NOVEL GALACTOSIDE INHIBITOR OF GALECTINS
20220259251 · 2022-08-18
Assignee
Inventors
Cpc classification
A61P29/00
HUMAN NECESSITIES
International classification
Abstract
A D-galactopyranose compound of formula (1)
##STR00001##
wherein, the pyranose ring is beta-D-galactopyranose, and pharmaceutical composition including these compounds. These are high affinity galectin-1 and/or 3 inhibitors. Also, methods for treating a disorder relating to the binding of a galectin-1 and/or -3 to a ligand in which these compounds or pharmaceutical compositions are administered.
Claims
1-15. (canceled)
16. A D-galactopyranose compound of formula (1) ##STR00156## wherein the pyranose ring is β-D-galactopyranose, A1 is ##STR00157## wherein the asterix * indicates the nitrogen atom of the triazole ring that is covalently attached to the galactopyranose; wherein Het.sup.1 is a five or six membered heteroaromatic ring selected from the group consisting of formulas 2 to 10, wherein the asterix * indicates the carbon atom of the heteroaromatic ring that is covalently attached to the triazole group in formula A.sup.1: ##STR00158## wherein R.sup.2 to R.sup.23, R.sup.27, R.sup.35 and R.sup.36 are independently selected from H; halogen; OH; CN; SH; S—C.sub.1-6 alkyl; C.sub.1-6 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; iso-propyl, optionally substituted with a F; O-cyclopropyl optionally substituted with a F; O-isopropyl optionally substituted with a F; OC.sub.1-6 alkyl optionally substituted with a F; NR.sup.24R.sup.25, wherein R.sup.24 is selected from H and C.sub.1-6 alkyl, and R.sup.25 is selected from H, C.sub.1-3 alkyl, and COR.sup.26, wherein R.sup.26 is selected from H, and C.sub.1-6 alkyl; wherein B1 is selected from the group consisting of a heteroaryl, an aryl and a heterocycloalkyl, optionally substituted with one or more groups selected from a) C.sub.1-6 alkyl optionally substituted with one or more of C.sub.1-6 alkyl, amino, CN, halogen, hydroxy, C.sub.1-6 alkoxy, carboxy, alkoxycarbonyl, H.sub.2NCO, b) R.sup.28—C.sub.1-6 alkyl, c) C.sub.3-6 cycloalkyl optionally substituted with one or more of C.sub.1-6 alkyl, amino, CN, halogen, or hydroxy, c) C.sub.1-6 alkenyl, d) C.sub.1-6 alkoxy, e) C.sub.1-6 alkylthio, f) C.sub.1-6 alkylsulfonyl, g) carbonyl substituted with any one of hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkylNH, ((R.sup.29)(R.sup.30)N)C.sub.1-6 alkylNH, or (pyridinyl)C.sub.1-6 alkylNH, h) (R.sup.31)(R.sup.32)N, i) C.sub.2-alkynyl, and j) R.sup.28; wherein R.sup.28 is selected from any one of a) phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, OH, C.sub.2-alkynyl, halogen, C.sub.1-6 alkyl, halo-C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy, halo-C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, carboxy, C.sub.1-6 alkoxycarbonyl, CONH.sub.2, and (R.sup.33)(R.sup.34)N; or b) (C.sub.1-6 alkyl-SO.sub.2)phenyl, (C.sub.1-6 alkyl SO.sub.2)(halo)phenyl, (aminoSO.sub.2)phenyl, (di-C.sub.1-6 alkylaminoSO.sub.2)phenyl, ((C.sub.1-6 alkyl-NHSO.sub.2)—C.sub.1-6 alkyl)phenyl, (pyrrolyl)phenyl, (imidazolyl)phenyl, (oxazolyl)phenyl, (tetrazolyl)phenyl, ((pyridinyl)methyl)phenyl, phenoxyphenyl, (benzyloxy)phenyl, ((methyl)thiazolyl)-phenyl, (thiazolyl)-benzenesulfamido, ((methyl)thiadiazolyl)benzenesulfamido, (methyl)-benzothiazolonyl, or fluoropyrazolopyrimidinyl; wherein R.sup.29 is hydrogen or C.sub.1-6 alkyl; R.sup.30 is hydrogen or C.sub.1-6 alkyl; or (R.sup.29)(R.sup.30)N taken together is any one of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, optionally substituted with one or more substituents selected from halogen, C.sub.1-6 alkyl, and hydroxy; R.sup.31 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, or C.sub.1-6 alkylsulfonyl; R.sup.32 is hydrogen or C.sub.1-6 alkyl; or (R.sup.31)(R.sup.32)N taken together is any one of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, optionally substituted with one or more substituents selected from halogen, C.sub.1-6 alkyl, and C.sub.1-6 alkylcarbonyl; R.sup.33 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, or C.sub.1-6 alkylsulfonyl; R.sup.34 is hydrogen or C.sub.1-6 alkyl; or (R.sup.33)(R.sup.34)N taken together is any one of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, optionally substituted with one or more substituents selected from halogen, C.sub.1-6 alkyl, and C.sub.1-6 alkylcarbonyl; R.sup.1 is selected from the group consisting of a) H, b) OH, c) OC.sub.1-6 alkyl optionally substituted with one or more halogen, phenyl, phenyl substituted with one or more groups selected form OH and halogen, CN, OR.sup.17, NR.sup.18R.sup.19, and CONH.sub.2, wherein R.sup.17 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.20—CONH— wherein R.sup.20 is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.18 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.21—CONH— wherein R.sup.21 is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.19 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.22—CONH— wherein R.sup.22 is selected from C.sub.1-3 alkyl and cyclopropyl, d) branched OC.sub.3-6 alkyl optionally substituted with one or more halogen, CN, OR.sup.23, NR.sup.24R.sup.25, and CONH.sub.2, wherein R.sup.23 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.26—CONH— wherein R.sup.26 is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.24 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.27—CONH— wherein R.sup.27 is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.25 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.28—CONH— wherein R.sup.28 is selected from C.sub.1-3 alkyl and cyclopropyl, e) cyclic OC.sub.3-6 alkyl optionally substituted with one or more halogen, CN, OR.sup.29, NR.sup.30R.sup.31, and CONH.sub.2, wherein R.sup.29 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.32—CONH— wherein R.sup.32 is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.30 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.33—CONH— wherein R.sup.33 is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.31 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.34—CONH— wherein R.sup.34 is selected from C.sub.1-3 alkyl and cyclopropyl, and f) a fluorine (F); or a pharmaceutically acceptable salt or solvate thereof.
17. The compound of claim 16 wherein Het1 is selected from the group consisting of ##STR00159## wherein R.sup.2 is selected from the group consisting of hydrogen, methyl, OH and halogen; R.sup.3 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen; R.sup.4 is selected from the group consisting of OH, C.sub.1-6 alkyl, halogen and amino; R.sup.5 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen; R.sup.35 and R.sup.36 are independently selected from hydrogen, C.sub.1-6 alkyl, amino and halogen.
