WO2015071780A1 - Dérivés d'hétérocyclyl substitués par alkylidine comme agents antibactériens - Google Patents

Dérivés d'hétérocyclyl substitués par alkylidine comme agents antibactériens Download PDF

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Publication number
WO2015071780A1
WO2015071780A1 PCT/IB2014/061104 IB2014061104W WO2015071780A1 WO 2015071780 A1 WO2015071780 A1 WO 2015071780A1 IB 2014061104 W IB2014061104 W IB 2014061104W WO 2015071780 A1 WO2015071780 A1 WO 2015071780A1
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compound
oxo
azetidin
prop
pharmaceutically acceptable
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PCT/IB2014/061104
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English (en)
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Takhi Mohamed
Subramanya Hosahalli
Sunil Kumar Panigrahi
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Aurigene Discovery Technologies Limited
Um Pharmauji Sdn. Bhd
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Publication of WO2015071780A1 publication Critical patent/WO2015071780A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to alkylidine substituted heterocyclyl derivatives of formula (1) which are useful as anti-bacterial agents.
  • the present invention also relates to the preparation of compounds of formula (1) and their use for the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder associated where there is an advantage in inhibiting Enoyl-ACP reductase enzyme (FABI) activity.
  • FABI Enoyl-ACP reductase enzyme
  • Fatty acid biosynthesis (or Fab) is an essential metabolic process for all living organisms. It is used to synthesize the metabolic precursors for membrane phospholipids in the cell wall. Fatty acids are synthesized by mammals (using enzyme FAS I) and bacteria (using enzyme FAS II) via substantially different biosynthetic mechanisms, thus providing the possibility of bacteria-specific drug targeting. Indeed, inhibitors targeting the various stages of the fatty acid biosynthetic pathway have been investigated as novel anti-bacterial agents. Broadly, the pathway of saturated fatty acid biosynthesis (FAB) is more or less similar in all organisms, however, the fatty acid synthase (FAS) enzymatic biosynthesis systems vary considerably with respect to their structural organization.
  • Mammalian fatty acid synthesis employs a multifunctional enzyme complex in which all enzymatic activities reside on a single polypeptide.
  • bacterial fatty acid synthesis (FAS-II) elongation cycle utilizes several distinct monofunctional enzymes with activity pertaining to respective enzyme peptides effecting fatty acid chain elongation and ultimately cell membrane production.
  • Enoyl acyl carrier protein reductase (Fabl) is the component of FAS- II that catalyzes the final reaction in the enzymatic sequence.
  • Fabl (a protein enzyme encoded by EnVM gene) acts as an enoyl-ACP reductase (Bergler, et al, (1994), J. Biol. Chem. 269, 5493-5496) in the final step of the reactions involved in each cycle of bacterial fatty acid biosynthesis. Further rounds of this cycle, adding two carbon atoms per cycle, eventually lead to palmitoyl-ACP (16- Carbon), and subsequently the cycle is blocked largely due to feedback inhibition of Fabl by palmitoyl- ACP (Heath, et al, (1996), J. Biol. Chem. 271 , 1833-1836).
  • FabI is among one of the major biosynthetic enzymes and appears to be a key moderator in the overall bacterial fatty acid biosynthetic pathway. Therefore, FabI may be one of the meaningful target for acquiring anti-bacterial role.
  • Recent literature including US7790716, US7741339, US7557125, US7524843, US7250424, US7049310, US6846819, US6765005, US6762201 , US6730684 and US6503903 also reveals that diverse compounds are known to possess FabI inhibitory activity and have anti-bacterial role, and, therefore, may be useful for the treatment of bacterial infections in mammals, particularly in man.
  • WO2013021051A1 WO2013080222A1, WO2011061214A1 and WO2008009122A1 also disclosed the compounds possesing FabI inhibitory activity and are used as anti-bacterial agents.
  • the present invention relates to alkylidine substituted heterocyclyl derivatives of formula (1) useful as anti-bacterial agents.
