WO2022020889A1 - Méthode de traitement du cytomégalovirus - Google Patents
Méthode de traitement du cytomégalovirus Download PDFInfo
- Publication number
- WO2022020889A1 WO2022020889A1 PCT/AU2021/050817 AU2021050817W WO2022020889A1 WO 2022020889 A1 WO2022020889 A1 WO 2022020889A1 AU 2021050817 W AU2021050817 W AU 2021050817W WO 2022020889 A1 WO2022020889 A1 WO 2022020889A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- optionally substituted
- group
- alkyl
- starting material
- pyrimidine
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 232
- 238000011282 treatment Methods 0.000 title claims abstract description 13
- 241000701022 Cytomegalovirus Species 0.000 title claims description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 134
- 238000011321 prophylaxis Methods 0.000 claims abstract description 8
- -1 2-ethyl-propyl Chemical group 0.000 claims description 95
- 229910052739 hydrogen Inorganic materials 0.000 claims description 49
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 27
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 25
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 21
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 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 claims description 16
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 125000002252 acyl group Chemical group 0.000 claims description 15
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 15
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 125000004641 (C1-C12) haloalkyl group Chemical group 0.000 claims description 9
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 9
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 9
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 8
- 229910006069 SO3H Inorganic materials 0.000 claims description 7
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 241000701024 Human betaherpesvirus 5 Species 0.000 claims description 2
- 206010011831 Cytomegalovirus infection Diseases 0.000 abstract description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 263
- 239000007858 starting material Substances 0.000 description 231
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 176
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 144
- 238000005160 1H NMR spectroscopy Methods 0.000 description 138
- 239000000203 mixture Substances 0.000 description 116
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- 230000002829 reductive effect Effects 0.000 description 62
- 239000000047 product Substances 0.000 description 57
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 52
- 125000000217 alkyl group Chemical group 0.000 description 50
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- 230000015572 biosynthetic process Effects 0.000 description 37
- 238000003786 synthesis reaction Methods 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
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- 125000003118 aryl group Chemical group 0.000 description 32
- 125000001072 heteroaryl group Chemical group 0.000 description 31
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
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- 239000007832 Na2SO4 Substances 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 21
- 241000700605 Viruses Species 0.000 description 20
- 239000012267 brine Substances 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- 239000003921 oil Substances 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- 238000010898 silica gel chromatography Methods 0.000 description 19
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- 125000000753 cycloalkyl group Chemical group 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- 125000003342 alkenyl group Chemical group 0.000 description 17
- 229940018563 3-aminophenol Drugs 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 125000004404 heteroalkyl group Chemical group 0.000 description 15
- 229910052794 bromium Inorganic materials 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 14
- 229910052801 chlorine Inorganic materials 0.000 description 14
- 229910052731 fluorine Inorganic materials 0.000 description 14
- 238000004949 mass spectrometry Methods 0.000 description 14
- 125000001424 substituent group Chemical group 0.000 description 14
- 0 *c(c(C(N(*)*)=O)n[n]1c(-c(c(*)n[n]2)c2I)c2)c1nc2N(*)* Chemical compound *c(c(C(N(*)*)=O)n[n]1c(-c(c(*)n[n]2)c2I)c2)c1nc2N(*)* 0.000 description 13
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 229910052740 iodine Inorganic materials 0.000 description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 125000003545 alkoxy group Chemical group 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 229910052717 sulfur Inorganic materials 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 9
- 125000002950 monocyclic group Chemical group 0.000 description 9
- 125000004430 oxygen atom Chemical group O* 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
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- 239000007864 aqueous solution Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 7
- 125000003710 aryl alkyl group Chemical group 0.000 description 7
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- 125000004446 heteroarylalkyl group Chemical group 0.000 description 7
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 7
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 7
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 7
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- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
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- 238000002360 preparation method Methods 0.000 description 6
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- WBZRNVWIKQDPNS-UHFFFAOYSA-N n-methyl-1-[3-(trifluoromethoxy)phenyl]methanamine Chemical compound CNCC1=CC=CC(OC(F)(F)F)=C1 WBZRNVWIKQDPNS-UHFFFAOYSA-N 0.000 description 1
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
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- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 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
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
Definitions
- the present invention relates to methods for the prophylaxis or treatment of cytomegalovirus infection in subjects, particularly humans.
- viruses There are a wide variety of viruses known in the world today as they are found in almost every known ecosystem in the world and are considered the most numerous types of biological entity. They are infectious agents are sub-microscopic and only replicate in the living cells of the host organism. To provide some indication of the diversity of viruses known in the world they have been found to infect animals, plants, microorganisms and bacteria. As such viruses are endemic in the world.
- cytomegalovirus An example of a virus that is common and indeed has almost become endemic is cytomegalovirus with it being estimated that by the age of 30 almost 50% of the adult population have been infected with cytomegalovirus (CMV). Once infected the human body retains the virus for the remainder of your life. As the virus remains in the body it can reactivate if the infected individual develops problems with their immune system.
- CMV cytomegalovirus
- the virus is generally passed from person to person through bodily fluids and it is therefore transmitted from person to person through blood, saliva, urine, semen and breast milk. As such there can be transmission from pregnant women to their unborn child and through incidental contact between individuals such as kissing. It is therefore very difficult to control the transmission of the virus given its endemic nature.
- CMV infection can have serious consequences for three main groups of individuals being (1 ) newborns who became infected with CMV before birth (congenital CMV), (2) infants who become infected during birth or shortly afterwards through exposure to blood or their mother's milk (perinatal CMV), and (3) people who have a compromised immune system such as individuals who have had an organ transplant, individuals infected with HIV and individuals undergoing chemotherapy by way of example.
