NZ736934B2 - Mono- or di-substituted indole derivatives as dengue viral replication inhibitors - Google Patents
Mono- or di-substituted indole derivatives as dengue viral replication inhibitors Download PDFInfo
- Publication number
- NZ736934B2 NZ736934B2 NZ736934A NZ73693416A NZ736934B2 NZ 736934 B2 NZ736934 B2 NZ 736934B2 NZ 736934 A NZ736934 A NZ 736934A NZ 73693416 A NZ73693416 A NZ 73693416A NZ 736934 B2 NZ736934 B2 NZ 736934B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- acceptable salt
- solvate
- pharmaceutically acceptable
- polymorph
- Prior art date
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- 208000001490 Dengue Diseases 0.000 title claims abstract 6
- 206010012310 Dengue fever Diseases 0.000 title claims abstract 6
- 208000025729 dengue disease Diseases 0.000 title claims abstract 6
- -1 di-substituted indole Chemical class 0.000 title claims abstract 6
- 229940123627 Viral replication inhibitor Drugs 0.000 title 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 28
- 239000003814 drug Substances 0.000 claims abstract 7
- 238000000034 method Methods 0.000 claims abstract 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 4
- 239000000203 mixture Substances 0.000 claims abstract 2
- 150000003839 salts Chemical class 0.000 claims 10
- 239000012453 solvate Substances 0.000 claims 9
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 4
- 238000005160 1H NMR spectroscopy Methods 0.000 claims 2
- 241000725619 Dengue virus Species 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 claims 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 2
- 150000002475 indoles Chemical class 0.000 claims 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000010076 replication Effects 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 229940124597 therapeutic agent Drugs 0.000 claims 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims 1
- 239000002841 Lewis acid Substances 0.000 claims 1
- 239000003443 antiviral agent Substances 0.000 claims 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims 1
- 239000012472 biological sample Substances 0.000 claims 1
- 230000031709 bromination Effects 0.000 claims 1
- 238000005893 bromination reaction Methods 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 150000007517 lewis acids Chemical class 0.000 claims 1
- SIDNNIWJYGJTCH-UHFFFAOYSA-N n-(3-methoxyphenyl)methanesulfonamide Chemical compound COC1=CC=CC(NS(C)(=O)=O)=C1 SIDNNIWJYGJTCH-UHFFFAOYSA-N 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 229960005486 vaccine Drugs 0.000 claims 1
- 208000036142 Viral infection Diseases 0.000 abstract 3
- 238000002360 preparation method Methods 0.000 abstract 3
- 230000009385 viral infection Effects 0.000 abstract 3
- 230000002265 prevention Effects 0.000 abstract 1
Classifications
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P31/12—Antivirals
-
- 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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/08—Bridged systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The present invention relates to mono- or di-substituted indole compounds, methods to prevent or treat dengue viral infections by using said compounds and also relates to said compounds for use as a medicine, more preferably for use as a medicine to treat or prevent dengue viral infections. The present invention furthermore relates to pharmaceutical compositions or combination preparations of the compounds, to the compositions or preparations for use as a medicine, more preferably for the prevention or treatment of dengue viral infections. The invention also relates to processes for preparation of the compounds.
Claims (17)
1. A compound having formula 9 or its stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof.
2. The compound according to claim 1, wherein said compound is: Enantiomer 9A, wherein 1H NMR (400 MHz, DMSO-d 6) d ppm 3.09 (s, 3 H) 3.73 (s, 3 H) 3.99 (s, 3 H) 6.26 (d, J=7.9 Hz, 1 H) 6.55 - 6.62 (m, 2 H) 6.91 (t, J=1.5 Hz, 1 H) 6.98 (dd, J=8.4, 2.0 Hz, 1 H) 7.07 (d, J=7.9 Hz, 1 H) 7.13 (d, J=2.0 Hz, 1 H) 7.21 (dd, J=8.8, 1.8 Hz, 1 H) 7.36 (d, J=8.4 Hz, 1 H) 7.59 (d, J=8.8 Hz, 1 H) 8.07 (d, J=0.9 Hz, 1 H) 8.55 (s, 1 H) 12.29 (br s, 1 H) LC/MS (method LC-A): Rt 1.20 min, MH+ 583 [a]D20: +130.3° (c 0.555, DMF) Chiral SFC (method SFC-E): Rt 3.10 min, MH+ 583, chiral purity 100%, or a ceutically acceptable salt, solvate or polymorph f.
