 ml) and partitioned between water and dichloromethane (3 x 200 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to gave ethyl-N-[l-(2- oxocyclopentyl) ethylidene] glycinate (42 g) as a red oil.
To the solution of 42 g (199 mmol) of the above crude product in ethanol (400 ml), the sodium ethoxide (27 g, 398 mmol) was added and was refluxed for 4 h. After completion of reaction, the reaction volume was reduced under vacuo and then diluted with water (200 ml), the solid thus obtained was filtered, washed with water (2 x 25 ml) and dried under vacuo at 60° C for 5 h to afford the titled compound (14 g) as colourless solid.
1H NMR (400 MHz, DMSOdg) δ : 1.22 - 1.25 (3H, t), 2.1 1 (3H, s), 2.21 - 2.23 (2H, m), 2.24 - 2.26 (2H, t), 2.65 - 2.68 (2H, t), 4.1 1 - 4.17 (2H, q), 10.96 (1H, s).
m/z = 194 (M+H)+
Step B: Preparation of Ethyl 2-amino-3-rnethyl-2, 4, 5, 6-tetrahydrocyclopenta|~c1pyrrol- 1 -carboxylate
To the solution of 10 g (51.8 mmol) of the product of step A in N, N-dimethylformamide (100 ml), the sodium hydride (4.16 g, 104 mmol) was added under inert atmosphere at room temperature and stirred for lh. Then the solution of monochloramine (prepared as in example 1, Step A) in diethyl ether (3%, 900 ml) was added dropwise to reaction mixture and stirred for 1 h, which was further treated with solution of sodium thiosulphate (141 g, 571 mmol) in water (700 ml). The reaction mixture was partitioned between water and diethyl ether (3 x 300 ml). The combined organic layer was washed with water (100 ml x 2) and dried over anhydrous sodium sulphate, evaporated under vacuo to afford the titled compound (12 g) as yellow oil. The crude product was used in the next step without purification.
1H NMR (400 MHz, CDC13) 5 : 1.22 - 1.26 (3H, t), 2.11 (3H, s), 2.13 - 2.20 (2H, m), 2.47 - 2.51 (2H, t), 2.68 - 2.72 (2H, t), 4.12 - 4.18 (2H, q), 5.95 (2H, s).
m/z = 209 (M+H)+
Step C: Preparation of Ethyl 3-methyl-2-r(trifiuoroacetyl) aminol-2, 4. 5, 6- tetrahvdrocvclopenta[~c|pyrrol-l-carboxylate
To the solution of 11 g (52.8 mmol) of the product of Step B of example 5 in dichloromethane (100 ml), the triethylamine (15.28 ml, 105.7 mmol) was added at 0° - 10°C and stirred for 30 min. Then the solution of trifluoroacetic anhydride (1 1.4 ml, 79.3 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 10 h. After completion of reaction, the mixture was diluted with water (50 ml) and pH was neutralized using sodium bicarbonate solution and partitioned between water and dichloromethane (3 x 200 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (12.8 g) as yellow oil. The crude product was used in the next step without purification.
!H NMR (400 MHz, DMSOd6) δ : 1.20 - 1.26 (3H, t), 2.1 1 (3H, s), 2.18 - 2.25 (2H, m), 2.53 - 2.57 (2H, t), 2.68 - 2.78 (2H, t), 4.12 - 4.18 (2H, q), 12.68 (1H, s).
m/z = 303 (M-H)+
Step D: Preparation of Ethyl 3 -methyl-2- [methyl (trifluoroacetyl amino]-2, 4, 5, 6- tetrahydrocyclopentafclpyrrole- 1 -carboxylate
To the solution of 12 g (39.4 mmol) of the product of Step C of example 5 in acetonitrile (100 ml), the potassium carbonate (13.6 g, 98.6 mmol) was added at 0° -10° C and stirred for 30 min. Then the solution of iodomethane (7.5 ml, 1 18.4 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 10 h. After completion of reaction, the mixture was diluted with water (50 ml) and partitioned between water and ethyl acetate (3 x 200 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (12.8 g) as brown oil. The crude product was used in the next step without purification.
1H NMR (400 MHz, DMSOd6) δ : 1.20 - 1.26 (3H, t), 2.11 (3H, s), 2.19 - 2.26 (2H, m), 2.54 - 2.57 (2H, t), 2.65 - 2.73 (2H, t), 4.06 (3H, s), 4.12 - 4.18 (2H, q)..
m/z = 319 (M+H)+
Step E: Preparation of Ethyl 3-methyl-2-(methylamino)-2, 4, 5, 6-tetrahvdrocyclopertta [clpyrrole- 1 -carboxylate
To the solution of 12 g (37.7 mmol) of the product of Step D of example 5 in ethanol (50 ml), the sodium ethoxide (5.13 g, 75.4 mmol) was added at 10° C - 20° C and stirred for 5 h. After completion of reaction, the mixture was diluted with water (100 ml) and concentrated under vacuo. Then it was partitioned between water and ethyl acetate (3 x 200 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo, the residue was purified by column chromatography on silica gel using 5% ethyl acetate in hexane as the eluent to provide the titled compound (9.8 g) as colourless solid.
JH NMR (400 MHz, DMSO-d6) 5 : 1.23 - 1.26 (3H, t), 2.12 (3H, s), 2.15 - 2.21 (2H, m), 2.50 - 2.51 (3H, d), 2.58 - 2.60 (2H, t), 3.29. - 3.36 (2H, t), 4.14 - 4.22 (2H, q), 6.12 - 6.16 (1H, q).
m/z = 223 (M+H)+
Step F: Preparation of 3-Methyl-2-(methylamino)-2, 4, 5. 6-tetrahvdro cyclopenta \c] pyrrole- 1-carboxylic acid
To the solution of 9.5 g (42.7 mmol) of the product of Step E of example 5 in ethanol (100 ml), the solution of potassium hydroxide (24 g, 427.9 mmol) was added in water (100 ml) and refluxed for 8 h. After completion of reaction, the mixture volume was reduced under vacuo and pH was adjusted to 6 using dilute hydrochloric acid. The solid thus obtained was filtered, washed with water (50 ml x 2) and dried under vacuo at 60° C for 4 h to provide the titled compound (6.4 g) as a white solid. lE NMR (400 MHz, DMSOd6) δ : 2.13 (3H, s), 2.15 - 2.20 (3H, m), 2.47 - 2.49 (2H, t),
2.57 (3H, s), 2.68 - 2.71 (2H, t), 6.69 (1H, s), 12.05 (lH, s).
m/z = 193 (M-H)+
Step G : Preparation of 1.8-Dimethyl-6J-dihvdrocvclopentar3.41pyrrolori.2-d1 Γ13.41 oxadiazine-2,4( 1 H, 5H)-dione
To the solution of 6 g (30.9 mmol) of the product of Step F of example 5. in 1, 4-dioxane (50 ml), the triphosgene (13.74 g, 46.3 mmol) was added at room temperature and stirred for 10 h. After completion of reaction, the mixture was diluted with water (50 ml) and pH was neutralized using sodium bicarbonate solution and partitioned between water and ethyl acetate (3 x 100 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (7.6 g) as brown oil. The crude product was used in the next step without purification. 'H MR (400 MHz, DMSO-d6) δ : 2.13 (3H, s), 2.15 - 2.20 (3H, m), 2.47 - 2.50 (2H, t), 2.60 - 2.63 (2H, t), 6.69 (1H, s).
m/z = 221 (M+H)+
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.
To the solution of diethyl malonate (51 g, 318.2 mmol) in N, N-dimethylacetamide (10 ml), the sodium hydride (2.54 g, 63.6 mmol) was added portionwise under inert atmosphere at room temperature and stirred for 30 min. Then the solution of 7 g (31.8 mmol) of the product of Step G of example 5 in N, N-dimethylacetamide (10 ml) was added dropwise to the reaction mixture and was heated to 120° C for 12 h. After completion of reaction, the mixture was diluted with water (50 ml) and pH was neutralized using dilute hydrochloric acid and partitioned between water and ethyl acetate (3 x 200 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo The residue was purified by column chromatography on silica gel using 2 -5% ethyl acetate in hexane as the eluent to provide the titled compound (4.6 g) as colourless solid. lH NMR (400 MHz, DMSOd6) 8 : 126 - 1.29 (3H, t), 2.29 - 2.33 (2H, m), 2.47 (3H, s), 2.61 - 2.64 (2H, t), 2.84 - 2.88 (2H, t), 3.62 (3H, s), 4.28 - 4.32 (2H, q), 13.69 (1H, s). m/z = 291 (M+H)+
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
To the solution of 4 g (13.7 mmol) of the product of Step H of example 5 in toluene (40 ml) containing triethylamine (9ml, 41.9 mmol), the glycine ethyl ester.HCl (6 g, 27.9 mmol) was added and refluxed for 3 h. After completion of reaction, the mixture was diluted with water (50 ml) and partitioned between water and ethyl acetate (3 x 100 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 2 - 5% ethyl acetate in dichloromethane as the eluent to provide the titled compound (3.7 g) as colourless solid.
Ή NMR (400 MHz, DMSOd6) 5 : 1.19 - 1.23 (3H, t), 2.26 - 2.33 (2H, m), 2.53 (3H, s), 2.62 - 2.65 (2H, t), 2.85 - 2.89 (2H, t), 3.76 (3H, s), 4.1 1 - 4.16 (4H, m), 9.94 - 9.97 (lH, t).
m/z - 348 (M+H)+
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
To the solution of 3.5 g (10.1 mmol) Step I of example 5 in ethanol (30 ml), the solution of sodium hydroxide (0.8 g, 20.1 mmol) in water was added at room temperature and stirred for 4 h. After completion of reaction, the mixture was diluted with water (50 ml) and pH was adjusted to 2 using dilute hydrochloric acid and the reaction volume was reduced under vacuo. The solid thus obtained was filtered, washed with water (2 x 25 ml) and dried under vacuo at 60° C for 5 h to afford the titled compound (1.6 g) as colourless solid.
1H NM (400 MHz, DMSOd6) δ : 2.26 - 2.33 (2H, m), 2.52 (3H, s), 2.61 - 2.65 (2H, t), 2.85 - 2.88 (2H, t), 3.76 (3H, s), 4.05 - 4.06 (2H, d), 9.92 - 9.95 (1H, t), 12.98 (1H, s). m/z = 318 (M-H)+
Example 6:
Preparation of N-{f4-hvdroxy-l,5,7-trimethyl-6-(morpholin-4-vI)-2-oxo-l,2- dihydropyrrolo [l,2-b]pyridazin-3-yllcarbonyl)glycine (Compound no. 8)
Figure imgf000061_0001
Step A : Preparation of 3-(Morpholin-4-yl pentane-2.4-dione
To the solution of morpholine (15 g, 172 mmol) in dichloromethane containing triethylamine (50 ml, 344 mmol), the 3-chloro-2,4-pentanedione (25 ml, 2.6 mmol) was added dropwise at room temperature and stirred for 8 h. After completion of reaction, the mixture was diluted with water (100 ml) and partitioned between water and ethyl acetate (3 x 200 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 30% ethyl acetate in hexane as the eluent to provide the titled compound (17 g) as colourless oil. *H NMR (400 MHz, CDC13) δ : 2.15 - 2.16 (6H, s), 2.57 - 2.60 (2H, m), 2.82 - 2.85 (2H, m), 3.55 - 3.58 (2H, m), 3.60 - 3.62 (2H, m), 4.31 (1H, s).
m/z = 186 (M+H)+
Step B : Preparation of Ethyl-3, 5-dimethyl-4-(morpholin-4-vn-lH-pyrrole-2-carboxylate
To the solution of 17 g (91.8 mmol) of the product of Step A of example 6 in ethanol (100 ml) containing triethylamine (26.5 ml, 183.6 mmol), the ethyl glycinate (19.2 g, 137.7 mmol) was added at room temperature and stirred for 10 h. After completion of reaction, the mixture was diluted with water (100 ml) and the volume was reduced under vacuo. Then it was partitioned between water and ethyl acetate (3 x 200 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the Ethyl-N-[3-(morpholin-4-yl)-4-oxopentan-2-y]jdene]glycinate (25 g) as a brown oil.
!H NMR (400 MHz, CDC13) δ : 1.22 - 1.23 (3H, t), 1.24 (6H, s), 3.5 (4H, m), 3.78 (4H, m), 4.15 - 4.17 (2H, q).
m/z = 271 (M+H)+
To the solution of above said crude product (25 g, 92.5 mmol), sodium metal (4.26 g, 185 mmol) in ethanol was added and refluxed for 4 h. After completion of reaction, the mixture was diluted with water (200 ml) and reduced the volume under vacuo. Then it was partitioned between water and ethyl acetate (3 x 300 ml). The combined organic , layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 20% ethyl acetate in hexane as the eluent to provide the titled compound (10 g) as brown solid.
1H NMR (400 MHz, CDC13) δ : 1.2 - 1.28 (3H, t), 2.9 (6H, s), 2.87 - 2.89 (4H, m), 3.62 - 3.64 (4H, m), 4.15 - 4.21 (2H, q), 10.97 (lH, s). \ m/z = 253 (M+H)+ Step C : Preparation of Ethyl l-amino-3, 5-dimethyl-4-rmorpholin-4-yl lH-pyrrol-2- carboxylate
To the solution of 10 g (39.6 mmol) of the product of Step B of example 6 in N, N- dimethylformamide (100 ml), the sodium hydride (3.17 g, 79.3 mmol) was added under inert atmosphere at room temperature and stirred for 1 h. Then the solution of monochloramine (prepared as in Step A of example 1) in diethyl ether (3%, 900 ml) was added dropwise to reaction mixture and stirred for 1 h, which was further treated with solution of sodium thiosulphate (141 g, 541 mmol) in water (700 ml). The reaction mixture was partitioned between water and diethyl ether (3 x 200 ml). The combined organic layer was washed with water (100 ml x 2) and dried over anhydrous sodium sulphate, evaporated under vacuo to afford the titled compound (12 g) as yellow oil. The crude product was used in the next step without purification.
]H NMR (400 MHz, CDC13) δ : 1.23 - 1.29 (3H, t), 2.19 (3H, s), 2.21 (3H, s), 2.50- 2.53 (4H, m), 2.87 - 2.89 (4H, m), 4.19 - 4.24 (2H, q), 6.26 - 6.30 (1H, m).
m/z = 268 (M+H)+
Step D: Preparation of Ethyl 3, 5-dimethyl-4-('moφholin-4-yl -l -|"(trif]υoroacetvΠ aminol-lH-pyrrol-2-carboxylate
To the solution of 11 g (41.2 mmol) of the product of Step C of example 6 in dichloromethane (100 ml), the triethylamine (17.86 ml, 123.5 mmol) was added at 0° - 10°C and stirred for 30 min. Then the solution of trifluoroacetic anhydride (11.53 ml 82.3 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 10 h. After completion of reaction, the mixture was diluted with water (50 ml) and pH was neutralized using sodium bicarbonate solution and partitioned between water and dichloromethane (3 x 200 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (12.4 g) as yellow oil. The crude product was used in the next step without purification. 'H NMR (400 MHz, DMSOdg) δ : 1.12 - 1.18 (3H, t), 2.5 (3H, s), 2.86 (4H, m),3.3 (3H, s), 3.6 (4H, rn), 4.00 - 4.06 (2H, q).
mix = 364 (M+H)+
Step E: Preparation of Ethyl 3, 5-dimethyl-l -[methyl (trifluoroacetyl) aminol- 4- (morpholin-4-yl)- 1 H-pyrroIe-2-carboxylate
To the solution of 12 g (33.2 mmol) of the product of Step D of example 6 in acetonitrile (100 ml), the potassium carbonate (13.78 g, 99.7 mmol) was added at 0° -10° C and stirred for 30 min. Then the solution of iodomethane (6.5 ml, 99.7 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 10 h. After completion of reaction, the mixture was diluted with water (50 ml) and partitioned between water and ethyl acetate (3 x 200 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (1 1.8 g) as brown oil. The crude product was used in the next step without purification.
'H NMR (400 MHz, DMSOd6) δ : 1.19 - 1.23 (3H, t), 2.03 (3H, s), 2.14 (3H, s), 2.28 (3H, s), 2.52 - 2.57 (4H, m) 3.66 - 3.70 (4H, m), 4.04 - 4.1 (2H, q).
m/z = 378 (M+H)+
Step F: Preparation of Ethyl 3. 5-dimethyl-l-fmethylamino)- 4-fmorpholin-4-yl)-lH- pyrrole-2-carboxylate
To the solution of 11 g (29.1 mmol) of the product of Step E of example 6 in ethanol (50 ml), the sodium ethoxide (4.4 g, 64.1 mmol) was added at 10° C - 20° C and stirred for 5 h. After completion of reaction, the mixture was diluted with water (100 ml) and concentrated under vacuo. Then it was partitioned between water and ethyl acetate (3 x 200 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 5% ethyl acetate in hexane as the eluent to provide the titled compound (9.4 g) as colourless oil. JH NMR (400 MHz, DMSO-d6) δ : 1.26 - 1.29 (3H, t), 2.19 (3H, s), 2.21 (3H, s), 2.51 - 2.52 (3H, d), 2.87 - 2.89 (4H, t), 3.62 - 3.64 (4H, t), 4.19 - 4.24 (2H, q), 6.26 - 6.30 (1H, q)
m/z = 282 (M+H)+
Step G; Preparation of 3, 5 -Dimethyl- l-(methylamino) - 4-fmorpholin-4-ylVlH-pyrrole- 2-carboxylic acid
To the solution of 4.9 g (32 mmol) of the product of Step F of example 6 in ethanol (100 ml), the solution of potassium hydroxide (18 g, 320.3 mmol) in water (100 ml) was added and refluxed for 8 h. After completion of reaction, the mixture volume was reduced under vacuo and pH was adjusted to 6 using dilute hydrochloric acid. The solid thus obtained was filtered, washed with water (50 ml x 2) and dried under vacuo at 60° C for 4 h to provide the titled compound (5.8 g) as a brown solid.