  • P-Q is a linker selected from -C-, -C-C-, -C-0-, -C-C-C-, -C-N-C-, -C-0-C-; wherein P-Q linker is optionally substituted with one or more R5 to meet the desired valency requirements;
  • Ri is se logen, nitro, cyano, hydroxyl and alkyl
  • R 2 is wherein, Ring A is optionally substituted 4-6 membered monocyclic ring containing 0-2 heteroatoms independently selected from N and S; wherein the optional substituent at each occurrence is independently selected from one or more R4;
  • R3 is selected from hydrogen and alkyl
  • R4 is selected from halogen, alkyl and alkoxy
  • each R5 is independently selected from halogen, alkyl, cyano and -C(0)Oalkyl; alternatively, two of the R5 groups on the same carbon atom can be taken together to form a 3-6 membered spiro ring optionally containing a heteroatom, wherein the heteroatom is ⁇ ' ;
  • 'n' is an integer selected from 1 and 2;
  • 'p' is an integer selected from 0 and 1.
  • composition comprising alkylidine substituted heterocyclyl derivatives of formula (1) and processes for preparing thereof.
  • novel alkylidine substituted heterocyclyl derivatives of formula (1) it relates to the use of novel alkylidine substituted heterocyclyl derivatives of formula (1), its pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof, including mixtures thereof in all suitable ratios wherever applicable as a medicament for the treatment and prevention of disorder or diseases by inhibitory action on enzymes- Fabl or FabK or both.
  • Embodiments of the present application provides novel alkylidine substituted heterocyclyl derivatives of formula (1) useful as anti-bacterial agents.
  • One of the embodiment of the present invention provides compound of formula (1):
  • P-Q is a linker selected from -C-, -C-C-, -C-0-, -C-C-C-, -C-N-C-, -C-0-C-; wherein P-Q linker is optionally substituted with one or more R 5 to meet the desired valency requirements;
  • Ri is se logen, nitro, cyano, hydroxyl and alkyl
  • R 2 is wherein, Ring A is optionally substituted 4-6 membered monocyclic ring containing 0-2 heteroatoms independently selected from N and S; wherein the optional substituent at each occurrence is independently selected from one or more R4;
  • R3 is selected from hydrogen and alkyl
  • R4 is selected from halogen, alkyl and alkoxy
  • each R5 is independently selected from halogen, alkyl, cyano and -C(0)Oalkyl; alternatively, two of the R5 groups on the same carbon atom can be taken together to form a 3-6 membered spiro ring optionally containing a heteroatom, wherein the heteroatom is ⁇ ' ;
  • 'n' is an integer selected from 1 and 2;
  • 'p' is an integer selected from 0 and 1.
  • Ring A is selected from thiophene, thiazole and optionally substituted phenyl.
  • halogen is fluoro
  • alkyl is methyl
  • alkoxy is methoxy
  • the compound of formula (1) is a compound of formula l a):
  • R 2 is selected from thiazole and phenyl.
  • R 5 at each occurrence is alkyl; in particular alkyl is methyl.
  • the compound of formula (1) is a compound of formula (lb)
  • Ri, R 2 , R 3 , R5 and 'n' are same as defined in formula (1);
  • X is selected from C and O.
  • R 5 at each occurrence is selected from hydrogen and alkyl; in particular alkyl is methyl and ethyl.
  • the compound of formula (1) is a compound of formula (lc)
  • X is selected from C, O and NR 5 ;
  • Ri, R 2 , R3, R5 and 'n' are same as defined in claim 1.
  • R 5 is hydrogen and -C(0)Oalkyl; in particular alkyl is tert-butyl.
  • the compound of formula (1) is selected from the group consisting of
  • the definition of "compounds of formula (1)" inherently includes all stereoisomers of the compound of formula (1) either as pure stereoisomer or as amixture of two or more stereomers.
  • stereoisomers includes enantiomers, diasteroisomers, racemates, cis isomers, trans isomers and mixture thereof.
  • the absolute configuration at an asymmetric atom is specified by either R or S.
  • Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • a specific stereisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1 % of the other isomers.
  • the invention further provides the use of alkylidine substituted heterocyclyl derivatives of formula (1) in combination with anti-bacterial agents such as cephalosporins, quinolones and fluoroquinolones, penicillins, penicillins and beta lactamase inhibitors, carbepenems, monobactams, macrolides and lincosamines, glycopeptides, rifampin, oxazolidonones, tetracyclines, aminoglycosides, streptogramins, sulfonamides, and the like.
  • anti-bacterial agents such as cephalosporins, quinolones and fluoroquinolones, penicillins, penicillins and beta lactamase inhibitors, carbepenems, monobactams, macrolides and lincosamines, glycopeptides, rifampin, oxazolidonones, tetracyclines, aminoglycosides, streptogramins,
  • antibiotic agent does not include an agent that is a Fabl inhibitor, so that the combinations of the present invention in certain instances will include one agent that is a Fabl inhibitor and another agent that is not other anti-bacterial compounds.
