WO2024069378A1 - Novel compounds for the treatment of mammalian infections - Google Patents
Novel compounds for the treatment of mammalian infections Download PDFInfo
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- WO2024069378A1 WO2024069378A1 PCT/IB2023/059482 IB2023059482W WO2024069378A1 WO 2024069378 A1 WO2024069378 A1 WO 2024069378A1 IB 2023059482 W IB2023059482 W IB 2023059482W WO 2024069378 A1 WO2024069378 A1 WO 2024069378A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- oxetan
- piperazin
- phenyl
- methyl
- formula
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 88
- 208000015181 infectious disease Diseases 0.000 title claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 241000192125 Firmicutes Species 0.000 claims abstract description 10
- -1 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one Chemical compound 0.000 claims description 84
- 238000000034 method Methods 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
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- 125000005843 halogen group Chemical group 0.000 claims description 5
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
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- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- KXYJCOMKJRZAEN-UHFFFAOYSA-N n,n-dimethylformamide;ethanamine Chemical compound CCN.CN(C)C=O KXYJCOMKJRZAEN-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- LVSJDHGRKAEGLX-UHFFFAOYSA-N oxolane;2,2,2-trifluoroacetic acid Chemical compound C1CCOC1.OC(=O)C(F)(F)F LVSJDHGRKAEGLX-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 210000004708 ribosome subunit Anatomy 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- BZORURUBWYXNAX-UHFFFAOYSA-N tert-butyl 4-(oxetan-3-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1COC1 BZORURUBWYXNAX-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the present invention relates to novel compounds of the Formula (I), their stereoisomers, their suitable pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation. These compounds show activity against bacterial infection. BACKGROUND OF THE INVENTION As per World Health Organization (WHO) statistics, ⁇ 50000 patients die from infectious diseases every day worldwide.
- WHO World Health Organization
- Linezolid is approved antibiotic for Gram-positive bacterial infections.
- Linezolid and other oxazolidinone class of agents inhibits bacterial protein synthesis by binding to the peptidyl transferase center of the 50S ribosomal subunit and interfering with the placement of the aminoacyl-tRNA.
- thrombocytopenia is the most common adverse effect associated with Linezolid treatment especially in children (Arch Argent Pediatr 2017; 115(5): 470-475). Other major side effect includes peripheral & ocular neuropathy.
- WO 2017/156519 describes small molecules with activity against gram negative bacteria.
- WO 2017/070024 describes substituted oxazolidinone derivatives and use thereof as antibacterial agents.
- WO 2020/021468 describes novel compounds for the treatment of tuberculosis.
- the other documents that describe oxazolidinone class of inhibitors including, CN 1749256, WO 2010/058423, WO 2017/015106, WO 2014/141218, WO 2013/054275, WO 2010/036000, WO 2007/023507, WO 2005/005420 are also disclosed.
- SUMMARY OF THE INVENTION discloses novel compounds of the Formula (I).
- the compounds of the present invention are useful in the treatment of the human or animal body, by regulation of bacterial protein synthesis.
- the compounds of this invention are therefore suitable for the treatment of bacterial infection especially related to Gram-positive bacteria.
- the main objective of the present invention is to provide novel compounds of Formula (I), novel intermediates involved in their synthesis, their stereoisomers, their suitable pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures suitable for the treatment of bacterial infection.
- novel compounds of the present invention for the treatment of mammalian infections such as skin infections, lung infections and tissue infections, by administering a therapeutically effective & non-toxic amount of the compound of Formula (I), or their pharmaceutically acceptable compositions to the mammals.
- a pharmaceutical composition comprising the compound of Formula (I) and second therapeutic agent for the treatment of mammalian infections caused by Gram-positive bacteria.
- the present invention also relates to compounds of the Formula (I-a) or their suitable pharmaceutically acceptable salts, Wherein Q, R 1 , R 2 and Y are as defined above.
- the present invention also relates to compounds of the Formula (I-b) or their suitable pharmaceutically acceptable salts, Wherein Q, R 1 , R 2 and Y are as defined above.
- radicals described above may be selected from: - the “alkyl” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, and the like; - the “alkoxy” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbon attached to oxygen atom, selected from Methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso- butoxy, pentyloxy, hexyloxy and the like; - the “acyloxy” group used either alone or in combination with other radicals, denotes
- aminoalkyl refers to an alkyl group in which one or more hydrogen atom of the alkyl is replaced with an amino group, as defined herein.
- aryl or “aromatic” group used either alone or in combination with other radicals, is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like;
- the “heterocyclyl” or “heterocyclic” group used either alone or in combination with other radicals is selected from suitable saturated, partially saturated or unsaturated aromatic or non-aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen;
- the heterocycle group wherever applicable, may consists of appropriate number of
- Preferred “(C 1 -C 6 )alkyl” group of R 3 , R 4 and R 5 is selected from methyl, ethyl, n-propyl, iso-propyl;
- Preferred “(C 3 -C 6 )cycloalkyl” group of R 3 , R 4 and R 5 is selected from cyclopropyl and cyclobutyl;
- Preferred “heteroaryl” group of R 3 and R 4 is selected from triazolyl, isoxazolyl, thienyl, furyl. Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
- Preferred compounds according to the present invention include but are not limited to: 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (S)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; N-((3-(3,5-difluoro-4-(4-(oxe
- novel compounds of this invention may be prepared using the reactions and techniques as shown in scheme below and described in this section.
- the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being affected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the present invention. It will also be well appreciated that one or more of the reactants may be protected and deprotected for facile synthesis by techniques known to persons skilled in the art. It will also be appreciated that one or more of the compounds of the present invention may exist in stereoisomeric and/or diastereomeric forms. Such stereoisomers as well as their optical antipodes are to be construed to be within the scope of the present invention.
- Scheme 1 Synthesis of compounds of general Formula (I)
- the compound of the general Formula (I) can be prepared by following general scheme 1.
- the compound (IV) can be obtained by reacting compounds of the Formula (II) with (III) in the presence of base such as TEA, DIPEA, Na 2 CO 3 , K 2 CO 3 , NaH etc. in solvents such as THF, DMF, MeOH, CH 3 CN etc.
- the compounds of general Formula (V) can be obtained by reduction using SnCl 2 .2H 2 O in EtOAc or catalytic hydrogenation using hydrogen gas and palladium charcoal as catalyst in solvents such as THF, MeOH etc.
- the compounds of the general Formula (VI) can be obtained by reacting (V) with benzyl oxy carbonyl chloride using NaHCO 3 as a base in solvents such as EtOAc, CH 3 CN, THF etc.
- Compounds of the Formula (VII) can be obtained by treating it with racemic epichlorohydrin using base such as cesium carbonate, n-BuLi in appropriate solvents such as THF, DMF etc. It was then reacted with sodium azide in DMF at high temperature to get azide derivative (VIII).
- the compound of the general Formula (I) can also be prepared by following general scheme 2.
- compound (V II I ) c an be reacte d with Norbornadiene or vinyl acetate under refluxing conditio n i n p resence or ab s e n ce of solvent such as Dioxane to get triazole derivative (I) .
- Scheme 3 Synthesis of comp o unds of general Formula (I-a & I-b)
- the compound (I) prepared following scheme 1 and scheme 2 can be converted into its corresponding enantiomers (I-a) and (I-b) using chiral preparative HPLC purification technique.