3. The compound, according to claim 1, wherein said compound is: Enantiomer 9B, wherein 1H NMR (400 MHz, DMSO-d 6) d ppm 3.09 (s, 3 H) 3.73 (s, 3 H) 3.99 (s, 3 H) 6.26 (d, J=7.9 Hz, 1 H) 6.56 - 6.62 (m, 2 H) 6.92 (t, J=2.0 Hz, 1 H) 6.98 (dd, J=8.1, 2.0 Hz, 1 H) 7.07 (d, J=7.9 Hz, 1 H) 7.13 (d, J=2.0 Hz, 1 H) 7.22 (dd, J=8.8, 1.8 Hz, 1 H) 7.36 (d, J=8.4 Hz, 1 H) 7.59 (d, J=8.8 Hz, 1 H) 8.07 (d, J=0.9 Hz, 1 H) 8.55 (s, 1 H) 12.30 (br s, 1 H) LC/MS (method LC-A): Rt 1.20 min, MH+ 583 [a]D20: -133.2° (c 0.5, DMF) Chiral SFC (method SFC-E): Rt 3.50 min, MH+ 583, chiral purity 100%, or a pharmaceutically acceptable salt, solvate or polymorph thereof.
4. The compound, a pharmaceutically acceptable salt, or e f according to any one of claims 1 to 3, wherein said compound is in a crystalline or an amorphous form.
5. The compound, a pharmaceutically acceptable salt, or solvate f according to any one of claims 1 to 4, wherein said compound is in an vated form.
6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a stereo- isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers.
7. Use of a nd according to any one of claims 1 to 5 or a stereo- isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof or a pharmaceutical composition ing to claim 6 in the cture of a ment.
8. Use of a compound according to any one of claims 1 to 5 or a stereo- isomeric form, a ceutically acceptable salt, solvate or polymorph thereof or a pharmaceutical composition according to claim 6 in the manufacture of a medicament for the treatment of dengue in a human.
9. The use of a compound according to claim 8, wherein the compound is to be administered as a crystalline or amorphous product.
10. A use of a compound represented by the following structural formula (I) a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof; wherein: R1 is OCF3, R2 is H and R3 is H, in the manufacture of a medicament for ting the replication of dengue virus(es) in a human patient.
11. The use of a compound according to claim 10 further comprising an additional therapeutic agent.
12. The use of claim 11 wherein said additional therapeutic agent is selected from an antiviral agent or dengue vaccine, or both.
13. The use of a compound according to claim 10, wherein the compound is to be administered as a crystalline or amorphous product.
14. A use of a compound ented by the following structural formula (I) a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof; wherein: R1 is OCF3, R2 is H and R3 is H, for inhibiting the replication of dengue virus(es) in a biological sample.
15. A method for the sis of a compound according to any one of claims 1 to 3 comprising the steps of: a) converting 2-(4-chloromethoxyphenyl)acetic acid (II) to the corresponding 2- (4-chloromethoxyphenyl)acetyl chloride (III) with a chlorination t; b) Friedel-Crafts reaction of the acid chloride (III) with a substituted indole of l a (IV) med using a Lewis acid reagent in a suitable solvent and under suitable reaction conditions, to provide the 3-acylated indole of l formula (V), wherein R1 is OCF3, R2 is H and R3 is H; c) bromination of (V) with a reagent in a suitable solvent, to provide the compounds of general formula (VI); d) reaction of the compounds of general formula (VI) with 3-methoxy (methylsulfonyl)-aniline (VII) in a suitable t and using a base to provide the compounds of general formula I as racemic mixtures; e) chiral separation of the compounds of general a I to provide the enantiomers A and B of general formula I, wherein R1 is OCF3, R2 is H and R3
16. The compound of claim 1, substantially as herein described with reference to any one of the examples thereof.
17. The use of claim 10 or 14, substantially as herein described with nce to any one of the examples thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP15166900 | 2015-05-08 | ||
| EP16163342 | 2016-03-31 | ||
| PCT/EP2016/059975 WO2016180696A1 (en) | 2015-05-08 | 2016-05-04 | Mono- or di-substituted indole derivatives as dengue viral replication inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ736934A NZ736934A (en) | 2023-11-24 |
| NZ736934B2 true NZ736934B2 (en) | 2024-02-27 |
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