  • a preferred composition is comprising a compound of formula (1) and Cyclosporin A, FK506, rapamycin, 40-(2- hydroxy)ethyl-rapamycin.
  • compositions may comprise a compound of formula (1) and a rheumatoid arthritis active agent selected from leflunomide, etanercept (Enbrel), infliximab (Remicade), anakinra (Kineret), adalimumab (Humira), rituximab (Rituxan), and abatacept (Orencia).
  • a rheumatoid arthritis active agent selected from leflunomide, etanercept (Enbrel), infliximab (Remicade), anakinra (Kineret), adalimumab (Humira), rituximab (Rituxan), and abatacept (Orencia).
  • alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms; in particular alkyl is Ci- Qo alkyl group which may have 1 to 10 (inclusive) carbon atoms in it; in more particular alkyl is Ci-Ce alkyl group which may have 1 to 6 (inclusive) carbon atoms in it and in more preferred particular alkyl is C1-C4 alkyl group which may have 1 to 4 (inclusive) carbon atoms in it.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • An alkyl group can be unsubstituted or substituted with one or more suitable groups.
  • Alkoxy refers to the group alkyl-O- or -O-alkyl, where alkyl group is as defined above.
  • Exemplary Ci-Cioalkyl group containing alkoxy groups include but are not limited to methoxy, ethoxy, «-propoxy, wo-propoxy, «-butoxy and i-butoxy.
  • An alkoxy group can be unsubstituted or substituted with one or more suitable groups.
  • Halogen or "halo” includes fluorine, chlorine, bromine or iodine.
  • Cyano refers to -CN group.
  • Hydroxy or “Hydroxyl” refers to -OH group.
  • Niro refers to -N0 2 group.
  • Cycloalkyl refers to a non-aromatic, saturated or unsaturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system.
  • Representative examples of a cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl and the like.
  • a cycloalkyl can be unsubstituted or substituted with one or more suitable groups.
  • Heterocyclyl includes the definitions of "heterocycloalkyl” and “heteroaryl”.
  • the term “Heterocycloalkyl” refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 10 member having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(0) 2 , NH and C(O).
  • Exemplary heterocycloalkyl groups include piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1 ,3- dioxolanyl, 1,4-dioxanyl and the like.
  • a heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups.
  • Heteroaryl refers to monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one heteroatom selected from oxygen, sulphur and nitrogen.
  • C5-C10 heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, thiadiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1 ,2,4- triazole, 1 -methyl- 1 ,2,4-triazole, lH-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenz
  • Bicyclic heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heterocyclyl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom.
  • a heteroaryl group can be unsubstituted or substituted with one or more suitable groups.
  • Hetero atom refers to a sulfur, nitrogen or oxygen atom.
  • fused as used herein with respect to two polyatomic, cyclic rings means that such rings have two adjacent atoms thereof common to both rings.
  • the two adjacent atoms can be C or N.
  • the fused ring can be 4-6 membered ring inclusive of the fused bond.
  • membered ring can embrace any cyclic structure.
  • membered is meant to denote the number of skeletal atoms that constitute the ring.
  • cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, and thiophene are 5 -membered rings.
  • suitable groups
  • Comprise or “Comprising” is generally used in the sense of include, that is to say permitting the presence of one or more features or components.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable derivatives” is taken to mean an active ingredient, which comprises a compound of the formula (1) in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier.
  • the pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.
  • the terms “treat”, “treating” or “treatment” encompass either or both responsive and prophylaxis measures, e.g., measures designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms.
  • responsive and prophylaxis measures e.g., measures designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms.
  • the terms “treat,” “treating” or “treatment” include, but are not limited to, prophylactic and/or therapeutic treatments.
  • the terms "subject” or “patient” are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human.
  • the subject is a subject in need of treatment or a subject with a disease or disorder.
  • the subject can be a normal subject.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered.
  • terapéuticaally effective amount refers to a sufficient amount of a compound or a composition being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • “Pharmaceutically acceptable” means that, which is useful in preparing a pharmaceutical composition that is generally safe, non- toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • compositions can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods.