- Scheme 4 Synthesis of compounds of general Formula (I-a)
- the compound of the general Formula (I-a) can be prepared by following general scheme 4.
- the compound of the general Formula (I-a) can also be prepared by following general scheme 5.
- compound (XI) can be reacted with Norbornadiene or vinyl acetate under refluxing condition in presence or absence of solvent such as Dioxane to get triazole derivative (I-a).
- Step 4 benzyl (3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate
- NaHCO 3 15.25 g, 18.2 mmol
- benzyl chloroformate 11.36 g, 66.63 mmol
- Step 5 5-(chloromethyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl) oxazolidin-2-one
- n- butyl lithium 9.22 ml (2.5 M), 23.05 mmol
- rac-epichlorohydrin 0.13 mL, 2.73 mmol
- Step 7 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)oxazolidin-2-one
- norbornadiene 0.93 mL, 9.13 mmol
- Step 2 (R)-(3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl methanesulfonate
- TEA 1.98 ml, 14.21 mmol
- methanesulfonyl chloride 0.89 ml, 11.37 mmol
- Step 3 (R)-5-(azidomethyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one
- sodium azide 2.9 g, 44.7 mmol
- Step 4 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)oxazolidin-2-one
- step g 5.32 mmol
- Dioxane norbornadiene
- Step 1 tert-butyl (R)-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)(isoxazol-3-yl)carbamate
- tert-butyl isoxazol-3-ylcarbamate 0.346 gm, 1.877 mmol
- K 2 CO 3 0.371 gm, 2.68 mmol
- Step 2 (S)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one
- TFA 1.9 mL, 24.64 mmol
- Step 2 (S)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)-2-hydroxyacetamide
- Step 2 (S)-2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide
- TFA 4.1 mL, 53.3 mmol
- Step 2 3-fluoro-4-(4-(oxetan-3- 1- aniline
- Pd/C cat.
- Step 3 benzyl (3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate
- NaHCO 3 0.73 g, 8.71 mmol
- benzyl chloroformate 1.29 g, 3.78 mmol
- Step 4 (R)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5- (hydroxymethyl)oxazolidin-2-one
- n-butyl lithium (2.33 ml (2.5 M)
- 5.84 mmol 5- (hydroxymethyl)oxazolidin-2-one
- reaction mixture was stirred for an additional 1 h at -78°C.
- the reaction mixture was allowed to warm to RT and stirred for 16 h.
- the reaction mixture was diluted with water and EtOAc. Organic layer was separated, dried over Na 2 SO 4 , and concentrated to get the title product.
- Step 5 (R)-(3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl methanesulfonate
- TEA 1.61 ml, 11.53 mmol
- methanesulfonyl chloride 0.39 ml, 4.99 mmol
- Step 6 (R)-5-(azidomethyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one
- Step 7 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)oxazolidin-2-one
- norbornadiene (0.59 gm, 6.38 mmol)
- Reaction mixture was stirred at 100 0 C for 16 h. After complete conversion of starting material, the reaction mixture was concentrated and purified by column chromatography.
- Step 1 (S)-5-(aminomethyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one 5
- Pd/C Cat.
- sodium borohydride (0.24 gm, 6.38 mmol
- Step 2 (S)-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin- 15 5-yl)methyl)-2-hydroxyacetamide
- Step 2 (S)-2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide
- TFA 2.1 mL, 27.6 mmol
- Step 2 (S)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one
- TFA 0.89 mL, 11.59 mmol
- MIC Minimum inhibitory concentration
- MRSA Staphylococcus aureus
- VRS2 Staphylococcus aureus
- PRSP NR-46411 Streptococcus pneumoniae ATCC 700904
- MIC protocol MIC determination was done by using the reference broth microdilution method as described by the Clinical and Laboratory Standards Institute (CLSI). Briefly, bacterial cells were cultured on Mueller Hinton agar plates. Stock solutions of compounds and positive controls were prepared in DMSO. Subsequent dilutions of compounds were prepared in cation adjusted Mueller Hinton broth (CAMHB).
- test compounds were added in desired concentrations and incubated for 96h. Chloramphenicol was used in the assay as MPS inhibition control. After 96 h, the cells were fixed with 4% paraformaldehyde for 20min, then treated with 0.5% acetic acid to stop alkaline phosphatase activity. The cells were then treated with permeabilization buffer (1% triton x-100) for 30min followed by blocking with the blocking buffer (AbCAM mitogenesis in cell ELISA kit #ab110217) for 2 h. The cells were then probed for COX-1 and SDH-A using the antibodies provided in the kit.
- the protein levels were measured in the kinetic mode using Spectramax (Molecular Devices, US) and the ratio of COX-1 to SDH-A expression was calculated. The ratio with respect to the concentration of the test compounds were utilized to derive the half-maximal inhibitory concentration using GraphPad Prism.
- the compounds of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts, or pharmaceutical compositions containing them are useful as a medicament for the mammalian infections and suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
- the quantity of active component, that is, the novel compounds of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon several factors such as the particular application method, the potency of the particular compound and the desired concentration.
- novel compounds of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
- the pharmaceutical compositions further comprise an effective amount of an antibacterial agent.
- the dosage of antibacterial agent may vary within wide limits and should be adjusted, in each particular case, to the individual conditions. 5
- Use of the novel compounds of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts of the present invention use for the treatment of mammalian infection caused by Gram-positive bacteria.
- the mammalian infection caused by Gram-positive bacteria includes but not limited to skin infections, lung infections and tissue infections.
- the present invention includes a method for the treatment of mammalian infection caused by Gram-positive bacteria at least one of but not limited to skin infections, lung infections and tissue infections by administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the novel compound of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically 15 acceptable salts.
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Abstract
The present invention provides novel compounds of Formula (I) or its pharmaceutically acceptable salts. The novel compounds reported in present invention are suitable for the treatment against infection caused by Gram-positive bacteria.
Description
NOVEL COMPOUNDS FOR THE TREATMENT OF MAMMALIAN INFECTIONS FIELD OF INVENTION The present invention relates to novel compounds of the Formula (I), their stereoisomers, their suitable pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation. These compounds show activity against bacterial infection.