18. The compound of claim 16 wherein Het1 is selected from the group consisting of ##STR00160##
19. The compound of claim 16 wherein B1 is selected from the group consisting of pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, phenyl, or indolyl; optionally substituted with a group selected from a) C.sub.1-6 alkyl optionally substituted with one or more of C.sub.1-6 alkyl, halogen, hydroxy, C.sub.1-6 alkoxy, carboxy, alkoxycarbonyl, H.sub.2NCO, b) R.sup.28—C.sub.1-6 alkyl, c) C.sub.3-6 cycloalkyl optionally substituted with one or more of C.sub.1-6 alkyl, halogen, or hydroxy, c) C.sub.1-6 alkenyl, d) C.sub.1-6 alkoxy, e) C.sub.1-6 alkylthio, f) C.sub.1-6 alkylsulfonyl, g) carbonyl substituted with any one of hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkylNH, ((R.sup.29)(R.sup.30)N)C.sub.1-6 alkylNH, or (pyridinyl)C.sub.1-6 alkylNH, h) (R.sup.31)(R.sup.32)N, and j) R.sup.28; wherein R.sup.28, R.sup.29, R.sup.39, R.sup.31 and R.sup.32 are as defined in claim 1.
20. The compound of claim 16 wherein B1 is selected from the group consisting of pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, phenyl, or indolyl; optionally substituted with a group selected from a) C.sub.1-6 alkyl optionally substituted with one or more of halogen, and j) R.sup.28; wherein R.sup.28 is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, OH, C.sub.2-alkynyl, halogen, C.sub.1-6 alkyl, halo-C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy, halo-C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, carboxy, C.sub.1-6 alkoxycarbonyl, and CONH.sub.2.
21. The compound of claim 16 wherein B1 is selected from pyrazolyl or triazolyl; optionally substituted with a group selected from methyl, CF.sub.3, and R.sup.28; wherein R.sup.28 is selected form the group consisting of phenyl, pyridyl, benzimidazolyl, and benzothiazolyl, optionally substituted with one or more substituents selected from the group consisting of halogen, C.sub.1-6 alkyl, halo-C.sub.1-6 alkyl, and C.sub.3-6 cycloalkyl.
22. The compound of claim 16 wherein R.sup.1 is selected from H, OH, OC.sub.1-4 alkyl, or OC.sub.1-4 alkyl substituted with at least one from the group consisting of phenyl and phenyl substituted with one or more groups selected form OH and halogen.
23. The compound of claim 16 wherein R.sup.1 is selected from OH and OC.sub.1-3 alkyl.
24. The compound of claim 16 selected from the group consisting of: 6-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
25. A pharmaceutical composition comprising the compound of claim 16 and optionally a pharmaceutically acceptable additive.
26. A method for treatment of a disorder relating to the binding of a galectin-1 and/or -3 to a ligand in a mammal, wherein a therapeutically effective amount of at least one compound according to claim 16 is administered to a mammal in need of said treatment.
27. The method of claim 26, wherein said disorder is selected from the group consisting of inflammation; Inflammation induced thrombosis; Atopic dermatitis; Acute coronary syndrome; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; local fibrosis such as Dupuytren's disease and Peyronie's disease; fibrotic complications of other therapies such as coronary stents, bile duct stents, cerebral artery stents, ureter stents; scleroderma; scarring; keloid formation; covid-19; acute lung injury; ARDS; viral pneumonitis, aberrant scar formation; surgical adhesions; septic shock; cancer, such as colorectal cancer, other gastrointestinal carcinomas such as pancreatic cancer, gastric cancer, biliary tract cancer, lung cancers, mesothelioma, female cancers like breast cancer, ovarian cancer, uterine cancer, cancer of the cervix uteri, cancer of the salpingx, cerebral cancers such as medulloblastomao, glioma, meningioma, sarcomas of the bones and muscles and other sarcomas, leukemias and lymphomas, such as T-cell lymphomas; transplant rejection; metastasising cancers; ageing; Dementia; Alzheimers; TGFbeta driven bone disease such as osteogenesis imperfecta; Pulmonary hypertension; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Rheumatoid lung; Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; viral infections such as influenza virus, HIV, Herpes virus, Coronaviruses, Hepatitis C; metabolic disorders; heart disease; heart failure; pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer, and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases; diabetes; type I diabetes; type 2 diabetes; insulin resistens; obesity; Marfans syndrome; Loeys-Dietz syndrome; nephropathy; Diastolic HF; fibrotic lung complications of aPD1 and other CPI therapies; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, liver disorders, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease; uterine disease such as uterine fibroids and uterine or cervical fibrosis.
Description
DETAILED DESCRIPTION OF THE INVENTION
[0146] The present compounds of formula (1) differ from prior art compounds particularly in that the pyranose ring is β-D-galactopyranose. It is important to emphasize that alpha and beta anomers are very different isomers and it is by no means considered to be obvious to the skilled person to expect same or similar activity of both anomers. Consequently, alpha and beta anomers do not in general posses the same activity, and this is common knowledge to the skilled person. The compounds of the present invention are novel β-D-galactopyranose compounds that unexpectedly have shown very high affinity and specificity for galectin-1 and are considered novel potent drug candidates. Some of the novel β-D-galactopyranose compounds have both galectin-1 and galectin-3 affinity and, as such have a broader disease treatment profile compared to selective galectin-1 inhibitors.
[0147] In broad aspect the present invention concerns a β-D-galactopyranose compound of formula (1)
##STR00027##
wherein
[0148] the pyranose ring is β-D-galactopyranose, and A1, B1 and R1 are as defined above; as well as a pharmaceutically acceptable salt or solvate thereof.
[0149] Preferably Het1 is selected from the group consisting of
##STR00028##
In another embodiment Het1 is
##STR00029##
When Het1 is formula 2
##STR00030##
[0150] R.sup.2 is selected from the group consisting of hydrogen, methyl, OH, Cl, Br and F;
[0151] R.sup.3 is hydrogen.
When Het1 is formula 3
##STR00031##
[0152] R.sup.4 is selected from the group consisting of OH, Cl, Br, F and amino;
[0153] R.sup.5 is hydrogen.
[0154] In another embodiment Het1 is formula 3
##STR00032##
Wherein R.sup.4 is selected from the group consisting of OH, Cl, CH.sub.3, Br, F and amino; R.sup.5 is hydrogen.
[0155] In a further embodiment Het1 is
##STR00033##
wherein R.sup.4 is CH.sub.3 and R.sup.5 is H,
[0156] Typically, Het1 is selected from the group consisting of
##STR00034##
Each of these Het1 groups are individual embodiments and can be subject to a claim in combination with any one of R1 and/or B1. For instance, Het1 is
##STR00035##
and R1 and B1 are selected from any one of the above embodiments.
[0157] Preferably B.sup.1 is triazolyl; optionally substituted with one or more groups selected from a) C.sub.1-6 alkyl optionally substituted with one or more of C.sub.1-6 alkyl, amino, CN, halogen, hydroxy, C.sub.1-6 alkoxy, carboxy, alkoxycarbonyl, H.sub.2NCO, b) R.sup.28—C.sub.1-6 alkyl, c) C.sub.3-6cycloalkyl optionally substituted with one or more of C.sub.1-6 alkyl, amino, CN, halogen, or hydroxy, c) C.sub.1-6 alkenyl, d) C.sub.1-6 alkoxy, e) C.sub.1-6 alkylthio, f) C.sub.1-6 alkylsulfonyl, g) carbonyl substituted with any one of hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkylNH, ((R.sup.9)(R.sup.30)N)C.sub.1-6 alkylNH, or (pyridinyl)C.sub.1-6 alkylNH, h) (R.sup.31)(R.sup.32)N, i) C.sub.2-alkynyl, and j) R.sup.2;
wherein R.sup.28, R.sup.29, R.sup.30, R.sup.31 and R.sup.32 are as defined above in the first aspect.