- the present invention provides a method of prophylaxis or treatment of Cytomegalovirus infection in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (I): [0012] wherein
- R 1 , R 2 and R 3 are each independently selected from the group consisting of H and C 1 -
- R 4 is selected from the group consisting of H and C 1 -C 12 alkyl
- R 5 is selected from the group consisting of H, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 heteroaryl group, optionally substituted C 6 -C 18 arylC 1 -C 12 alkyl-, and optionally substituted C 1 -C 18 heteroaryl C 1 -C 12 alkyl-;
- R 6 is selected from the group consisting of H, C 1 -C 12 alkyl, C 3 -C 6 cycloalkyl and C 1 -C 5 heterocycloalkyl;
- R 7 is selected from the group consisting of H and C 1 -C 12 alkyl
- R 8 is selected from the group consisting of H, C 1 -C 12 alkyl, optionally substituted C 6 - C 18 aryl, optionally substituted C 1 -C 18 heteroaryl, optionally substituted C 6 -C 18 arylC 1 -C 12 alkyl-, and optionally substituted C 1 -C 18 heteroarylC 1 -C 12 alkyl-;
- R 7 and R 8 when taken together with the nitrogen atom to which they are attached form a C 2 -C 12 heterocyclic group
- the group may be a terminal group or a bridging group. This is intended to signify that the use of the term is intended to encompass the situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety.
- alkyl alkyl
- alkylene alkylene
- R e , R f , R g and R h are each independently selected from the group consisting of H, C 1 -C 12 alkyl, C 1 -C 12 haloalkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 10 heteroalkyl, C 3 - C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 1 -C 12 heterocycloalkyl, C 1 -C 12 heterocycloalkenyl, C 6 -C 18 aryl, C 1 -C 18 heteroaryl, and acyl, or any two or more of R a , R b , R c and R d , when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
- Examples of particularly suitable optional substituents include F, Cl, Br, I, CH 3 , CH 2 CH 3 , OH, OCH 3 , CF 3 , OCF 3 , NO 2 , NH 2 , and CN.
- examples of acyl include acetyl and benzoyl.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the carbonyl carbon.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the nitrogen atom.
- alkenyl as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-12 carbon atoms, more preferably 2-10 carbon atoms, most preferably 2-6 carbon atoms, in the normal chain.
- the group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z.
- the alkenyl group is preferably a 1 -alkenyl group.
- alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.
- the group may be a terminal group or a bridging group.
- alkenyloxy refers to an alkenyl-O- group in which alkenyl is as defined herein.
- Preferred alkenyloxy groups are C 1 -C 6 alkenyloxy groups.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the oxygen atom.
- Alkyl as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a C 1 -C 12 alkyl, more preferably a C 1 -C 10 alkyl, most preferably C 1 - C 6 unless otherwise noted.
- suitable straight and branched C 1 -C 6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like.
- the group may be a terminal group or a bridging group.
- Alkylamino includes both mono-alkylamino and dialkylamino, unless specified.
- Mono-alkylamino means an Alkyl-NH- group, in which alkyl is as defined herein.
- Dialkylamino means a (alkyl) 2 N- group, in which each alkyl may be the same or different and are each as defined herein for alkyl.
- the alkyl group is preferably a C 1 -C 6 alkyl group.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the nitrogen atom.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the carbonyl carbon.
- Alkyloxy refers to an alkyl-O- group in which alkyl is as defined herein.
- the alkyloxy is a C 1 -C 6 alkyloxy. Examples include, but are not limited to, methoxy and ethoxy.
- the group may be a terminal group or a bridging group.
- Alkyloxyalkyl refers to an alkyloxy-alkyl- group in which the alkyloxy and alkyl moieties are as defined herein.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the alkyl group.
- Alkyloxyaryl refers to an alkyloxy-aryl- group in which the alkyloxy and aryl moieties are as defined herein.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the aryl group.
- the alkyl group is preferably a C 1 -C 6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the carbonyl carbon.
- Alkyloxycycloalkyl refers to an alkyloxy-cycloalkyl- group in which the alkyloxy and cycloalkyl moieties are as defined herein.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the cycloalkyl group.
- Alkyloxyheteroaryl refers to an alkyloxy-heteroaryl- group in which the alkyloxy and heteroaryl moieties are as defined herein.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the heteroaryl group.
- Alkyloxyheterocycloalkyl refers to an alkyloxy-heterocycloalkyl- group in which the alkyloxy and heterocycloalkyl moieties are as defined herein.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the heterocycloalkyl group.
- the alkyl group is preferably a C 1 -C 6 alkyl group.
- Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the sulfur atom.
- the alkyl group is preferably a C 1 -C 6 alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the sulfur atom.
- Alkynyl as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-12 carbon atoms, more preferably 2-10 carbon atoms, more preferably 2-6 carbon atoms in the normal chain.
- Exemplary structures include, but are not limited to, ethynyl and propynyl.
- the group may be a terminal group or a bridging group.
- Alkynyloxy refers to an alkynyl-O- group in which alkynyl is as defined herein.
- Preferred alkynyloxy groups are C 1 -C 6 alkynyloxy groups.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the oxygen atom.
- Aminoalkyl means an NH 2 -alkyl- group in which the alkyl group is as defined herein.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the alkyl group.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the sulfur atom.
- Aryl as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring.
- aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C 5-7 cycloalkyl or C 5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.
- the group may be a terminal group or a bridging group.
- an aryl group is a C6-C18 aryl group.
- Arylalkenyl means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein.
- exemplary arylalkenyl groups include phenylallyl.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the alkenyl group.
- Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as defined herein.
- Preferred arylalkyl groups contain a C 1-5 alkyl moiety.
- Exemplary arylalkyl groups include benzyl, phenethyl, 1 -naphthalenemethyl and 2-naphthalenemethyl.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the alkyl group.
- Arylalkyloxy refers to an aryl-alkyl-O- group in which the alkyl and aryl are as defined herein.
- the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
- Arylamino includes both mono-arylamino and di-arylamino unless specified.
- Mono-arylamino means a group of formula aryINH-, in which aryl is as defined herein.
- Di-arylamino means a group of formula (aryl) 2 N- where each aryl may be the same or different and are each as defined herein for aryl.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the nitrogen atom.