BACKGROUND OF THE INVENTION As per World Health Organization (WHO) statistics, ∼50000 patients die from infectious diseases every day worldwide. Evolution of multi-drug-resistant bacteria especially methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), penicillin-resistant, vancomycin-resistant Enterococcus (VRE), Streptococcus pneumoniae (PRSP), and other Gram-positive bacteria make clinical treatment very challenging. Linezolid is approved antibiotic for Gram-positive bacterial infections. Linezolid and other oxazolidinone class of agents inhibits bacterial protein synthesis by binding to the peptidyl transferase center of the 50S ribosomal subunit and interfering with the placement of the aminoacyl-tRNA. They do not bind to mammalian cytoplasmic ribosomes, but do bind to mitochondrial ribosomes which is responsible for bone marrow toxicity. Thrombocytopenia is the most common adverse effect associated with Linezolid treatment especially in children (Arch Argent Pediatr 2017; 115(5): 470-475). Other major side effect includes peripheral & ocular neuropathy. There is a high unmet need in identifying novel oxazolidinones devoid of such toxicities and which can offer safer alternative to the linezolid treatment in tackling Gram-positive bacterial infections. WO 2017/156519 describes small molecules with activity against gram negative bacteria. WO 2017/070024 describes substituted oxazolidinone derivatives and use
thereof as antibacterial agents. WO 2020/021468 describes novel compounds for the treatment of tuberculosis. The other documents that describe oxazolidinone class of inhibitors including, CN 1749256, WO 2010/058423, WO 2017/015106, WO 2014/141218, WO 2013/054275, WO 2010/036000, WO 2007/023507, WO 2005/005420 are also disclosed. SUMMARY OF THE INVENTION The present invention discloses novel compounds of the Formula (I). The compounds of the present invention are useful in the treatment of the human or animal body, by regulation of bacterial protein synthesis. The compounds of this invention are therefore suitable for the treatment of bacterial infection especially related to Gram-positive bacteria. EMBODIMENTS OF THE INVENTION The main objective of the present invention is to provide novel compounds of Formula (I), novel intermediates involved in their synthesis, their stereoisomers, their suitable pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures suitable for the treatment of bacterial infection. In another embodiment is provided pharmaceutical compositions containing compounds of Formula (I), their stereoisomers, their suitable pharmaceutically acceptable salts, solvates and their mixtures having suitable pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture. In a further another embodiment is provided the use of the novel compounds of the present invention for the treatment of mammalian infections such as skin infections, lung infections and tissue infections, by administering a therapeutically effective & non-toxic amount of the compound of Formula (I), or their pharmaceutically acceptable compositions to the mammals. In yet another embodiment is provided a method of treatment of the mammalian infection caused by Gram-positive bacteria using compound of Formula (I) or their pharmaceutically acceptable compositions to the mammals.
In final embodiment is provided a pharmaceutical composition comprising the compound of Formula (I) and second therapeutic agent for the treatment of mammalian infections caused by Gram-positive bacteria. DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention relates to compounds of the Formula (I) or their stereoisomers, their suitable pharmaceutically acceptable salts,
Wherein, Q represents O, NR6, S(O)p; p = 0-2 integer; Y represents OR3, NR3R4, NHC(O)R5; R1 is selected from H, F, Cl, CH3, CN, OH and OCH3; m =1-4 integer; R2 is selected from H, F, CH3, OH; n = 1-8 integer; R3 and R4 is independently selected from H, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, heterocyclyl and heteroaryl each of which may be further optionally substituted; R3 and R4 taken together with the nitrogen to which they are attached may form a 4- to 8- membered heterocyclyl or heteroaryl with optionally 1 to 3 additional heteroatoms selected from O, S, or N and may be further be optionally substituted; wherein (C1- C6)alkyl, (C3-C6)cycloalkyl, aryl, heterocyclyl and heteroaryl groups are optionally substituted by halo, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)acyloxy, haloalkyl, NO2, CN and NH2; R5 is independently selected from aminoalkyl, hydroxyalkyl, aryl and heteroaryl each of which may be further optionally substituted; wherein aryl and heteroaryl groups are optionally substituted by halo, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)acyloxy, haloalkyl, NO2, CN and NH2; R6 = H, CN, (C1-C6)alkyl, haloalkyl, -COCH3; -COO(C1-C6)alkyl. The present invention also relates to compounds of the Formula (I-a) or their suitable pharmaceutically acceptable salts,
Wherein Q, R1, R2 and Y are as defined above. In a preferred embodiment, Q represents O; Y represents NR3R4, NHC(O)R5; R1 is F; m =1-2; R2 is H. The present invention also relates to compounds of the Formula (I-b) or their suitable pharmaceutically acceptable salts,
Wherein Q, R1, R2 and Y are as defined above. In a preferred embodiment, Q represents O; Y represents NR3R4, NHC(O)R5; R1 is F; m =1-2; R2 is H. In a further embodiment the groups, radicals described above may be selected from: - the “alkyl” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, and the like; - the “alkoxy” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbon attached to oxygen atom, selected from Methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso- butoxy, pentyloxy, hexyloxy and the like; - the “acyloxy” group used either alone or in combination with other radicals, denotes a linear or branched radial containing acyl group attached to oxygen atom, selected from acetyloxy, propionyloxy and like;
- the “cycloalkyl”, or “alicyclic” group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; - the “haloalkyl” group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups; - The term “hydroxyalkyl” as used herein and unless otherwise indicated, refers to an alkyl group in which one or more hydrogen atom of the alkyl is replaced with a hydroxy group, as defined herein. - The term “aminoalkyl” as used herein and unless otherwise indicated, refers to an alkyl group in which one or more hydrogen atom of the alkyl is replaced with an amino group, as defined herein. - the “aryl” or “aromatic” group used either alone or in combination with other radicals, is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like; - the “heterocyclyl” or “heterocyclic” group used either alone or in combination with other radicals, is selected from suitable saturated, partially saturated or unsaturated aromatic or non-aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen; In one embodiment, the heterocycle group, wherever applicable, may consists of appropriate number of carbon atoms and include from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, p = 0-2; - the “heteroaryl” or “heteroaromatic” group used either alone or in combination with other radicals, is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S; - the term “stereoisomers” used anywhere in the specification indicates that compounds of the present invention show (R) and (S) configuration. Further preferred embodiments are those disclosed below.
Preferred “(C1-C6)alkyl” group of R3, R4 and R5 is selected from methyl, ethyl, n-propyl, iso-propyl; Preferred “(C3-C6)cycloalkyl” group of R3, R4 and R5 is selected from cyclopropyl and cyclobutyl; Preferred “heteroaryl” group of R3 and R4 is selected from triazolyl, isoxazolyl, thienyl, furyl. Suitable groups and substituents on the groups may be selected from those described anywhere in the specification. Preferred compounds according to the present invention include but are not limited to: 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (S)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; (R)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; (S)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; 2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin- 5-yl)methyl)acetamide; (R)-2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; (S)-2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; 3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (R)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one;
(S)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (S)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)- 2-hydroxyacetamide; (R)-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; (S)-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; 2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)acetamide; (R)-2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin- 5-yl)methyl)acetamide; (S)-2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin- 5-yl)methyl)acetamide; 3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (R)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (S)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one. The novel compounds of this invention may be prepared using the reactions and techniques as shown in scheme below and described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being affected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of