!H NMR (400 MHz, DMSOd6) 5 : 1.10 (6H, m), 1.34 - 1.42 (4H, m), 2.18 (4H, m), 3.44
(3H, s). .
m/z = 253 (M-H)+
Step H : Preparation of 1.5,7-Τπιηέΐ1ΐν1-6-^οφΐΊθΗη-4-ν1)-4Η-ρνΓΓο]οΓ1.2-ά1 fl .3,4] oxadiazine-2,4(l HVdione
To the solution of 5.5 g (21.7 mmol) of the product of Step G of example 6 in 1, 4- dioxane (50 ml), the triphosgene (8.5 g, 32.6 mmol) was added at room temperature and stirred for 10 h. After completion of reaction, the mixture was diluted with water (50 ml) and pH was neutralized using sodium bicarbonate solution and partitioned between water and ethyl acetate (3 x 200 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (4.6 g) as brown oil. The crude product was used in the next step without purification. '
Ή NMR (400 MHz, DMSO-d6) δ : 1.22 - 1.29 (6H, m), 3.08 - 3.15 (2H, m), 3.26 - 3.36 (2H, m), 3.44 (3H, s), 3.47 (4H, m), 3.56 (3H, s)
m/z = 280 (M+H)+ Step I : Preparation of Ethyl 1.5.7-trimethyl-2,4-dioxo-6-rmorpholin-l-yl l,2,3,4- tetrahydropyrrolo[T.2-b]pyridazine-3-carboxylate
To the solution of diethyl malonate (23 g, 143.3 mmol) in N, N-dimethylacetamide (10 ml), the sodium hydride (0.42 g, 28.6 mmol) was added portionwise under inert atmosphere at room temperature and stirred for 10 min. Then the solution of 4 g (14.3 mmol) of the product of Step H of example 6 in N,N-dimethyIacetamide (10 ml) was added dropwise to the reaction mixture and was heated to 120° C for 12 h. After completion of reaction, the mixture was diluted with water (50 ml) and pH was neutralized using dilute hydrochloric acid and partitioned between water and ethyl acetate (3 x 200 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo The residue was purified by column chromatography on silica gel using 2 -5% ethyl acetate in hexane as the eluent to provide the titled compound (2.6 g) as brown oil.
!H NMR (400 MHz, DMSOd6) δ : 1.26 - 1.29 (3H, t), 1.96 (3H, s), 2.49 - 2.51 (4H, t), 2.78 (3H, s), 2.98 (3H, s), 3.62 - 3.67 (4H, t), 4.18 - 4.20 (2H, q),.
m/z = 350 (M+H)+
Step J : Preparation of Ethyl Ν-ΙΓ Ι^,Τ-ϋΊΓηΒΦνΙ^^^ΐοχο-ό- ΓηοφΗοΙίη^-νΠ-Ι^.Β^- tetrahydropyrrolo[l,2-b1pyridazin-3-yl)carbonyl]glycinate
To the solution of 2.5 g (7.1 mmol) of the product of Step I of example 6 in toluene (30 ml) containing triethylamine (9 3.1 ml, 21.5 mmol), the glycine ethyl ester.HCl (2 g, 14.3 mmol) was added and refluxed for 3 h. After completion of reaction, the mixture was diluted with water (50 ml) and partitioned between water and ethyl acetate (3 x 100 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 2 - 5% ethyl acetate in dichloromethane as the eluent to provide the titled compound (1.4 g) as brown solid. ¾ NMR (400 MHz, DMSOd6) δ . 1.25 - 1.28 (3H, t), 1.96 (3H, s), 2.52 - 2.54 (4H, t), 2.78 (3H, s), 2.98 (3H, s), 3.64 - 3.68 (4H, t), 4.08 - 4.10 (2H, d),.4.14 -4.16 (2H, q). m/z = 407 (M+H)+
Step K ; Preparation of N-{r4-hvdroxy-L5.7-trimethyl-6-(morpholin-4-yl -2-oxo-l,2- dihydropyrrolo Γ 1 ,2-b1pyridazin-3 -yll carbonyl) glycine
To the solution of 1.2 g (2.9 mmol) of the product of Step J of example 6 in ethanol (10 ml), the solution of sodium hydroxide (0.23 g, 5.9 mmol) in water was added at room temperature and stirred for 4 h. After completion of reaction, the mixture was diluted with water (20 ml) and pH was adjusted to 2 using dilute hydrochloric acid and the reaction volume was reduced under vacuo. The solid thus obtained was filtered, washed with water (2 x 25 ml) and dried under vacuo at 60° C for 5 h to afford the titled compound (0.7 g) as brown solid.
]H NMR (400 MHz, DMSOd6) δ : 2.42 (3H , s) , 2.49 (3H , s) , 2.98 - 3.00 (4H , t) , 3.66 - 3.68 (4H , t) , 3.71 (3H , s) , 4.02 - 4.04 (2H , d) , 10.00 (1H , s)
m/z = 377 (M-H)+
Example 7:
Preparation of N-(f4-hvdroxy-l,5,7-trimethyl-6-(morpholin-4-ylcarbonyl -2-oxo-l,2- dihvdropyrrolo[l,2-b1pyridazin-3-yl1carbonyl)glvcine (Compound no. 7)
Figure imgf000067_0001
Step A: Preparation of 4-tert-Butyl-2-ethyl-3.5-dimethyl-lH-pyrrole-2.4-dicarboxylate
To the solution of ethyl acetoacetate (20g, 125 mmol) in acetic acid, the sodium nitrite (17.25g, 125 mmol) was added at -10°c and stirred for 30 min to afford the ethyl-2- (hydroxyimino)-3-oxobutanoate. This was added dropwise to the solution of tert butyl acetoacetate (47 g, 125 mmol) in acetic acid containing zinc dust (24 g, 375 mmol) at 80° C and stirred for 2 h. After completion of reaction, the mixture was cooled, filtered through celite and partitioned between water and ethyl acetate (3 x 300 ml). The combined organic layer was dried over sodium sulphate and evaporated under vacuo to afford the titled compound (10 g) as a colourless solid.
1H NMR (400 MHz, DMSOd6) δ : 1.19 - 1.24 (3H , t), 1.42 (9H, s), 2.32 (3H, s), 2.38 (3H, s), 4.14 - 4.16 (2H, q), 11.69. (1H, s).
m/z = 267 (M-H)+
Step B : Preparation of 4-tert-Butyl 2-ethyl l-amino-3, 5-dimethyl-lH-pyrrol-2.4- dicarboxylate
To the solution of 5 g (18.7 mmol) of the product of Step A of example 7 in N, N- dimethylformamide (50 ml), the sodium hydride (1.5 g, 37.5 mmol) was added at room temperature under inert atmosphere and stirred for 1 h. Then the solution of monochloramine (prepared as in Step A of example 1) in diethyl ether (3%, 500 ml) was added and stirred for 1 h. After completion of reaction, the solution of sodium thiosulphate (78.6 g, 317 mmol) was added and partitioned between water and diethyl ether (3 x 100 ml). The combined organic layer was dried over sodium sulphate and evaporated under vacuo to afford the titled compound (6.2 g) as brown oil. The crude product was used in the next step without purification.
Ή NMR (400 MHz, DMSOd6) δ : 1.27 - 1.30 (3H, t), 1.49 (9H, s), 2.41 (3H, s), 2.43 (3H, s), 4.27 - 4.28 (2H, q), 6.16 (2H, s).
m/z = 283 (M+H)+ Step C : Preparation of 4-tert-Butyl 2-ethyl 3, S-dimetfayl-l -fftrifluoroacetvD amino!- 1H- pyrrol-2. 4-dicarboxylate
To the solution of 6 g (21.2 mmol) of the product of Step B of example 7 in dichloromethane (60 ml), the triethylamine (9.2 ml, 63.8 mmol) was added at 0° - 10°C and stirred for 30 min. Then the solution of trifluoroacetic anhydride (5.5 ml 39 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 10 h. After completion of reaction, the mixture was diluted with water (50 ml) and pH was neutralized using sodium bicarbonate solution and partitioned between water and dichloromethane (3 x 100 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (6.4 g) as brown oil. The crude product was used in the next step without purification.
Ή NMR (400 MHz, DMSOd6) δ : 1.24 - 1.26 (3H, t), 1.51 (9H, s), 2.28 (3H, s), 2.47 (3H, s), 4.20 - 4.23 (2H, q), 13.04 (1H, s).
m/z = 377 (M-H)+
Step D : Preparation of 4-tert-Butyl-2 -ethyl 3. 5-dimethyl-l -rmethyl (trifluoroacetyl) amino]- 1 H-pyrrole-2, 4-dicarboxylate
To the solution of 6 g (15.8 mmol) of the product of Step C of example 7 in acetonitrile (100 ml), the potassium carbonate (4.38 g, 31.7 mmol) was added at 0° -10° C and stirred for 30 min. Then the solution of iodomethane (2.1 ml, 31.7 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 4 h. After completion of reaction, the mixture was diluted with water- (50 ml) and partitioned between water and ethyl acetate (3 x 100 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (5.7 g) as brown oil. The crude product was used in the next step without purification.
1H NMR (400 MHz, DMSOd6) δ : 1.23 - 1.27 (3H, t), 1.52 (9H, s), 2.41 (3H, s), 2.49 (3H, s), 3 8 (3H, s) 4.22 - 4.26 (2H, q).
m/z = 393 (M+H)+ Step E : Preparation of 5-(EthoxycarbonylV2. 4-dimethyl-l-f methyl (trifluoroacetyl) amino!- H-pyrrole-3-carboxylic acid
To the solution of 5.5 g (14 mmol) of the product of Step D of example 7 in dichloromethane (50 ml), the trifluoroacetic acid (2.1 ml, 28.0 mmol) was added at 10° - 20° C and stirred for 30 min. After completion of reaction, the mixture was diluted with water (50 ml) and partitioned between water and dichloromethane (2 x 100 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (4.9 g) as brown oil.
1H NMR (400 MHz, DMSOd6) δ : 1.22 - 1.25 (3H, t), 2.43 (3H, s), 2.51 ( H, s), 3.27 (3H, s), 4.21 - 4.26 (2H, q), 12 (1H, s).
m/z = 335 (M-l)+
Step F : Preparation of Ethyl 3. 5-dimethyl-l -[methyl (trifluoroacetyl) aminol-4- (morpholin-4-ylcarbonyl)- 1 H-pyrrole-2-carboxylate
To the solution of 4.5 g (13.4 mmol) of the product of Step E of example 7 in dichloromethane (50 ml) containing N-ethyl diisopropylamine (5 ml, 27 mmol), 1- hydroxy benzotriazole (3.63 g, 27 mmol) & l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (5.2g, 27 mmol) was added at 0° C - 10° C and stirred for 30 min. Then the morpholine (2.3 ml, 26.7 mmol) was added at room temperature and stirred for 2h. After completion of reaction, the mixture was washed with saturated solution of sodium bicarbonate (2 x 50 ml) followed by citric acid solution (2 x 50 ml) and then partitioned between water and dichloromethane (2 x 100 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (4.8 g) as brown oil.
■H NMR (400 MHz, DMSOde) δ : 1.19 - 1.28 (3H, t), 2.12 (3H, s), 2.22 (3H, m),
.21 - 3.33 (4H, m), 3.56 (3H, m), 3.65 (4H, m), 4.20 - 4.23 (2H, q).
m/z = 406 (M+H)+. Step G : Preparation of Ethyl 3. 5-dimethyl-l-('methylaminoV4-imorpholin-4- ylcarbonyl -1 H-pyrrole-2-carboxylate
• To the solution of 4.5 g (11.1 mmol) of the product of Step F of example 7 in ethanol (50 ml), sodium ethoxide (1.6g, 22.2 mmol) was added at 10° C - 20° C and stirred for 1 h. After completion of reaction, the mixture was diluted with water (100 ml) and concentrated under vacuo. Then it was partitioned between water and ethyl acetate (3 x 100 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 30% ethyl acetate in hexane as the eluent to provide the titled compound (4.4 g) as colourless solid.
1H NMR (400 MHz, DMSOd6) δ : 1.22 - 1.25 (3H, t), 2.14 (3H, s), 2.16 (3H, s), 2.57 - 2.59 (3H, d), 3.26 - 3.29 (2H, m) 3.38 - 3.41 (6H, m), 4.22 - 4.28 (2H, q), 6.32 - 6.36 (1H, q).
m/z = 310 (M+H)+
Step H : Preparation of 3, 5-Diroethyl-l -fmethylamino) - 4-fmorpholin-4-ylcarbonyl)- lH-pyrrole-2-carboxylic acid
To the solution of 4.2 g (13.5 mmol) of the product of Step G of example 7 in ethanol (50 ml), the solution of potassium hydroxide (7.6 g, 135 mmol) in water (50 ml) was added and refluxed for 8 h. After completion of reaction, the mixture volume was reduced under vacuo and pH was adjusted to 6 using dilute hydrochloric acid. The solid thus obtained was filtered, washed with water (50 ml x 2) and dried under vacuo at 60° C for 4 h to provide the titled compound (3.4 g) as a colourless solid.
Ή NMR (400 MHz, DMSOd6) δ : 2.08 - 2.16 (6H, s), 2.60 (3H, s), 3.29 - 3.57 (8H, m). m/z =280 (M-H)+i. · " 2010/000664
71
Step I : Preparation of .1.5,7-Trimethyl-6-imorpholin-4-ylcarbonvn-4 H-pyrroloiL2- d]\l .3,41oxadiazine-2.4( 1 HVdione
To the solution of 3 g (10.6 mmol) of the product of Step H of example 7 in 1, 4-dioxane (50 ml), the triphosgene (4.7 g, 16 mmol) was added at room temperature and stirred for 10 h. After completion of reaction, the mixture was diluted with water (50 ml) and pH was neutralized using sodium bicarbonate solution and partitioned between water and ethyl acetate (3 x 100 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (3.3 g) as brown oil. The crude product was used in the next step without purification.
1H NMR (400 MHz, DMSOd6) 5 : 1.18 (3H, s), 2.03 (3H, s), 2.19 (3H, s), 3.29 - 3.55 (8H, m).
m/z =308 (M+H)+.
Step J : Preparation of Ethyl 4-hydroxy-l, 5, 7-trimethyl-6-(morpholin-4-ylcarbonyl)-2- oxo-1, 2-dihydropyrrolo Π , 2-b] pyridazine-3-carboxylate
To the solution of diethyl malonate (17.2 g, 107.5 mmol) in N, N-dimethylacetamide (50 ml), the sodium hydride (0.86 g, 21.5 mmol) was added portionwise under inert atmosphere at room temperature and stirred for 10 min. Then the solution of 3.3 g (10.7 mmol) of the product Step I of example 7 in N,N-dimethylacetamide (10 ml) was added dropwise to the reaction mixture and was heated to 120° C for 12 h. After completion of reaction, the mixture was diluted with water (50 ml) and pH was neutralized using dilute hydrochloric acid and partitioned between water and ethyl acetate (3 x 200 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 2 -5% ethyl acetate in hexane as the eluent to provide the titled compound (2.2 g) as brown oil.
Ή NMR (400 MHz, DMS0d6) δ : 1.23 - 1.30 (3H, t), 2.28 (3H, s), 2.44 (3H, s), 2.57 - .59 (3H, d), 3.28 (3H, s), 3.51 - 3.53 (2H, m), 3.62 - 3.64 (6H, m), 4.28 - 4.34 (2H, q), 14.11 (lH, s). 664
72 m/z = 378 ( +H)+ iStep : Preparation of Ethyl N-(r 4-hvdroxy-1.5.7-trimethyl-6-(morpholin-4- a
ylcarbonyI)2-oxo-L2-dihvdropyrrolo[l,2-blpyridazin-3-yl)carbonyllglycinate
To the solution of 1 g (2.6 mmol ) of the product of Step J of example 7 in toluene (50 ml) containing triethylamine (0.8 ml, 5.3 mmol), the glycine ethyl ester.HCl (0.75, 5.3 mmol) was added and refluxed for 3 h. After completion of reaction, the mixture was diluted with water (50 ml) and partitioned between water and ethyl acetate (3 x 100 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 30% ethyl acetate in dichloromethane as the eluent to provide the titled compound (0.8 g) as colourless solid.
Ή NMR (400 MHz, DMSOd6) δ :1.19 - 1.23 (3H, t), 2.29 (3H, s), 2.48 (3H, s), 3.29 - 3.31 (2H, m), 3.51 - 3.53 (2H, m), 3.59 - 3.63 (4H, m), 3.76 (3H, s), 4.10 - 4.17 (4H, m), 9.95 -9.98 (1H, t).
m/z = 435 (M+H)+
Step L : Preparation of N-{r4-hydroxy-1.5,7-trimethyl-6-(morpholin-4-ylcarbonyl)-2-
Figure imgf000073_0001
To the solution of 0.8 g (1.84 mmol) of the product of Step K of example 7 in ethanol (30 ml), the solution of sodium hydroxide (0.15 g, 3.7 mmol) in water was added at room temperature and stirred for 4 h. After completion of reaction, the mixture was diluted with water (20 ml) and pH was adjusted to 2 using dilute hydrochloric acid and the reaction volume was reduced under vacuo. The solid thus obtained was filtered, washed with water (2 x 25 ml) and dried under vacuo at 60° C for 5 h to afford the titled compound (0.6 g) as colourless solid.
Ή NMR (400 MHz, DMSOd6) δ : 2.30 (3H , s), 2.49 (3H , s), 3.32 (2H, s), 3.52 (2H, s), 3.65 (4H , s), 3.76 (3H, s), 4.06 - 4.08 (2H, d), 9.94 (1H , s). m/z = 405 (M-H)+
EXAMPLE 8;
Preparation of N-K4-hvdroxy-l,6-dimethvI-2-oxo-5-phenyl-l,2-dihvdronyrrolofl,2- blpyridazin-3-vI)carbonvnglycine (Compound no. 17)
Figure imgf000074_0001
Step A : Preparation of (2-Nitro-prop-l-en-l -y])benzene
To the solution of benzaldehyde (5 g, 47 mmol) in acetic acid (100 ml), nitroethane (3.5 ml, 47 mmol) & ammonium acetate (7.2g, 93.5 mmol) was added and refluxed for 5 h. After the completion of reaction, it was poured into water (100 ml) and the pH was neutralised with sodium bicarbonate solution and partitioned between water and ethyl acetate (3 x 100 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using hexane as the eluent to provide the titled compound (2.8 g) as yellow solid.
]H NMR (400 MHz, DMSOd6) δ : 2.41 (3H, s), 7.49 - 7.53 (3H, m), 7.59 - 7.61 (2H, dd) 8.10 (lH, s).
m z = 163 (M+H)+
Step B : Preparation of Ethyl isocyanoacetate
To the solution of glycine ethyl ester hydrochoride (10 g, 71.6 mmol) in triethylamine (35 ml, 430 mmol), the ethy formate (11.3 ml, 78.5 mmol) was added and refluxed for 12 h. After completion of reaction, the reaction mixture was filtered and the filtrate was evaporated under vacuo to afford the ethyl N-formylglycinate (8.4 g) as colourless oil. . Ή NMR (400 MHz, DMSOd6) δ : 1.12 - 1.15 (3H, t), 4.02 (2H, q), 4. 82 (2H, s). m/z = 163 (M+H)+
The solution of N-formylglycinate (8.4gm, 60 mmol) in dichloromethane (100 ml) containing triethylamine (23 ml, 160mmol) was cooled to -10° C and phosphorous oxychloride (5.9 ml, 60mmol) was added dropwise and stirred for 1 h. After the completion of reaction, the pH was neutralised with sodium bicarbonate solution and partitioned between water and dichloromethane (3 x 100 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to provide the titled compound (5.3 g) as brown oil.