- Arylheteroalkyl means an aryl-heteroalkyl- group in which the aryl and heteroalkyl moieties are as defined herein.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the heteroalkyl group.
- Aryloxy refers to an aryl-O- group in which the aryl is as defined herein.
- the aryloxy is a C 6 -C 18 aryloxy, more preferably a C 6 -C 10 aryloxy.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the oxygen atom.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the sulfur atom.
- a "bond” is a linkage between atoms in a compound or molecule. The bond may be a single bond, a double bond, or a triple bond.
- Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring.
- Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
- the cycloalkenyl group may be substituted by one or more substituent groups.
- a cycloalkenyl group typically is a C 3 -C 12 alkenyl group. The group may be a terminal group or a bridging group.
- Cycloalkyl refers to a saturated monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane.
- a cycloalkyl group typically is a C 3 -C 12 alkyl group. The group may be a terminal group or a bridging group.
- Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as defined herein.
- Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the alkyl group.
- Cycloalkylalkenyl means a cycloalkyl-alkenyl- group in which the cycloalkyl and alkenyl moieties are as defined herein.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the alkenyl group.
- Cycloalkylheteroalkyl means a cycloalkyl-heteroalkyl- group in which the cycloalkyl and heteroalkyl moieties are as defined herein.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the heteroalkyl group.
- Cycloalkyloxy refers to a cycloalkyl-O- group in which cycloalkyl is as defined herein.
- the cycloalkyloxy is a C 1 -C 6 cycloalkyloxy. Examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the oxygen atom.
- Cycloalkenyloxy refers to a cycloalkenyl-O- group in which the cycloalkenyl is as defined herein.
- the cycloalkenyloxy is a C 1 -C 6 cycloalkenyloxy.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the oxygen atom.
- Haloalkyl refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine.
- a haloalkyl group typically has the formula C n H (2n+1-m) X m wherein each X is independently selected from the group consisting of F, Cl, Br and I.
- n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3.
- m is typically 1 to 6, more preferably 1 to 3.
- Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl.
- Haloalkenyl refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br and I.
- Haloalkynyl refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br and I.
- Fluorogen represents chlorine, fluorine, bromine or iodine.
- “Fleteroalkyl” refers to a straight- or branched-chain alkyl group preferably having from 2 to 12 carbons, more preferably 2 to 6 carbons in the chain, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by a heteroatomic group selected from S, O, P and NR’ where R’ is selected from the group consisting of FI, optionally substituted C 1 -C 12 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 6 -C 18 aryl, and optionally substituted C 1 -C 18 heteroaryl.
- heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.
- heteroalkyl also include hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkyloxy C 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, C 1 - C 6 alkylaminoC 1 -C 6 alkyl, and di(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl.
- the group may be a terminal group or a bridging group.
- “Fleteroalkyloxy” refers to a heteroalkyl-O- group in which heteroalkyl is as defined herein.
- the heteroalkyloxy is a C 2 -C6heteroalkyloxy.
- the group may be a terminal group or a bridging group.
- “Heteroaryl” either alone or part of a group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur.
- the group may be a monocyclic or bicyclic heteroaryl group.
- heteroaryl examples include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, pheno
- Heteroarylalkyl means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as defined herein.
- Preferred heteroarylalkyl groups contain a lower alkyl moiety.
- Exemplary heteroarylalkyl groups include pyridylmethyl.
- the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
- Heteroarylalkenyl means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as defined herein.
- the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
- Heteroarylheteroalkyl means a heteroaryl-heteroalkyl- group in which the heteroaryl and heteroalkyl moieties are as defined herein.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the heteroalkyl group.
- Heteroaryloxy refers to a heteroaryl-O- group in which the heteroaryl is as defined herein.
- the heteroaryloxy is a C 1 -C 18 heteroaryloxy.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the oxygen atom.
- Heterocyclic refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom.
- heterocyclic moieties include heterocycloalkyl, heterocycloalkenyl and heteroaryl.
- Heterocycloalkenyl refers to a heterocycloalkyl group as defined herein but containing at least one double bond.
- a heterocycloalkenyl group typically is a C 2 - C 12 heterocycloalkenyl group.
- the group may be a terminal group or a bridging group.
- Heterocycloalkyl refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered.
- heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3- diazapane, 1 ,4-diazapane, 1 ,4-oxazepane, and 1 ,4-oxathiapane.
- a heterocycloalkyl group typically is a C 2 -C 12 heterocycloalkyl group. The group may be a terminal group or a bridging group.
- Heterocycloalkylalkyl refers to a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as defined herein.
- exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the alkyl group.
- Heterocycloalkylalkenyl refers to a heterocycloalkyl-alkenyl- group in which the heterocycloalkyl and alkenyl moieties are as defined herein.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the alkenyl group.
- Heterocycloalkylheteroalkyl means a heterocycloalkyl-heteroalkyl- group in which the heterocycloalkyl and heteroalkyl moieties are as defined herein.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the heteroalkyl group.
- Heterocycloalkyloxy refers to a heterocycloalkyl-O- group in which the heterocycloalkyl is as defined herein.
- the heterocycloalkyloxy is a C 1 - C 6 heterocycloalkyloxy.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the oxygen atom.
- Heterocycloalkenyloxy refers to a heterocycloalkenyl-O- group in which heterocycloalkenyl is as defined herein.
- the Heterocycloalkenyloxy is a C 1 -C 6 Heterocycloalkenyloxy.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the oxygen atom.
- Hydroalkyl refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an OH group.
- a hydroxyalkyl group typically has the formula C n H (2n+1-x) (OH) x.
- n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3.
- x is typically 1 to 6, more preferably 1 to 3.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the sulfur atom.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the nitrogen atom.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the sulfur atom.
- the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the nitrogen atom.
- Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.
- Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds.
- each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
- pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the above-identified compounds and include pharmaceutically acceptable acid addition salts and base addition salts.
- Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid.
- Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propanoic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic.
- base addition salts may be prepared by ways well known in the art using organic or inorganic bases.