optimizing the formation of the compounds of the present invention. It will also be well appreciated that one or more of the reactants may be protected and deprotected for facile synthesis by techniques known to persons skilled in the art. It will also be appreciated that one or more of the compounds of the present invention may exist in stereoisomeric and/or diastereomeric forms. Such stereoisomers as well as their optical antipodes are to be construed to be within the scope of the present invention. It will also be well appreciated that one or more of these compounds may be converted to their suitable salts and other derivatives based on the specific groups present on the compounds, which can be well comprehended by persons skilled in the art. Such salts and/or other derivatives, as the case may be should also be construed to be within the scope of the present invention. Scheme 1: Synthesis of compounds of general Formula (I)
The compound of the general Formula (I) can be prepared by following general scheme 1. The compound (IV) can be obtained by reacting compounds of the Formula (II) with (III) in the presence of base such as TEA, DIPEA, Na2CO3, K2CO3, NaH etc. in solvents such as THF, DMF, MeOH, CH3CN etc. The compounds of general Formula (V) can be
obtained by reduction using SnCl2.2H2O in EtOAc or catalytic hydrogenation using hydrogen gas and palladium charcoal as catalyst in solvents such as THF, MeOH etc. The compounds of the general Formula (VI) can be obtained by reacting (V) with benzyl oxy carbonyl chloride using NaHCO3 as a base in solvents such as EtOAc, CH3CN, THF etc. Compounds of the Formula (VII) can be obtained by treating it with racemic epichlorohydrin using base such as cesium carbonate, n-BuLi in appropriate solvents such as THF, DMF etc. It was then reacted with sodium azide in DMF at high temperature to get azide derivative (VIII). Reduction of (VIII) using Triphenyl phosphine in mixture of THF and water gave compounds (I, when Y = NH2). Alternatively, reduction can also be achieved using catalytic hydrogenation using H2/Pd- C system. It was further reacted with appropriate acid derivative using general amide bond formation techniques as described in Tetrahedron 2005, 61, 10827 to get compounds of the Formula (I) with amide linkage. Scheme 2: Synthesis of compounds of general Formula (I)
The compound of the general Formula (I) can also be prepared by following general scheme 2. Compound (VII) can also be reacted with appropriate amine derivatives to get compounds of the general Formula (I, when Y = NR3R4). Compoun
d of the general can be reacted with triazole in presence of
Formula (VII)
b
ase such as Na2CO3, K2CO3
etc. in solvents such as DMF, CH3CN etc. to get compound (I
,
wh
en Y = triazole). Alternatively, compound (V
II
I
) c
an be
reacte
d with Norbornadiene or vinyl acetate under
refluxing conditio
n i
n p
resence or
ab
s
e
n
ce of solvent such as Dioxane to get triazole derivative (I)
. Compound (VII) can be reacted with (IX) in presence of base such as Na
2CO3, K2CO
3 etc. in solvents such as DMF, CH3C
N e
tc. f
ollowed
by
deprotection using TFA in
D
CM
to
get compound (I,
when Y = aminoisoox
az
ole
)
. Scheme 3: Synthesis of comp
o
unds of general Formula (I-a & I-b)
The compound (I) prepared following scheme 1 and scheme 2 can be converted into its
corresponding enantiomers (I-a) and (I-b) using chiral preparative HPLC purification
technique. Scheme 4: Synthesis of compounds of general Formula (I-a)
Alternatively, the compound of the general Formula (I-a) can be prepared by following general scheme 4. Compounds of the Formula (I-a, when Y = OH) can be obtained by treating (VI) with n-butyl lithium and R-glycidyl butyrate in THF. It was then converted into mesylate derivatives (X) using methane sulfonyl chloride and TEA in solvents such as THF, CH3CN, DCM etc., which was then reacted with sodium azide in DMF at high temperature to get azide derivative (XI). Reduction of (XI) using Triphenyl phosphine in mixture of THF and water gave compounds (I-a, when Y = NH2). Alternatively, reduction can also be achieved using catalytic hydrogenation using H2/Pd-C system. It was further reacted with appropriate acid derivative using general amide bond formation techniques as described in Tetrahedron 2005, 61, 10827 to get compounds of the Formula (I-a) with amide linkage. Scheme 5: Synthesis of compounds of general Formula (I-a)
The compound of the general Formula (I-a) can also be prepared by following general scheme 5. Compound (X) can be reacted with appropriate amine derivatives to get compounds of the general Formula (I-a, when Y = NR3R4). Compound of the general Formula (X) can be reacted with triazole in presence of base such as Na2CO3, K2CO3 etc. in solvents such as DMF, CH3CN etc. to get compound (I-a, when Y = triazole). Alternatively, compound (XI) can be reacted with Norbornadiene or vinyl acetate under refluxing condition in presence or absence of solvent such as Dioxane to get triazole derivative (I-a). Compound (X) can be reacted with (IX) in presence of base such as Na2CO3, K2CO3 etc. in solvents such as DMF, CH3CN etc. followed by deprotection using TFA in DCM to get compound (I-a, when Y = aminoisooxazole). The invention is explained in greater detail by the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. The chemical shifts (δ) in
NMR spectra are reported in parts per million (ppm) relative to Tetramethyl silane (TMS), in either CDCl3 or DMSO-d6 solution. Mass spectra (ESI-MS) were obtained on Shimadzu LC-MS 2010-A spectrometer.
List of Abbreviations CH3CN: Acetonitrile CDCl3: Deuterated chloroform DIPEA: Disopropyl ethyl amine DMF: Dimethyl formamide DCM: Dichloromethane DMSO-d6: Hexadeuterodimethyl sulfoxide EDC.HCl: N-(3-Dimethyl aminopropyl)-N’-ethyl carbodiimide hydrochloride EtOH: Ethanol EtOAc: Ethyl acetate HOBT: 1-Hydroxy benzotriazole K2CO3: Potassium carbonate MeOH: Methanol Na2CO3: Sodium carbonate Na2SO4: Sodium sulfate NaH: Sodium Hydride NaHCO3: Sodium bicarbonate Pd/C: palladium carbon SnCl2.2H2O: Stannous chloride dihydrate TEA: Triethyl amine TFA: Trifluoroacetic acid THF: Tetrahydrofuran 1H NMR: Proton Nuclear Magnetic Resonance h: Hour(s) RT: room temperature [25-30 °C] min: Minute(s) J: Coupling constant in units of Hz Hz: Hertz
Preparation of compounds EXAMPLE 1 Preparation of 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)oxazolidin-2-one
Step 1: tert-butyl 4-(oxetan-3-yl)piperazine-1-carboxylate
To a stirring solution of tert-butyl piperazine-1-carboxylate (4.99 g, 26.8 mmol) and oxetan-3-one (1.93 g, 26.8 mmol) in DCM was added Sodium triacetoxyborohydride (8.5 g, 40.2 mmol) at 0-5°C and stirred for 16 h at 25-30°C. Reaction mixture was diluted with DCM and washed with aq NaHCO3. Organic layer was separated, dried and evaporated under reduced pressure to get the product. ESI-MS (m/z) : 243.16 (M+H)+. Step 2: 1-(2,6-difluoro-4-nitrophenyl)-4-(oxetan-3-yl)piperazine
To a stirring solution of product of step 1 (7.12 g, 29.42 mmol) in DCM was added TFA (13.6 ml, 176.3 mmol) at 0-5°C and stirred for 3 h at 25-30°C. After completion of reaction, DCM was evaporated under reduced pressure to get the crude product which was diluted with DMF (70 mL). To this was added K2CO3 (9.2 g, 66.8 mmol) and 1,2,3- trifluoro-5-nitrobenzene (4.26 g, 24.1 mmol) and stirred for 4 h at 80°C. Reaction mixture was then diluted with water and solid obtained was filtered to get the title product. ESI-MS (m/z): 300.1 (M+H)+. Step 3: 3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)aniline
To a stirring solution of product of step 2 (6.0 g, 20.05 mmol) in THF was added Pd/C (cat.) at RT and stirred it for 16 h under hydrogen atmosphere. After completion of reaction, it was filtered through celite and filtrate was evaporated to get the title product. ESI-MS (m/z): 270.13 (M+H)+. Step 4: benzyl (3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate
To a stirring solution of product of step 3 (16.3 g, 60.5 mmol) in THF was added NaHCO3 (15.25 g, 18.2 mmol) and benzyl chloroformate (11.36 g, 66.63 mmol) at 0-5°C. The reaction mixture was stirred at 25-30°C for 2 h. Reaction mixture was diluted with EtOAc and water. Organic layer was separated, dried and evaporated under reduced pressure to get the product. ESI-MS (m/z) : 404.16 (M+H)+. Step 5: 5-(chloromethyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl) oxazolidin-2-one
To a stirring solution of product of step 4 (1 g, 2.479 mmol) in dry THF was added n- butyl lithium (9.22 ml (2.5 M), 23.05 mmol) followed by rac-epichlorohydrin (0.213 mL, 2.73 mmol) at -78°C. The resultant solution was stirred at 50°C for 16 h. The reaction mixture was diluted with water and EtOAc. Organic layer was separated, dried over Na2SO4, and concentrated to get the title product. ESI-MS (m/z): 388.3 (M+H)+.