¾ NMR (400 MHz, DMSOd6) δ : 1.12 -1.15 (3H, t), 4.02 (2H, q), 4. 82 (2H, s).
m/z = 114 (M+H)+
Step C: Preparation of 4-Methyl-3-phenyl-l H-pyrrole-2-carboxylate
To the solution of 2.8g (16.8 mmol) of the product of Step B of example 8 in tetrahydrofuran containing potassium carbonate (4g, 29.6 mmol), ethyl isocyanoacetate (2.1 g, 18.5 mmol) was added at room temperature and stirred for 16 h.
After completion of reaction, it was poured in water and partitioned between water and ethyl acetate (3 x 50 ml). The combined organic layer was dried over sodium sulphate and evaporated under vacuo. The residue was purified by column cliromatography on silica gel using 5% ethylacetate in hexane as eluent to afford the titled compound (2.6 g) as colourless oil.
'H NMR (400 MHz, DMSOd6) δ : 1.05 - 1.08 (3H, t), 1.90 (3H, s), 4.02 - 4.07 (2H, q), 6.85 - 6.86 (2H, d), 7.25 - 7.28 (3H, t), 7.34 - 7.36 (2H, m), 1 1.56 (1H, s).
m/z = 230 (M+H)+ Step D: Preparation of Ethyl- l-amino-4-methyl-3 -phenyl- 1 H-pyrrole-2-carboxylate
To the solution of 2.6 g (11.3 mmol) of the product of Step C of example 8 in N, N- dimethylformamide (20 ml), the sodium hydride (lg, 22.7 mmol) was added under inert atmosphere at room temperature and stirred for Ih. Then the solution of monochloramine (prepared according to Step A of example 1) in diethyl ether (320 ml) was added and stirred for 30 min. After completion of reaction the solution of sodium thiosulphate (26 g) in water was added and the reaction mixture was partitioned between water and diethyl ether (3 x 200 ml). The combined organic layer was dried over sodium sulphate and evaporated under vacuo to afford the titled compound (3.5 g) as brown oil. The crude product was used in next step without purification.
Ή NMR (400 MHz, DMSOd6) δ : 1.05 - 1.1 (3H, t), 1.83- 1.85 (3H, s), 4.01 - 4.06 (2H, q), 6.22 (2H, s), 6.89(1H, s), 7.17 - 7.19 (2H, m), 7.25 - 7.29 (1H, m), 7.32 - 7.36 (2H, m).
m/z =245 (M+H)+
Step E: Preparation of Ethyl 4-methyl-3-phenyl-l -["ftrifluoroacetyl) aminol-lH-pyrrole- 2-carboxylate
To the solution of 3.2 g (13.1 mmol) of the product of Step D of example 8 in dichloromethane (100 ml), the triethylamine (5.7 ml, 39.3 mmol) was added at 0° -10°C and stirred for 30 min. Then the solution of trifluoroacetic anliydride (3.7 ml, 26.2 mmol) was added dropwise at room temperature and stirred for 2 h. After completion of reaction, the reaction mixture was partitioned between water and dichloromethane (3 x 50 ml). The combined organic layer was dried over sodium sulphate and evaporated under vacuo to afford the titled compound (3.6 g) as browm oil. The crude product was used in next step without purification.
Ή NMR (400 MHz, DMSOdg) δ : 0.86 - 0.91 (3H, t), 1,87 (3H, s), 3.96 - 4.07 (2H, q), 7.14 (1H, s), 7.23 - 7.25 (2H, m), 7.26 - 7.28 (IH, m), 7.31 - 7.38 (2H, m).
m z = 339 (M-H)+ Step F: Preparation of Ethyl 4-methvH-rmethyl(trifluoroacetyl aminol- 3-phenyl-lH- pyrrole-2-carboxylate
To the solution of 3.6 g (10.5 mmol) of the product of Step E of example 8 in acetonitrile (100 ml), the potassium carbonate (3 g, 21 mmol) was added at 0° - 10°C and stirred for 30 min. Then the solution of iodomethane (1.3 ml, 21 mmol) was added dropwise at room temperature and stirred for 10 h. After completion of reaction, the reaction mixture was partitioned between water and ethyl acetate (3 x 100 ml). The combined organic layer was dried over sodium sulphate and evaporated under vacuo to afford the titled compound (2.9 g) as brown oil. The crude product was used in next step without purification.
Ή NMR (400 MHz, DMSOd6) δ : 0.89 - 0.92 (3H, t), 1.87 (3H, s), 3.28 (3H, s), 3.99 - 4.00 (2H, q), 7.22 - 7.25 (3H, m), 7.32 - 7.40 (3H, m),
m/z = 355 (M+H)+
Step G: Preparation of Ethyl 4-methyl-l-(methylamino -3-phenyl-lH-pyrrole-2- carboxylate
To the solution of 2.8 g (7.9 mmol) of the product of Step F of example 8 in ethanol (50 ml), the sodium ethoxide (1 g, 15.8 mmol) was added at 10°C - 20°C and stirred for 1 h. After completion of reaction, the reaction mixture was partitioned between water and ethyl acetate (3 x 100 ml). The combined organic layer was dried over sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 5 % ethyl acetate in hexane as eluent to provide the titled compound (1.4 g) as brown oil.
Ή NMR (400 MHz, DMSOd6) δ : 0.90 - 0.93 (3H, t), 1.84 (3H, s), 2.70 - 2.71 (3H, d), 3.97 - 4.04 (2H, q), 7.0 (1H, s), 7.19 - 7.21 (2H, m), 7.25 - 7.27 (1H, m), 7.32 - 7.36 (2H, m).. ' '
m/z = 259 (M+H)+ Step H: Preparation of 4-Methyl-l-(methylamino)-3 -phenyl- lH-pyrrole-2-carboxylic acid
To the solution of 1.2 g (4.6 mmol) of the product of Step G of example 8 in ethanol (20 ml), the solution of potassium hydroxide (2.7 g, 46 mmol) in water (10 ml) was added and refluxed for 3 h. After completion of reaction, the pH was adjusted to 6 with dilute hydrochloric acid and the solid was filtered, washed with water (2 x 25 ml), dried under vacuo at 60° C for 4 h to afford the titled compound (0.8 g) as colourless solid.
■H MR (400 MHz, DMSOd6) δ : 1.84 (3H, s), 2.71 - 2.72 (3H, d), 6.51 - 6.54 (1H, m), 7.01 - 7.02 (1H, s), 7.18 - 7.19 (1H, dd), 7.20 - 7.21 (1H, dd), 7.27 - 7.30 (1H, m), 7.33 - 7.35 (2H, m).
m/z = 229 (M-H)+
Step I: Preparation of l ,6-Dimethyl-5-phenyl-4H-pyrrolo[T,2-d] |"1.3,4"|oxadiazine- 2,4(1 HVdione
To the solution of 0.8 g (3.4 mmol) of the product of Step H of example 8 in 1, 4-dioxane (10 ml), the triphosgene (2 g, 6.9 mmol) was added at room temperature and stirred for 10 h. After completion of reaction, the pH was neutralised with solution of sodium bicarbonate in water and the reaction mixtures was partitioned between water ethyl acetate (3 x 100 ml). The combined organic layer was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (1.2 g) as brown oil. The crude product was used in next step without purification.
Ή NMPv (400 MHz, DMSOd6) δ : 1.8 (3H, s), 2.72 - 2.73 (3H, d), 6.51 - 6.54 (1H, m), 7.01- 7.02 (1H, s), 7.18 - 7.19 (1H, dd), 7.20 - 7.21 (1H, dd), 7.27 - 7.30 (1H, m), 7.33 - 7.35 (2H, m).
m/z = 257 (M+H)+ Step J: Preparation of Ethyl 4-hvdroxy-L6-dimethyl-2-oxo-5-phenyl-1.2- dihydrop yrrolo Γ 1 ,2-b1pyridazine-3 -carboxylate
To the solution of diethyl malonate (7.5 g, 46.8 mmol) in N, N-dimethylacetamide (10 ml), the sodium hydride (0.42 g, 9.3 mmol) was added under inert atmosphere and stirred for 10 min. Then the solution of 1.2 g (4.6 mmol) of the product of Step I of example 8 in N,N-dimethylacetamide (10 ml) was added drop wise and heated at 120°C for 12h. After completion of reaction, the reaction mixture was partitioned between water and ethyl acetate (3 x 200 ml). The combined organic layer was dried over sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 2 - 5 % ethyl acetate in dichloromethane as eluent to provide the titled compound (0.8 g) as colourless solid.
Ή NMR (400 MHz, DMSOd6) δ : 1.26 - 1.33 (3H, t), 2.52 (3H, s) , 3.64 (3H, s), 4.29 - 4.37 (2H, q), 7.31 - 7.35 (1H, m), 7.44 - 7.52 (4H, m), 14.26 (1H, s).
m/z = 327 (M+H)+
Step K: Preparation of Ethyl N-rf4-hydroxy-l ,6-dimethyl-2-oxo-phenyl-1.2- dihydropyrrolo ri.2-b1pyridazin-3-yncarbonyl1glycinate
To the solution of 0.28 g (1.6 mmol) of the product of Step J of example 8 in toluene (10 ml) containing triethylamine (0.3 ml, 1.6 mmol), the glycine ethyl ester.HCl (0.24 gm, 1.6 mmol) was added and refluxed for 2h. After completion of reaction, the reaction mixture was partitioned between water and ethyl acetate (3 x 50 ml). The combined organic layer was dried over sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 12 - 15 % ethyl acetate in hexane as eluent to provide the titled compound (0.22 g) as colourless solid.
'H NMR (400 MHz, DMSOd6) δ : 1.19 - 1.24 (3H,t), 2.53 (3H,s) , 3.73 (3H,s), 4.13-4.19 (4H,m),7.31-7.35 (lH,m), 7.44-7.48 (2H,t), 7.52-7.54 (2H,m), 7.67-7.73 (lH,m), 7.96 (lH,s), 10.16-10.19 (lH,t).
m/z = 382 (M-H)+ Step L; Preparation of N-f(4-hvdroxy-l,6-dimethyl-2-ox0-5-phenyl-l,2-dihvdropyrrolo [ 1.2-b1pyridazin-3 -yDcarbonyll glycine
To the solution of 0.15 g (0.4 mmol) of the product of Step K of example 8 in ethanol (10 ml), the solution of sodium hydroxide (0.031 g, 0.8 mmol) in water (2 ml) was added at room temperature and stirred for 30 min. After completion of reaction, the pH was neutralized and the solid was filtered, washed with water (2 x 25 ml) and dried under vacuo at 60° C for 5 h to provide the titled compound (0.08 g) as colourless solid.
1H NMR (400 MHz, DMSOd6) δ : 2.57 (3H , s) , 3.79 (3H, s), 4.16 - 4.18 (2H, d), 7.41 - 7.43 (1H , t), 7.50 - 7.52 (2H , m), 7.59 - 7.61 (2H , m) , 10.23 (1H , s).
m/z = 354 (M-l)+
Example 9
N-[(l-benzvI-4-hvdroxy-2-oxo-l,2-dihvdropyridazinofl,6-aIbenziniidazoi-3- vDcarbonyllglycine (Compound No. 44)
Figure imgf000080_0001
Step A : Preparation of tert-butyl 2-(2-nitrophenyl)hydrazinecarboxylate
To the solution of l-fluoro-2-nitrobenzene (50 g, 354.4 mmol) in toluene (1 1), tert-butyl carbazate (93.6 g, 700 mmol) was added at room temperature and refluxed for 24 h. The reaction mixture was partitioned between water and ethyl acetate (3 x 300 ml). The combined organic layers was dried over sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 10% ethyl acetate in hexane as the eluent to provide the titled compound (30 g) as brown oil !H NM (400 MHz, DMSOd6) δ : 1.43 (9H, s), 6.82 - 6.86 (IB, t), 7.10 (1H, d), 7.58 - 7.62 (1H, t), 8.06 - 8.09 (lH, d), 9.18 (1H, s), 9.3 (1H, bs).
m/z = 254 (M+H)+
Step B : Preparation of tert-butyl 2-(2-aminophenyl)hvdrazinecarboxylate
To the solution of 20 g (78.9 mmol) of the product of Step A (example 9) in ethylacetate (200 ml), the Palladium charcoal (10%, 4 g) and acetic acid (4 g, 66.6 mmol) was added at room temperature and stirred under hydrogen atmosphere (500 psi) for 6 h. After completion of reaction, the mixture was filtered through celite, washed with saturated sodium bicarbonate solution (2 x 100 ml) and partitioned between water and ethyl acetate (3 x 300 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo to afford the titled compound (1 1.8 g) as a brown solid. The crude product was used in the next step without purification.
Ή NMR (400 MHz, DMSOd6) δ : 1.43 (9H, s), 4.6 (2H, s), 6.44 - 6.59 (5H, m), 8.69 (I I I, bs)
m/z = 224 (M+H)+
Step C: Preparation of ethyl l-ritert-butoxycarbonyl)amino1-lH-benzimidazole-2- carboxylate
To the solution of 1 1.5 g (5 L5 mmol) of the product of Step B (example 9) in ethanol (100 ml), the ethyl glyoxalate (5.8 g, 56.8 mmol) was added at room temperature and stirred for 30 min. Then the iodine (2.6 g, 20.4 mmol) was added to the reaction mixture and stirred at room temperature for 2 h. After completion of reaction, the mixture was evaporated under vacuo and partitioned between water and ethyl acetate (3 x 200 ml). The combined organic layer was washed with saturated sodium bicarbonate solution (100 ml) and dried over anhydrous sodium sulphate, evaporated under vacuo. The residue was purified by column chromatography on silica gel using 15% ethyl acetate in hexane as the eluent to provide the titled compound (8g) as yellow solid ¾ NMR (400 MHz, DMSOdg) δ : 1.33 - 1.37 (3H, t), 1.43 (9H, s), 4.35 - 4.44 (2H, q), 7.37 - 7.40 (1H, m), 7.47 - 7.48 (2H, m), 7.75 - 7.82 (1H, m), 10.74 (1H, s)
m/z = 304 (M-H)+
Ste D ; Preparation of ethyl l-rbenzyl(tert-butoxycarbonyl)aminol-lH-benzimidazole-2- carboxylate
To the solution of 8 g (26.2 mmol) of the product of Step C (example 9) in acetonitrile (100 ml) containing potassium carbonate (7.2 g, 52.3 mmol) was cooled to 10°· C, then the benzyl bromide (4.9 g, 28.6 mmol) was added dropwise and stirred at room temperature for 4 h. After completion of reaction, the mixture was partitioned between water and ethyl acetate (3 x 100 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 15% ethyl acetate in hexane as the eluent to provide the titled compound (8 g) as yellow solid.
Ή NMR (400 MHz, DMSOd6) δ : 1.33 - 1.37 (3H, t), 1.43 (9H, s), 4.14 - 4.17 (2H, q), 4.60 - 4.70 (1H, m), 5.18 - 5.38 (1H, m), 6.88 (2H, m), 7.23 - 7.27 (8H, m), 7.70 - 7.74 (lH, m).
[m/z = 396 (M+H)+
Step E : Synthesis of ethyl l-(benzylamino)-lH-benzimidazole-2-carboxylate
To the solution of 4.8 g (20.2 mmol) of the product of Step D (example 9) in ethanol (40 ml), the concentrated hydrochloric acid (16 ml) was added dropwise at 10° C and stirred for 2 h. After completion of reaction, the mixture was diluted with water (100 ml) and the pH was neutralized using sodium bicarbonate solution. The solid thus obtained was filtered, washed with water (2 x 50 ml), and dried under vacuo at 60° C for 4 h to provide the titled compound (5 g) as yellow solid.
Ή NMR (400 MHz, DMSOd6) δ : 1.28 - 1.36 (3H, t), 4.24 - 4.26 (2H, d), 4.34 -4.39 (2H, q), 7.14 - 7.17 (1H, m), 7.28 - 7.31 (5H, m), 7.35 - 7.41 (1H, m), 7.52 - 7.54 (1H, d), 7.71 - 7.73 (1H, d) .m/z = 296 (M+H)+
Step F : Preparation of ethyl 1 benzyl(3-ethoxy-3-oxopropanovDarnino1-lH- benzimidazole-2-carboxylate
To the solution of 5g (16.9 mmol) of the product of Step E (example 9) in dichloromethane (100 ml) containing triethylamine (6.12 g, 60.6 mmol), the ethyl malonyl chloride (7.8 g, 52 mmol) ) was added at 0° - 5° C and stirred for 2 h; After completion of reaction, the mixture was partitioned between water and dicnloromethane (3 x 150 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 30 % ethyl acetate in hexane as the eluent to provide the titled compound (3.5 g) as colourless solid.
Ή NMR (400 MHz, DMSOd6) δ : 0.85 - 0.87 (3H, t), 1.23 - 1.27 (3H, t), 3.15 -3.19 (2H, d), 3.76 - 3.80 (2H, m), 4.16 - 4.19 (2H, q), 4.86 - 5.07 (2H, m), 6.98 - 7.00 (2H, m), 7.17 - 7.26 (4H, m), 7.36 - 7.42 (2H, m), 7.80 - 7.82 (2H, m).
m/z = 410 (M+H)+
Step G : Synthesis of ethyl l-benzyl-4-hydroxy-2-oxo-l,2-dihydropyridazinon .6- albenzimidazole-3-carboxylate
To the solution of 3.5 g (8.5 mmol) of the product of Step F (example 9) in tetrahydrofuran (20 ml), the l,8-diazabicyclo[5.4.0]undec-7-ene (3.9 g 25.6 mmol, DBU) was added at room temperature and refluxed for 5 h. After completion of reaction, the mixture volume was reduced under vacuo, diluted with water (100 ml) and was acidified using dilute hydrochloric acid to pH 3. The solid thus obtained was filtered, washed with water (2 x 50 ml), and dried under vacuo at 60° C for 4 h to afford the titled compound (2.5 g) as colourless solid.
JH NMR (400 MHz, DMSOd6) δ : 1.23 - 1.27 (3H, t), 4.13 - 4.26 (2H, d), 7.24 -7.26 (3H, m), 7.30 - 7.37 (3H, m), 7.42 - 7.46 (1H, m), 7.77 - 7.83 (2H, m). m/z = 364 (M+H)+
Step H : Synthesis of N-,rd-benzyl-4-hvdroxy-2-oxo-l,2-dihydropyridazinori,6- a] benzimidazol-3 - vDcarbonyll glycine :
To the solution of 0.2 g (0.5 mmol) of the product of Step G (example 9) in 2-methoxy ethanol (10 ml), the glycine sodium salt hydrate (0.33 g, 0.8 mmol) was added and refluxed for 6 h. After completion of reaction, the mixture was cooled to 0° C, diluted with water (10 ml) and was acidified using dilute hydrochloric acid to pH 2. The solid thus obtained was filtered, washed with water (2 x 25 ml), and dried under vacuo at 60° C for 4 h to afford the titled compound (0.08 g) as colourless solid.