[0158] Typically, B1 is a triazolyl substituted with a group selected from any one of a) phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, OH, C.sub.2-alkynyl, halogen, C.sub.1-6 alkyl, halo-C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy, halo-C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, carboxy, C.sub.1-6 alkoxycarbonyl, CONH.sub.2, and (R.sup.33)(R.sup.34)N; orb) (C.sub.1-6 alkyl-SO.sub.2)phenyl, (C.sub.1-6 alkyl SO.sub.2)(halo)phenyl, (aminoSO.sub.2)phenyl, (di-C.sub.1-6 alkylaminoSO.sub.2)phenyl, ((C.sub.1-6 alkyl-NHSO.sub.2)—C.sub.1-6 alkyl)phenyl, (pyrrolyl)phenyl, (imidazolyl)phenyl, (oxazolyl)phenyl, (tetrazolyl)phenyl, ((pyridinyl)methyl)phenyl, phenoxyphenyl, (benzyloxy)phenyl, ((methyl)thiazolyl)-phenyl, (thiazolyl)-benzenesulfamido, ((methyl)thiadiazolyl)benzenesulfamido, (methyl)-benzothiazolonyl, or fluoropyrazolopyrimidinyl.
[0159] In a specific embodiment B1 is selected from pyrazolyl or triazolyl; optionally substituted with a group selected from halogen, C.sub.1-6 alkyl, halo-C.sub.1-6 alkyl, phenyl, benzimidazolyl, and benzothiazolyl, optionally substituted with one or more substituents selected from the group consisting of halogen, C.sub.1-6 alkyl, halo-C.sub.1-6 alkyl, and C.sub.3-6 cycloalkyl.
[0160] In a more specific embodiment B1 is selected from pyrazolyl, such as 1,2-pyrazolyl, substituted with a group selected from phenyl and benzothiazolyl, optionally substituted with one or two substituents selected from the group consisting of halogen, C.sub.1-6-alkyl, and halo-C.sub.1-6 alkyl.
[0161] In a further specific embodiment B1 is selected from triazolyl, such as 1,2,4-triazolyl, substituted with a group selected from methyl, CF.sub.3, phenyl, pyridinyl, benzimidazolyl, and benzothiazolyl, optionally substituted with one or more substituents selected from the group consisting of halogen, C.sub.1-6 alkyl, halo-C.sub.1-6 alkyl, and C.sub.3-6 cycloalkyl.
[0162] In a specific embodiment B1 is a 1,2,4-triazolyl substituted with one or two of a CF.sub.3, a methyl, a phenyl optionally substituted with a halogen or C.sub.1-4 alkyl, such as one to three Br, Cl or methyl. In another specific embodiment B1 is a 1,2,4-triazolyl substituted with one or two of a methyl, a benzothiazole, e.g. a benzo[d]thiazole, optionally substituted with a C.sub.1-4 alkyl, such as a methyl. In a further specific embodiment B1 is a 1,2,4-triazolyl substituted with one or two of a methyl, a benzimidazolyl, optionally substituted with one or more C.sub.1-6 alkyl, such as methyl. In a further specific embodiment B1 is a 1,2,4-triazolyl substituted with one or two of a methyl, a pyridinyl, optionally substituted with one or more halogen or C.sub.3-6 cycloalkyl, such as cyclopropyl.
[0163] Preferably, R.sup.1 is selected from the group consisting of H, OH, O-methyl, O-ethyl, and O-isopropyl, typically H, OH or methoxy. In a further embodiment, R.sup.1 is selected from OH or methoxy.
[0164] Typically, the compound of formula (1) is selected from any one of: [0165] 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1,3-dideoxy-1-[4-(2-methylbenzo[d]thiazol-6-yl)-4H-1,2,4-triazole-3-yl]-β-D-galactopyranoside, [0166] 1-[4-(3-chlorophenyl)-4H-1,2,4-triazole-3-yl]-1,3-dideoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside, [0167] 1-[4-(5-chloro-2-methylphenyl)-5-(trifluoromethyl)-4H-1,2,4-triazole-3-yl]-1,3-dideoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-β-D-galactopyranoside, [0168] 1-[4-(2,5-dichlorophenyl)-4H-1,2,4-triazole-3-yl]-1,3-dideoxy-3-[4-(4-methylthiazol-2-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside, [0169] 1-[1-(2-bromo-5-chlorophenyl)-3-methyl-1H-1,2,4-triazole-5-yl]-1,3-dideoxy-3-[4-(thiazol-2-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside, [0170] 3-[4-(2-aminothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1,3-dideoxy-1-[4-(2-methylbenzo[d]thiazol-6-yl)-4H-1,2,4-triazole-3-yl]-β-D-galactopyranoside, and [0171] 1-[1-(2-bromo-5-chlorophenyl)-3-methyl-1H-1,2,4-triazole-5-yl]-1,2,3-trideoxy-3-[4-(thiazol-4-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside.
[0172] Preferably, the compound of formula (1) is selected from any one of: [0173] 6-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-4H-1,2,4-triazol-4-yl}-2-methylbenzothiazole, [0174] 3-Chloro-1-{3-{3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranosyl}-4H-1,2,4-triazol-4-yl}benzene, [0175] 5-Chloro-1-{3-{3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-β-D-galactopyranosyl}-5-trifluoromethyl-4H-1,2,4-triazol-4-yl}-2-methylbenzene, [0176] 2,5-Dichloro-1-{3-{3-deoxy-3-[4-(4-methylthiazol-2-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranosyl}-4H-1,2,4-triazol-4-yl}benzene, [0177] 2-Bromo-5-chloro-1-{3-{3-Deoxy-3-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranosyl}-5-methyl-1H-1,2,4-triazol-4-yl}benzene, [0178] 6-{3-{3-[4-(2-Aminothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-4H-1,2,4-triazol-4-yl}-2-methylbenzothiazole, [0179] 2-Bromo-5-chloro-1-{3-{3-Deoxy-3-[4-(4-thiazolyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranosyl}-5-methyl-1H-1,2,4-triazol-4-yl}benzene, [0180] 6-{3-{3-Deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranosyl}-4H-1,2,4-triazol-4-yl}-2-methylbenzothiazole, [0181] 1-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-5-methyl-4H-1,2,4-triazol-4-yl}-5-chloro-2-(trifluoromethyl)benzene, [0182] 6-{5-{3-Deoxy-3-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole, [0183] 5-Chloro-1-{3-{3-deoxy-3-[4-(4-methylthiazol-2-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranosyl}-5-methyl-4H-1,2,4-triazol-4-yl}-2-(trifluoromethyl)benzene, [0184] 5-Chloro-1-{3-{3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]β-D-galactopyranosyl}-5-methyl-4H-1,2,4-triazol-4-yl}-2-(trifluoromethyl)benzene, [0185] 6-{5-{3-Deoxy-3-[4-(2-methylthiazol-4-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole, [0186] 6-{5-{3-Deoxy-3-[4-(5-thiazolyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole, [0187] 1-{3-{3-[4-(2-Aminothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-5-methyl-1H-1,2,4-triazol-4-yl}-5-chloro-2-(trifluoromethyl)benzene, [0188] 1-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-5-methyl-1H-1,2,4-triazol-4-yl}-5-chloro-2-(trifluoromethyl)benzene, [0189] 1-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-β-D-galactopyranosyl}-5-methyl-4H-1,2,4-triazol-4-yl}-5-chloro-2-(trifluoromethyl)benzene, [0190] 3-{5-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-5-chloro-2-cyclopropylpyridine, [0191] 1-{3-{3-[4-(2-Aminothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-5-methyl-4H-1,2,4-triazol-4-yl}-5-chloro-2-(trifluoromethyl)benzene, [0192] 5-Chloro-1-{3-{3-deoxy-3-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranosyl}-5-methyl-4H-1,2,4-triazol-4-yl}-2-(trifluoromethyl)benzene, [0193] 6-{3-{3-Deoxy-3-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranosyl}-4H-1,2,4-triazol-4-yl}-2-methylbenzothiazole, [0194] 6-{3-{3-Deoxy-3-[4-(4-methylthiazol-2-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranosyl}-4H-1,2,4-triazol-4-yl}-2-methylbenzothiazole, [0195] 6-{5-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole, [0196] 6-{5-{3-[4-(2-Aminothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-3-methyl-1H-1,2,4-triazol-1-yl}-2-methylbenzothiazole, [0197] 6-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-β-D-galactopyranosyl}-5-methyl-4H-1,2,4-triazol-4-yl}-2-methylbenzothiazole, [0198] 6-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-5-methyl-4H-1,2,4-triazol-4-yl}-2-methylbenzothiazole, [0199] 5-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-5-methyl-4H-1,2,4-triazol-4-yl}-N-3-methylbenzimidazole, [0200] 1-{5-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-1H-1,2-pyrazol-1-yl}-5-chloro-2-(trifluoromethyl)benzene, and [0201] 6-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-1H-1,2-pyrazol-1-yl}-2-methylbenzothiazole.