Step 6: 5-(azidomethyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl) oxazolidin-2-one
To stirring solution of product of step 5 (1.2 g, 3.09 mmol) in DMF (40 ml) was added sodium azide (1.0 g, 15.47 mmol). Reaction mixture was stirred at 800C for 3 h. After complete conversion of starting material, the reaction mixture was diluted with cold water and obtained white solid was filtered. ESI-MS (m/z): 395.3 (M+H)+. Step 7: 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)oxazolidin-2-one
To stirring solution of product of step 6 (600 mg, 1.521 mmol) in Dioxane was added norbornadiene (0.93 mL, 9.13 mmol). Reaction mixture was stirred at 1000C for 16 h. After complete conversion of starting material, the reaction mixture was concentrated and purified by column
NMR (DMSO-d6): 8.17 (d, J = 0.8 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.23-7.18 (m, 2H), 5.16-5.12 (m, 1H), 4.82 (d, J = 5.2 Hz, 2H), 4.55 (t, J = 6.4 Hz, 2H), 4.45 (t, J = 6.0 Hz, 2H), 4.19 (t, J = 9.2 Hz, 1H), 3.87-3.84 (m, 1H), 3.47-3.44 (m, 1H), 3.09 (s, 4H), 2.36 (s, 4H). ESI-MS (m/z): 421.18 (M+H)+. EXAMPLE 2 Preparation of (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)oxazolidin-2-one
Step 1: (R)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5- (hydroxymethyl)oxazolidin-2-one
To a stirring solution of product step (6.2 g, 15.38 mmol) in dry THF was added n-butyl lithium (9.22 ml (2.5 M), 23.05 mmol) at -78°C. The resultant solution was stirred at -78 °C for 1 h and then (R)-glycidyl butyrate (2.44 g, 16.91 mmol) was dropwise added at -78°C. The reaction mixture was stirred for an additional 1 h at -78°C. The reaction mixture was allowed to warm to RT and stirred for 16 h. The reaction mixture was diluted with water and EtOAc. Organic layer was separated, dried over Na2SO4, and concentrated to get the title product. 1H NMR (DMSO-d6): 7.33-7.27 (m, 2H), 5.21 (t, 1H), 4.72-4.69 (m, 1H), 4.56-4.53 (m, 2H), 4.47-4.44 (m, 2H), 4.04 (t, 1H), 3.81-3.77 (m, 1H), 3.69-3.64 (m, 1H), 3.57-3.51 (m, 1H), 3.48-3.45 (m, 1H), 3.09 (s, 4H), 2.36 (s, 4H). ESI-MS (m/z): 370.15 (M+H)+. Step 2: (R)-(3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl methanesulfonate
To a stirring solution of product obtained above in step 1 (3.5 g, 9.48 mmol) in DCM was added TEA (1.98 ml, 14.21 mmol) and methanesulfonyl chloride (0.89 ml, 11.37 mmol) at 0-5°C. Reaction mixture was stirred for 2 h at 25-30°C. After completion of reaction it was diluted with DCM and washed with water. DCM layer was separated, dried over Na2SO4 and evaporated to get the title product which was directly used for next step.
Step 3: (R)-5-(azidomethyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one
To a stirring solution of product obtained above in step 2 (4.0 g, 8.95 mmol) in DMF (40 ml) was added sodium azide (2.9 g, 44.7 mmol). Reaction mixture was stirred at 800C for 5 h. After complete conversion of starting material, the reaction mixture was diluted with cold water and solid obtained was filtered. ESI-MS (m/z): 395.16 (M+H)+. Step 4: (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)oxazolidin-2-one
To a stirring solution of step g, 5.32 mmol) in Dioxane was added norbornadiene (3.3 mL, 31.9 mmol). Reaction mixture was stirred at 1000C for 16 h. After complete conversion of starting material, the reaction mixture was concentrated and purified by column chromatography. 1H NMR (DMSO-d6): 8.17 (d, J = 0.8 Hz, 1H), 7.77 (d, J = 1.2 Hz, 1H), 7.24-7.18 (m, 2H), 5.16-5.12 (m, 1H), 4.82 (d, J = 5.2 Hz, 2H), 4.55 (t, J = 6.6 Hz, 2H), 4.45 (t, J = 6.2 Hz, 2H), 4.19 (t, J = 9.2 Hz, 1H), 3.88-3.84 (m, 1H), 3.47-3.44 (m, 1H), 3.09 (s, 4H), 2.36 (s, 4H). ESI-MS (m/z): 421.18 (M+H)+. EXAMPLE 3 Preparation of (S)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5- ((isoxazol-3-ylamino)methyl)oxazolidin-2-one
Step 1: tert-butyl (R)-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)(isoxazol-3-yl)carbamate
To a stirring solution of product of step 2 (Example-2) (0.6 gm, 1.341 mmol) in DMF (6 ml) was added tert-butyl isoxazol-3-ylcarbamate (0.346 gm, 1.877 mmol) and K2CO3 (0.371 gm, 2.68 mmol) at RT. Reaction mixture was stirred for 16 h at 100oC. Reaction mixture was diluted with water and the precipitated solid was filtered to get title product. ESI-MS (m/z): 536.15 (M+H)+. Step 2: (S)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one
To a stirring solution of product obtained above in step 1 (0.66 gm, 1.232 mmol) in DCM (6 mL) was added TFA (1.9 mL, 24.64 mmol) at 0oC. Reaction mixture was stirred for 2 h then diluted with DCM (30 mL) and washed with aq. NaHCO3. Organic layer was separated, dried and evaporated under reduced pressure to get the crude product which
was purified by preparative HPLC to get title product. (DMSO-d6): 8.40 (s, 1H), 8.39-7.25 (m, 2H), 6.55 (t, J = 6.0 Hz, 1H), 5.99 (d, J = 2.0 Hz, 1H), 4.89-4.86 (m, 1H), 4.56-4.53 (m, 2H), 4.46-4.44 (m, 2H), 4.11 (t, J = 9.0 Hz, 1H), 3.78-3.75 (m, 1H), 3.47- 3.41 (m, 3H), 3.09 (m, 4H), 2.36 (m, 4H). ESI-MS (m/z): 436.10 (M+H)+. EXAMPLE 4 Preparation of (S)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)-2-hydroxyacetamide
Step 1: (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one
To stirring solution of product of step 3 (Example-2) (0.4 g, 1.014 mmol) in mixture of THF (10 mL) and EtOH (2 mL) was added Pd/C (30 mg) followed by sodium borohydride (0.23 gm, 6.09 mmol). The reaction mixture was stirred at RT for 1 h and passed it through hyflow. Filtrate was washed with water (30 mL) and extracted by DCM. Organic layer was separated, dried and evaporated under reduced pressure to get the product.1H NMR (DMSO-d6): 7.32-7.25 (m, 2H), 4.72-4.61 (m, 3H), 4.59-4.53 (m, 2H), 4.04 (t, 1H), 3.84-3.80 (m, 1H), 3.49-3.43 (m, 1H), 3.09 (s, 4H), 2.86-2.74 (m, 2H), 2.36 (s, 4H), 1.95 (bs, 2H). ESI-MS (m/z): 369.10 (M+H)+. Step 2: (S)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)-2-hydroxyacetamide
To a stirring solution of product obtained above in step 1 (0.5 gm, 1.357 mmol) and HOBT (0.27 gm, 1.764 mmol) in DMF (5 ml) was added Glycolic acid (0.26 gm, 3.39 mmol) followed by DIPEA (0.71 ml, 4.07 mmol) and EDC.HCl (0.78 gm, 3.39 mmol). Reaction mixture was stirred for 16 h at RT. Reaction mixture was diluted with water and the precipitated solid was filtered to get the crude product which was purified by preparative HPLC to get title