  • oral including buccal or sublingual
  • rectal nasal
  • topical including buccal, sublingual or transdermal
  • vaginal or parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • Novel alkylidine substituted heterocyclyl derivatives of formula (1), its pharmaceutically acceptable salts and stereoisomers thereof and the other active ingredients can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes can be formed from suitable lipids or phospholipids or both, such as, for example, cholesterol, stearylamine or phosphatidylcholines or the like.
  • a therapeutically effective amount of a compound of the formula (1) and of the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating doctor or vet.
  • an effective amount of a compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to lOmg/kg of body weight per day.
  • the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same.
  • An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se.
  • the present invention relates to a process for preparing alkylidine substituted heterocyclyl derivatives of formula (1).
  • An embodiment of the present invention provides the FABI inhibitor compounds according to formula (1) may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present invention claimed herein. All temperatures are in degrees Celsius (°C) unless otherwise noted.
  • the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2 H ("D"), 3 ⁇ 4 U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I and 125 I.
  • Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.
  • Another embodiment of the present invention provides methods useful for making the compounds of formula (1) are set forth in the examples below and generalized in below scheme.
  • One of skill in the art will recognize that the below scheme can be adapted to produce the compounds of formula (1) and their pharmaceutically acceptable salts and stereoisomers thereof.
  • Another embodiment of the present invention provides methods useful for making the compounds of formula (1) are set forth in the examples below and generalized in below scheme.
  • One of skill in the art will recognize that the below schemecan be adapted to produce the compounds of formula (1) and pharmaceutically accepted salts of compounds of formula (1) according to the present invention. Wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented herein by below scheme.
  • the formula 1.0 can undergo Arbuzov reaction with triethyl phosphite at a temperature of about 120°C to 150°C for about 16-48 h to provide 2.0.
  • the compound-A (ieri-butyl 4-oxoazetidine-l-carboxylate or tert-butyl 3-oxopyrrolidine-l -carboxylate) can undergo Wittig reaction with formula 1.1 to provide formula 1.2.
  • This reaction can be carried out in suitable solvents such as DCM, toluene, THF, diethyl ether, and the like, in the presence of suitable base such as NaOBu', KOBu', NaHMDS, LiHMDS, BuLi and their molar solutions and the like, at a temperature of about -30°C to 20-35°C for about 16-48 h.
  • suitable base such as NaOBu', KOBu', NaHMDS, LiHMDS, BuLi and their molar solutions and the like
  • compound-A teri-butyl 4-oxoazetidine-l-carboxylate or tert-butyl 3- oxopyrrolidine-l-carboxylate
  • Wittig horner reaction with formula 2.0 to provide formula 1.2.
  • This reaction can be carried out in suitable solvents such as THF, toluene, benzene and the like, in the presence of suitable base such as NaH, NaOBu', KOBu' and the like, at a temperature of about 20-35X! to 85°C for about 2-16 h.
  • suitable base such as NaH, NaOBu', KOBu' and the like
  • the Boc- deprotection of formula 1.2 can be carried out by using the suitable deprotecting agents such as TFA, HC1 in ether solutions and the like, in suitable solvents such as DCM, diethyl ether, THF and the like, at a temperature of about 0°C to 20-35°C for about 2-6 h to provide formula 1.3.
  • the compounds of the present invention of formula- 1 can be synthesized from formula 1.3 and 1.6 through acid-amine coupling, alternatively from formula- 1.4 and 1.5 through Pd catalyzed C-C bond formation.
  • the reactions progresses can be monitored by conventional methods such as TLC/NMR7LC-MS/ES-MS.
  • the formula 1.4 can be synthesized by treating formula 1.3 with acryloyl chloride in presence of suitable solvents such as DCM, THF, diethyl ether and the like, in the presence of suitable base such as Triethylamine, pyridine and the like, at a temperature of about 0°C to 20-35°C for about 3-16 h.
  • suitable solvents such as DCM, THF, diethyl ether and the like
  • suitable base such as Triethylamine, pyridine and the like
  • the acid-amine coupling of formula 1.3 with formula 1.6 can be carried out by a conventional amide bond formation method by using a suitable coupling reagents such as benzotriazole-containing coupling reagents such as 1 -hydroxybenzotriazole (HOBt), benzotriazole-l-yloxytris (dimethylamino)phosphoniumhexafluorophosphate and 2-(lH- benzotriazol-l-yl)-l,l ,3,3-tetra methyluroniumhexafluorophosphate and also the dicarboimides containing reagent such as l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodi imide, HATU and the like, in a suitable solvent such as DMF, THF, DMSO or DCM and the like, in the presence of suitable bases such as TEA, DIPEA and the like, at
  • the compound of formula-1 can be synthesized by treating formula 1.4 with formula 1.5 through Pd-catalyzed C-C coupling reaction.