[0202] The skilled person will understand that it may be necessary to adjust or change the order of steps in the processes a1-a22, and such change of order is encompassed by the aspects of the process as described above in the reaction schemes and accompanying description of the process steps.
[0203] Furthermore, the skilled person will understand that the processes described above and hereinafter the functional groups of intermediate compounds may need to be protected by protecting groups.
[0204] Functional groups that it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include optionally substituted and/or unsaturated alkyl groups (e.g. methyl, allyl, benzyl or tert-butyl), trialkyl silyl or diarylalkylsilyl groups (e.g. t-butyldimethylsilyl, t-butyldipheylsilyl or trimethylsilyl), AcO(acetoxy), TBS(t-butyldimethylsilyl), TMS(trimethylsilyl), PMB (p-methoxybensyl), and tetrahydropyranyl. Suitable protecting groups for carboxylic acid include (C.sub.1-6)-alkyl or benzyl esters. Suitable protecting groups for amino include t-butyloxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)-ethoxy-methyl or 2-trimethylsilylethoxycarbonyl (Teoc). Suitable protecting groups for S include S—C(═N)NH.sub.2, TIPS.
[0205] The protection and deprotection of functional groups may take place before or after any reaction in the above-mentioned processes.
[0206] Furthermore the skilled person will appreciate, that, in order to obtain compounds of the invention in an alternative, and on some occasions more convenient manner, the individual process steps mentioned hereinbefore may be performed in different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This may negate, or render necessary, the need for protecting groups.
[0207] In a still further embodiment the compound (1) is on free form. “On free form” as used herein means a compound of formula (1), either an acid form or base form, or as a neutral compound, depending on the substitutents. The free form does not have any acid salt or base salt in addition. In one embodiment the free form is an anhydrate. In another embodiment the free form is a solvate, such as a hydrate.
[0208] In a further embodiment the compound of formula (1) is a crystalline form. The skilled person may carry out tests in order to find polymorphs, and such polymorphs are intended to be encompassed by the term “crystalline form” as used herein.
[0209] When the compounds and pharmaceutical compositions herein disclosed are used for the above treatment, a therapeutically effective amount of at least one compound is administered to a mammal in need of said treatment.
[0210] The term “C.sub.1-x alkyl” as used herein means an alkyl group containing 1-x carbon atoms, e.g. C.sub.1-5 or C.sub.1-6, such as methyl, ethyl, propyl, butyl, pentyl or hexyl.
[0211] The term “branched C.sub.3-6 alkyl” as used herein means a branched alkyl group containing 3-6 carbon atoms, such as isopropyl, isobutyl, tert-butyl, isopentyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl.
[0212] The term “C.sub.3-x cycloalkyl” as used herein means a cyclic alkyl group containing 3-x carbon atoms, e.g. C.sub.3-6 or C.sub.3-7, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 1-methylcyclopropyl.
[0213] The term “C.sub.5-7 cycloalkyl” as used herein means a cyclic alkyl group containing 5-7 carbon atoms, such as cyclopentyl, cyclohexyl, or cycloheptyl.
[0214] The term “Oxo” as used herein means an oxygen atom with double bonds, also indicated as ═O.
[0215] The term “CN” as used herein means a nitril.
[0216] The term “halogen” as used herein means Cl, F, Br or I.
[0217] The term “halo-C.sub.1-6 alkyl” as used herein means one or more halogens linked to a C.sub.1-6 alkyl, such as CF.sub.3, CH(Cl)CHF.sub.2.
[0218] The term “C.sub.1-6 alkoxy” as used herein means an oxygen linked to a C.sub.1-6 alkyl, such as methoxy or ethoxy.
[0219] The term “C.sub.1-6 alkylthio” as used herein means a sulphur linked to a C.sub.1-6 alkyl, such as thiomethoxy or thioethoxy.
[0220] The term “halo-C.sub.1-6 alkoxy” as used herein means one or more halogens linked to a C.sub.1-6 alkoxy, such as CH(F.sub.2)CH(Br)O—.
[0221] The term “C.sub.1-6 alkoxycarbonyl” as used herein means a C.sub.1-6 alkoxy linked to a carbonyl, such as methoxycarbonyl (CH.sub.2OC(═O)).
[0222] The term “a five or six membered heteroaromatic ring” as used herein means one five membered heteroaromatic ring or one six membered heteroaromatic ring.
[0223] The five membered heteroaromatic ring contains 5 ring atoms of which one to four are heteroatoms selected from N, O, and S. The six membered heteroaromatic ring contains 6 ring atoms of which one to five are heteroatoms selected from N, O and S. Examples include thiophene, furan, pyran, pyrrole, imidazole, pyrazole, isothiazole, isooxazole, pyridine, pyrazine, pyrimidine and pyridazine. When such heteroaromatic rings are substituents they are termed thiophenyl, furanyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl. Also included are oxazoyl, thiazoyl, thiadiazoly, oxadiazoyl, and pyridonyl.