NMR (DMSO-d6): 8.07 (t, J = 6.2 Hz, 1H), 7.30-7.22 (m, 2H), 5.56 (bs, 1H), 4.79-4.73 (m, 1H), 4.56-4.53 (m, 2H), 4.47-4.44 (m, 2H), 4.08 (t, J = 9.0 Hz, 1H), 3.83 (s, 2H), 3.79-3.75 (m, 1H), 3.51-3.40 (m, 3H), 3.09 (s, 4H), 2.36 (s, 4H). ESI-MS (m/z): 427.17 (M+H)+. EXAMPLE 5 Preparation of (S)-2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide
Step 1: tert-butyl (S)-(2-(((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)amino)-2-oxoethyl)carbamate
To a stirring solution of step gm, 2.71 mmol) and HOBT (0.54 gm, 3.53 mmol) in DMF (10 ml) was added Boc-Gly-OH (0.95 gm, 5.43 mmol)
followed by DIPEA (1.42 ml, 8.14 mmol) and EDC.HCl (1.56 gm, 8.14 mmol). Reaction mixture was stirred for 16 h at RT. Reaction mixture was diluted with water and the precipitated solid was filtered to get title product which was used for next step. Step 2: (S)-2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide
To a stirring solution of product obtained above in step 1 (1.4 gm, 2.66 mmol) in DCM (15 mL) was added TFA (4.1 mL, 53.3 mmol) at 0oC. Reaction mixture was stirred for 2 h then diluted with DCM (30 mL) and washed with aq.NaHCO3. Organic layer was separated, dried and evaporated under reduced pressure to get the crude product which was purified by preparative HPLC to get title product.
NMR (DMSO-d6): 8.17 (bs, 1H), 7.28-7.25 (m, 2H), 4.78-4.71 (m, 1H), 4.56-4.53 (m, 2H), 4.47-4.44 (m, 2H), 4.07 (t, J = 9.0 Hz, 1H), 3.75 (m, 1H), 3.49-3.45 (m, 3H), 3.10 (s, 6H), 2.36 (s, 4H), 1.81 (bs, 2H). ESI-MS (m/z): 426.20 (M+H)+. EXAMPLE 6 Preparation of (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)oxazolidin-2-one
Step 1: 1-(2-fluoro-4-nitrophenyl)-4-(oxetan-3-yl)piperazine
To a stirring solution of product of step 1 (Example-1) (1.0 g, 4.13 mmol) in DCM (10 mL) was added TFA (1.91 ml, 24.76 mmol) at 0-5°C and stirred it for 3 h at 25-30°C. After completion of reaction, DCM was evaporated under reduced pressure to get the crude product which was diluted with DMF (5 mL). To this was added K2CO3 (1.41 g, 10.20 mmol) and 1,2-difluoro-4-nitrobenzene (0.58 g, 3.67 mmol) and stirred for 4 h at 80°C. Reaction mixture was then diluted with water obtained solid was filtered to get the title product. ESI-MS (m/z): 282.13 (M+H)+. Step 2: 3-fluoro-4-(4-(oxetan-3- 1- aniline
To a stirring solution of product of step 1 (0.83 g, 2.95 mmol) in THF was added Pd/C (cat.) at RT and stirred it for 16 h under hydrogen atmosphere. After completion of reaction, it was filtered through celite and filtrate was evaporated to get the title product. ESI-MS (m/z): 252.15 (M+H)+. Step 3: benzyl (3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate
To a stirring solution of product of step 2 (0.73 g, 2.90 mmol) in THF was added NaHCO3 (0.73 g, 8.71 mmol) and benzyl chloroformate (1.29 g, 3.78 mmol) at 0-5°C. The reaction mixture was stirred at 25-30°C for 2 h. After completion of reaction it was diluted with EtOAc and water. Organic layer was separated, dried and evaporated under reduced pressure to get the product. ESI-MS (m/z): 386.17 (M+H)+. Step 4: (R)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5- (hydroxymethyl)oxazolidin-2-one
To a stirring solution of product of step 3 (1.5 g, 3.89 mmol) in dry THF (40 mL) was added n-butyl lithium (2.33 ml (2.5 M), 5.84 mmol) at -78°C. The resultant solution was stirred at -78 °C for 1 h and then (R)-glycidyl butyrate (0.62 g, 4.28 mmol) was dropwise added at -78°C. The reaction mixture was stirred for an additional 1 h at -78°C. The reaction mixture was allowed to warm to RT and stirred for 16 h. The reaction mixture was diluted with water and EtOAc. Organic layer was separated, dried over Na2SO4, and concentrated to get the title product. 1H NMR (DMSO-d6): 7.53-7.50 (m, 1H), 7.49-7.18 (m, 1H), 7.08-7.04 (m, 1H), 5.21 (s, 1H), 4.71-4.65 (m, 1H), 4.58-4.54 (m, 2H), 4.47-4.44 (m, 2H), 4.04 (t, J = 9.0 Hz, 1H), 3.81-3.77 (m, 1H), 3.68-3.64 (m, 1H), 3.57-3.50 (m, 1H), 3.48-3.44 (m, 1H), 3.00 (s, 4H), 2.33 (s, 4H). ESI-MS (m/z): 352.24 (M+H)+. Step 5: (R)-(3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl methanesulfonate
To a stirring solution of product of step 4 (1.35 g, 3.84 mmol) in DCM was added TEA (1.61 ml, 11.53 mmol) and methanesulfonyl chloride (0.39 ml, 4.99 mmol) at 0-5°C. Reaction mixture was stirred for 2 h at 25-30°C. After completion of reaction it was diluted with DCM and washed with water. DCM layer was separated, dried over Na2SO4 and evaporated to get the title product which was directly used for next step. Step 6: (R)-5-(azidomethyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one
To stirring solution of product of step 5 (1.6 g, 3.73 mmol) in DMF (10 ml) was added Sodium Azide (1.4 g, 22.35 mmol). Reaction mixture was stirred at 800C for 5 h. After complete conversion of starting material, the reaction mixture was diluted with cold water and solid obtained was filtered. ESI-MS (m/z): 377.4 (M+H)+. Step 7: (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)oxazolidin-2-one
To stirring solution of product of step 6 (0.4 g, 1.06 mmol) in Dioxane was added norbornadiene (0.59 gm, 6.38 mmol). Reaction mixture was stirred at 1000C for 16 h. After complete conversion of starting material, the reaction mixture was concentrated and purified by column chromatography. 1H NMR (DMSO-d6): 8.17 (d, J = 0.8 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.42-7.37 (m, 1H), 7.13-7.03 (m, 2H), 5.15-5.09 (m, 1H), 4.82 (d, J = 4.8 Hz, 2H), 4.57-4.54 (m, 2H), 4.47-4.44 (m, 2H), 4.20 (t, J = 9.2 Hz, 1H), 3.87-3.83 (m, 1H), 3.49-3.34 (m, 1H), 3.00 (m, 4H), 2.33 (s, 4H). ESI-MS (m/z): 403.18 (M+H)+. EXAMPLE 7 Preparation of (S)-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)-2-hydroxyacetamide
Step 1: (S)-5-(aminomethyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one
5 To stirring solution of product of step 6 (Example-6) (0.4 g, 1.06 mmol) in mixture of THF (10 mL) and EtOH (3 mL) was added Pd/C (Cat.) followed by sodium borohydride (0.24 gm, 6.38 mmol). The reaction mixture was stirred at RT for 1 h and passed it through hyflow. Filtrate was washed with water (30 mL) and extracted by DCM. Organic layer was separated, dried and evaporated under reduced pressure to get the