- suitable organic bases include simple amines such as methylamine, ethylamine, triethylamine and the like.
- suitable inorganic bases include NaOFI, KOFI, and the like.
- terapéuticaally effective amount or "effective amount” is an amount sufficient to effect beneficial or desired clinical results.
- An effective amount can be administered in one or more administrations.
- An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
- R 1 , R 2 and R 3 are each independently selected from the group consisting of H and C 1 -C 12 alkyl.
- R 1 is H. In some embodiments R 1 is C 1 -C 12 alkyl. In some embodiments R 1 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl- propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
- R 2 is H. In some embodiments R 2 is C 1 -C 12 alkyl. In some embodiments R 2 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2- ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2- methyl, pentyl, and hexyl.
- R 3 is H. In some embodiments R 3 is C 1 -C 12 alkyl. In some embodiments R 3 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2- ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2- methyl, pentyl, and hexyl.
- R 1 is H, and this provides compounds of formula (la):
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as described above.
- R 2 is H, and this provides compounds of formula (lb):
- R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as described above.
- R 3 is H, and this provides compounds of formula (lc): Formula (lc) or a pharmaceutically acceptable salt thereof
- R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and R 8 are as described above.
- R 1 is H
- R 2 is H
- R 3 is H and this provides compounds of formula (II):
- R 4 is selected from the group consisting of H and C 1 -C 12 alkyl. In some embodiments R 4 is H. In some embodiments R 4 is C 1 -C 12 alkyl. In some embodiments R 4 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
- R 1 is H
- R 2 is H
- R 3 is H
- R 4 is H and this provides compounds of formula (III): Formula (III) or a pharmaceutically acceptable salt thereof
- R 5 , R 6 , R 7 and R 8 are as described above.
- R 5 is selected from the group consisting of H, optionally substituted C 6 -C 18 aryl optionally substituted C 1 -C 18 heteroaryl group, optionally substituted C 6 -C 18 arylC 1 -C 12 alkyl-, and optionally substituted C 1 -C 18 heteroarylC 1 -C 12 alkyl-.
- R 5 is H. In some embodiments R 5 is optionally substituted C 6 -C 18 aryl. In some embodiments R 5 is optionally substituted C 1 -C 18 heteroaryl. In some embodiments R 5 is optionally substituted C 6 -C 18 arylC 1 -C 12 alkyl-. In some embodiments R 5 is optionally substituted C 1 -C 18 heteroarylC 1 -C 12 alkyl-.
- R 5 is an optionally substituted C 6 -C 18 aryl. Examples of this group include optionally substituted phenyl and optionally substituted naphthyl. In some embodiments R 5 is optionally substituted phenyl.
- R 5 is optionally substituted phenyl moiety of the formula A:
- each R a is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, SH, NH 2 , CF 3 , OCF 3 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 1 - C 12 haloalkyl optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 - C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 - C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 heteroaryl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyl
- R 9 and R 10 are each independently selected from the group consisting of H and C 1 -C 12 alkyl.
- R 5 is optionally substituted phenyl moiety selected from the group consisting of:
- each R a is as defined above.
- each R a is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, SH, NH 2 , NHCOCH 3 , CF 3 , OCHF 2, OCF 3 , C 1 -C 12 alkyl and C 1 -C 12 alkyloxy.
- each R a is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3, Cl, Br, F, I, OH, NO 2 , NH 2 , N(CH 3 ) 2 , NHCOCH 3 , NHSO 2 CH 3, NHSO 2 CH 2 CH 3, CN, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , OCH 2 CH 2 OCH 3, OC 6 H 5 , OCH 2 C(CH 3 ) 3 , OCH 2 cycloproply, O-tetrahydropyran, piperazine, 4- methyl piperazine, 4-acyl-piperazine, morpholine, CF 3 , OCHF 2, and OCF 3 .
- R 1 is H
- R 2 is H
- R 3 is H
- R 4 is H
- R 5 is a moiety of the formula A and this provides compounds of formula (IV):
- R a , R 6 , R 7 and R 8 are as described above.
- the group R 5 is an optionally substituted C1-C18 heteroaryl group.
- Suitable heteroaryl groups include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole,
- R 5 is selected from the group consisting of:
- each V 1 , V 2 , V 3 and V 4 are independently selected from the group consisting of N and CR B ;
- each R B is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, SH, NH 2 , CF 3 , OCF 3 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 1 - C 12 haloalkyl optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 - C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 - C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 heteroaryl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted
- R 9 and R 10 are each independently selected from the group consisting of H and C 1 -C 12 alkyl.
- Y is selected from the group consisting of S, O, and NH.
- R 5 is selected from the group consisting of:
- R 5 is selected from the group consisting of:
- each R B is as defined above.
- each R B is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, SH, NH 2 , NHCOCH 3 , CF 3 , OCHF 2, OCF 3 , C 1 -C 12 alkyl and C 1 -C 12 alkyloxy.
- each R B is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3, Cl, Br, F, I, OH, NO 2 , NH 2 , NHSO 2 CH2CH 2 CH 3, CN, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2, OC 6 H 5 , OCH 2 CCH, OCH 2 cycloproply, CF 3 , OCHF 2, and OCF 3 .
- R 5 is optionally substituted C 6 -C 18 arylC 1 -C 12 alkyl
- the optionally substituted C 6 -C 13 aryl is as described above for R 5 .
- the alkyl is typically selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2- ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
- R 5 is substituted C 1 - C 18 heteroaryl C 1 -C 12 alkyl
- the optionally substituted C 1 -C 18 heteroaryl is as described above for R 5 .
- the alkyl is typically selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl- butyl, pentyl, 2-methyl, pentyl, and hexyl.
- R 6 is selected from the group consisting of H, C 1 -C 12 alkyl, C 3 -C 6 cycloalkyl; C 1 -C 5 heterocycloalkyl. In one embodiment R 6 is H. In one embodiment R 6 is C 1 -C 12 alkyl. In one embodiment R 6 is C 3 -C 6 cycloalkyl. In one embodiment R 6 is C 1 -C 5 heterocycloalkyl.
