WO2009133560A1 - Dérivés de bis-(nucléotide monophosphate) cycliques non hydrolysables et perméables et leurs utilisations - Google Patents
Dérivés de bis-(nucléotide monophosphate) cycliques non hydrolysables et perméables et leurs utilisations Download PDFInfo
- Publication number
- WO2009133560A1 WO2009133560A1 PCT/IL2009/000456 IL2009000456W WO2009133560A1 WO 2009133560 A1 WO2009133560 A1 WO 2009133560A1 IL 2009000456 W IL2009000456 W IL 2009000456W WO 2009133560 A1 WO2009133560 A1 WO 2009133560A1
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- WO
- WIPO (PCT)
- Prior art keywords
- hydrocarbyl
- compound
- derivative
- nucleotide monophosphate
- identified
- Prior art date
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- -1 nucleotide monophosphate Chemical class 0.000 title claims abstract description 88
- 125000004122 cyclic group Chemical group 0.000 title claims abstract description 55
- 239000002773 nucleotide Substances 0.000 title claims abstract description 52
- 230000000694 effects Effects 0.000 claims abstract description 18
- 230000007921 bacterial pathogenicity Effects 0.000 claims abstract description 17
- 230000032770 biofilm formation Effects 0.000 claims abstract description 17
- 230000009467 reduction Effects 0.000 claims abstract description 17
- 230000001580 bacterial effect Effects 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 14
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 14
- 230000019491 signal transduction Effects 0.000 claims abstract description 12
- 230000033228 biological regulation Effects 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 100
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 229910052717 sulfur Chemical group 0.000 claims description 19
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 15
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- 150000003839 salts Chemical class 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
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- 230000002068 genetic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 description 1
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical group O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
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- 229940047889 isobutyramide Drugs 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
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- 239000002609 medium Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
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- 125000002950 monocyclic group Chemical group 0.000 description 1
- LSMZHPCHKDMYMQ-UHFFFAOYSA-N n-[chloro(methyl)phosphoryl]-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C(C)C)P(C)(Cl)=O LSMZHPCHKDMYMQ-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([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
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
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- 125000001805 pentosyl group Chemical group 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 1
- 125000005642 phosphothioate group Chemical group 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
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- 230000001737 promoting effect Effects 0.000 description 1
- DZMOLBFHXFZZBF-UHFFFAOYSA-N prop-2-enyl dihydrogen phosphate Chemical compound OP(O)(=O)OCC=C DZMOLBFHXFZZBF-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 108010062513 snake venom phosphodiesterase I Proteins 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 108010068698 spleen exonuclease Proteins 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
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- 108700012359 toxins Proteins 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- AVBGNFCMKJOFIN-UHFFFAOYSA-N triethylammonium acetate Chemical compound CC(O)=O.CCN(CC)CC AVBGNFCMKJOFIN-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- 108010050327 trypticase-soy broth Proteins 0.000 description 1
- 229940118696 vibrio cholerae Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
-
- 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
Definitions
- S. aureus is an important pathogen of humans, and biofilm formation is essential for its virulence and pathogenesis, as well as for its ability to resist antibiotic treatment. Moreover, its biofilm formation is strongly associated with BAP, an EAL protein likely to be a c- di-GMP phosphodiesterase (Lasa, 2006). Karaolis et at. demonstrated that extra- cellular addition of c-di-GMP showed activity against isolates of S. aureus, including methicillin resistant S. aureus (MRSA).
- MRSA methicillin resistant S. aureus
- R 2 is H, Ci-C 5 alkyl or absent
- R 7 and R 8 each independently is H, halogen, O-hydrocarbyl, S-hydrocarbyl,
- NR 1 ]R 12 heteroaryl, unsubstituted hydrocarbyl or hydrocarbyl substituted by halogen, CN, SCN, NO 2 , OR 11 , SR 11 , NR 11 R 12 or heteroaryl, wherein R 11 and R 12 each independently is H or hydrocarbyl or R 11 and R 12 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocyclic ring optionally containing 1-2 further heteroatoms selected from oxygen, nitrogen or sulfur, the additional nitrogen being unsubstituted or substituted by alkyl substituted by halogen, hydroxyl or phenyl;
- step a compound 8 (900 mg, 1.2 mmol) and phosphoramidite 9 (1.15 mg 1.2 mmol) were dissolved in acetonitrile (8 ml), powdered molsieves (3A, 400 mg) were added and the mixture was then stirred for 30 min. IMP (400 mg, 2.4 mmol) was added and the mixture was stirred for 1 h. 31 P-NMR analysis revealed complete conversion ( 31 P-NMR: ⁇ 139.8, 139.5 and 119.0 (broad) ppm). The mixture was diluted with EtOAc (50 ml) and filtered over glass filter.