10 NMR (DMSO-d6): 7.52-7.48 (m, 1H), 7.21-7.18 (m, 1H), 7.09-7.04 (m, 1H), 4.63-4.45 (m, 3H), 4.47-4.44 (m, 2H), 4.02 (t, J = 8.8 Hz, 1H), 3.84-3.80 (m, 1H), 3.50-3.44 (m, 1H), 3.00 (s, 4H), 2.87-2.76 (m, 2H), 2.33 (s, 4H), 1.89 (bs, 2H). ESI-MS (m/z): 351.19 (M+H)+. Step 2: (S)-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin- 15 5-yl)methyl)-2-hydroxyacetamide
To a stirring solution of product of step 1 (0.5 gm, 1.43 mmol) and HOBT (0.28 gm, 1.85 mmol) in DMF (5 ml) was added Glycolic acid (0.27 gm, 3.57 mmol) followed by DIPEA (0.75 ml, 4.28 mmol) and EDC.HCl (0.82 gm, 4.28 mmol). Reaction mixture was
stirred for 16 h at RT. Reaction mixture was diluted with water and the precipitated solid was filtered to get the crude product which was purified by preparative HPLC to get title product.1H NMR (DMSO-d6): 8.07 (t, J = 6.0 Hz, 1H), 7.49-7.45 (m, 1H), 7.19-7.16 (m, 1H), 7.09-7.04 (m, 1H), 5.55 (t, J = 5.6 Hz, 1H), 4.77-4.71 (m, 1H), 4.58-4.54 (m, 2H), 4.47-4.44 (m, 2H), 4.08 (t, J = 8.8 Hz, 1H), 3.83 (d, J = 6.0 Hz, 2H), 3.79-3.75 (m, 1H), 3.49-3.41 (m, 3H), 3.00 (s, 4H), 2.33 (s, 4H). ESI-MS (m/z): 409.16 (M+H)+. EXAMPLE 8 Preparation of (S)-2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)- 2-oxooxazolidin-5-yl)methyl)acetamide
Step 1: tert-butyl (S)-(2-(((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)amino)-2-oxoethyl)carbamate
To a stirring solution of product of step 1 (Example-7) (0.5 gm, 1.427 mmol) and HOBT (219 mg, 1.427 mmol) in DMF (5 ml) was added Boc-Gly-OH (0.5 gm, 2.85 mmol) followed by DIPEA (0.75 ml, 4.28 mmol) and EDC.HCl (821 mg, 4.28 mmol). Reaction mixture was stirred for 16 h at RT. Reaction mixture was diluted with water and the precipitated solid was filtered to get title product. ESI-MS (m/z): 508.25 (M+H)+. Step 2: (S)-2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide
To a stirring solution of product obtained above in step 1 (0.7 gm, 1.38 mmol) in DCM (10 mL) was added TFA (2.1 mL, 27.6 mmol) at 0oC. Reaction mixture was stirred for 2 h then diluted with DCM (20 mL) and washed with aq.NaHCO3. Organic layer was separated, dried and evaporated under reduced pressure to get the crude product which was purified by preparative HPLC to get title
NMR (DMSO-d6): 8.18 (bs, 1H), 7.49-7.45 (m, 1H), 7.18-7.16 (m, 1H), 7.09-7.04 (m, 1H), 5.76-4.69 (m, 1H), 4.58- 4.54 (m, 2H), 4.47-4.44 (m, 2H), 4.08 (t, J = 9.0 Hz, 1H), 3.75-3.71 (m, 1H), 3.50-3.45 (m, 3H), 3.17 (s, 2H), 2.99 (m, 4H), 2.42 (m, 4H), 1.99 (bs, 2H). ESI-MS (m/z): 408.17 (M+H)+. EXAMPLE 9 Preparation of (S)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol- 3-ylamino)methyl)oxazolidin-2-one
Step 1: tert-butyl (R)-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)(isoxazol-3-yl)carbamate
To a stirring solution of product of step 5 (Example-6) (0.25 gm, 0.582 mmol) in DMF (3 ml) was added tert-butyl isoxazol-3-ylcarbamate (0.129 gm, 0.699 mmol) and K2CO3 (0.161 gm, 1.164 mmol) at RT. Reaction mixture was stirred for 16 h at 100oC. Reaction mixture was diluted with water and the precipitated solid was filtered to get title product. ESI-MS (m/z): 518.22 (M+H)+. Step 2: (S)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one
To a stirring solution of product obtained above in step 1 (0.3 gm, 0.58 mmol) in DCM (5 mL) was added TFA (0.89 mL, 11.59 mmol) at 0oC. Reaction mixture was stirred for 2 h then diluted with DCM (15 mL) and washed with aq.NaHCO3. Organic layer was separated, dried and evaporated under reduced pressure to get the crude product which was purified by preparative HPLC to get title
NMR (DMSO-d6): 8.39 (d, J = 1.6 Hz, 1H), 7.52-7.47 (m, 1H), 7.19-7.16 (m, 1H), 7.09-7.04 (m, 1H), 6.56 (t, J = 6.2 Hz, 1H), 6.00 (d, J = 2.0 Hz, 1H), 4.89-4.84 (m, 1H), 4.58-4.54 (m, 2H), 4.47-4.44 (m, 2H), 4.11 (t, J = 9.0 Hz, 1H), 3.79-3.75 (m, 1H), 3.50-3.38 (m, 3H), 3.00 (m, 4H), 2.33 (m, 4H). ESI-MS (m/z): 418.16 (M+H)+. Biological evaluation: Minimum inhibitory concentration (MIC) determination: Following strains were used for MIC testing: Staphylococcus aureus (MRSA) ATCC 33591 Staphylococcus aureus (VRS2) NR-46411 Streptococcus pneumoniae (PRSP) ATCC 700904 MIC protocol:
MIC determination was done by using the reference broth microdilution method as described by the Clinical and Laboratory Standards Institute (CLSI). Briefly, bacterial cells were cultured on Mueller Hinton agar plates. Stock solutions of compounds and positive controls were prepared in DMSO. Subsequent dilutions of compounds were prepared in cation adjusted Mueller Hinton broth (CAMHB). Compounds were tested by serial double dilution in 96 well plates. Inoculum densities were maintained at 5 X 104 cells per well. Plates were incubated at 37 ⁰C for 20-24 hrs before being read at 620 nm in Multiskan reader (Thermo). Linezolid was taken as positive control. All QC results were within specified ranges as published in CLSI document M100–S25 Mitochondrial protein synthesis (MPS) modulators assay: Human hepatocyte cell line, HepG2 was used to assess the mitochondrial protein synthesis inhibition of test compounds. The cells were plated at 6000 cell /well in 96 well tissue culture plates and allowed to grow for 16 h. To these cells, test compounds were added in desired concentrations and incubated for 96h. Chloramphenicol was used in the assay as MPS inhibition control. After 96 h, the cells were fixed with 4% paraformaldehyde for 20min, then treated with 0.5% acetic acid to stop alkaline phosphatase activity. The cells were then treated with permeabilization buffer (1% triton x-100) for 30min followed by blocking with the blocking buffer (AbCAM mitogenesis in cell ELISA kit #ab110217) for 2 h. The cells were then probed for COX-1 and SDH-A using the antibodies provided in the kit. The protein levels were measured in the kinetic mode using Spectramax (Molecular Devices, US) and the ratio of COX-1 to SDH-A expression was calculated. The ratio with respect to the concentration of the test compounds were utilized to derive the half-maximal inhibitory concentration using GraphPad Prism.