[0224] The term “a heterocycle, such as heteroaryl or heterocycloalkyl” as used herein means a heterocycle consisting of one or more 3-7 membered ring systems containing one or more heteroatoms and wherein such ring systems may optionally be aromatic. The term “a heteroaryl” as used herein means a mono or bicyclic aromatic ringsystem containing one or more heteroatoms, such as 1-10, e.g. 1-6, selected from O, S, and N, including but not limited to oxazolyl, oxadiazolyl, thiophenyl, thiadiazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridonyl, pyrimidonyl, quinolinyl, azaquionolyl, isoquinolinyl, azaisoquinolyl, quinazolinyl, azaquinazolinyl, bensozazoyl, azabensoxazoyl, bensothiazoyl, or azabensothiazoyl. The term “a heterocycloalkyl” as used herein means a mono or bicyclic 3-7 membered alifatic heterocycle containing one or more heteroatoms, such as 1-7, e.g. 1-5, selected from O, S, and N, including but not limited to piperidinyl, tetrahydropyranyl, tetrahydrothipyranyl, or piperidonyl.
[0225] The term “treatment” and “treating” as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. The treatment may either be performed in an acute or in a chronic way. The patient to be treated is preferably a mammal; in particular, a human being, but it may also include animals, such as dogs, cats, cows, sheep and pigs.
[0226] The term “a therapeutically effective amount” of a compound of formula (1) of the present invention as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as “therapeutically effective amount”. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary.
[0227] In a still further aspect, the present invention relates to a pharmaceutical composition comprising the compound of formula (1) and optionally a pharmaceutically acceptable additive, such as a carrier or an excipient.
[0228] As used herein “pharmaceutically acceptable additive” is intended without limitation to include carriers, excipients, diluents, adjuvant, colorings, aroma, preservatives etc. that the skilled person would consider using when formulating a compound of the present invention in order to make a pharmaceutical composition.
[0229] The adjuvants, diluents, excipients and/or carriers that may be used in the composition of the invention must be pharmaceutically acceptable in the sense of being compatible with the compound of formula (1) and the other ingredients of the pharmaceutical composition, and not deleterious to the recipient thereof. It is preferred that the compositions shall not contain any material that may cause an adverse reaction, such as an allergic reaction. The adjuvants, diluents, excipients and carriers that may be used in the pharmaceutical composition of the invention are well known to a person skilled within the art.
[0230] As mentioned above, the compositions and particularly pharmaceutical compositions as herein disclosed may, in addition to the compounds herein disclosed, further comprise at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier. In some embodiments, the pharmaceutical compositions comprise from 1 to 99% by weight of said at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier and from 1 to 99% by weight of a compound as herein disclosed. The combined amount of the active ingredient and of the pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier may not constitute more than 100% by weight of the composition, particularly the pharmaceutical composition.
[0231] In some embodiments, only one compound as herein disclosed is used for the purposes discussed above.
[0232] In some embodiments, two or more of the compounds as herein disclosed are used in combination for the purposes discussed above.
[0233] The composition, particularly pharmaceutical composition comprising a compound set forth herein may be adapted for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via the respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder. Therefore, the pharmaceutical composition may be in the form of, for example, tablets, capsules, powders, nanoparticles, crystals, amorphous substances, solutions, transdermal patches or suppositories.
[0234] Further embodiments of the process are described in the experimental section herein, and each individual process as well as each starting material constitutes embodiments that may form part of embodiments.
[0235] The above embodiments should be seen as referring to any one of the aspects (such as ‘method for treatment’, ‘pharmaceutical composition’, ‘compound for use as a medicament’, or ‘compound for use in a method’) described herein as well as any one of the embodiments described herein unless it is specified that an embodiment relates to a certain aspect or aspects of the present invention.
[0236] All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.
[0237] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.
[0238] Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
[0239] The terms “a” and “an” and “the” and similar referents as used in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
[0240] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Unless otherwise stated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also pro-vide a corresponding approximate measurement, modified by “about,” where appropriate).
[0241] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.
[0242] The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise indicated. No language in the specification should be construed as indicating any element is essential to the practice of the invention unless as much is explicitly stated.
[0243] The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability and/or enforceability of such patent documents.
[0244] The term “and/or” as used herein is intended to mean both alternatives as well as each of the alternatives individually. For instance, the expression “xxx and/or yyy” means “xxx and yyy”; “xxx”; or “yyy”, all three alternatives are subject to individual embodiments.
[0245] The description herein of any aspect or embodiment of the invention using terms such as “comprising”, “having”, “including” or “containing” with reference to an element or elements is intended to provide support for a similar aspect or embodiment of the invention that “consists of”, “consists essentially of”, or “substantially comprises” that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context). This invention includes all modifications and equivalents of the subject matter recited in the aspects or claims presented herein to the maximum extent permitted by applicable law.
[0246] The present invention is further illustrated by the following examples that, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realizing the invention indiverse forms thereof.
Experimental Procedures (Evaluation of Kd Values)
[0247] The affinity of Example 1-29 for galectins were determined by a fluorescence anisotropy assay where the compound was used as an inhibitor of the interaction between galectin and a fluorescein tagged saccharide probe as described Sörme, P., Kahl-Knutsson, B., Huflejt, M., Nilsson, U. J., and Leffler H. (2004) Fluorescence polarization as an analytical tool to evaluate galectin-ligand interactions. Anal. Biochem. 334: 36-47, (Sörme et al., 2004) and Monovalent interactions of Galectin-1 By Salomonsson, Emma; Larumbe, Amaia; Tejler, Johan; Tullberg, Erik; Rydberg, Hanna; Sundin, Anders; Khabut, Areej; Frejd, Torbjorn; Lobsanov, Yuri D.; Rini, James M.; et al, From Biochemistry (2010), 49(44), 9518-9532, (Salomonsson et al., 2010).
TABLE-US-00001 Gal-1 Gal-3 Kd Kd Example Name Structure (μM) (μM) 1 6-{3-{3-[4-(4-Chlorothiazol-2- yl)-1H-1,2,3-triazol-1-yl]-3- deoxy-β-D-galactopyranosyl}- 4H-1,2,4-triazol-4-yl}-2- methylbenzothiazole
Synthesis of Examples and Intermediates
General Experimental
[0248] Nuclear Magnetic Resonance (NMR) spectra were recorded on a 400 MHz Bruker AVANCE U11500 instrument or a Varian instrument at 400 MHz, at 25 TC. Chemical shifts are reported in ppm (d) using the residual solvent as internal standard. Peak multiplicities are expressed as follow: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplet; q, quartet; m, multiplet; br s, broad singlet. LC-MS were acquired on an Agilent 1200 HPLC coupled with an Agilent MSD mass spectrometer operating in ES (+) ionization mode. Column: XBridge C18 (4.6×50 mm, 3.5 μm) or SunFire C18 (4.6×50 mm, 3.5 μm). Solvent A water+0.1% TFA and solvent B Acetonitrile+0.1% TFA or solvent A water (10 mM Ammonium hydrogen carbonate) and solvent B Acetonitrile. Wavelength: 254 nM. Alternatively, LC-MS were acquired on an Agilent 1100 HPLC coupled with an Agilent MSD mass spectrometer operating in ES (+) ionization mode. Column: Waters symmetry 2.1×30 mm C.sub.18 or Chromolith RP-18 2×50 mm. Solvent A water+0.1% TFA and solvent B Acetonitrile+0.1% TFA. Wavelength 254 nm.