- step a a heterogeneous solution of phosphoramidite 30 (10.0 g, 10.3 mmol), powdery molsieves (3A 5 2.00 g) and allylalcohol (0.88 ml, 12.9 mmol) in acetonitrile (40 ml) was stirred for 30 min at room temperature under N 2 atmosphere. IMP (3.5 g, 20.75 mmol) was then added to the reaction mixture and stirring was continued for additional 30 min.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne de nouveaux dérivés de bis-(nucléotide monophosphate) cycliques non hydrolysables et perméables et des compositions pharmaceutiques les renfermant. Les dérivés de bis-(nucléotide monophosphate) cycliques de la présente invention sont utiles pour le traitement d’infections bactériennes, en particulier, pour la perturbation de la régulation bactérienne et/ou de la transduction bactérienne des signaux, la perturbation ou la réduction de la pathogénicité bactérienne et/ou la perturbation ou la réduction d’une activité associée à la pathogénicité bactérienne telle que la formation de biofilm.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4871208P | 2008-04-29 | 2008-04-29 | |
| US61/048,712 | 2008-04-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2009133560A1 true WO2009133560A1 (fr) | 2009-11-05 |
Family
ID=40947594
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IL2009/000456 WO2009133560A1 (fr) | 2008-04-29 | 2009-04-30 | Dérivés de bis-(nucléotide monophosphate) cycliques non hydrolysables et perméables et leurs utilisations |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2009133560A1 (fr) |
Cited By (18)
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| CN103936805A (zh) * | 2013-01-18 | 2014-07-23 | 昆山市工业技术研究院小核酸生物技术研究所有限责任公司 | 一种核苷酸和/或寡核苷酸及其制备方法 |
| WO2014179335A1 (fr) | 2013-04-29 | 2014-11-06 | Memorial Sloan Kettering Cancer Center | Compositions et procédés pour altérer la signalisation par un second messager |
| US9718848B2 (en) | 2015-12-03 | 2017-08-01 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
| US9724408B2 (en) | 2013-05-18 | 2017-08-08 | Aduro Biotech, Inc. | Compositions and methods for activating stimulator of interferon gene-dependent signalling |
| US9770467B2 (en) | 2012-06-08 | 2017-09-26 | Aduro Biotech, Inc. | Compositions and methods for cancer immunotherapy |
| US10047115B2 (en) | 2015-01-29 | 2018-08-14 | Glaxosmithkline Intellectual Property Development Limited | Cyclic dinucleotides useful for the treatment of inter alia cancer |
| WO2018152450A1 (fr) | 2017-02-17 | 2018-08-23 | Eisai R&D Management Co., Ltd. | Composés dinucléotidiques cycliques pour le traitement du cancer |
| US10176292B2 (en) | 2013-07-31 | 2019-01-08 | Memorial Sloan-Kettering Cancer Center | STING crystals and modulators |
| WO2019043634A2 (fr) | 2017-08-30 | 2019-03-07 | Beijing Xuanyi Pharmasciences Co., Ltd. | Di-nucléotides cycliques en tant que stimulateurs de modulateurs de gènes d'interféron |
| US10450341B2 (en) | 2014-06-04 | 2019-10-22 | Glaxosmithkline Intellectual Property Development Limited | Cyclic di-nucleotides as modulators of STING |
| WO2019232392A1 (fr) | 2018-06-01 | 2019-12-05 | Eisai R&D Management Co., Ltd. | Méthodes de traitement du cancer de la vessie |
| US10980825B2 (en) | 2016-12-01 | 2021-04-20 | Takeda Pharmaceutical Company Limited | Cyclic dinucleotide |
| CN112867727A (zh) * | 2018-10-12 | 2021-05-28 | 上海济煜医药科技有限公司 | 环二核苷酸类化合物及其应用 |
| US11542293B2 (en) | 2017-11-10 | 2023-01-03 | Takeda Pharmaceutical Company Limited | Sting modulator compounds, and methods of making and using |
| US11691990B2 (en) | 2018-08-16 | 2023-07-04 | Eisai R&D Management Co., Ltd | Salts of compounds and crystals thereof |
| US11725024B2 (en) | 2020-11-09 | 2023-08-15 | Takeda Pharmaceutical Company Limited | Antibody drug conjugates |
| US11787833B2 (en) | 2019-05-09 | 2023-10-17 | Aligos Therapeutics, Inc. | Modified cyclic dinucleoside compounds as sting modulators |
| US11873319B2 (en) | 2013-05-03 | 2024-01-16 | The Regents Of The University Of California | Cyclic di-nucleotide induction of type I interferon |
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| CN103936805A (zh) * | 2013-01-18 | 2014-07-23 | 昆山市工业技术研究院小核酸生物技术研究所有限责任公司 | 一种核苷酸和/或寡核苷酸及其制备方法 |
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| AU2014260015B2 (en) * | 2013-04-29 | 2019-11-14 | Memorial Sloan Kettering Cancer Center | Compositions and methods for altering second messenger signaling |
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| WO2014179335A1 (fr) | 2013-04-29 | 2014-11-06 | Memorial Sloan Kettering Cancer Center | Compositions et procédés pour altérer la signalisation par un second messager |
| US10131686B2 (en) | 2013-04-29 | 2018-11-20 | Memorial Sloan Kettering Cancer Center | Compositions and methods for altering second messenger signaling |
| EP4398254A3 (fr) * | 2013-04-29 | 2024-10-23 | Memorial Sloan Kettering Cancer Center | Compositions et procédés pour modifier la signalisation d'un second messager |
| US11873319B2 (en) | 2013-05-03 | 2024-01-16 | The Regents Of The University Of California | Cyclic di-nucleotide induction of type I interferon |
| US10653774B2 (en) | 2013-05-18 | 2020-05-19 | Aduro Biotech, Inc. | Compositions and methods for activating “stimulator of interferon gene”-dependent signalling |
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