Compounds of the present invention show antibacterial activity against various Gram- positive bacterial strains as reflected in their MIC values described in Table 1. Further, compounds have shown lower potential for mitochondrial protein synthesis inhibition as reflected in higher MPS IC50 of compounds of the present invention in MPS assay compared with Linezolid. Hence, compounds of the present invention have improved safety profile over Linezolid. Table 1:
The novel compounds of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known. The compounds of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts, or pharmaceutical compositions containing them are useful as a medicament for the mammalian infections and suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration. The quantity of active component, that is, the novel compounds of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon several factors such as the particular application method, the potency of the particular compound and the desired concentration. The novel compounds of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by
techniques and processes and concentrations as are well known. The pharmaceutical compositions further comprise an effective amount of an antibacterial agent. The dosage of antibacterial agent may vary within wide limits and should be adjusted, in each particular case, to the individual conditions. 5 Use of the novel compounds of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts of the present invention use for the treatment of mammalian infection caused by Gram-positive bacteria. In some embodiments, the mammalian infection caused by Gram-positive bacteria includes but not limited to skin infections, lung infections and tissue infections. 10 In some embodiments, the present invention includes a method for the treatment of mammalian infection caused by Gram-positive bacteria at least one of but not limited to skin infections, lung infections and tissue infections by administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the novel compound of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically 15 acceptable salts.
Claims
We claim: 1. Compounds of general Formula (I), their stereoisomers, their suitable pharmaceutically acceptable salts,
Wherein, Q represents O, NR6, S(O)p; p = 0-2 integer; Y is selected from OR3, NR3R4, NHC(O)R5; R1 is selected from H, F, Cl, CH3, CN, OH and OCH3; m is selected from 1-4; R2 is selected from H, F, CH3, OH; n is selected from 1-8; R3 and R4 is independently selected from H, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, heterocyclyl and heteroaryl, each of which is substituted or unsubstituted; R3 and R4 taken together with the nitrogen to which they are attached to form a 4- to 8- membered heterocyclyl or heteroaryl with 1 to 3 additional heteroatoms selected from O, S, or N, which is substituted or unsubstituted; wherein substitutions on (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, heterocyclyl and heteroaryl groups selected from halo, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)acyloxy, haloalkyl, NO2, CN and NH2; R5 is selected from aminoalkyl, hydroxyalkyl, aryl and heteroaryl each of which is substituted or unsubstituted; wherein substitutions on (C1-C6)alkyl, aryl, heterocyclyl and heteroaryl groups selected from halo, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)acyloxy, haloalkyl, NO2, CN and NH2; R6 = H, CN, (C1-C6)alkyl, haloalkyl, -COCH3; -COO(C1-C6)alkyl. 2. The compound as claimed in claim 1 having Formula (I-a) or their suitable pharmaceutically acceptable salts
Wherein, Q, R1, R2 and Y are as defined in claim 1. 3. The compound as claimed in claim 2, wherein Q is O; Y is selected from NR3R4, NHC(O)R5; R1 is F; m is selected form 1-2; R2 H. 4. The compound as claimed in claim 1 having Formula (I-b) or their suitable pharmaceutically acceptable salts,
Wherein, Q, R1, R2 and Y are as defined in claim 1. 5. The compound as claimed in claim 4, wherein Q is O; Y is selected from NR3R4, NHC(O)R5; R1 is F; m is selected form 1-2; R2 is H. 6. Compounds of Formula (I) or their suitable pharmaceutically acceptable salts as claimed in claim 1 are selected from: 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)oxazolidin-2-one; (S)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)oxazolidin-2-one; N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; (R)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)-2-hydroxyacetamide; (S)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)-2-hydroxyacetamide;
2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; (R)-2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; (S)-2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; 3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (R)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (S)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (S)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; (R)-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; (S)-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; 2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; (R)-2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; (S)-2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide;
3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (R)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (S)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one. 7. Pharmaceutical composition comprising compound of Formula (I) or Formula (I- a) or Formula (I-b) or their suitable pharmaceutically acceptable salts as claimed in claim 1, 2 and 4 and suitable pharmaceutically acceptable excipients. 8. Use of the compounds as claimed in claim 1, 2 and 4 for the treatment of mammalian infections, by administering a therapeutically effective & non-toxic amount of the compound of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts, or their suitable pharmaceutically acceptable compositions to the mammals. 9. Use of the compounds as claimed in claim 8 for the treatment of mammalian infections wherein mammalian infections is caused by Gram-positive bacteria. 10. Method of treating mammalian infections in a subject which comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts as claimed in claim 1, 2 and 4 or their suitable pharmaceutical composition. 11. Method of treating mammalian infections as claimed in claim 10 wherein mammalian infections is caused by Gram-positive bacteria.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993023384A1 (en) * | 1992-05-08 | 1993-11-25 | The Upjohn Company | Oxazolidinones containing a substituted diazine moiety and their use as antimicrobials |
| WO2017156519A1 (en) * | 2016-03-11 | 2017-09-14 | The Board Of Trustees Of The University Of Illinois | Small-molecules active against gram-negative bacteria |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993023384A1 (en) * | 1992-05-08 | 1993-11-25 | The Upjohn Company | Oxazolidinones containing a substituted diazine moiety and their use as antimicrobials |
| WO2017156519A1 (en) * | 2016-03-11 | 2017-09-14 | The Board Of Trustees Of The University Of Illinois | Small-molecules active against gram-negative bacteria |
Non-Patent Citations (1)
| Title |
|---|
| CLAUDIA FOTI: "Oxazolidinone Antibiotics: Chemical, Biological and Analytical Aspects", MOLECULES, MDPI AG, CH, vol. 26, no. 14, CH , pages 4280, XP093157149, ISSN: 1420-3049, DOI: 10.3390/molecules26144280 * |
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