- R 6 is C 1 -C 12 alkyl.
- suitable values of R 6 include methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3- dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
- a particularly preferred value of R 6 is isopropyl.
- R 6 is C 3 -C 6 cycloalkyl.
- suitable values of R 6 include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- R 6 is C 1 -C 5 heterocycloalkyl.
- suitable values of R 6 include azetidine, oxetane, thietane, pyrrolidine, oxolane, thiolane, piperidine, oxane, and thiane.
- R 7 is selected from the group consisting of H and C 1 -C 12 alkyl, or R 7 and R 8 when taken together with the nitrogen atom to which they are attached form a monocyclic or bicyclic C 2 -C 12 heterocycloalkyl group.
- R 7 is H.
- R 7 is C 1 -C 12 alkyl.
- suitable values of R 7 include methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl- butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
- R 7 is Methyl.
- R 8 is selected from the group consisting of H, C 1 -C 12 alkyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 heteroaryl, optionally substituted C 6 -C 18 arylC 1 -C 12 alkyl-, and optionally substituted C 1 -C 18 heteroarylC 1 -C 12 alkyl
- R 8 is H.
- R 8 is C 1 -C 12 alkyl.
- suitable values of R 8 include methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl- butyl, 2-ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
- R 8 is Methyl.
- R 8 is optionally substituted C 6 -C 18 aryl. Examples of this group include optionally substituted phenyl and optionally substituted naphthyl. In some embodiments R 8 is optionally substituted phenyl.
- R 8 is optionally substituted phenyl moiety of the formula B:
- each R c is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, SH, NH 2 , CF 3 , OCF 3 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 1 -C 12 haloalkyl optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 - C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 - C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 heteroaryl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyl
- R 8 is optionally substituted phenyl moiety of the selected from the group consisting of:
- each R c is as defined above.
- each R c is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, SH, NH 2 , NHCOCH 3 , CF 3 , OCHF 2, OCF 3 , C 1 - C 12 alkyl and C 1 -C 12 alkyloxy.
- each R c is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3, Cl, Br, F, I, OH, NO 2 , NH 2 , NHSO 2 CH2CH 2 CH 3, CN, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2, OC 6 H 5 , OCH 2 CCH, OCH 2 cycloproply, CF 3 , OCHF 2, and OCF 3 .
- R 8 is optionally substituted C 1 -C 13 heteroaryl.
- Suitable heteroaryl groups include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazole,
- heteroaryl is a pyridyl moiety it may be a 2-pyridyly, a 3- pyridyl or a 4-pyridyl.
- R 8 is selected from the group consisting of:
- each V 1 , V 2 , V 3 and V 4 are independently selected from the group consisting of N and CR D ;
- each R D is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, SH, NH 2 , CF 3 , OCF 3 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 1 - C 12 haloalkyl optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 - C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 - C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 heteroaryl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted
- R 9 and R 10 are each independently selected from the group consisting of H and C 1 -C 12 alkyl.
- Y is selected from the group consisting of S, O, and NH.
- R 8 is selected from the group consisting of:
- R 8 is selected from the group consisting of:
- each R D is as defined above.
- each R D is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, SH, NH 2 , NHCOCH 3 , CF 3 , OCHF 2, OCF 3 , C 1 -C 12 alkyl and C 1 -C 12 alkyloxy.
- each R D is independently selected from the group consisting of H, CH 3 , CH2CH 3 , CH2CH2CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , Cl, Br, F, I, OH, NO 2 , NH 2 , NHSO 2 CH2CH2CH 3 , CN, OCH 3 , OCH2CH 3 , OCH2CH2CH 3 , OCH(CH 3 ) 2, OC 6 H 5 , OCH2CCH, OCH 2 cycloproply, CF 3 , OCHF 2, and OCF 3 .
- R 8 is optionally substituted C 6 -C 18 arylC 1 -C 12 alkyl
- the optionally substituted C 6 -C 18 aryl is as described above for R 8 .
- the alkyl is typically selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2- ethyl-butyl, pentyl, 2-methyl, pentyl, and hexyl.
- the alkyl is methyl such that the alkyl is a methylene group joining the aryl group to the nitrogen.
- R 8 is substituted C 1 - C 18 heteroaryl C 1 -C 12 alkyl-.
- the optionally substituted C 1 -C 18 heteroaryl is as described above for R 8 .
- the alkyl is typically selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl- butyl, pentyl, 2-methyl, pentyl, and hexyl.
- R 7 and R 8 when taken together with the nitrogen atom to which they are attached form a a C 2 -C 12 heterocyclic group.
- the a C 2 -C 12 heterocyclic group may be any suitable C 2 -C 12 heterocyclic group and may be monocyclic or bicyclic heterocyclic group. In one embodiment the a C 2 -C 12 heterocyclic group is monocyclic. In one embodiment the a C 2 - C 12 heterocyclic group is bicyclic.
- the C 2 -C 12 heterocyclic group may consist of fully saturated rings, fully unsaturated rings or combinations thereof. For example, it may contain one saturated ring and one unsaturated ring.
- the C 2 -C 12 heterocyclic group is a group of the formula C:
- each R D is independently selected from the group consisting of H, halogen, OH, NO 2 , CN, SH, NH 2 , CF 3 , OCF 3 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 1 - C 12 haloalkyl optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 - C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 - C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 heteroaryl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkeny
- each R 9 and R 10 are independently selected from the group consisting of H and C 1 -C 12 alkyl;
- n is an integer selected from 1 and 2.
- the C 2 -C 12 heterocyclic group is a group of the formula D:
- the C 2 -C 12 heterocyclic group is a group of the formula E:
- each R D is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3, Cl, Br, F, I, OH, NO 2 , NH 2 , NHSO 2 CH 2 CH 2 CH 3, CN, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2, OC 6 H 5 , OCH 2 C(CH 3 ) 3 , OCH 2 cycloproply, CF 3 , OCHF 2, and OCF 3 .