'H NMR (400 MHz, DMSOde) δ : 4.16 - 4.18 (2H, d), 5.93 (2H, s), '7.27 - 7.31 (2H, m), 7.35 - 7.38 (4H, m), 7.39 - 7.40 (1H, m), 7.68 - 7.70 (1H, d), 7.86 - 7.88 (1H, d).
m/z = 391 (M-H)+
The following representative compounds of the present invention were prepared in analogus' manner by following the synthetic routes as described above:
Table-l:
Comp. Compound name NMR Mass No.
N-[(l-benzyl-4-hydroxy-8- ]H NMR (DMSOdg) δ: 2.25 - m/z: 394 methyl-2-oxo-2,5,6,7-tetrahydro- 2.27 (2H, t), 2.34 (3H, s), 2.55 - (M-H)+ lH-cyclopenta [3,4]pyrrolo[l,2- 2.57 (2H, t), 2.82 - 2.86 (2H, t),
b]pyridazin-3-yl)carbonyl] 4.01 - 4.02 (2H, d), 5.51 (2H, s),
glycine 7.06 - 7.08 (2H, d), 7.19 - 7.26
(1H, d), 7.29 - 7.33 (2H, m),
9.90 (lH, s)
N-[(l -ethyl-4-hydroxy-8-methyl- Ή NMR (DMSOd6) <5: 0.96 - m/z: 332 2-oxo-2,5,6,7-tetrahydro-lH- 1.00 (3H, t), 2.29 - 2.32 (2H, t), (M-H)+ cyclopenta [3,4]pyrrolo[l,2- 2.42 (3H, s), 2.63 - 2.67 (2H, t),
b]pyridazin-3 -yl)carbonyl] 2.81 - 2.86 (2H, t), 4.03 - 4.08
glycine (2H, d), 4.24 - 4.27 (2H, m) , 0664
84
Comp. Compound name NMR Mass
No.
9.89 (1H, s)
4 N-[(4-hydroxy-l-methyl-2-oxo- 1H NMR (DMSOd6) δ: 4.13 (5H, m/z: 314 l ,2dihydropyridazino[l,6- s), 7.25 - 7.40 (3H, m), 7.84 - (M-H)+ a]indol-3-yl)carbonyl] glycine 7.86 (lH, d), 8.14 - 8.16 (1H, d),
10.14 (lH, s), 12.98 (1H, bs)
5 N-[(4-hydroxy-l ,9-dimethyl-2- Ή NMR (DMSOd6) δ: 1.69 (4H, m/z: 332 oxo-l ,2,5,6,7,8-hexahydro- s), 2.20 (3H, s), 2.39 (2H, s), (M-H)+ pyridazino[6,l-a]isoindol-3- 2.73 (2H, s), 3.50 (3H, s), 3.82
yl)carbonyl]glycine sodium salt (2H, s)
6 N-[(4-hydroxy-l ,5,7-trimethyl- Ή NMR (DMSOd6) δ: 2.32 (3H, m/z: 294 2-oxo-l,2-dihydropyrroIo[l,2- s), 2.56 (3H, s), 3.75 (3H, s), (M+H)+ b]pyridazin-3-yl) carbonyl] 4.06 - 4.07 (2H, d), 6.18 (1H, s),
glycine 9.96 (1H, s), 13.0 (1H, bs)
9 N-{[4-hydroxy-l ,5,7-trimethyI- ;H NMR (DMSOd6) δ: 1.50 - m/z: 375
2- oxo-6-(piperidin-l-yl)-l ,2- 1.58 (6H, m), 2.39 (3 H, s), 2.49 (M-H)+ dihydropyrrolo[l ,2-b]pyridazin- (3H, s), 2.95 - 2.96 (4H, d), 3.70
3- yl]carbonyl} glycine (3H, s), 3.97 - 3.98 (2H, d), 9.98
(IH, s)
10 N-[(7-fluoro-4-hydroxy-l- 1H NMR (DMSOd6) δ: 4.12 (5H, m/z: 332 methyl-2-oxo-l,2-dihydro- s), 7.39 - 7.28 (2H, m), 7.61 - (M-H)+ pyridazino[l ,6-a]indol-3- 7.64 (IH, dd), 8.20 - 8.21 (IH,
yl)carbonyl] glycine m), 10.14 (IH, s)
1 1 N-[(4-hydroxy- l-methyl-2-oxo- JH NMR (DMSOd6) δ: 1.69 - m/z: 320 1 ,2,6,7,8,9-hexahydro- 1.76 (4H, m) , 2.59 (2H, s), 3.10 (M+H)+ pyridazino[l,6-a]indol-3- (2H, s), 3.83 (3H, s), 4.06 - 4.07
yl)carbonyl] glycine (2H, d), 6.65 (IH, s), 10.00 (1H5
s), 13.00 (lH, bs)
13 N-[(4-hydroxy-l ,8-dimethyl-2- ]H NMR (DMSOd6) δ: 1.39 - m/z: 334 oxo-2,5,6,7-tetrahydro-lH- 1.41 (3H, d), 2.26 - 2.33 (2H, (M+H)+ cyclopenta[3,4]pyrrolo[l,2- m), 2.52 (3H, s), 2.61 - 2.67 (2H,
b]pyridazin-3-yljcarbonyl] t), 2.85 - 2.89 (2H, t), 3.76 (3H,
alanine s), 4.41 - 4.48 (IH, m), 10.09
(IH, s), 13.0 (IH, s) 0664
85
Comp. Compound name NMR Mass
No.
14 N-[(4-hydroxy-l-methyl-2-oxo- Ή NMR (DMSOd6) δ: 1.40 - m/z: 332 1,2,6,7,8,9-hexahydro- 1.42 (3H, d), 1.69 - 1.77 (4H, (M-H)+ pyridazino[l,6-a]indol-3- m), 2.58 - 2.61 (2H, t), 3.11 - yl)carbonyl] alanine 3.14 (2H, t), 3.83 (3H, s), 4.42 -
4.48 (IH, m), 6.66 (IH, s), 10.15
(IH, s), 13.06 (IH, s)
15 N-[(4-hydroxy- 1,5,6,7- Ή NMR (DMSOd6) 6: 1.98 (3H, m z: 306 tetramethyl-2-oxo-l,2- s), 2.30 (3H, s), 2.46 (3H, s), (M-H)+ dihydropyrrolo[l,2-b] pyridazin- 3.70 (3H, s), 4.05 - 4.07 (2H, d),
3-yl)carbonyl] glycine 9.90 (IH, s)
16 N-[(4-hydroxy-l, 5,6,7- 1H NMR (DMSOd6) δ: 1.41 (3H, m/z: 320 tetramethyl-2-oxo-l,2- d), 1.98 (3H, s), 2.30 (3H, s), (M-H)+ dihydropyrrolo[l,2-b] pyridazin- 2.46 (3H, s), 3.71 (3H, s), 4.40 - 3-yl)carbonyl] alanine 4.42 (IH, m), 10.12 (IH, s),
13.20 (lH, s)
18 N-[(4-hydroxy-l-methyl-2-oxo- Ή NMR (DMSOd6) δ: 2.37 - m/z: 304 2,6,7,8-tetrahydro-lH- 2.44 (2H, m), 2.64 - 2.67 (2H, (M-H)+ cyclopenta[4,5]pyrrolo[l,2- m), 3.27 - 3.29 (2H, m), 3.81
b]pyridazin-3-yl)carbonyl] (3H, s), 4.06 - 4.08 (2H, d), 6.64
glycine (IH, s), 10.09 (IH, s), 13.00
(lH, s)
19 N-[(4-hydroxy-l,6-dimethyl-2- !H NMR (DMSOd6) δ: 1.42 - m/z: 368 oxo-5-phenyI-l,2-dihydro - 1.44 (3H, d), 2.51 (3H, s), 3.72 (M-H)+ pyrrolo[l,2-b] pyridazin-3- (3H, s), 4.45 - 4.52 (IH, m), 7.31
yl)carbonyl] alanine - 7.35 (IH, m), 7.44 - 7.48 (2H,
m), 7.51 - 7.53 (2H, m), 7.95
(lH, s), 10.33 (lH, s)
20 N-[(4-hydroxy-l,6-dimethyI-2- Ή NMR (DMSOd6) δ: 2.48 m/z: 368 oxo-5-phenyl-l,2-dihydro- (3H, s), 3.00 (3H, s), 3.66 (3H, (M-H)+ pyrrolo[l,2-b]pyridazin-3- s), 4.12 (2H, s), 7.29 - 7.33 (IH,
yl)carbonyl]-N-methyl glycine m), 7.42 - 7.50 (4H, m), 7.80
(IH, s) ·
21 N-[(4-hydroxy-l,9-dimethyl-2- Ή NMR (DMSOdg) δ: 1.48 - m/z: 346 oxo-1, 2,5,6,7,8-hexahydro- 1.50 (3H, d), 1.80 - 1.82 (4H, t), (M-H)+ pyridazino[6,l-a]isoindol-3- 2.29 (3H, s), 2.49 - 2.52 (2H, t)
yl)carbonyl] alanine 3.02 - 3.04 (2H, t), 3.79 (3H, s),
4.53 - 4.58 (lH, m) 00664
86
Comp. Compound name NM Mass No.
24 2- { [(4-Hydroxy- 1 -methyl -2-oxo- 1H NMR (DMSOd6) δ: 1.42 - m/z: 382 1 ,2-dihydropyridazino - [ 1 ,6- 1.43 (4H, m), 1.50 - Ί.85 (4H, (M-H)+ a]indol-3-yl)carbonyl] -amino} m), 2.74 - 2.75 ( IH, m), 4.1 1
cyclohexanecarboxylic acid (3H, s), 4.41 (IH, m), 7.24 - 7.27
(2H, m), 7.35 - 7.39 (lH, t),
7.83 - 7.85 (lH, d), 8.13 - 8.15
(lH, d), 10.45 - 10.47 (IH, d),
12.50 (lH, bs)
25 N- [(4-hydroxy-7-methoxy- 1 - 1H NMR (DMSOd6) δ: 3.81 (3H, m/z: 344 methyl-2-oxo-l,2-dihydro - s), 4.10 (3H, s), 4.1 1 - 4.12 (2H, (M-H)+ pyridazino [l,6-a]indol-3-yl) - d), 7.0 - 7.01 (lH, d), 7.15 (IH,
carbonyl] glycine s), 7.25 (IH, s), 8.04 - 8.06 (IH,
d), 10.16 (IH, bs)
26 N-[(4-hydroxy- 1 -methyl-2-oxo- •H NMR (DMSOd6) δ: 2.98 (3H, m/z: 328 1 ,2-dihydropyridazino- [1,6- s), 4.00 (3H, s), 4.1 1 - 4.12 (2H, (M-H)+ a]indol-3 -yl)carbonyl] -N-methyl d), 7.18 - 7.31 (3H, m), 7.78 - glycine 7.79 ( IH, d), 8.03 - 8.05 (IH, d)
27 N-[(4-hydroxy- 1 -methyl-2-oxo- Ή NMR (DMSOd6) δ: 3.79 (5H, m/z: 314
1.2- dihydropyridazino [ 1 ,6- s), 6.85 (IH, s), 7.21 - 7.23 (1H, (M-H)+ a] indol-3 -yl)carbonyl]glycine t), '7.33 - 7.35 (IH, t), 7.72 - sodium salt 7.73 (lH, d), 10.54 (IH, s)
28 N-[(4-hydroxy-l,6-dimethyl-2- Ή NMR (DMSOdg) δ: 2.38 (3H, m/z: 354 oxo-5-phenyl-l ,2- s), 3.49 (3H, s), 3.76 (2H, s), (M+H)+ dihydropyrrolofl ,2-b]pyridazin- 7.20 - 7.35 ( 6H, m)
3-yl)carbonyl]glycine sodium
salt
29 2- { [(4-Hydroxy- 1 -methyl-2-oxo- 'H NMR (DMSOd6) 5: 4.19 m/z: 383 1 ,2dihydropyridazino [1 ,6- (3H), 7.29 - 7.42 (3H, dd), 7.87 (M-H)+ a] indol-3 -yl)carbonyl] amino } - (lH, s), 8.14 - 8.17 (2H, dd)
1.3- thiazole-4-carboxylic acid
30 N-[(6-cyclohexyl-4-hydroxy- Ή NMR (DMSOd6) δ: 1.24 - m/z: 374 1 ,5,7-trimethyl -2-oxo- 1 ,2- 1.39 (4H, m), 1.64 - 1.72 (4H, (M-H)+ dihydropyrrolo[l ,2b]pyridazin- m), 1.77 - 1.80 (2H, d), 2.41
3 -yl)carbonyl] glycine (3H, s) , 2.47 (3H, s) , 2.63 (IH,
m), 3.64 (3H , s), 4.02 - 4.03
(2H, d) , 9.95 (1 H, s).
31 N- [(7-chloro-4 -hydroxy- 1 - 1H NMR (DMSOd6) δ: 4.06 (3H, m/z: 348 methyI-2-oxo- 1 ,2-dihydros), 4.06 - 4.07 (2H, d), 7.19 (IH, (M-H)+ pyridazino [l ,6-a]indol-3- s), 7.27 - 7.30 (IH, dd), 7.86
yl)carbonyl]glycine (lH, d), 8.11 - 8.13 (lH, d),
10.06 (lH, s), 12.6 (IH, s). Comp. Compound name NMR Mass No.
32 N-[(4,7-dihydroxy-l-methyl-2- 1H NMR (DMSOd6) δ: 4.1 (3H, m/z: 330 oxo- 1 ,2-dihydropyridazino- [ 1 ,6- s), 4.12 - 4.13 (2H, d), 6.91 - (M-H)+ a]indoI-3-yl)carbonyl] glycine 6.93 (1H, dd), 7.05 - 7.08 (1H,
d), 7.08 (lH, s), 7.98 - 8 (lH, d),
9.4 (lH, s), 10.16 (lH, t), 12.98
(1H, s).
34 1 -[(4-Hydroxy- l,6-dimethyl-2- 1H NMR (DMSOd6) δ: 1.25 (1H, m/z: 410 oxo-5-phenyl-l ,2-dihydro- s), 1.52 - 1.61 (2H, m), 1.78 - (M+H)+ pyrrolo[l,2-b]pyridazin-3- 1.84 (2H, t), 2.05 (1H, s), 2.48
yl)carbonyl]piperidine-4- (3H, s), 2.9 - 3 (2H, m), 3.65
carboxylic acid (3H, s), 3.96 (2H, m), 7.29 - 7.38
(2H, m), 7.42 - 7.53 (3H, m), 7.7
(1H, s), 12.3 (1H, s)
N-[(5,7-diethyI-4-hydroxy- 1 - Ή NMR (DMSOd6) δ: 1.16 - 1.2 m/z: 320 methyl-2-oxo- 1 ,2-dihydro- (3H, t), 1.21 - 1.25 (3H, t), 2.78 - (M-H)+ pyrrolo[l ,2-b]pyridazin-3- 2.84 (2H, q), 2.90 - 2.96 (2H, q),
yl)carbonyl]glycine 3.7 (3H, s), 3.95 - 3.97 (2H, d),
6.26 (1H, s), 9.97 (1H, s)
4- { [(4-Hydroxy- 1 -methyl-2-oxo Ή NMR (DMSOd6) δ: 4.15 (3H, m/z: 376 1 ,2-dihydropyridazino- [1 ,6- s), 7.27 - 7.39 (3H, m), 7.78 - (M-H)+ a]indol-3-yl)carbonyl] 7.86 (3H, dd), 7.96 - 7.98 (2H,
amino} benzoic acid d), 8.1 (1H, s), 12.49 (1H, s),
12.87 (1H, s).
N- [( 1 -benzyl-4-hydroxy-2-oxo- 1 H NMR (DMSOd6) $: 4.13 - 390 1 ,2-dihydropyridazino [ 1 ,6- 4.14 (2H, d), 5.81 (2H, s), 7.16 - (M-H)4 a]indol-3-yl)carbonyl]glycine 7.32 (8H, m), 7.70 - 7.80 (2H,
dd), 10.05 (lH, bs)
38 N-[(l-benzyl-4-hydroxy-5- Ή NMR (DMSOd6) δ: 2.66 (3H, 404
methyl-2-oxo- 1 ,2- s), 4.12 - 4.13 (2H, dj, 5.73 (2H, (M-H)+ dihydropyridazino [ 1 ,6-a]indol-3 - s), 7.14 - 7.29 (7H, m), 7.68 - yl)carbonyl]glycine 7.70 (lH, m), 7.78 - 7.80 (1H,
d), 10.07 (1H, bs)
39 N-[(l-benzyl-4-hydroxy-2-oxo- Ή NMR (DMSOd6) δ: 1.03 - 396
1,2,6,7,8,9- 1.06 (2H, s), 1.33 - 1.39 (4H, m), (M+H)+ hexahydropyridazino [ 1 ,6- 2.06 (2H, s), 3.83 - 4.01 (2H, d),
a]indol-3 -yl)carbonyl]glycine 5.55 (2H, s), 6.66 (1H, s), 7.01 - 7.08 (2H, d), 7.18 - 7.33 (3H,
m), 9.95 (1H, bs) Comp. Compound name NMR Mass No.