  • the Pd-catalyzed C-C coupling reaction can be carried out in suitable polar solvents such as DMF, propionitrile, ACN, THF or DMSO and the like, in a suitable bases such as TEA, DIPEA and the like, by using catalysts such as Pd(OAc)2, ⁇ ( ⁇ 13 ⁇ 4)2 ⁇ 2, Pd2(dba)3 and the like, in the presence of ligands P(o-tolyl)3, P(m-tolyl)3, P(p-tolyl)3 and the like, at a temperature of about 100-130°C for about 12-48 h.
  • suitable polar solvents such as DMF, propionitrile, ACN, THF or DMSO and the like
  • a suitable bases such as TEA, DIPEA and the like
  • catalysts such as Pd(OAc)
  • the microwave chemistry was performed on a CEM Explorer.
  • this reaction can be conducted in presence of Potassium teri-butoxide or n-Butyllithium instead of LiHMDS in presence of suitable solvents such as toluene or diethylether.
  • the lithium salt of ethyl isobutyrate was added dropwise over 30 min and the reaction mixture was allowed to stir at -78°C for 2 h, then allowed to 20-35°C and continued stirring at 20-35°C for 16 h.
  • the reaction mixture was quenched with NH 4 CI solution (50 mL), diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na 2 S0 4 and filtered.
  • Step-(i) Synthesis of 2,2-dimethyl-2H-pyridor3,2-biri,41oxazin-3(4H)-one (18.1)
  • Step-(ii) Synthesis of 7-bromo-2.2-dimethyl-2H-pyridor3.2-biri.41oxazin-3(4H)-one (Intermediate- 18)
  • Example-I Synthesis of (£T)-6-(3-(3-benzylideneazetidin- l-yl ' )-3-oxoprop-l-en-l -yl ' )-3 ,4- dihydro- 1 ,8-naphthyridin-2( 1 H)-one (Compound- 1 ).
  • reaction mixture was poured into ice water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (30 mL), dried over on anhydrous Na 2 S0 4 and filtered.
  • Example-II Synthesis of (£T)-tert-butyl 2-oxo-7-(3-oxo-3-(3-(thiazol-2-ylmethyl ene azetidin-l-yl prop-l -en-l-yl -2,3-dmydro-lH-pyridor2,3-eiri,41diazepine-4(5H ' )-
  • Example-Ill Synthesis of (£ )-7-(3-oxo-3-(3-(thiazol-2-ylmethylene ' )azetidin-l-yl ' )prop-l- -l-yl)-4,5-dihydro-lH-pyridor2,3-eiri ,41diazepin-2(3H)-one hydrochloride (Compound-
  • Example-IV Synthesis of 3,3-dimethyl-6-((£T)-3-oxo-3-((£ )-3-(thiazol-4-ylmethylene ' ) pyrrolidin- 1 -yDprop- 1 -en- 1-ylV 3,4-dihydro- 1 ,8-naphthyridin-2( 1 H)-one (Compound-26) &
  • Step-(i) Synthesis of diethyl (thiazol-4-ylmethyl)phosphonate (26a).
  • Triethyl phosphite (15 mL) was added to 4-(chloromethyl)thiazole (2.1 g, 15.79 mmol) at 20-35°C and the reaction mixture was allowed to stir at 140°C for 24 h. Then the reaction mixture was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 10% methanol/dichloromethane as an eluent to get the desired compound as an oily liquid (3.5 g, 93%); LC-MS: 236.1 (M+l) + .
  • FabI ASSAY PROTOCOL Compounds were evaluated for their potency to inhibit Staphylococcus aureus FabI in a spectrophotometric assay adapted from the reported protocol used by Kaplan et al., with some modifications [Kaplan N, Albert M, Awrey D, Bardouniotis E, Berman /, Clarke T, Dorsey M, Hafkin B, Ramnauth /, Romanov V, Schmid M.B, Thalakada R, Yethon /, Pauls H.W 2012. Mode of Action, In Vitro Activity, and In Vivo Efficacy of AFN-1252, a selective antistaphylococcal FabI Inhibitor. Antimicrobial Agents and Chemotherapy 56 (l l) p.5865-5874)].