- the R 9 group is selected from the group consisting of H, methyl, ethyl, isopropyl, propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, and hexyl.
- R 9 is selected from the group consisting of H, methyl and ethyl.
- R 9 is H.
- R 9 is methyl.
- R 9 is ethyl.
- the R 10 group is selected from the group consisting of H, methyl, cyclopropylmethyl, ethyl, isopropyl, propyl, cyclopropyl, 3,3-dimethyl-propyl, butyl, isobutyl, cyclobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, hexyl, phenyl and pyridine-2-yl.
- R 10 is selected from the group consisting of H, methyl and ethyl.
- R 10 is H.
- R 10 is methyl.
- R 10 is ethyl.
- R e , R f , R g and R h are each independently selected from the group consisting of H, C 1 -C 12 alkyl, C 1 -C 12 haloalkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 1 oheteroalkyl, C 3 - C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 1 -C 12 heterocycloalkyl, C 1 -C 12 heterocycloalkenyl, C 6 -C 18 aryl, C 1 -C 18 heteroaryl, and acyl, or any two or more of R a , R b , R c and R d , when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
- each optional substituent is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3, Cl, Br, F, I, OH, NO 2 , NH 2 , CN, OCH 3 , OCH 2 CH 2 CH 3 , CF 3 , and OCF 3 .
- optionally substituted includes a fused ring such as a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring or a heteroaryl ring.
- Examples of specific compounds of Formula (I) for use in the present invention include:
- CMV Cytomegalovirus
- the inhibition of the Ctomegalovirus may be carried out in any of a number of ways known in the art. For example, if inhibition of the virus in vitro is desired, an appropriate amount of the compound may be added to a solution containing the virus (such as in an assay for example). In circumstances where it is desired to inhibit Cytomegalovirus in a subject (such as a human), the inhibition of the virus typically involves administering the compound to a subject infected with the virus.
- the compounds may find a multiple number of applications in which their ability to inhibit Cytomegalovirus mentioned above can be utilised. Accordingly, the present invention provides a method of prophylaxis or treatment of Cytomegalovirus infection in a subject, the method comprising administering an effective amount of a compound of formula (I) to a subject in need thereof.
- the subject is a human.
- the compounds of the invention may be used to inhibit any known Cytomegalovirus and can, at least in theory, be used in the prophylaxis or treatment of any cytomegalovirus infection.
- the subject is a human.
- the virus is human betaherpesvirus 5.
- Administration of compounds within Formula (I) to humans can be by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion.
- the active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose.
- the activator compound may be selectively toxic or more toxic to rapidly proliferating cells, e.g. cancerous tumours, than to normal cells.
- the compounds of the invention can be administered in any form or mode which makes the compound bioavailable.
- One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances.
- the compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient.
- a pharmaceutically acceptable carrier diluent or excipient.
- the compounds of the invention while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility.
- compositions which are formulated depending on the desired mode of administration.
- the present invention provides a pharmaceutical composition including a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.
- the compositions are prepared in manners well known in the art.
- the invention in other embodiments provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
- a pack or kit can be found a container having a unit dosage of the agent(s).
- the kits can include a composition comprising an effective agent either as concentrates (including lyophilized compositions), which can be diluted further prior to use or they can be provided at the concentration of use, where the vials may include one or more dosages.
- single dosages can be provided in sterile vials so that the physician can employ the vials directly, where the vials will have the desired amount and concentration of agent(s).
- Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
- the compounds of the invention may be used or administered in combination with one or more additional drug(s) for the treatment of the disorder/diseases mentioned.
- the components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds of the invention may be administered sequentially or simultaneously with the other drug(s).
- the compounds of the invention may be used in a combination therapy. When this is done the compounds are typically administered in combination with each other. Thus, one or more of the compounds of the invention may be administered either simultaneously (as a combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable where the therapeutic profile of each compound is different such that the combined effect of the two drugs provides an improved therapeutic result.
- compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
- suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
- Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
- compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.
- the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
- the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
- compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
- the active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3- butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifier
- the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
- suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
- compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- Dosage forms for topical administration of a compound of this invention include powders, patches, sprays, ointments and inhalants.
- the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
- the amount of compound administered will preferably treat and reduce or alleviate the condition.
- a therapeutically effective amount can be readily determined by an attending diagnostician using conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration, the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances.
- a preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day.
- a more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day.
- a suitable dose can be administered in multiple sub-doses per day.
- the compounds for use in the methods of the present invention may be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes including the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available.
- the preparation of compounds of the embodiments is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare other agents of the various embodiments.
- the reactions for preparing compounds of the invention can be carried out in suitable solvents, which can be readily selected by one of skill in the art of organic synthesis.
- suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
- a given reaction can be carried out in one solvent or a mixture of more than one solvent.
- suitable solvents for a particular reaction step can be selected by the skilled artisan.
- Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups.
- the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
- the chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.
- Reactions can be monitored according to any suitable method known in the art.
- product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), or mass spectrometry, or by chromatography such as high-performance liquid chromatography (HPLC) or thin layer chromatography.
- spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), or mass spectrometry
- chromatography such as high-performance liquid chromatography (HPLC) or thin layer chromatography.
- ambient temperature e.g. a reaction temperature
- room temperature e.g. a temperature from about 20 oC to about 30 oC.
- BoC 2 O di-tert-butyl dicarbonate
- c-Hex cyclohexane
- CDCI 3 deuterated chloroform
- CD 3 OD deuterated methanol
- DIPEA N,N-diisopropylethylamine
- LiHMDS lithium bis(trimethylsilyl)amide
- MsCI methanesulfonyl chloride
- n-BuLi n -butyllithium
- NaHCO 3 sodium bicarbonate
- NaOH sodium hydroxide
- Pd(dppf)Cl2 [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with DCM
- PE Pulleum Ether
- ppm parts per million
- TFA trifluoroacetic acid
- Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance-400 spectrometer ( 1 H at 400.13 MHz and 13 C at 100.62 MHz). Proton chemical shifts are reported in ppm from an internal standard of residual chloroform (7.26 ppm), dimethylsulfoxide (2.50 ppm) or methanol (3.31 ppm). Each resonance was assigned according to the following convention; chemical shift ( ⁇ ) (multiplicity, coupling constant(s) in Hz, integration). Carbon chemical shifts are reported in parts per million (ppm) using an internal standard of residual chloroform (77.16 ppm), dimethylsulfoxide (39.52 ppm) or methanol (49.00 ppm).