N-{[4-hydroxy-6-(4- Ή NMR (DMSOd6) 5: 2.29 400 methoxyphenyl)-l ,5,7-trimethyl- (3H, s), 2.40 (3H, s), 3.71 (3H, (M+H)+
2- oxo-l ,2-dihydropyrrolo[l ,2- s), 3.79 (3H, s), 3.81 (2H, s),
b]pyridazin-3- 7.00 - 7.02 (2H, d), 7.19 - 7.21
yl] carbonyl} glycine (2H, d), 10.02 (1H, bs)
N-[(6-benzyl-4-hydroxy- 1 ,5,7- Ή NMR (DMSOd6) 5: 2.30 382 trimeihyl-2-oxo- 1 ,2- (3H, s), 2.4,8 (3H, s), 3.72 (3H, (M-H)+ dihydropyrrolo[l ,2-b]pyridazin- s), 3.84 (2H, s), 4.04 - 4.05 (2H,
3- yl)carbonyl]glycine d), 7.12 - 7.28 (5H, m), 9.96
(1H, bs)
42 N-{ [4-hydroxy- l,5-dimethyl-2- Ή NMR (DMSOd6) δ: 1.23 - 372 oxo-9-(propan-2-yl)- 1 ,2- 1.30 (6H, d), 2.63 (3H, s), 3.28
dihydropyridazino [ 1 ,6-a]indol-3 - (3H, s), 3.72 - 3.78 (lH, m), 4,12 yl] carbonyl } glycine - 4.13 (2H, d), 7.22 - 7.26 (1H,
t), 7.42 - 7.44 (1H, d), 7.65 - 7.67 (1H, d), 9.75 (1H, bs),
13.00 (lH, bs)
43 N- {[4-hydroxy- 1 ,5-dimethyI-2- Ή NMR (DMSOd6) δ: 1.25 - 370 oxo-7-(propan-2-yl)- 1 ,2- 1.29 (6H, d), 2.67 (3H, s), 3.00 - (M-H)+ dihydropyridazino [ 1 ,6-a] indol-3 - 3.05 (lH, m), 4.03 - 4.04 (3H,
yl] carbonyl } gl ycine d), 4.10 - 4.12 (2H, d), 7.29 -
7.31 (lH, d), 7.63 (1H, s), 7.97 - 7.99 (lH, d), 10.15 (1H, bs),
13.00 (1H, bs)
N- [(4-hydroxy- 1 -methyl-2- Ή NMR (DMSOd6) δ: 4.16 - 315 1 ,2-dihydropyridazino[ 1 ,6- 4.17 (2H, d), 4.19 (3H, s), 7.44 - (M-H)+ a]benzimidazol-3- 7.49 (2H, m), 7.89 - 7.92 (1H,
yl)carbonyl]glycine m), 8.25 - 8.28 (lH, m), 10.31
(1H, bs)
N-{[l-(2-fluorobenzyl)-4- Ή NMR (DMSOd6) δ: 4.14 - 411 hydroxy-2-oxo- 1 ,2- 4.16 (2H, d), 5.88 (2H, s), 7.04 - (M+H)+ dihydropyridazino[l ,6- 7.12 (lH, m), 7.29 - 7.41 (4H,
a] benzimi dazol -3 - m), 7.54 - 7.56 (2H, d), 7.88 - yl] carbonyl } glycine 7.90 (lH, d), 10.17 (1H, bs) Comp. Compound name NMR Mass No.
47 N-{[l-(3-fluorobenzyl)-4- NMR (DMSOd6) δ: 4.15 - 411 hydroxy-2-oxo- 1 ,2- 4.17 (2H, d), 5.90 (2H, s), 7.10 - (M+H)+ dihydropyridazino [ 1,6- 7.14 (lH, m), 7.23 - 7.24 (1H,
a]benzimidazol-3- d), 7.28 - 7.32 (2H, m), 7.37 - yl] carbonyl} glycine 7.43 (2H, m), 7.58 - 7.60 (1H,
d), 7.87 - 7.89 (1H, d), 10.21
(lH, bs)
N- { [1 -(4-chlorobenzyl)-4- 1H NMR (DMSOde) δ: 4.16 - 427 hydroxy-2-oxo- 1 ,2- 4.17 (2H, d), 5.90 (2H, s), 7.29 - (M+H)+ dihydropyridazino [1 ,6- 7.42 (6H, m), 7.63 - 7.65 (1H,
a]benzimidazol-3- d), 7.87 - 7.89 (1H, d), 10.21
yl] carbonyl } glycine (1H, bs)
N-[(l -ethyl-4-hydroxy-2-oxo- Ή NMR (DMSOd6) δ: 1.38 - 329 1 ,2-dihydropyridazino [1,6- 1.41 (3H, t), 4.16 - 4.17 (2H, d), (M-H)+ a]benzimidazol-3- 4.71 - 4.76 (2H, q) , 7.47 - 7.53
yl)carbonyl]glycine (2H, m), 7.92 - 7.94 (1H, m),
8.07 - 8.09 (1H, m), 10.30 (1H,
bs)
N- { [4-hydroxy-2-oxo- 1 -(propan- Ή NMR (DMSOd6) δ: 1.68 (6H, 343 2-yi)- 1 ,2-dihydropyridazino [1,6- d), 4.15 - 4.16 (2H, d), 4.97 - (M-H)+ a]benzimidazol-3- 5.04 (lH, m), 7.47 - 7.54 (2H,
yl] carbonyl } glycine m), 7.84 - 7.94 (2H, m), 10.21
(1H, bs)
N-{[4-hydroxy-l-(2- Ή NMR (DMSOd6) δ: 0.92 (6H, 359 methylpropyl)-2-oxo-l ,2- d), 4.16 - 4.20 (2H, d), 4.61 - (M+H)+ dihydropyridazino[l,6- 4.63 (2H, d), 7.48 - 7.55 (2H,
a] benzimidazol-3 - m), 7.92 - 8.02 (2H, m), 10.28
yl] carbonyl } glycine (lH, bs)
N- { [ 1 -(cyclopropylmethyl)-4- 1H NMR (DMSOd6) δ: 0.42 - 357 hydroxy-2-oxo- 1,2- 0.53 (4H, m), 1.20 - Ί.23 (1H, (M+H)+ dihydropyridazino[l,6- m), 416 - 4.17 (2H, d), 4.66 - a] benzimidazol-3 - 4.67 (2H, d), 7.49 - 7.57 (2H,
yl] carbonyl } glycine m), 7.94 - 7.96 (lH, d), 8.19 - 8.22 (lH, d), 10.26 (lH, bs)
53 N-[(7-fluoro-4-hydroxy-l- !H NMR (DMSOd6) δ: 4.16 (2H, 335 methyl-2-oxo-l,2- d), 4.18 (3H, s), 7.34 - 7.40 (1H, (M+H)+ dihydropyridazino[l ,6- m), 7.71 - 7.74 (1H, dd), 8.30 - a]benzimidazol-3- 8.35 (lH, m), 10.29 (1H, bs),
yl)carbonyl]glycine 13.03 (1H, bs) Comp. Compound name NMR Mass No.
N-{[l-(4-chlorobenzyl)-7- 1H NMR (DMSOd6) β: 4.16 - 443 fluoro-4-hydroxy-2-oxo- 1 ,2· 4.24 (2H, d), 5.88 (2H, s), 7.21 - (M-H)+ dihydropyridazino [1,6- 7.29 (2H, m), 7.37 - 7.44 (3H,
a]benzimidazol-3 - m), 7.62 - 7.65 (1H, m), 7.69 - yl] carbonyl } glycine 7.72 (lH, m), 10.20 (lH, bs)
N-{[4-hydroxy-l-(4- 1H NMR (DMSOd6) δ: 3.68 (3H, 423 met oxybenzyl)-2-oxo-l ,2- s), 4.13 - 4.18 (2H, d), 5.85 (2H, (M+H)+ dihydropyridazino [1 ,6- s), 6.87 - 6.89 (2H, m), 7.24 - a]benzimidazol-3 - 7.41 (4H, ra), 7.77 - 7.87 (2H,
yljcarbonyl} glycine dd), 10.26 (1H, bs)
N-{[4-hydroxy-l-(2- 1H NMR (DMSOde) δ: 2.45 (3H, 406 methylbenzyl)-2-oxo- 1 ,2- s), 4.13 - 4.14 (2H, d), 5.74 (2H, (M+H)+ dihydropyridazino[l,6- s), 7.07 - 7.09 (2H, m), 7.21 - a]benzimidazol-3 - 7.24 (3H, m), 7.32 - 7.35 (2H,
yl] carbonyl } glycine m), 7.86 - 7.88 (lH, m), 10.26
(1H, bs)
57 N-({4-hydroxy-2-oxo-l-[4- 1H NMR (DMSOde) δ: 4.15 - 461 (trifluoromethyl)benzyl]- 1 ,2- 4.16 (2H, d), 5.98 (2H, s), 7.28 - (M+H)+ dihydropyridazinO[l ,6- 7.32 (1H, m), 7.37 - 7.40 (1H,
a]benzimidazol-3- m), 7.58 - 7.60 (1H, m), 7.64 - yl}carbonyl)glycine 7.65 (2H, m), 7.72 - 7.74 (2H,
m), 7.87 - 7.90 (lH, m), 10.19
(1H, bs)
N-({7-fluoro-4-hydroxy-2-oxo- 'H MR (DMSOde) δ: 4.16 - 479 l-[4-(trifluoromethyl)benzyl]- 4.17 (2H, d), 5.98 (2H, s), 7.22 - (M+H)+ 1 ,2-dihydropyridazino [ 1 ,6- 7.27 (lH, m), 7.57 - 7.60 (1H,
a]benzimidazol-3- m), 7.64 - 7.66 (2H, m), 7.72 - yl } carbonyl)glycine 7.74 (3H, m)
N- { [ l'-(cyclohexylmethyl)-4- Ή NMR (DMSOde) δ: 0.78 - 399 hydroxy-2-oxo- 1 ,2- 0.94 (4H, d), 1.33 - 1.48 (6H, (M+H)+ dihydropyridazino [1,6- m), 3.98 - 4.04 (2H, d), 4.31 - a]benzimidazol-3- 4.41 (1H, m), 4.51 - 4.57 (2H, s), yljcarbonyl } glycine 7.29 - 7.38 (2H, m), 7.72 - 7.93
(2H, m) Comp. Compound name NMR Mass No.
60 N-({4-hydroxy-2-oxo-l-[2- 1H NMR (DMSOd6) δ: 4.14 - 461 (trifluoromethyl)benzyl]- 1 ,2- 4.16 (2H, d), 5.92 (2H, s), 7.15 - (M+H)+ dihydropyridazino [1 ,6- 7.17 (1H, m), 7.25 - 7.27 (1H,
a]benzimidazol-3- ra), 7.37 - 7.39 (1H, m), 7.59 - yl } carbonyl)glycine 7.67 (3H, m), 7.92 - 7.95 (2H,
d), 10.12 (1H, bs), 13.03 (1H,
bs)
N-[(4-hydroxy-l-{[6- ]H NMR (DMSOd6) δ: 3.06 - 479 (morpholin-4-yl)pyridin-2 3.17 (4H, t), 3.34 - 3.52 (4H, t), (M+H)+ yljmethyl} -2-oxo- 1 ,2- 3.96 - 4.09 (2H, d), 5.75 (2H, s), dihydropyridazino [1,6- 6.39 - 6.40 (2H, d), 7.29 - 7.37
a]benzimidazol-3 - (3H, m), 7.75 - 7.93 (2H, m),
yl)carbonyl] glycine 10.12 (lH, bs)
N- { [4-hydroxy-2-oxo- 1 - Ή NMR (DMSOde) 5: 4.16 - 394 (pyridin-2-ylmethyl)- 1 ,2- 4.17 (2H, d), 6.02 (2H, s), 7.25 (M+H)+ dihydropyridazino [1,6- 7.29 (2H, m), 7.35 - 7.38 (1H, t), a]benzimidazol-3- 7.54 - 7.58 (1H, d), 7.75 - 7.79
yl] carbonyl } glycine (2H, m), 7.84 - 7.86 (1H, d),
8.44 - 8.45 (IH, d), 10.21 (1H,
bs), 13.03 (IH, bs)
63 N-{[l-(2,4-dichlorobenzyl)-4- 'H NMR (DMSOd6) 5: 4.14 - 461 hydroxy-2-oxo- 1 ,2- 4.15 (2H, d), 5.75 (2H, s), 7.21 - (M+H)+ dihydropyridazino [1,6- 7.23 (IH, d), 7.30 - 7.38 (3H,
a]benzimidazol-3- m), 7.45 - 7.47 (lH, d), 7.83 - yl] carbonyl } glycine 7.84 (IH, d), 7.90 - 7.92 (lH, d)
10.14 (IH, bs), 13.03 (IH, bs)
64 1 -[(4-hydroxy- 1 -methyl -2-oxo- Ή NMR (DMSOde) δ: 1.23 - 369 1 ,2-dihydropyridazino [ 1 ,6- 1.50 (2H, m), 1.76 - 1.90 (2H, (M-H)+ a]benzimidazol-3- m), 2.89 - 3.16 (2H, m), 3.66 - yI)carbonyl]piperidine-4- 3.85 (2H, m), 4.1 1 (3H, s), 4.29 - carboxylic acid 4.34 (lH, m), 7.38 - 7.48 (2H,
m), 7.82 - 7.86 (lH, d), 8.19 - 8.25 (IH, d)
65 N-{[l-(2-fluorobenzyl)-4- Ή NMR (DMSOd6) δ: 3.71 (3H, 423 hydroxy-2-oxo- 1 ,2- s), 4.65 - 4.68 (IH, m), 5.88 (2H, (M-H)+ dihydropyridazino [1,6- s), 7.09 - 7.12 (lH, t), 7.32 - 7.42
a]benzimidazol-3^ (5H, m), 7.52 - 7.54 (IH, d),
yl] carbonyl } alanine 7.88 - 7.90 (lH, d), 10.28 (IH,
bs) Comp. Compound name NMR Mass No.
N-[(l -ethyl-4-hydroxy-2-oxo- Ή NMR (DMSOd6) δ: 1.36 - 343 1 ,2-dihydropyridazino [1 ,6- 1.39 (3H, t), 2.58 - 2.67 (2H, t), (M-H)+ a]benzimidazol-3-yl)carbonyl] 3.58 - 3.63 (2H, d), 4.69 - 4.74
b-alanine (2H, d), 7.46 - 7.52 (2H, m),
7.91 - 7.93 (1H, m), 8.06 - 8.08
(lH, m), 10.25 (1H, bs)
67 l-[(l-benzyl-4-hydroxy-2-oxo- 1H NMR (DMSOd6) 6: 1.45 - 445 1 ,2-dihydropyridazino [1 ,6- 1.82 (4H, m), 2.83 - 2.99 (3H, (M-H)+ a]benzimidazol-3- m), 3.66 - 3.68 (IH, m), 4.37 - yl)carbonyl]piperidine-4- 4.39 (IH, m), 5.59 - 5.70 (2H,
carboxylic acid m), 7.05 - 7.36 (7H, m), 7.55 - 7.67 (IH, m), 7.82 - 7.86 (IH,
m), 12.19 - 12.22 (IH, bs)
N-{[l-(4-cyanobenzyl)-4- 'H NMR (DMSOd6) δ: 4.16 - 416 hydroxy-2-oxo- 1 ,2- 4.23 (2H, m), 5.97 (2H, s), 7.29 (M-H)+ dihydropyridazino [1 ,6- - 7.39 (2H, m), 7.42 - 7.54 (IH,
a] benzimidazol-3 - m), 7.65 - 7.66 (2H, m), 7.77 - yljcarbonyl} glycine 7.92 (3H, m), 10.18 (IH, bs),
13.03 - 13.12 (lH, bs)
N-{[l-(2-chloro-6- Ή NMR (DMSOd6) 6: 4.1 1 - 443 fluorobenzyl)-4-hydroxy-2-oxo 4.12 (2H, d), 6.01 (2H, s), 7.14 - (M-H)+ 1 ,2-dihydropyridazino[ 1 ,6- 7.17 (lH, m), 7.37 - 7.44 (4H,
ajbenzimidazol-3- m), 7.90 - 7.94 (2H, m), 10.04
yl] carbonyl } glycine (IH, bs)
N-[(4-hydroxy-2-oxo- 1 -propyl- Ή NMR (DMSOd6) δ: 0.95 - 343 1 ,2-dihydropyridazino [1 ,6- 0.97 (3H, t), 1.79 - 1.80 (2H, m), (M-H)+ a]benzimidazol-3- 4.15 - 4.17 (2H, t) , 4.67 - 4.69
yI)carbonyl]glycine (2H,d), 7.50 - 7.53 (2H, m), 7.92
- 8.01 (2H, dd), 10.30 (lH, bs)
71 N-[(l -cyclohexyl-4-hydroxy-2- Ή NMR (DMSOd6) δ: 1.12 - 385 oxo- 1 ,2-dihydropyridazino [ 1 ,6- 1.23 (6H, m), 1.54 - 1.66 (4H, (M+H)+ a]benzimidazol-3- m), 3.08 - 3.24 (lH, m) , 3.98 - yl)carbonyl]glycine 4.0 (2H, d), 7.30 - 7.34 (lH, t),
7.38 - 7.42 (IH, t), 7.62 - 7.64
(lH, d), 7.72 - 7.74 (IH, d), 9.30
(l'H, bs) 0664
93
Comp. Compound name NMR Mass
No.
72 N-{[l-(biphenyl-4-ylmethyl)-4- 1H NMR (DMSOd6) δ: 4.05 467 hydroxy-2-oxo-l,2- (2H, s) , 5.81 (2H, s), 7.15 - 7.38 (M-H)+ dihydropyridazino[l ,6- (6H, m), 7.40 - 7.42 (2H, m),
a]benzimidazol-3- 7.55 - 7.59 (3H, m), 7.76 - 7.85
yl]carbonyl}glycine (2H, m), 10.36 (1H, bs)
Combination Therapy
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 (Ϊ). When a compound of Formula (I) is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula (I) is preferred. Accordingly, 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).
Pharmaceutical compositions
In another embodiment of the invention there is provided 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
94 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. Some example of suitable 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 thereof.
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.
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.
Biological testing:
In Vitro Erythropoietin induction:
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.
Table-2:
Compound Number Concentration Erythropoietin
( uM ) ( fold induction)
~ __ , __ _
2 200 +
3 200 ++
4 200 ++++
5 50 +++++
6 ^200 ++++
7 200 +
8 50 ++
9 12.5 ++
10 200 ++++
11 50 ~ ++++
12 200 +++
13 200 +++
14 200 ++++
15 200 ++++
16 200 +++
17 100 +++ Compound Number Concentration Erythropoietin
( uM ) ( fold induction)
18 200 ++++
19 200 +
20 200 ++
21 200 +
22 200 +
23 200 ++
24 . 200 +
25 100 ++++
26 200 +
27 200 +++++
28 12.5 +
29 50 +
30 100 +
31 100 ++++
32 200 +++
33 200 +
35 . 200 +++
36 50 . +
37 200 +
38 200 +
39 200 +
40 50 +++
41 200 +
42 200 +
42 200 +++
44 . 200 +++
45 50 . +
46 100 +++
47 200 +++ Compound Number Concentration Erythropoietin
( uM ) ( fold induction)
48 100 ++++
49 200 +++
50 ' 50 ++
51 50 +
52 200 +++
53 100 ++
54 200 +++
55 200 ++++
56 100 +++
57 200 +++
58 200 ++
59 6.25 +
60 25 + '
61 200 ++ ·
62 200 +++
63 12.5 +
+ indicates <2 fold ; ++ indicates 2-4 fold; +++ indicates 5-8 fold;
++++ indicates 9-16 fold; +++++ indicates >16 fold induction
of erythropoietin respectively, relative to vehicle control.
Above data indicates that the compounds of the present invention significantly elevate the expression of erythropoietin in cells.