[0249] Preparative HPLC was performed on a Gilson 215. Flow: 25 mL/min Column: XBrige prep C18 10 μm OBD (19×250 mm) column. Wavelength: 254 nM. Solvent A water (10 mM Ammonium hydrogen carbonate) and solvent B Acetonitrile. Alternatively, preparative HPLC were acquired on a Gilson system. Flow: 15 ml/min Column: kromasil 100-5-C18 column. Wavelength: 220 nm. Solvent A water+0.1% TFA and solvent B Acetonitrile+0.1% TFA.
[0250] The following abbreviations are used
aq: aqueous
Calcd: Calculated
MeCN: Acetonitrile
CuI: Copper Iodide
DCM: Dichloromethane
DIPEA: Diisopropylethylamine
DMF: N,N-dimethylformamide
[0251] ESI-MS: Electrospray ionization mass spectrometry
EtOAc or EA: Ethylacetate
Et.SUB.3.N: Triethylamine
[0252] h: hour(s)
HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
HPLC: High performance liquid chromatography
LC: Liquid Chromatography
MeCN: Acetonitrile
[0253] mL: milliliter
MeOH: Methanol
[0254] MeOD: Deuterated methanol
mm: millimeter
mM: millimolar
MS: Mass spectroscopy
nm: nanometer
NaOMe: Sodium methoxide
N.SUB.2.: Nitrogen gas
[0255] NMR: Nuclear magnetic resonance
PE: petroleum ether
pH: acidity
Prep: Preparative
[0256] rt: Room temperature
TFA: trifluoroacetic acid
THF: Tetrahydrofuran
TMS: Trimethylsilyl
UV: Ultraviolet
[0257] Å: Ångstrom
[0258] When naming examples and intermediates with aryl groups connected directly to C1 of the galactose unit the following methodology has been used. The highest priority has been given to the aryl furthest away from the galactose C1, regardless of IUPAC rules.
Example 1
6-{3-{3-[4-(4-Chlorothiazo-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0259] ##STR00065##
[0260] A solution of 6-{3-{4,6-O-benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0261] Example 2-5 and 7 are made by the general experimental 1 below from their respective azide aa2-aa5 and aa7
##STR00066##
General Experimental 1
[0262] A solution of 1 equivalent of 3-azido-β-D-galactopyranoside and Het.sup.1-CC-TMS 1-3 equivalents is dissolved in 10-40 volumes of DMF and added to 1-3 equivalents of L-ascorbic acid sodium salt and 0.1-2 equivalents of copper sulfate pentahydrate. This reaction mixture is stirred at rt until all starting materials are consumed or over night. The solvents are removed in vacuo and the residue is purified by chromatographic methods such as Prep.HPLC to give the title compound.
[0263] Compounds of the structure 3-azido-β-D-galactopyranoside used as starting material in General experimental 1 can be made by the synthesis described in WO2019067702A1.
Example 2
1-[4-(3-chlorophenyl)-4H-1,2,4-triazole-3-yl]-1,3-dideoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside
[0264] ##STR00067##
[0265] In this example the 3-azido-β-D-galactopyranoside is 3-azido-1-[4-(3-chlorophenyl)-4H-1,2,4-triazole-3-yl]-1,3-dideoxy-β-D-galactopyranoside and Het.sup.1-CC-TMS is 4-(2-trimethylsilylethynyl)thiazol-2-ol which are reacted in according to the general experimental 1 to give the title compound.
Example 3
1-[4-(5-chloro-2-methylphenyl)-5-(trifluoromethyl)-4H-1,2,4-triazole-3-yl]-1,3-dideoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside
[0266] ##STR00068##
[0267] In this example the 3-azido-β-D-galactopyranoside is 3-azido-1-[4-(5-chloro-2-methylphenyl)-5-(trifluoromethyl)-4H-1,2,4-triazole-3-yl]-1,3-dideoxy-β-D-galactopyranoside and Het.sup.1-CC-TMS is 4-(2-trimethylsilylethynyl)thiazol-2-ol which are reacted in according to the general experimental 1 to give the title compound.
Example 4
1-[4-(2,5-dichlorophenyl)-4H-1,2,4-triazole-3-yl]-1,3-dideoxy-3-[4-(4-methylthiazol-2-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside
[0268] ##STR00069##
[0269] In this example the 3-azido-β-D-galactopyranoside is 3-azido-1-[4-(2,5-dichlorophenyl)-4H-1,2,4-triazole-3-yl]-1,3-dideoxy-β-D-galactopyranoside and Het.sup.1-CC-TMS is 4-methyl-2-((trimethylsilyl)ethynyl)thiazole which are reacted in according to the general experimental 1 to give the title compound.
Example 5
1-[1-(2-bromo-5-chlorophenyl)-3-methyl-1H-1,2,4-triazole-5-yl]-1,3-dideoxy-3-[4-(thiazol-2-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside
[0270] ##STR00070##
[0271] In this example the 3-azido-β-D-galactopyranoside is 3-azido-1-[1-(2-bromo-5-chlorophenyl)-3-methyl-1H-1,2,4-triazole-5-yl]-1,3-dideoxy-β-D-galactopyranoside and Het.sup.1-CC-TMS is 2-((trimethylsilyl)ethynyl)thiazole which are reacted in according to the general experimental 1 to give the title compound.
Example 6
6-{3-{3-[4-(2-Aminothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0272] ##STR00071##
[0273] A solution of 6-{3-{4,6-O-benzylidene-3-{4-[2-(di-tert-butoxycarbonylamino)thiazol-4-yl]-1H-1,2,3-triazol-1-yl}-3-deoxy-β-
Example 7
1-[1-(2-bromo-5-chlorophenyl)-3-methyl-1H-1,2,4-triazole-5-yl]-1,2,3-trideoxy-3-[4-(thiazol-4-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside
[0274] ##STR00072##
[0275] In this example the 3-azido-β-D-galactopyranoside is 3-azidol-[1-(2-bromo-5-chlorophenyl)-3-methyl-1H-1,2,4-triazole-5-yl]-1,2,3-trideoxy-β-D-galactopyranoside and Het.sup.1-CC-TMS is 4-((trimethylsilyl)ethynyl)thiazole which are reacted in according to the general experimental 1 to give the title compound.
Example 8
6-{3-{3-Deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-β-
[0276] ##STR00073##
[0277] A solution of 6-{3-{4,6-O-benzylidene-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranosyl}-4H-1,2,4-triazol-4-yl}-2-methylbenzothiazole (50 mg, 0.07 mmol) in DCM/TFA (6 mL, 19:1) was stirred 6 h at rt. Et.sub.3N was added to neutralize the TFA. The mixture was evaporated and purified by prep HPLC (MeCN/H.sub.2O (10 mmol/L NH.sub.4HCO.sub.3), X-Select10 μm 19*250 mm, 20 mL/min, UV 254) to give the title compound (19 mg, 52%). ESI-MS m/z calcd for [C.sub.21H.sub.20N.sub.8O.sub.5S.sub.2] [M+H].sup.+: 529.1; found: 529.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.87 (s, 1H), 8.92 (s, 1H), 8.41 (d, J=2.0 Hz, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.70 (dd, J=8.0, 2.0 Hz, 1H), 6.70 (s, 1H), 5.45 (d, J=5.6 Hz, 1H), 5.37 (s, 1H), 4.90-4.81 (m, 3H), 4.35 (d, J=8.8 Hz, 1H), 3.90 (d, J=4.4 Hz, 1H), 3.73 (t, J=6.0 Hz, 1H), 3.57-3.46 (m, 2H), 2.85 (s, 3H).