- Method A 1. Equipment Information, LC model: Agilent 1200 (Pump type: Binary
- Method B 1 ) LC: Agilent Technologies 1290 series, Binary Pump, Diode Array Detector. Colum: Agilent EclipsePlus RRHD C18, 1.8 ⁇ m, 3.0x50 mm. Mobile phase: A: 0.05% Formate in water (v/v), B: 0.05% Formate in MeCN(v/v). Flow Rate: 1 .0 mL/min at 40 °C. Detector: 214 nm, 254 nm.
- MS G6120A, Quadruple LC/MS; Ion Source: ESI, Signal: positive, TIC: 70-1000 m/z, Fragmentor: 60, Threshold: 5, Gain: 1 , Drying gas flow: 10 L/min, Nebulizer pressure: 35 psi,
- LCMS-P2-3min - 1 LC: Agilent Technologies 1290 series, Binary Pump, Diode Array Detector. Colum: Agilent EclipsePlus RRHD C18, 1.8 ⁇ m, 3.0x50 mm .
- Mobile phase A: 0.05% Formate in water (v/v), B: 0.05% Formate in MeCN(v/v).
- Flow Rate 1 .0 mL/min at 40 °C.
- Detector 214 nm, 254 nm.
- MS G6120A, Quadrupole LC/MS, Ion Source: ESI, Signal: positive, TIC: 70-1000 m/z, Fragmentor: 60, Threshold: 5, Gain: 1 , Drying gas flow: 10 L/min, Nebulizer pressure: 35 psi.
- Method C -LC model Waters 2695 alliance. (Pump: Quaternary Pump, Detector: 2996 Photodiode Array Detector), MS model: Micromass ZQ. Parameters of LCMS- LC: Column: Xbridge-C18, 2.5 ⁇ m, 2.1 ⁇ 30 mm, Column temperature: 30°C. Acquisition of wavelength: 214 nm, 254 nm.
- Sample preparation The sample was dissolved in methanol, the concentration about 1—10 mg/mL , then filtered through the syringes filter with 0.22 ⁇ m. (Injection volume: 1 ⁇ 10pL)
- Method D LC model Waters 2695 alliance. (Pump: Quaternary Pump, Detector: 2996 Photodiode Array Detector), MS model: Micromass ZQ, Parameters of LCMS -LC: Column: Xbridge-C18, 3.5 ⁇ m, 2.1x50 mm. Column temperature: 20°C. Acquisition of wavelength: 214 nm, 254 nm. Mobile phase: A: 0.05% HCOOH aqueous solution, B: CAN. Run time: 8 min. MS: Ion source: ES+ (or ES-) MS range: 100 ⁇ 1000 m/z. Capillary: 3 kV Cone: 40 V Extractor: 3 V. Drying gas flow: 800 L/hr cone: 50 L/hr. Desolvation temperature: 500°C. Source temperature: 120°C. Run time: 8 min
- Sample preparation The sample was dissolved in methanol, the concentration about 1 ⁇ 10 mg/mL , then filtered through the syringes filter with 0.22 ⁇ m. (Injection volume: 1 ⁇ 10 ⁇ L).
- TLC Thin layer chromatography
- the appropriately protected diacid moiety (I) is reacted with the appropriately functionalized acetylene in the presence of a strong base to form II.
- Compound II is then reacted with hydrazine to form the 5 membered heterocyclic ring compound (III).
- Compound III is then reacted with a suitably substituted diacid to form the amide IV which is then cyclised to form the bicyclic heteroaromatic compound V.
- compound V is then reacted with POCI 3 to insert chloro groups for further elaboration of the substituents of the ring (compound VI).
- this scheme depicts one mode of formation of an advanced intermediate for the synthesis of compounds of the invention. Variation of the R group on the acetylene and the ester group on the starting diacid allows for a number of different advanced intermediates to be made using this technique.
- Step 1 ethyl 5-(3-ethoxy-3-oxopropanamido)-1H-pyrazole-3-carboxylate (XII).
- Step 7 5-(benzyl(methyl)amino)-N-(3-hydroxyphenyl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-2-carboxamide (XVIII)
- step 5 -1-(4-chlorophenyl)-N-methylmethanamine; starting material used in step 7 4-chloroaniline; 1 HNMR (400 MHz, DMSO-d 6 ) ⁇ 13.52 (s, 1 H), 10.30 (s,
- step 5 isoindoline
- step 7 3-(4- methylpiperazin-1-yl)aniline
- step 4 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-1 H-pyrazole; starting material used in step 5 - isoindoline.
- step 4 - 1 Starting material used in step 4 - 1 ,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole, starting material used in step 5 - isoindoline, starting material used in step 7 - 4-aminophenol, 1 HNMR (400 MHz, DMSO-d 6 ) ⁇ 9.68 (s, 1H), 9.41 (s, 1H), 7.49- 7.31 (m, 5H), 7.18-7.07 (m, 2H), 6.61 (s, 1 H), 6.55-6.48 (m, 2H), 4.93 (s, 4H), 3.80 (s, 3H), 2.29 (s, 3H), 2.20 (s, 3H).
- Step 7 ethyl 5-(isoindolin-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo [1,5-a]pyrimidine-2- carboxylate (XXV)
- Step 8 5-(isoindolin-2-yl)-3-methyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2- carboxylic acid (XXVI)
- aqueous phase was adjusted to pH 5 with aqueous HCI (1 M) and then the organics were extracted with Et 2 O (2 x 200mL). The organics were washed by brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOFI, 100:1) to give the title product (44.2 g, 71%) as a yellow oil.