In vitro induction of Adrenomedullin:
Hep3B cell line (ATCC HB8064) was employed. Induction of adrenomedullin was carried out for the indicated dose of compounds for 6 hours duration. At the end of 6 hours, cells were lysed and total RNA was isolated. Expression of adrenomedullin mRNA along-with expression of 18S rRNA was monitored by real-time PCR. Adrenomedullin mRNA expression was normalized relative to the expression of 18S rRNA. The results were expressed as fold induction of adrenomedullin mRNA relative to vehicle treated control. Table-3:
Compound Concentration (uM) Adrenomedullin mRNA
Number (Fold Induction)
1 200 ++++
4 200 ++ .
5 50 ++++
11 50 ++++
14 200 +++
54 200 , ++
55 100 ++
56 100 +
57 200 +
61 200 +
+ indicates <2 fold ; ++ indicates 2-4 fold; +++ indicates 5-8 fold;
++++ indicates > 8 fold induction of adrenomedullin mRNA respectively, relative to vehicle control.
Above data indicates that the compounds of the present invention significantly elevate the expression of adrenomedullin in cells.
In Vitro induction of vascular endothelial growth factor (VEGF):
Hep3B cell line (ATCC HB8064) was employed. Induction of VEGF 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 VEGF by ELISA (R&D systems, USA). The results were expressed as fold induction as compared to vehicle control.
Table-4:
Compound Number Concentration (uM) VEGF (Fold Induction)
1 200 ++
4 200 ++
11 50 ++
14 200 ++ Compound Number Concentration (uM) VEGF (Fold Induction)
44 200 ++
46 100 ++
47 200 ++
48 100 +++
49 200 +++ 52 200 +++
+ indicates <2 fold ; ++ indicates 2-4; +++ indicates < 4 fold induction of VEGF relative to vehicle control)
Above data indicates that the compounds of the present invention significantly elevate the expression of VEGF in cells.
Effect of compounds of present invention on anemia associated with Chronic Renal Failure (CKD):
The efficacy of the test compound to correct anemia associated with CKD was studied in an animal model of anemia - 5/6 nephrectomized (5/6 NX) rats 28'29'30 Animals were randomized based upon anemia and kidney dysfunction parameters and divided into two groups. One group received compound-4 (20mg/kg; b.i.d. i.p) for seven days while the control received respective vehicle. Blood sampling was done on day 3, 7 and 1 1 post initiation of drug administration to check early markers of anemia correction.
Results:
Treatment with the test compound resulted in significant increase in circulating EPO levels ranging from 350-1900 pg/ml as compared with undetectable levels (<45 pg/ml) of circulating EPO in vehicle control. There was about 2 fold increase in reticulocyte production index on day 3 in treatment group compared to control group. Similarly there was about 40% increase in hemoglobin content, hematocrit percent and erythrocyte count on day 11 post initiation of treatment compared to control
Effect of compound of present invention on ischemia-reperfusion injury to Kidney:
The efficacy of test compound to improve renal function was evaluated in a renal ischemia and reperfusion induced acute kidney injury model in rats. Rats were randomised into two groups, compound treated and vehicle control. Before initiation of bilateral renal ischemia, the animals in compound treatment group received multiple doses of compound no. 11 (i.e. pre treated) and control group received vehicle by i.p route.
Induction of Renal ischemia and reperfusion in rats:
All animals were anesthetized with pentobarbital sodium (50 mg/kg body wt). Homeothermic blanket was used to maintain a constant body temperature of 37°C during surgery and ischemia. A midline incision was made at the ventral side to access the kidneys and both renal pedicle were isolated and occluded for 35 mins using microclips, which was verified by the change of the renal color. After an ischemic period of 35 min, the microclips were removed and reperfusion initiated. The abdomen was closed and skin & muscles sutured and animal allowed to recover. Blood sample of 300 μΐ was taken via sublingual vein puncture at various predetermined time points.
RESULTS:
Renal function improvement was assessed by measuring serum creatinine and BUN and expressed below as % reduction from their control group at 24hrs post initiation of ischemia.
Table-5;
Compound No. i.p.Dose % reduction
(mg/kg) Ser.Creatinine BUN
Compound-11 0.1 41.0 31.0
(Multiple dose)
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Claims

L A Compound of formula (I)
Figure imgf000103_0001
X= C, N
ΤΓΤ" = Single or double bond
(I)
Wherein:
Ri & R2 are independently selected from the group consisting of hydrogen, R7, - N(R9) (R9), -N(R9) (R7), -S02(R7), -S02(R9), - N(R9)(S02-R7), - N(R9)(S02-R9), - N(R9)(CO- R7), - N(R9)(CO-R9) and -C1 -8alkyl; wherein (C1-8alkyl) is optionally substituted with one or more substituents selected from R7, halo, cyano, nitro, -C(0)(R9), -C(0)(R7), -C(0)0- R9, -C(0)0-R7, -C(0)N(R9)(R9), -C(0)N(R9)(R7), -COCF3, -0(R9), -OR7, -NHOH - N(R9)(R9), -S020-R9, -S020-R7, -SR9, -SR7, -S(0)(C1-8 alkyl), -S(0)(R7), -S02(R9), -S02(R7), -S02(Ci-3alkyl)-R7, -S02N(R9)(R9), -S02N(R9)(R7), -S02CF3, -N(R9)(R9), -N(R9)(R7), -N(R9)(CO- R9), -N(R9)(CO- R7), -N(R9)(C(0)-CF3) , -N(R9)(C(0)0-R9), -N(R9)(C(0)0-R7), -N(R9)(S02- C1-8 alkyl), -N(R9)(S02- R7), -N(R9)(S02-CF3), - N(R9)C(0)N(R9)(R9), -N(R9)C(0)N(R9)(R7), -N(R9)C(0)C(0)N(R9)(R9), -N(R9)C(0) C(0)N(R9)(R7), -N(R9)C(S)N(R9)(R9), -N(R9)C(S)N(R9)(R7), -N(R9)S02N(R9)(R9), - N(R9)S02N(R9)( R7), oxo or thioxo; wherein, the above said Ci-8alkyl may be straight, branched chain or cyclic, and may contain one or two double or triple bonds; or
Ri and R2 are taken together with the nitrogen atom to which they are attached form five to ten membered 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 R8; R7 at each occurrence is selected from:
1) opitionally substituted monocyclic or bicyclic three to ten membered cycloalkyl,
2) optionally substituted monocyclic or bicyclic five to ten membered aryl,
3) optionally substituted monocyclic or bicyclic five to ten membered heterocyclyl or
4) optionally substituted monocyclic or bicyclic five to ten membered heteroaryl, wherein heterocycle or heteroaryl contain one or more heteroatom selected from nitrogen, oxygen and sulphur;
R7 may be optionally substituted with one or more R8; wherein R8 is independently selected from the group consisting of halo, cyano, nitro, -Ci-8alkyl, -C(0)CF3, CF3, - NHOH, -S02CF3, -(C1-3alkyl)m -N(R9)(CO-R9), -(C1-3alkyl)m -N(R9)(CO- aryl),-(Ci- 3alkyl)m -N(R9)(CO- heteroaryl), -(d.3arkyl)m -N(R9)(CO- heterocyclyl), -(C1-3alkyl)m - N(R9)(S02-R9), -(C1-3alkyl)m -N(R9)(S02- CF3), -(C1-3alkyl)m -N(R9)(S02- aryl), -(Ci. 3alkyl)m -N(R9)(S02- heteroaryl), -(C1-3alkyl)m -N(R9)(S02- heterocyclyI),-(Ci-3alkyl)m - N(R9)(C(0)0-R9), -(C1-3alkyl)m -N(R9)(C(0)0-aryl), -(C1-3alkyl)m -N(R9)(C(0)0- heteroaryl),-(C1-3alkyl)ra-N(R9)(C(0)0-heterocyclyl), -(C1-3alkyl)m-N(R9)C(0)N(R9)(R9), -(C1-3alkyl)m-N(R9)C(0)N(R9)(aryl), -(C1-3alkyl)m-N(R9)C(0)N(R9)(heteroaryl), -(d. 3alkyl)m-(R9)C(0)N(R9)(heterocyclyl), -(C1-3alkyl)m -N(R9)C(0)C(0)N(R9)(R9), -(C,. 3alkyl)m-N(R9)C(0)C(0)N(R9)(aryl), -(C1-3alkyl)m -N(R9)C(0)C(0)N(R9)(heteroaryl), - (C1-3alkyl)m-N(R9)C(0)C(0)N(R9) (heterocyclyl), -(Ci.3alkyl)m -N(R9)C(S)N(R9)(R9), - (C1-3alkyl)m-N(R9)C(S)N(R9)(aryl), -(C1-3alkyl)m -N(R9)C(S)N(R9)(heteroaryl), -(d. 3alkyl)m -N(R9)C(S)N(R9)(heterocyclyl), -(C1-3alkyl)m -N(R9)S02N(R9)(R9), -(d- 3alkyl)m-N(R9)S02N(R9)(aryl), -(C1-3alkyl)m-N(R9)S02N(R9) (heteroaryl), -(C1-3alkyl)m - N(R9)S02N(R9)(heterocyclyl), oxo, thioxo, -NHC(NH)NH2, -(C1-3alkyl)m-0(R9), -(Ci. 3alkyl)m-OC(0)(R9), -(C1-3alkyl)m-0(aryl), -(C1-3alkyl)m-0 (heteroaryl), -(C1-3alkyl)m- O(heterocyclyl), -(C1-3alkyl)m-S(R9), -(C1-3alkyl)m -S-aryl, -(Ci-3alkyl)m -S-heteroaryl, - (C1-3alkyl)m -S-heterocylyl, -(Ci-3alkyl)m-N((R9)(R9), -(C1-3alkyl)m-N(R9)(aryl), -(Q. 3alkyl)m-N(R9)(heteroaryl), -(Ci-3alkyl)m-N(R9)(heterocyclyl), -(C1-3alkyl)m-C(0)(R9), - (Ci-3alkyl)m-C(0)(aryl),-(C1-3alkyl)m-C(0)(heteroaryl), -(C1-3alkyl)m-C(0)(heterocyclyl),- (C1-3alkyl)m-C(0)N(R9)(R9),-(C1-3alkyl)m-C(0)N(R9)(aryl),-(C1-3alkyl)m-C
(heteroaryl), -(C1-3alkyl)m-C(0)N(R9) (heterocyclyl), -(C1-3alkyl)m -C(0)0-(R9), -(d. 3alkyl)m -C(0)0-aryl, -(C1-3alkyl)m-C(0)0-heteroaryl, -(C1-3alkyl)m -C(0)0-heterocyclyl, -(C1-3alkyl)m -S(0)(Ci-8 alkyl), -(C1-3alkyl)m-S(0)(aryl), -(C]-3alkyl)m-S(0)(heteroaryl), - (C1-3alkyl)m -S(0)(heterocyclyl), -(Ci-3alkyl)m -S02(d-8 alkyl), -(C1-3alkyl)m-S02(aryl), - (C1-3alkyl)m-S02(rieteroaryl), -(C1-3alkyl)m-S02(heterocyclyl),-(C1-3alkyl)m-S02N(R9)(R9) ,-(C1-3alkyl)m-S02 N(R9)(aryl), -(C1-3alkyl)m -S02 N(R9)(heteroaryl), -(C1-3alkyl)m -S02 N(R9)(heterocyclyl), -(C1-3alkyl)m -S(0)20(C1-8 alkyl), -(C1-3alkyl)m -S(0)20-(aryl), -(C 3alkyl)m -S(0)20-(heteroaryl), -(Ci-3alkyl)m -S(0)20-(heterocyclyl), -(C1-3alkyl)m -aryl, - (C1-3alkyl)m-heteroaryl and -(C1-3alkyl)m -heterocyclyl; wherein, the above said alkyl may be straight, branched chain or cyclic, and may contain one or two double or triple bonds; m is 0 or 1 ;
R9 is hydrogen or (Ci-8alkyl); wherein, the above said C] -8alkyl 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-3alkyl)amino, di(C1- 3alkyl)amino, -S(C1-3 alkyl), -C5.io aryl and -C1-3 alkoxy; wherein, Ci-3alkoxy may be straight or branched, may contain one or two double or triple bonds;
R is selected from the group consisting of R7, CF3, -C(0)CF3, -S02CF3 and -Ci-salkyl; wherein, the said C]-8alkyl 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 R7, halo, cyano, nitro, -NHOH, CF3, -COCF3, -S02CF3, -C(0)(R9), -C(0)(R7)s -C(0)(C,.3alkyl-R7), -C(0)0-R9, -C(0)0-R7, -C(0)N(R9)(R9), -C(0)N(R9)(R7), -SR9, -SR7, -S(0)(C1-8 alkyl), -S(0)(R7), -S02(R9), -S02(R7), -S02(C1-3alkyl)- R7, -S02N(R9)(R9), -S02N(R9)(R7), -S02CF3, -OR9, -OR7, -N(R9)(R9), -N(R9)(R7), -N(R9)(C(0)-R9), -N(R9)(C(0)-R7), -N(R9)(S02-C1-8alkyi), -N(R9)(S02-R7), -N(R9)(S02-CF3), -N(R9)C(0)N(R9)(R9), -N(R9)C(0)N(R9)(R7), - N(R9)C(0)C(0)N(R9)(R9), -N(R9)C(0)C(0)N(R9)(R7), -N(R9)C(S)N(R9)(R9), - N(R9)C(S)N(R9)( R7), -N(R9)S02N(R9)(R9), -N(R9)S02N(R9)( R7), oxo, thioxo, -S020- (R9) and -S020-(R7);
R4, R5 and Rs are each independently selected from the group consisting of -hydrogen, OH, SH, oxo, thioxo, halo, cyano, nitro, -NHOH, CF3, -COCF3, -S02CF3, -C]-8alkyl, -(Ci. 8alkyl)m -N(R9)(C(0)- R9), -(C1-8alkyl)m -N(R9)(C(0)- R7), -(Ci-8alkyl)m-N(R9)(S02- R9), -(C1-8alkyl)m -N(R9)(S02- R7), -(C1-8alkyl)m-N(R9)(S02-CF3), -(C1-8alkyl)m-N(R9)C(0)0- R9, -(C1-8alkyl)m -N(R9)C(0)0-R7, -(C1-8alkyl)m -N(R9)C(0)N(R9)(R9), -(C1-8alkyl)m- N(R9)C(0)N(R9)(R7), -(C1-8alkyl)m-N(R9)C(0)C(0)N(R9)(R9), -(C1-8alkyl)m - N(R9)C(0)C(0)N(R9)(R7), -(C1-8alkyl)m-N(R9)C(S)N(R9)(R9), -(C1-8alkyl)m-N(R9) C(S)N(R9)( R7), -(C1-8alkyl)m -N(R9)S02N(R9)(R9), -(C1-8alkyl)m -N(R9)S02N(R9)( R7), -(C1-8alkyl)m -R7, -(C1-8alkyl)m -OR9, -(C1-8alkyl)m -OR7, -(C1-8alkyl)m-SR9, -(C1-8alkyl)m - SR7, -(C1-8alkyl)m -N((R9) (R9), -(C1-8alkyl)m -N(R9)(R7), -(C1-8alkyl)m -C(0)(R9), -(d. 8alkyl)m -C(0)(R7), -(C1-8alkyl)m -C(0)N(R9)(R9), -(C]-8alkyl)m -C(0)N(R9)(R7), -(Q. 8alkyl)m -C(0)0-(R9), -(C1-8alkyl)m -C(0)0- R7, -(Ci.8alkyl)m -S(O) (R9), -(CI-8alkyl)m - S(0)(R7), -(CI-8alkyl)m -S02(R9), -(C1-8alkyl)m -S02(R7), -(C1-8alkyl)m -S02(C1-3alkyl-R7), -(C1-8alkyl)m -S02N(R9)(R9), -(C1-8alkyl)m -S02 N(R9)(R7), -(C1-8alkyl)m -S(0)20-(R9), - (C1-8alkyl)m -S(0)20-(R7) and -NHC( H)NH2; wherein, the above said C,-8alkyl may be straight, branched chain or cyclic, and may contain one or two double or triple bonds; or R4 and R5 are joined together to form a ring R7 or
R5 and R6 are joined together to form ring R7; with a proviso that when X=C, R3 is alkyl or alkyl substituted by aryl, R4, R5, R6 is independently hydrogen or chloro and
c) R] is hydrogen then R2 is not -CH2COOH or
d) R2 is hydrogen then R[ is not -CH2COOH.
2. The compound of formula (I) as claimed in claim 1, wherein at least one of the X is N.
3. The compound as claimed in claim 1 or 2, wherein R4 and R5 are joined together to form a ring R7.
4. The compound as claimed in claim 1 or 2, wherein R5 and R6 are joined together to form a ring R7.
5. The compound as claimed in claim 1 or 2, wherein j is optionally substituted -C]. galkyl.
6. The compound as claimed in claim 1 or 2, wherein Ki is R7.
7. The compound as claimed in claim 1 or 2, wherein
Figure imgf000107_0001
and R2 are taken together with the nitrogen atom to which they attached form five to ten membered heterocyclyl or heteroaryl ring.