  • the enzymatic assay is based on the decrease in absorbance at 340 nm resulting from the oxidation of NADPH accompanying the reduction of enoyl - ACP, catalyzed by 5. aureus FabI enzyme.
  • the assay buffer was 100 mM Sodium ADA (N-[2-Acetamido] iminodiacetic acid) buffer, pH 6.5.
  • 20 ⁇ 1 of FabI enzyme (2400ng/assay) and ⁇ of NADH (375 ⁇ ) were pre-incubated with test compounds for 30 minutes and the reaction was started by adding 10 ⁇ of Crotonoyl CoA (250 ⁇ ).
  • IC 50 values were estimated by fitting the dose-response data to sigmoidal dose response (variable slope), curve fitting program using Graphpad Prism software V5.
  • IC 50 values of the selected compounds of present invention were provided in table A, Compounds exhibiting IC50 values ⁇ 0.3 ⁇ were grouped as 'a' , and compounds exhibiting IC50 value in the range IC50 value >0.31 ⁇ were grouped as 'b' .
  • Table A FABI inhibition activity of the selected compounds (IC 50 ).
  • test compound required quantity of the test compound was weighed and dissolved in suitable solvent to yield lmg/ml stock solution.
  • the stock solution was diluted in MHB / CAMHB (Mueller Hinton Broth/Cation adjusted Mueller Hinton Broth) by serial two fold dilutions of the compounds in 96 well microtitre trays.
  • Organisms were grown in MHA overnight at 35 ⁇ 2°C and the inoculum was prepared by directly suspending colonies from an overnight grown culture in 0.9% saline or MHB and the optical density(OD) adjusted at 625nm which corresponds to 0.5 Mc Farland (1-2 x 10 8 cfu/ml) and cultures were further diluted 1 :1000 times. To each of the wells of the microtitre tray, 50 ⁇ .

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés d'hétérocyclyl substitués par alkylidine de formule (1), qui peuvent être thérapeutiquement utiles comme agents antibactériens, plus particulièrement comme inhibiteurs de FabI; I dans lesquels P, Q, Ri, R2, R3 et « n » ont les même sens donnés dans la description, et des sels pharmaceutiquement acceptables ou des stéréoisomères pharmaceutiquement acceptables de ces derniers qui sont utiles pour le traitement et la prévention de maladies ou troubles, en particulier leur utilisation pour des maladies ou troubles dans lesquels il y a un avantage à inhiber l'activité enzyme enoyl-ACP réductase (FABI). La présente invention concerne également des procédés pour la synthèse et l'administration des composés inhibiteurs de FabI. La présente invention concerne également des formulations pharmaceutiques comprenant au moins un des composés inhibiteurs de FabI conjointement avec un support, un diluant ou un excipient pharmaceutiquement acceptable pour ces derniers.
PCT/IB2014/061104 2013-11-12 2014-04-30 Dérivés d'hétérocyclyl substitués par alkylidine comme agents antibactériens WO2015071780A1 (fr)

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IN5133/CHE/2013 2013-11-12
IN5133CH2013 2013-11-12

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011061214A1 (fr) * 2009-11-18 2011-05-26 Fab Pharma Sas Nouveaux acrylamides hétérocycliques et leur utilisation en tant que produits pharmaceutiques
WO2013021051A1 (fr) * 2011-08-10 2013-02-14 Janssen R&D Ireland 3,4-dihydro-1h[1,8]naphtyridinones substituées par homopipéridinyle antibactériennes
WO2013021052A1 (fr) * 2011-08-10 2013-02-14 Janssen R&D Ireland 3,4-dihydro-1h[1,8]naphtyridinones substituées par pipéridinyle antibactériennes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011061214A1 (fr) * 2009-11-18 2011-05-26 Fab Pharma Sas Nouveaux acrylamides hétérocycliques et leur utilisation en tant que produits pharmaceutiques
WO2013021051A1 (fr) * 2011-08-10 2013-02-14 Janssen R&D Ireland 3,4-dihydro-1h[1,8]naphtyridinones substituées par homopipéridinyle antibactériennes
WO2013021052A1 (fr) * 2011-08-10 2013-02-14 Janssen R&D Ireland 3,4-dihydro-1h[1,8]naphtyridinones substituées par pipéridinyle antibactériennes

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