- Step 2 Ethyl 5-amino-4-isopropyl-1H-pyrazole-3-carboxylate (IXXX) [0330] A mixture of ethyl 5-amino-4-isopropyl-1 H-pyrazole-3-carboxylate (44.2 g, 0.24 mol) and N 2 H 4 H 2 O (23 mL , 0.31 mol) in AcOH (40 ml.) and toluene (400 ml.) was refluxed overnight using Dean Stark trap. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and saturated NaHCO 3 (100mL, 1/1). The organics were dried over Na 2 SO 4, filtered, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (DCM:MeOH, 100:1) to give the desired product (23 g, 51%) as a yellow solid.
- DCM:MeOH, 100:1 silica gel column chromatography
- Step 7 ethyl 5-(isoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2- carboxylate (XXXIV)
- Step 8 5-(isoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2- carboxylic acid (XXXV)
- Step 9 N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-3-isopropyl-7-(1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (XXXVI)
- Example 86 5-(5-chloroisoindolin-2-yl)-N-(3-hydroxyphenyl)-3-isopropyl-7-(1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (100) [0353] Starting material used in step 7 - 5-chloroisoindoline, starting material used in step 9 - 3-aminophenol.
- Step 1 ethyl 3-cyano-3-cyclopropyl-2-oxopropanoate (XXXVII)
- Step 2 ethyl 5-amino-4-cyclopropyl-1H-pyrazole-3-carboxylate (XXXVIII) [0376] A mixture of ethyl 3-cyano-3-cyclopropyl-2-oxopropanoate (28.0 g, 0.15 mol) and N 2 H 4 H 2 O (15.5 g, 0.31 mol) in a mixture AcOH (40 ml.) and toluene (400 ml.) was refluxed overnight using a Dean Stark trap. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and an aqueous saturated solution of NaHCC>3.
- Step 3 ethyl 4-cyclopropyl-5-(3-ethoxy-3-oxopropanamido)-1H-pyrazole-3- carboxylate(XXXIX)
- Step 4 ethyl 3-cyclopropyl-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (XL)
- Step 7 ethyl-3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1 ,5- a]pyrimidine-2-carboxylate (XLIII)
- Step 8 3-cyclopropyl-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2- carboxylic acid (XLIV)
- Step 9 3-cyclopropyl-5-(isoindolin-2-yl)-N-(3-methoxyphenyl)-7-(1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (XLV)
- the mixture was diluted with H 2 O (100 ml.) and the organics were removed with Et 2 O (2 x 100 mL ).
- the aqueous phase was adjusted to pH 5 with an aqueous solution of HCI (6M) and the aqueous were extracted with Et 2 O (3 x 100 mL ).
- the combined organics were washed with brine (300 mL ), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the desired product (7.5 g, 89%) as a yellow oil.
- Step 4 ethyl 4-(tert-butyl)-5-(3-ethoxy-3-oxopropanamido)-1 H-pyrazole-3-carboxylate (XLIX)
- Step 5 ethyl 3-(tert-butyl)-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (L)
- Step 7 ethyl 3-(tert-butyl)-5-chloro-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2- carboxylate (Lll)
- Step 8 ethyl 3-(tert-butyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine- 2-carboxylate (LIII)
- Step 10 3-(tert-butyl)-N-(3-hydroxyphenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4- yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (LV)
- step 8 isoindoline
- step 10 N-(3- aminophenyl)acetamide
- step 8 isoindoline
- step 10 1-(4- (3-aminophenyl)piperazin-1-yl)ethan-1-one
- step 8 isoindoline.
- Example 118 N-(3-(4-acetylpiperazin-1-yl)phenyl)-3-(tert-butyl)-5-(5-chloroisoindolin-2- yl)-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (90) [0406] Starting material used in step 8 - 5-chloroisoindoline, Starting material used in step 10 - Starting material: 1 -(4-(3-aminophenyl)piperazin-1-yl)ethan-1 -one.
- Step 6 ethyl 5,7-di hydroxy-3- (tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2- carboxylate (LXI)
- Step 7 ethyl 5,7-dichloro-3- (tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-2- carboxylate (LXII)
- Step 8 ethyl 5-chloro-7--(1H-pyrazol-4-yl)-3- (tetrahydro-2H-pyran-4-yl)pyrazolo [1,5- a]pyrimidine- 2- carboxylate (LXIII)
- Step 9 ethyl 5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo [1,5-a]pyrimidine-2-carboxylate (LXIV)
- Step 10 5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)pyrazolo[1 ,5- a]pyrimidine-2-carboxylic acid (LXV)
- Step 11 N-(3-chlorophenyl)-5-(isoindolin-2-yl)-7-(1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran- 4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (LXVI)
- TCID 50 Median Tissue Culture Infectious Dose
- TCID 50 signifies the concentration at which 50% of the cells are infected when a test tube or well plate upon which cells have been cultured is inoculated with a diluted solution of viral fluid.
- EC 50 refers to the concentration of a drug, which induces a response halfway between the baseline and maximum after a specified exposure time. Put another way it is the concentration of drug required to obtain a 50% result.
- CC 50 refers to the 50% cytotoxic concentration and is defined as the compound's concentration ( ⁇ g/mL) required for the reduction of ceil viability by 50%, which is calculated by regression analysis.
- Foetal calf serum (Gibco). Serum-free medium was used for viral infection.
- the virus was added at 100x TCID 50 to all cells in the infected groups. Cells in the uninfected groups were treated with blank medium.
- CPE cytopathic effect
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Abstract
La présente invention concerne une méthode de prophylaxie ou de traitement d'une infection à cytomégalovirus chez un sujet, la méthode comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un composé de formule (I).
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WO2018145080A1 (fr) * | 2017-02-06 | 2018-08-09 | Case Western Reserve University | Compositions et procédés de modulation de l'activité de la déshydrogénase à chaîne courte |
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