8. The compound as claimed in claim 1, which is selected from the group consisting of: N-[(4-hydroxy-l,8-dimethyl-2-oxo-2,5,6,7-tetrahydro-l H-cyclopenta [3,4] pyrrolo[l ,2-b] pyridazin-3 -yl)carbonyl] glycine;
N-[(l-benzyl-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro-lH-cyclopenta [3,4] pyrrolo [1 ,2-b]pyridazin-3-yl)carbonyl]gIycine;
N-[(l-ethyl-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro-lH-cyclopenta[3,4]pyrrolo [1 ,2-b]pyridazin-3-yl)carbonyl]glycine,-
N-[(4-hydroxy-l-methyl-2-oxo-l ,2-dihydropyridazino[l ,6-a]indol-3-yl) carbonyl] glycine; a
N-[(4-hydroxy-l ,9-dimethyl-2-oxo-l ,2,5,6,7,8-hexahydropyridazino[6,l -a] isoindol-3-yl) carbonyl] glycine sodium salt;
N-[(4-hydroxy- 1 ,5,7-trimethyl-2-oxo- 1 ,2-dihydropyrrolo [ 1 ,2-b]pyridazin-3 -yl).
carbonyl] glycine;
N- { [4-hydroxy- 1 ,5,7-trimethyl-6-(morpholin-4-ylcarbonyl)-2-oxo- 1,2- ,
dihydropyrrolo[l ,2-b]pyridazin-3-yl]carbonyl}glycine;
N- { [4-hydroxy- 1 ,5,7-trimethyl-6-(morpholin-4-yl)-2-oxo- 1 ,2-dihydropyrrolo [ 1 ,2-b] pyridazin-3-yl]carbonyl} glycine;
N- { [4-hydroxy- 1 ,5,7-trimethyl-2-oxo-6-(piperidin- 1 -yl)- 1 ,2-dihydropyrrolo[l ,2-b] pyridazin-3 -yl] carbonyl } glycine;
N-[(7-fluoro-4-hydroxy-l-methyl-2-oxo-l ,2-dihydropyridazino[l ,6-a]indol-3-yl) carbonyl] glycine;
N-[(4-hydroxy- 1 -methyl-2-oxo- 1 ,2,6,7,8,9-hexahydropyridazino[l ,6-a]indol-3-yl) carbonyl]glycine; N-[(4- ydroxy-l-methyl-2-oxo-l,2-di ydropyridazino[l,6-a]indol-3-yl)carbonyl]alanine;
N_[(4-hydroxy-l,8-dimethyl-2-oxo-2,5,6,7-tetrahydro-lH-cyclopenta[3,4]pyrrolo[l,2-b^ pyridazin-3-yl)carbonyl]alanine;
N-[(4-hydroxy-l-methyl-2-oxo-l,2,6,7,8,9-hexahydropyridazino[l,6-a]indol-3-yl) carbonyljalanine;
N-[(4-hydroxy-l,5,6,7-tetramethyl-2-oxo-l,2-dihydropyrrolo[l,2-b]pyridazin-3-yl) carbonyljglycine;
N-[(4-hydroxy-l,5,6,7-tetramethyl-2-oxo-l,2-dihydropyrrolo[l,2-b]pyridazin-3-yl) carbonyljalanine;
N-[(4-hydroxy-l,6-dimethyl-2-oxo-5-phenyl-l,2-dihydropyrrolo[l,2-b]pyridazin-3-yl) carbonyljglycine;
N-[(4-hydroxy-l-methyl-2-oxo-2,6,7,8-tetrahydro-lH-cyclopenta[4,5]pyrrolo[l,2-b] pyridazin-3 -yl)carbonyl] glycine;
N-[(4-hydroxy-l ,6-dimethyl-2-oxo-5-phenyI-l ,2-dihydropyrrolo[l ,2-b]pyridazin-3-yl) carbonyljalanine;
N-[(4-hydroxy-l,6-dimethyl-2-oxo-5-phenyl-l,2-dihydropyrrolo[l,2-b]pyridazin-3-yl) carbonyl] -N-methylgly cine ;
N-[(4-hydroxy-l,9-dimethyl-2-oxo-l, 2,5,6, 7,8-hexahydropyridazino[6,l-a]isoindol-3-yl) carbonyljalanine;
4-{[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl)carbonyl] amino }cyclohexanecarboxylic acid;
N- [(4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] indol-3 -yl)carbonyl]serine; 2-{[(4-hydroxy-l -methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl)carbonyl] amino }cyclohexanecarboxylic acid;
N-[(4-hydroxy-7-methoxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino [1 ,6-a]indol-3-yl) carbonyljglycine;
N-[(4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino[l ,6-aJindol-3-yl)carbonylJ-N- methylglycine;
N-[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl)carbonylJglycine sodium salt;
N- [(4-hydroxy- 1 ,6-dimethyl-2-oxo-5-phenyl- 1 ,2-dihydropyrrolo[l ,2-bJpyridazin-3-yl) carbonyljglycine sodium salt; 2-{[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazinoil,6-a]indol-3-yl)carbonyl] amino}-l,3-thiazole-4-carboxylic acid;
N-[(6-cyclohexyl-4-hydroxy- 1,5, 7-trimethyl -2-oxo- 1,2-dihy dropyrrolo[l, 2-b]pyridazin-3 - yl)carbonyl] glycine;
I N-[(7-chloro-4-hydr0xy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl)
carbonyl]glycine;
N-[(4,7-dihydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl] glycine;
1 - [(4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a] indol-3 -yl)carbonyl] piperidine-4-carboxylic acid;
l-[(4-hydroxy-l,6-dimethyl-2-oxo-5-phenyl-l,2-dihydropyrrolo[l,2-b]pyridazin-3-yl) carbonyl]piperidine-4-carboxylic acid;
N-[(5,7-diethyl-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyrrolo[l,2-b]pyridazin-3-yl) carbonyl] glycine;
4- { [(4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] indol-3 -yl)carbony 1] amino} benzoic acid;
N-[(l-benzyl-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl)carbonyl]glycine; . N-[(l-benzyl-4-hydroxy-5-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl] glycine;
N-[(l-benzyl-4-hydroxy-2-oxo-l,2,6,7,8,9-hexahydropyridazino[l,6-a]indol-3-yl) carbonyl]glycine;
N- { [4-hydroxy-6-(4-methoxyphenyl)- 1 ,5,7-trimethyl-2-oxo- 1 ,2-dihydropyrrolo[ 1 ,2-b] pyridazin-3-yl]carbonyl}glycine; ,
N-[(6-benzyl-4-hydroxy-l,5,7-trimethyl-2-oxo-l,2-dihydropyrrolo[l,2-b]pyridazin-3-yl) carbonyl]glycine;
N- { [4-hydroxy- 1 ,5-dimethyl-2-oxo-9-(propan-2-yl)- 1 ,2-dihydropyridazino[ 1 ,6-a] indol- 3 -yl] carbonyl } glycine;
N- { [4-hydroxy- 1 ,5-dimethyl-2-oxo-7-(propan-2-yl)- 1 ,2-dihydropyridazino [ 1 ,6-a] indol- 3 -yljcarbonyl } glycine;
N- [( 1 -benzyl-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] benzimidazol-3 -yl)carbonyl] glycine; N-[(4-hydroxy-l -methyl-2-oxo-l ,2-dihydropyridazino[l ,6-a]benzimidazol-3-yl) carbonyl] glycine;
N- { [ 1 -(2-fluorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] benzimidazol- 3-yl]carbonyl } glycine;
N- { [1 -(3-fluorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] benzimidazol- 3 -yl] carbonyl } glycine ;
N-{[l-(4-chlorobenzyl)-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a] benzimidazol- 3 -yl] carbonyl } glycine;
N-[(l-ethyl-4-hydroxy-2-oxo-l ,2-dihydropyridazino [1 ,6-a]benzimidazol-3-yl) carbonyl] glycine;
N- { [4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino[ 1 ,6-a] benzimidazol-3- yl] carbonyl} glycine;
N- { [4-hydroxy- 1 -(2-methylpropyl)-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] benzimidazol- 3 -yljcarbonyl } glycine;
N-{ [1 -(cyclopropylmethyl)-4-hydroxy-2-oxo-l ,2-dihydropyridazino [1 ,6-a]
benzimidazole-3 -yljcarbonyl } glycine;
N-[(7-fluoro-4-hydroxy- 1 -methyl -2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a] benzimidazol- 3-yl)carbonyl]glycine;
N- { [ 1 -(4-chlorobenzyl)-7-fluoro-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino [1 ,6-a] benzimidazol-3-yl]carbonyl} glycine;
N-{ [4-hydroxy- l-(4-methoxybenzyl)-2-oxo-l,2-dihydropyridazino[l,6-a] benzimidazol- 3 -yl] carbonyl } glycine;
N-{[4-hydroxy-l-(2-methylbenzyl)-2-oxo-l,2-dihydropyridazino[l,6-a] benzimidazol- 3 -yl] carbonyl } glycine;
N-({4-hydroxy-2-oxo-l-[4-(trifluoromethyl)benzyl]-l,2-dihydropyridazino[l,6-a] benzimidazol-3 -yl}carbonyl)glycine;
N-({7-fluoro-4-hydroxy-2-oxo-l-[4-(trifluoromethyl)benzyl]-l,2-dihydropyridazino [1,6-a] benzimidazol-3-yl}carbonyl)glycine;
N- { [1 -(cyclohexylmethyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino[l ,6-a] benzimidazol- 3 -yl]carbonyl } glycine;
N-({4-hydroxy-2-oxo- 1 - [2-(trifluoromethyl)benzyl]- 1 ,2-dihydropyridazino [ 1 ,6-a] benzimidazol-3 -yl } carbonyl) glycine; N-[(4-hydroxy-l - {[6-^οφ^1ϊη-4^1) ^ίάίη-2^1]ηιε 1} -2-oxo- 1 ,2- dihydropyridazino [l,6-a]benzimidazol-3-yl)carbonyl]glycine;
N.{[4-hydroxy-2-oxo-l-(pyridin-2-ylmethyl)-l,2-dihydropyridazino[l,6-a] benzimidazol- 3-yl]carbonyl}glycine;
N-{[l-(2,4-dichlorobenzyl)-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a] benzimidazol- 3-yl]carbonyl} glycine;
l-[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]benzimidazol-3-yl) carbonyl]piperidine-4-carboxylic acid;
N- { [ 1 -(2-fluorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a] benzimidazol- 3-yl] carbonyl} alanine;
N-[(l-ethyl-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6ra]benzimidazol-3-yl) carbonyl]- b-alanine;
1 -[( 1 -benzyl-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a]benzimidazol-3-yl) carbonyl]piperidine-4-carboxylic acid;
N- { [ 1 -(4-cyanobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a] benzimidazol- 3 -yl] carbonyl } glycine;
N- { [1 -(2-chloro-6-fluorobenzyl)-4-hydroxy -2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a] benzimidazol-3-yl]carbonyl}glycine;
N-[(4-hydroxy-2-oxo- 1 -propyl- 1 ,2-dihydropyridazirio [ 1 ,6-a]benzimidazol-3-yl) carbonyl] glycine;
N-[(l-cyclohexyl-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]benzimidazol-3- yl)carbonyl]glycine;
N- { [ 1 -(biphenyl-4-ylmethyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a]
benzimidazol-3 -yl] carbonyl } glycine;
N-[(4,8-dihydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl)carbonyl] glycine;
N-[(6-fluoro-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a]indol-3-yl) carbonyl]glycine;
N-[(8-fluoro-4-hydroxy-l,7-dimethyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl]glycine;
N-[(7,8-difluoro-4-hydroxy-l -methyl-2-oxo- 1 ,2-dihydropyridazino[l ,6-a]indol-3-yl) carbonyl] glycine; N (4-hydroxy-8-methoxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-y^ carbonyljglycine;
N-;[(4-hydroxy- 1 ,6,8-trimethyl-2-oxo- 1 ,2-dihydropyridazino[ 1 ,6-a]indol-3-yl)carbonyl] glycine;
N-[(8-cyano-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyljglycine;
N-{[4-hydroxy-l-methyl-8-(methylsulfonyl)-2-oxo-l,2-dihydropyridazino[l,6-a]indol- 3 -yl] carbonyl } glycine;
N-[(9-fluoro-4,6-dihydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyljglycine;
N-[(4,7,9-trihydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyljglycine;
N-[(6-fluoro-4-hydroxy-8-methoxy-l-methyl-2-oxo-l,2-dihydropyridazino[l ,6-a]indol- 3-yl)carbonyl]glycine;
N-[(8-chloro-6-fluoro-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-aJindol- 3 -yl)carbonylJ glycine;
N-[(8-tert-butyl-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-aJindol-3- yl)carbonyl]glycine;
N-[(4,8-dihydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-aJindol-3-yl)carbonyl] alanine;
N-[(4,8-dihydroxy-l,7,9 rimethyl-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyljglycine;
N-[(4,6-dihydroxy-8-methoxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-aJindol-3-yl) carbonyljglycine;
N-[(8-carbamoyl-4-hydroxy-l-metliyl-2-oxo-l,2-dihydropyridazino[l,6-aJindol-3-yl) carbonyljglycine;
N- [(4-hydroxy-7,9-dimethoxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a]indol-3 -yl) carbonyljglycine
N-{[6-(difluoromethoxy)-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a]indol- 3 -ylj carbonyl } glycine;
N- { [8-(acetyloxy)-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino [1 ,6-aJindol-3 -yl J carbonyljglycine; N- {[4-hydroxy- 1 -methyl -2-oxo-8-(trifluoromethyl)-l,2-dihydropyridazino[l,6-a]indol- 3-yl]carbonyl} glycine;
N_ { [4-hydroxy- 1 -methyl -2-oxo-6-(trifluoromethoxy)- 1 ,2-dihydropyridazino[ 1 ,6-a]indol- 3 -yl] carbonyl } glycine;
N- {[4-hydroxy- 1 -methyl-6-(morpholin-4-yl)-2-oxo-l ,2-dihydropyridazino [ 1,6-a] indol- 3 -yl] carbonyl} glycine;
N- { [4-hydroxy- 1 -methyl-6-(4-methylphenoxy)-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a]indol- 3 -yl] carbonyl} glycine;
N-{[4-hydroxy-2-oxo-l-(propan-2-yl)-8-(trifluoromethyl)-lj2-dihydropyridazino[l,6-a] indol-3-yl]carbonyl} glycine;
N-{[4-hydroxy-2-oxo-l-(propan-2-yl)-6-(trifluoromethoxy)-l,2-dihydropyridazino[l,6-a] indol-3 -yl] carbonyl } glycine;
N- { [4-hydroxy-8-methoxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino[ 1 ,6-a]indol- 3-yl]carbonyl} glycine;
N- { [6-(difluoromethoxy)-4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino [ 1 ,6-a] indol-3-yl]carbonyl}glycine;
N-{ [4-hydroxy- 1 -methyl-8-(methylsulfonyl)-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a]indol- 3-yl]carbonyl}alanine;
N-{[6-(difluoromethoxy)-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino [1 ,6-a]indol- 3 -yl] carbonyl} alanine;
N- { [8-chloro-4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino[ 1 ,6-a]indol-3- yl] carbonyl } glycine ;
N-[(l-cyclohexyl-4-hydroxy-8-methoxy-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl]glycine;
N- [( 1 -cyclohexyl-4,6-dihydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] indol-3 -yl) carbonyl] glycine;
N-[(l-cyclohexyl-6-fluoro-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl]glycine;
N-[(l-cyclopentyl-4,6-dihydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl]glycine;
N-[(l-cyclopentyl-4-hydroxy-8-methoxy-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl]glycine; if. N-[(l-cyclopentyl-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yi) carbonyl]glycine;
N-{ [1 -cyclopentyl-4-hydroxy-2-oxo-8-(trifluoromethyl)- 1 ,2-dihydropyridazino[ 1 ,6-a] indol-3 -yljcarbonyl} glycine;
N-[(l-cyclopentyl-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl)carbonyl] glycine; .