Example 9
1-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0278] ##STR00074##
[0279] A solution of 1-{3-{4,6-O-benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
Example 10
6-{5-{3-Deoxy-3-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]β-
[0280] ##STR00075##
[0281] To a solution of 6-{5-{4,6-O-benzylidene-3-deoxy-3-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]-β-
Example 11
5-Chloro-1-{3-{3-deoxy-3-[4-(4-methylthiazol-2-yl)-1H-1,2,3-triazol-1-yl]-β-
[0282] ##STR00076##
[0283] A solution of 1-{3-{4,6-O-benzylidene-3-deoxy-3-[4-(4-methylthiazol-2-yl)-1H-1,2,3-triazol-1-yl]β-
Example 12
5-Chloro-1-{3-{3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]β-
[0284] ##STR00077##
[0285] To a solution of 1-{3-{4,6-O-benzylidene-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-β-
Example 13
6-{5-{3-Deoxy-3-[4-(2-methylthiazol-4-yl)-1H-1,2,3-triazol-1-yl]β-
[0286] ##STR00078##
[0287] A solution of 6-{5-{4,6-O-benzylidene-3-deoxy-3-[4-(2-methylthiazol-4-yl)-1H-1,2,3-triazol-1-yl]β-
Example 14
6-{5-{3-Deoxy-3-[4-(5-thiazolyl)-1H-1,2,3-triazol-1-yl]β-
[0288] ##STR00079##
[0289] A solution of 6-{5-{4,6-O-benzylidene-3-deoxy-3-[4-(5-thiazolyl)-1H-1,2,3-triazol-1-yl]-β-
Example 15
1-{3-{3-[4-(2-Aminothazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0290] ##STR00080##
[0291] A solution of 1-{3-{4,6-O-benzylidene-3-{4-[2-(di-tert-butoxycarbonylamino)thiazol-4-yl]-1H-1,2,3-triazol-1-yl}-3-deoxy-β-
Example 16
1-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0292] ##STR00081##
[0293] A solution of 1-{3-{4,6-O-benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
Example 17
1-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-β-
[0294] ##STR00082##
[0295] To a solution of 1-{3-{4,6-O-benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-β-
Example 18
3-{5-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0296] ##STR00083##
[0297] A solution of 3-{5-{4,6-O-benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
Example 19
1-{3-{3-[4-(2-Aminothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0298] ##STR00084##
[0299] To a solution of 1-{3-{4,6-O-benzylidene-3-{4-[2-(di-tert-butoxycarbonylamino)thiazol-4-yl]-1H-1,2,3-triazol-1-yl}-3-deoxy-β-
Example 20
5-Chloro-1-{3-{3-deoxy-3-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]β-
[0300] ##STR00085##
[0301] A solution of 1-{3-{4,6-O-benzylidene-3-deoxy-3-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]-β-
Example 21
6-{3-{3-Deoxy-3-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]-β-
[0302] ##STR00086##
[0303] A solution of 6-{3-{4,6-O-benzylidene-3-deoxy-3-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]-β-
Example 22
6-{3-{3-Deoxy-3-[4-(4-methylthiazol-2-yl)-1H-1,2,3-triazol-1-yl]-β-
[0304] ##STR00087##
[0305] A solution of 6-{3-{4,6-O-benzylidene-3-deoxy-3-[4-(4-methylthiazol-2-yl)-1H-1,2,3-triazol-1-yl]β-
Example 23
6-{5-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0306] ##STR00088##
[0307] To a solution of 6-{5-{4,6-O-benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
Example 24
6-{5-{3-[4-(2-Aminothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0308] ##STR00089##
[0309] To a solution of 6-{5-{4,6-O-benzylidene-3-{4-[2-(di-tert-butoxycarbonylamino)thiazol-4-yl]-1H-1,2,3-triazol-1-yl}-3-deoxy-β-
Example 25
6-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-β-
[0310] ##STR00090##
[0311] To a solution of 6-{3-{4,6-O-benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-β-
Example 26
6-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0312] ##STR00091##
[0313] To a solution of 6-{3-{4,6-O-benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-D-galactopyranosyl}-5-methyl-4H-1,2,4-triazol-4-yl}-2-methylbenzothiazole (170 mg, 0.26 mmol) in DCM (12 mL) TFA (0.58 mL) was added and the mixture was stirred overnight at rt. Et.sub.3N was added at 0° C. to neutralize the TFA. The mixture was evaporated and purified by prep HPLC (MeCN/H.sub.2O (10 mmol/L NH.sub.4HCO.sub.3), X-Select10 μm 19*250 mm, 20 mL/min, UV 254) to give the title compound (85 mg, 58%). ESI-MS m/z calcd for [C.sub.22H.sub.21ClN.sub.8O.sub.4S.sub.2] [M+H].sup.+: 561.1; found: 561.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.52 (s, 1H), 8.32 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.79 (s, 1H), 7.63 (dd, J=8.8, 2.0 Hz, 1H), 5.59 (d, J=8.4 Hz, 1H), 5.28 (d, J=6.8 Hz, 1H), 4.94-4.80 (m, 3H), 4.19 (d, J=8.8 Hz, 1H), 3.91 (t, J=3.2 Hz, 1H), 3.62-3.59 (m, 1H), 3.53-3.41 (m, 2H), 2.87 (s, 3H), 2.29 (s, 3H).
Example 27
5-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0314] ##STR00092##
[0315] To a solution of 5-{3-{4,6-O-benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
Example 28
1-{5-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0316] ##STR00093##
[0317] A solution of 3,7-anhydro-6,8-O-benzylidene-5-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-5-deoxy-4-O-methoxymethyl-
Example 29
6-{3-{3-[4-(4-Chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0318] ##STR00094##
[0319] A solution of 3,7-anhydro-6,8-O-benzylidene-5-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-5-deoxy-4-O-methoxymethyl-
Intermediate 1
2,4,6-Tri-O-acetyl-3-azido-3-deoxy-β-
[0320] ##STR00095##
[0321] To a solution of 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-β-
Methyl 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
[0322] ##STR00096##
[0323] To a solution of 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-
2,6-Anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-
[0324] ##STR00097##
[0325] To a solution of methyl 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
6-[3-(3-Azido-4,6-O-benzylidene-3-deoxy-β-
[0326] ##STR00098##
[0327] To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
[0328] The mixture was concentrated and purified by column chromatography (EA:MeOH=20:1, Silica-CS 40 g, 30 mL/min, silica gel, UV 254) to give the product (760 mg, 74%). ESI-MS m/z calcd for [C.sub.23H.sub.21N.sub.7O.sub.4S] [M+H].sup.+: 492.1; found: 492.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.28 (s, 1H), 7.97-7.93 (m, 2H), 7.50 (dd, J=8.4, 2.0 Hz, 1H), 7.40-7.30 (m, 5H), 5.50 (s, 1H), 4.78 (t, J=10.0 Hz, 1H), 4.44 (d, J=9.2 Hz, 1H), 4.22 (d, J=3.2 Hz, 1H), 4.12-3.95 (m, 2H), 3.48-3.44 (m, 1H), 3.31 (d, J=0.8 Hz, 1H), 2.83 (s, 3H).