N-[(l-benzyl-6-fluoro-4-hydroxy-2-oxo-l,2-dihydropyridazino[l,6-a]indol-3-yl) carbonyl]glycine;
N-{[4-hydroxy-2-oxo-l-(pr'opan-2-yl)-l,2,6,7,8,9-hexahydropyridazino[l,6-a]indol-3-yl] carbonyl}alanine;
N-[(4-hydroxy-2-oxo-l-phenyl-l,2,6,7,8,9-hexahydropyridazino[l,6-a]indol-3-yl) carbonyljglycine;
N-[(4-hydroxy-l-methyl-2-oxo-2,6,7,8-tetrahydro-lH-cyclopenta[4,5]pyrrolo[l,2-b] pyridazin-3-yl)carbonyl]alanine;
N-{[4-hydroxy-2-oxo-l-(propan-2-yl)-2,6,7,8-tetrahydro-lH-cyclopenta[4,5]pyrrolo [ 1 ,2-b]pyridazin-3 -yljcarbonyl } alanine;
N- { [4-hydroxy-2-oxo- 1 -(propan-2-yl)-2,6,7,8-tetrahydro- 1 H-cyclopenta[4,5]pyrrolo · [1 ,2-b]pyridazin-3 -yljcarbonyl} glycine;
N- { [4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino [1 ,6-a]indol-3 -yl] carbonyljglycine;
N- { [4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino [ 1 ,6-a]indol-3 -yl] carbonyl } alanine;
N- [( 1 -cyclopentyl-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a]indol-3 -yl)carbonyl] alanine;
N-{[4-hydroxy-8-methyl-2-oxo-l-(propan-2-yl)-2,5,6,7-tetrahydro-lH-cyclopenta[3,4] pyrrolo[l,2-b]pyridazin-3-yl]carbonyl}alanine;
N- [(4-hydroxy- 1 ,9-dimethyl-2-oxo- 1 ,2,5,6,7,8-hexahydropyridazino[6, 1 -a]isoindol-3-yl) carbonyl]alanine;
N- { [4-hydroxy-9-methyl-2-oxo- 1 -(propan-2-yl)- 1 ,2,5,6,7,8-hexahydropyridazino[6, 1 -a] isoindol-3-yl]carbonyl}alanine;
N- [(4-hydroxy- 1 ,9-dimethyI-2-oxo- 1 ,2-dihydropyridazino [6, 1 -a]isoindol-3 -yl)carbonyl] glycine; N- { [4-hydroxy-9-methyl-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino[6, 1 -a]isoindol- 3 -yl] carbonyl} glycine;
N-[(4-hydroxy- 1 ,9-dimethyl-2-oxo- 1 ,2-dihydropyridazino [6, 1 -a] isoindol-3 -yl)carbonyl] alanine;
N- [(4-hydroxy- 1 ,9-dimethyl-2-oxo- 1 ,2,7,8-tetrahydropyridazino[6, 1 -a]isoindol-3-yl) carbonyl]glycine;
N- { [4-hydroxy-9-methyl-2-oxo- 1 -(propan-2-yl)- 1 ,2,7, 8-tetrahydropyridazino [6, 1 -a] isoindol-3 -yl] carbonyl } glycine;
N- [(4-hydroxy- 1 ,9-dimethyl-2-oxo- 1 ,2,7,8-tetrahydropyridazino [6, 1 -a]isoindol-3 -yl) carbonyl] alanine;
N- { [4-hydroxy-9-methyl-2-oxo- 1 -(propan-2-yl)- 1 ,2,7, 8-tetrahydropyridazino[6, 1 -a] isoindol-3 -yl] carbonyl } alanine;
N-[(4-hydroxy-l,7-dimethyl-2-oxo-l,2,6,7,8,9-hexahydropyrido [3',4':4,5]pyrrolo[l,2-b] pyridazin-3-yl)carbonyl]glycine
N- [(4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyrido [3 ',4' :4,5]pyrrolo [ 1 ,2-b]pyridazin-3 -yl) carbonyljglycine;
N- { [4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyrido[3',4':4,5]pyrrolo[ 1 ,2-b] pyridazin-3-yl]carbonyl}glycine;
N-[(l-benzyl-4-hydroxy-2-oxo-l,2-dihydropyrido[3,,4':4,5]pyrrolo[l,2-b]pyridazin-3-yl )carbonyl] glycine;
N-[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyrido[4',3':4,5]pyrrolo[l ,2-b]pyridazin-3-yl) carbonyl] glycine
N-{[4-hydroxy-2-oxo-l-(propan-2-yl)-l,2-dihydropyrido[4',3':4,5]pyrrolo[l,2-b] pyridazin-3 -yl] carbonyl } glycine;
l-[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyrido[4',3i:4,5]pyrrolo[l,2-b]pyridazin-3-yl) carbonyl]piperidine-4-carboxylic acid;
N-[(6-hydroxy-9-methyl-8-oxo-8,9-dihydropyrimido[5',4':4,5]pyrrolo[l,2-b]pyridazin- 7-yl)carbonyl]glycine;
N-{[6-hydroxy-8-oxo-9-(propan-2-yl)-8,9-dihydropyrimido[5',4':4,5]pyrrolo[l,2-b] pyridazin-7-yl]carbonyl} glycine;
N-[(9-benzyl-6-hydroxy-8-oxo-8,9-dihydropyrimido[5',4':4,5]pyrroIo[l,2-b]pyridazin-7- yl)carbonyl] glycine; N-{[5-(dimethylamino)-4:hydroxy-l -methyl-2-oxo-l ,2-dihydropyridazino[l ,6-a]indol- 3 -yl] carbonyl } glycine ;
N_ [5-(4-fluorophenyl)-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyrrolo [ 1 ,2-b]pyridazin- 3 -yl] carbonyl } glycine;
N- { [5-(4-fluorophenyl)-4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyrrolo [ 1 ,2-b] pyridazin-3 -yl] carbonyl } glycine;
N- { [4-hydroxy-5-(4-methoxyphenyl)- 1 -methyl-2-oxo- 1 ,2-dihydropyrrolo [ 1 ,2-b] pyridazin-3 -yl]carbonyl } glycine;
N-{[4-hydroxy-5-(4-methoxyphenyl)-2-oxo-l-(propan-2-yl)-l,2-dihydropyrrolo[l,2-b] pyridazin-3-yl]carbonyl}glycine;
N-{ [4-hydroxy-5-(4¾-hydroxyphenyl)- 1 -methyl-2-oxo- 1 ,2-dihydropyrrolo [1 ,2-b] pyridazin-3 -yl] carbonyl } glycine ;
N-{[4-hydroxy-5-(4-hydroxyphenyl)-2-oxo-l-(propan-2-yl)-l,2-dihydropyrrolo[l,2-b] pyridazin-3 -yl]carbonyl } glycine;
N- { [4-hydroxy-2-oxo-6-phenyl- 1 -(propan-2-yl)- 1 ,2-dihydropyrrolo[l ,2-b]pyridazin-3-yl] carbonyl}glycine;
N-[(4-hydroxy-l-methyl-2-oxo-6-phenyl-[, 2-b]dihydropyrrolo[l,2-b]pyridazin-3-yl) carbonyl]glycine;
N- { [6-(4-fluorophenyl)-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyrrolo [ 1 ,2-b]pyri dazin- 3 -yl] carbonyl } glycine;
N- { [6-(4-fluorophenyl)-4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyrrolo [ 1 ,2-b] pyridazin-3-yl]carbonyl}glycine;
N- { [4-hydroxy-6-(4-hydroxyphenyl)- 1 -methyl-2-oxo- 1 ,2-dihydropyrrolo[ 1 ,2-b] pyridazin-3 -yl]carbonyl } glycine;
N-{ [4-hydroxy-6-(4-methoxyphenyl)- 1 -methyl-2-oxo- 1 ,2-dihydropyrrolo [1 ,2-b] pyridazin-3 -yl] carbonyl } glycine;
N-{[4-hydroxy-6-(4-methoxyphenyl)-2-oxo-l-(propan-2-yl)-l,2-dihydropyrrolo[l,2-b] pyridazin-3-yl]carbonyl}glycine;
N-{[4-hydroxy-6-(4-methoxyphenyl)-5,7-dimethyl-2-oxo-l-(propan-2-yl)-l,2- dihydropyrrolo[l,2-b]pyridazin-3-yl]carbonyl}glycine;
N- [(8-fluoro-4-hydroxy- 1 -methyI-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a]benzimidazol-3 -yl) carbonyl]glycine; N (4-hydroxy-8-met oxy-l-methyl-2-oxo-l,2-di ydropyridazino[l,6-a]benzimidazo 3-yl)carbonyl]glycine;
N-{[4-hydroxy-l-methyl-2-oxo-8-(trifluoromethyl)-l ,2-dihydropyridazino[l,6-a] benzimidazol-3 -yl] carbonyl } glycine;
N-[(4-hydroxy-l,8-dimethyl-2-oxo-l,2-dihydropyridazino[l,6-a]benzimidazol-3-yl) carbonyljglycine;
N-[(8-chloro-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a]benzimidazol-3-yl) carbonyljglycine;
N-{[4-hydroxy-l-methyl-8-(moipholin-4-yl)-2-oxo-7-(trifluoromethyl)-l,2- dihydropyridazino[l,6-a]benzimidazol-3-yl]carbonyl}glycine;
N-[(4,7-dihydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]benzimidazol-3-yl) carbonyljglycine;
N- { [8-chloro-4-hydroxy- 1 -methyl-2-oxo-6-(trifluoromethyl)- 1 ,2-dihydropyridazino
[l,6-a]benzimidazoI-3-yl]carbonyl}glycine;
N-[(7-chloro-4-hydroxy-l,8-dimethyl-2-oxo-l,2-dihydropyridazino[l,6-a]benzimidazol- 3 -yl)carbonyl] glycine ;
N-[(8-carbamoyl-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a]benzimidazol- 3-yl)carbonyl]glycine;
N- { [8-fluoro-4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino [ 1 ,6-a]
benzimidazol-3 -yljcarbonyl} glycine;
N-{[4-hydroxy-8-methoxy-2-oxo-l-(propan-2-yl)-l,2-dihydropyridazino[l,6-a] benzimidazol-3 -yl] carbonyl } glycine;
N- { [4-hydroxy-2-oxo- 1 -(propan-2-yl)-8-(trifluoromethyl)- 1 ,2-dihydropyridazino [ 1 ,6-a] benzimidazol-3 -yl]carbonyl } glycine;
N-{[4-hydroxy-8-methyl-2-oxo-l -(propan-2-yl)-l ,2-dihydropyridazino [1 ,6-a]
benzimidazol-3-yl]carbonyl}glycine;
N-{[8-chloro-4-hydroxy-2-oxo-l-(propan-2-yl)-l,2-dihydropyridazino[l,6-a]
benzimidazol-3-yl]carbonyl} glycine;
N-{[4-hydroxy-8-(morpholin-4-yl)-2-oxo-l-(propan-2-yl)-7-(trifluoromethyl)-l,2- dihydropyridazino[l,6-a]benzimidazol-3-yl]carbonyl}glycine;
N-{[4,7-dihydroxy-2-oxo- 1 -(propan-2-yI)- 1 ,2-dihydropyridazino [ 1 ,6-a]benzimidazol- 3 -yl] carbonyl } glycine; N- { [8-chloro-4-hydroxy-2-oxo- 1 -(propan-2-yl)-6-(trifluoromethyl)- 1 ,2- dihydropyridazino[ 1 ,6-a]benzimidazol-3-yl]carbonyl} glycine;
N- { [7-chloro-4-hydroxy-8-methyl-2-oxo- 1 -(propan-2-yl)- 1 ,2-dihydropyridazino[ 1 ,6-a] benzimidazol-3 -yl] carbonyl } glycine;
N-[(8-hydroxy-6-oxo-5-phenyl-5,6-dihydroimidazo[l,2-b]pyridazin-7-yl)carbonyl] glycine;
N-[(8-hydroxy-5-methyl-6-oxo-5,6-dihydroimidazo[l,2-b]pyridazin-7-yl)carbonyl] glycine;
N-{[8-hydroxy-6-oxo-5-(propan-2-yl)-5,6-dihydroimidazo[l,2-b]pyridazin-7-yl] carbonyl} glycine;
N-[(5-benzyl-8-hydroxy-6-oxo-5,6-dihydroimidazo[l,2-b]pyridazin-7-yl)carbonyl] glycine
l-[(8-hydroxy-5-methyl-6-oxo-5,6-dihydroimidazo[l,2-b]pyridazin-7-yl)carbonyl] piperidine-4-carboxylic acid;
N-[(8-hydroxy-5-methyl-6-oxo-2-phenyl-5,6-dihydroimidazo[l,2-b]pyridazin-7-yl) carbonyljglycine;
N-{[8-hydroxy-6-oxo-2-phenyl-5-(propan-2-yl)-5,6-dihydroimidazo[l ,2-b]pyridazin- 7-yl]carbonyl}glycine;
N-[(4-hydroxy-l-methyl-2-oxo-l,2,5,6,7,8-hexahydropyridazino[l,6-b]indazol-3-yl) carbonyljglycine;
N-{[4-hydroxy-2-oxo-l-(propan-2-yl)-l,2,5,6,7,8-hexahydropyridazino[l ,6-b]indazol- 3 -yljcarbonyl } glycine;
N-[(4-hydroxy-l-methyl-2-oxo-l,2,5,6,7,8-hexahydropyridazino[l,6-b]indazol-3-yl) carbonyljalanine;
N- { [4-hydroxy-2-oxo- 1 -(propan-2-yl)- 1 ,2,5,6,7,8-hexahydropyridazino[ 1 ^-bJindazol-S- yl] carbonyl } alanine;
N-[(4-hydroxy-7-methyl-6-oxo-6,7-dihydropyrazolo[l,5-b]pyridazin-5-yl)carbonyl] glycine;
N-{[4-hydroxy-6-oxo-7-(propan-2-yl)-6,7-dihydropyrazolo[l,5-b]pyridazin-5-yl] carbonyljglycine;
N-[(7-benzyl-4-hydroxy-6-oxo-6,7-dihydropyrazoIo[l,5-b]pyridazin-5-yl)carbonyl] glycine; N.[(4-hydroxy-6-oxo-7-phenyl-6,7-dihydropyrazolo[l,5-b]pyridazin-5-yl)carbonyl] glycine;
l_[(4.hydroxy-7-methyl-6-oxo-6,7-dihydropyrazolo[l,5-b]pyridazin-5-yl)carbonyl] piperidine-4-carboxylic acid;
N-[(4-hydroxy-7-methyl-6-oxo-2-phenyl-6,7-dihydropyrazolo[l,5-b]pyridazin-5-yl) carbonyl]glycine;
N-{[4-hydroxy-6-oxo-2-phenyl-7-(propan-2-yl)-6,7-dihydropyrazolo[l,5-b]pyridazin- 5 -yl] carbonyl } glycine;
N-[(7-benzyl-4-hydroxy-6-oxo-2-phenyl-6,7-dihydropyrazolo[l,5-b]pyridazin-5-yl) carbonyl] glycine
N-{[4-hydroxy-7-methyl-6-oxo-2-(4-sulfamoylphenyl)-6,7-dihydropyrazolo[l,5-b] pyridazin- 5 -yl] carbonyl } glycine;
N {[4-hydroxy-6-oxo-7-(propan-2-yl)-2-(4-sulfamoylphenyl)-6,7-dihydropyrazolo[l,5-b] pyridazin-5-yl]carbonyl} glycine;
N-({2-[4-(acetylamino)phenyl]-4-hydroxy-6-oxo-7-(propan-2-yl)-6,7- dihydropyrazolo[l,5-b]pyridazin-5-yl}carbonyl)glycine;
N-({2-[4-(acetylamino)phenyl]-4-hydroxy-7-methyl-6-oxo-6,7-dihydropyrazolo[l ,5-b] pyridazin-5 -yl } carbonyl)gly cine;
N-{[4-hydroxy-2-(4-methoxyphenyl)-7-methyl-6-oxo-6,7-dihydropyrazolo[l,5-b] pyridazin-5 -yl] carbonyl} glycine;
N-{[4-hydroxy-2-(4-methoxyphenyl)-6-oxo-7-(propan-2-yl)-6,7-dihydropyrazolo
[ 1 ,5-b]pyridazin-5-yl] carbonyl } glycine;
N-({2-[4-(dimethylamino)phenyl]-4-hydroxy-7-methyl-6-oxo-6,7-dihydropyrazolo
[1 ,5-b]pyridazin-5-yl} carbonyl)glycine;
N-({2-[4-(dimethylamino)phenyl]-4-hydroxy-6-oxo-7-(propan-2-yl)-6,7- dihydropyrazolo [ 1 ,5-b]pyridazin-5-yl } carbonyl)glycine;
N-{[4-hydroxy-2-(3-methoxyphenyl)-7-methyl-6-oxo-6,7-dihydropyrazolo[l,5-b] pyridazin-5-yl]carbonyl}glycine;
N-{[4-hydroxy-2-(3-hydroxyphenyl)-7-methyl-6-oxo-6,7-dihydropyrazolo[l,5-b] pyridazin-5 -yl] carbonyl } glycine;
N-({2-[2-(acetyloxy)phenyl]-4-hydroxy-7-methyl-6-oxo-6,7-dihydropyrazolo[l,5-b] pyridazin-5-yl}carbonyl)glycine; N-({2-[2-chloro-5-(trifluoromethyl)phenyl]-4-hydroxy-7-methyl-6-oxo-6,7- dihydropyrazolo[l,5-b]pyridazin-5-yl}carbonyl)glycine;
N-({4.hydroxy-7-methyl-6-oxo-2-[4-(trifluoromethoxy)phenyl]-6,7-dihydropyrazolo [l,5-b]pyridazin-5-yl}carbonyl)glycine;
N-({4-hydroxy-7-methyl-6-oxo-2-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolp
[ 1 ,5-b]pyridazin-5-yl } carbonyl) glycine;
N-{[2-(4-fluorophenyl)-4-hydroxy-7-methyl-6-oxo-6,7-dihydropyrazolo[l,5-b]pyridazin- 5-yl]carbonyl}glycine;
N-{[2-(3-chlorophenyl)-4-hydroxy-7-methyl-6-oxo-6,7-dihydropyrazolo[l,5-b]pyridazin- 5-yl]carbonyl} glycine;
N-({4-hydroxy-7-methyl-6-oxo-2-[2-(trifluoromethyl)pheny]]-6,7-dihydropyrazolo
[l,5-b]pyridazin-5-yl}carbonyl)glycine;
N- [(4-hydroxy- 1 -methyl-2-oxo- 1,2,5 ,6-tetrahydropyridazino [ 1 ,6-b]indazol-3 -yl) carbonyljglycine;
N-{[l-(4-chlorobenzyl)-8-(dimethylamino)-4-hydroxy-2-oxo-l,2-dihydropyridazino
[ 1 ,6-a]benzimidazol-3 -yl] carbonyl } glycine;
N-{[8-(dimethylamino)-4-hydroxy-l-methyl-2-oxo-l,2-dihydropyridazino[l,6-a] benzimidazol-3-yl]carbonyl}glycine;
N- { [ 1 -(4-chlorobenzyl)-4-hydroxy-2-oxo-7-phenyl- 1 ,2-dihydropyridazino [ 1 ,6-a] benzimidazol-3-yl]carbonyl}glycine;
N-[(7-carbamoyl-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a]benzimidazol- 3-yl)carbonyl]glycine;
N- { [7-carbamoyl- 1 -(4-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino [1 ,6-a] benzimidazol-3 -yl] carbonyl } glycine ;
N- { [7-(benzyloxy)-4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyridazino[l ,6-a]
benzimidazol-3 -yl] carbonyl} glycine;
1 - { [ 1 -(4-chloroberrzyl)-4-hydroxy-7-methoxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-a] benzimidazol-3-yl]carbonyl}piperidine-4-carboxylic acid;
N-[(l-benzyl-4-hydroxy-2-oxo-l,2-dihydropyrido[3',2':4,5]imidazo[l,2-b]pyridazin-3-yl carbonyl] glycine;
N- [(4-hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydropyrido [3 ',2' :4,5] imidazo[ 1 ,2-b]pyridazin-3 -yl) carbonyl]glycine; N-[(l-benzyl-4-hydroxy-2-oxo-l,2-dihydropyr^
carbonyljglycine;
N-[(4-hydroxy-l-methyl-2-oxo-l,2-dihydropyrido[2^3^4,5]imidazo[l,2-b]pyridazin-3-yl) carbonyljglycine;
N-[(6-hydroxy-9-methyl-8-oxo-8,9-dihydropyridazino[l,6-e]purin-7-yl)carbonyl]glycine; N-[(9-berizyl-6-hydroxy-8-oxo-8,9-dihydropyridazino[l,6-e]purin-7-yl)carbonyl]glycine; N-[(9-hydroxy-2,4,6-trimethyl-7-oxo-6,7-dihydropyridazino[6,l-f]purin-8-yl)carbonyl] glycine;
N-[(6-berizyl-9-hydroxy-2,4-dimethyl-7-oxo-6,7-dihydropyridazino[6,l-f]purin-8-yl) carbonyljglycine;
N- { [ 1 -(4-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridazino [ 1 ,6-aJbenzimidazol-3 - ylj carbonyljglycine sodium salt and pharmaceutically acceptable salts thereof.
9. A pharmaceutical composition comprising a therapeutically effective amount of one or more compound of claim 1, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
10. A method of treating anemia in a mammal, including human being, the method comprising administering a therapeutically effective amount of a compound of claim 1.
11. A method of treating anemia of elderly or anemia associated with conditions like clironic diseases, renal failure, cancer, infection, dialysis, surgery, and chemotherapy in a mammal, the method comprising administering a therapeutically effective amount of a compound of claim 1.
12. A method for prevention or treatment of tissue damage caused by renal ischemia, cardiovascular ischemia, cerebrovascular ischemia, hepatic ischemia or peripheral vascular ischemia in a mammal, including human being, the method comprises administering a therapeutically effective amount of a compound of claim 1.
13. A method of 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 in a mammal, including human being, the method comprises administering a therapeutically effective amount of a compound of claim 1.
14. Use of compound of claim 1 for treating anemia in a mammal, including human being, by administering a therapeutically effective amount of the same.
15. Use of a compound of claim 1 for treating anemia of elderly or anemia associated with conditions like chronic diseases, renal failure, cancer, infection, dialysis, surgery, and chemotherapy in a mammal, by administering a therapeutically effective amount of the same .
16. Use of a compound of claim 1 for prevention or treatment of tissue damage caused by renal ischemia, cardiovascular ischemia, cerebrovascular ischemia, hepatic ischemia or peripheral vascular ischemia in a mammal, including human being, by administering a therapeutically effective amount of the same..
17. Use of a compound of claim 1 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 in a mammal, including human being, by administering a therapeutically effective amount of a compound of the same.
18. A compound of formula (I), its process for the preparation and pharmaceutical composition, as herein described with reference to the examples accompanying the specification.
PCT/IN2010/000664 2009-10-07 2010-10-06 Novel fused pyridazine derivatives WO2011048611A1 (en)

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