6-{3-{4,6-O-Benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0329] ##STR00099##
[0330] To a solution of 6-[3-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 6
tert-Butyl N-tert-butoxycarbonyl-N-[4-(2-trimethylsilylethynyl)thiazol-2-yl]carbamate
[0331] ##STR00100##
[0332] To a solution of 4-(2-trimethylsilylethynyl)thiazol-2-amine (2.00 g, 10.2 mmol) in DCM (50 mL) di-tert-butyl dicarbonate (4.45 g, 20.4 mmol), Et.sub.3N (5.68 mL, 40.8 mmol) and 4-(dimethylamino)pyridine (12.4 mg, 1.02 mmol) were added and the mixture was stirred 5 h at rt. Water (100 mL) was added, and the mixture was extracted with diethyl ether (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, evaporated and purified by column chromatography (PE/EA=I/0˜10/1, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to give the product (3.60 g, 89%). ESI-MS m/z calcd for [C.sub.18H.sub.28N.sub.2O.sub.4SSi] [M+H].sup.+: 397.2; found: 397.3. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.25-7.18 (m, 1H), 1.45 (d, J=2.8 Hz, 18H), 0.18 (d, J=2.8 Hz, 9H).
6-{3-{4,6-O-Benzylidene-3-{4-[2-(di-tea-butoxycarbonylamino)thiazol-4-yl]-1H-1,2,3-triazol-1-yl}-3-deoxy-β-
[0333] ##STR00101##
[0334] To a solution of 6-[3-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 8
6-{3-{4,6-O-Benzylidene-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]β-
[0335] ##STR00102##
[0336] To a solution of 6-[3-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 9
N-[5-Chloro-2-(trifluoromethyl)phenyl]acetamide
[0337] ##STR00103##
[0338] To a solution of 5-chloro-2-(trifluoromethyl)aniline (5.00 g, 25.6 mmol) and pyridine (3.03 g, 38.3 mmol) in DCM (50 mL) acetic anhydride (2.90 mL, 30.7 mmol) was added and the mixture was stirred overnight at rt under a nitrogen atmosphere. The mixture was poured into water (100 mL) and extracted with DCM (2×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (PE/EA=10/1-1/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (2.50 g, 41%). ESI-MS m/z calcd for [C.sub.9H.sub.7ClF.sub.3NO] [M+H].sup.+: 238.0; found: 238.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.33 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.40 (s, 1H), 7.19 (d, J=8.4 Hz, 1H), 2.22 (s, 3H).
N-[5-Chloro-2-(trifluoromethyl)phenyl]thioacetamide
[0339] ##STR00104##
[0340] To a solution of N-[5-chloro-2-(trifluoromethyl)phenyl]acetamide (2.50 g, 10.5 mmol) in toluene (20 mL) Lawesson's reagent (2.34 g, 5.79 mmol) was added and the mixture was stirred 2 h at 110° C. The mixture was evaporated and purified by column chromatography (PE/EA=10/1˜4/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (2.1 g, 79%). ESI-MS m/z calcd for [C.sub.9H.sub.7ClF.sub.3NS] [M+H].sup.+: 254.0; found: 254.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.52 (s, 1H), 8.09 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 2.76 (s, 3H).
Methyl N-[5-chloro-2-(trifluoromethyl)phenyl]ethanimidothioate
[0341] ##STR00105##
[0342] To a solution of N-[5-chloro-2-(trifluoromethyl)phenyl]thioacetamide (2.10 g, 8.28 mmol) in MeCN (40 mL) K.sub.2CO.sub.3 (1.70 g, 12.3 mmol) and iodomethane (1.03 mL, 16.6 mmol) were added and the mixture was stirred 2 h at rt under a nitrogen atmosphere. The mixture was concentrated, dissolved in EtOAc and washed with water and brine. The organic phase was dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (PE/EA=100/1˜50/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (1.80 g, 81%). ESI-MS m/z calcd for [C.sub.10H.sub.9ClF.sub.3NS] [M+H].sup.+: 268.0; found: 268.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.52 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.4, 1H), 6.75 (s, 1H), 2.40 (s, 3H), 2.06-1.91 (m, 3H).
1-[3-(3-Azido-4,6-O-benzylidene-3-deoxy-β-
[0343] ##STR00106##
[0344] To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
1-{3-{4,6-O-Benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0345] ##STR00107##
[0346] To a solution of 1-[3-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 10
(2-methyl-1,3-benzothiazol-6-yl)hydrazine
[0347] ##STR00108##
[0348] To a solution of 2-methyl-1,3-benzothiazol-6-amine (3.0 g, 18.3 mmol) in water (50 mL) hydrochloric acid (50 mL, 33% w/w) and AcOH (15 mL) were added. A solution NaNO.sub.2 (1.51 g, 21.9 mmol) in water (50 mL) was added dropwise at −10° C. and the resulting mixture was stirred 2 h under nitrogen atmosphere at −10° C. Tin(II) chloride dihydrate (8.24 g, 36.5 mmol) was added by small portions at −10° C. The resulting mixture was stirred 2 h under nitrogen atmosphere at −10° C. Then NaHCO.sub.3 (300 mL, 5% w/w) was added at 0 C. Water (200 mL) and DCM (100 mL) were added and the phases were separated. The aqueous phase was extracted with DCM (2×100 mL), and the combined organic phases were washed with water (50 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4 and evaporated to afford the product (2.30 g, 70%). ESI-MS m/z calcd for [C.sub.8H.sub.9N.sub.3S] [M+H].sup.+: 180.1; found: 180.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.66 (d, J=8.8 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.03 (s, 1H), 6.93 (dd, J=8.8, 2.0 Hz, 1H), 4.22 (s, 2H), 2.75 (s, 3H).
2,6-Anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
[0349] ##STR00109##
[0350] To a solution of methyl 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
6-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-β-
[0351] ##STR00110##
[0352] To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
6-{5-{4,6-O-Benzylidene-3-deoxy-3-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]β-
[0353] ##STR00111##
[0354] To a solution of 6-[5-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 11
4-Methyl-2-((trimethylsilyl)ethynyl)thiazole
[0355] ##STR00112##
[0356] To a solution of 2-bromo-4-methylthiazole (300 mg, 1.68 mmol) in THF (5 mL) ethynyl(trimethyl)silane (248 mg, 2.53 mmol), CuI (16 mg, 0.084 mmol) and bis(triphenylphosphine)palladium(II) chloride (59.1 mg, 0.084 mmol) and Et.sub.3N (0.47 mL, 3.37 mmol) were added and the mixture was stirred 2 h at 60° C. under a nitrogen atmosphere. The mixture was diluted with water (20 mL) and extracted with EA (3×20 mL). The organic phases were washed with brine, dried over MgSO.sub.4, concentrated and purified by column chromatography (PE/EA=20/1-10/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (225 mg, 68%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.87 (s, 1H), 2.45 (s, 3H), 0.26 (s, 9H).
1-{3-{4,6-O-Benzylidene-3-deoxy-3-[4-(4-methylthiazol-2-yl)-1H-1,2,3-triazol-1-yl]-β-
[0357] ##STR00113##
[0358] To a solution of 1-[3-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 12
1-{3-{4,6-O-Benzylidene-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]β-
[0359] ##STR00114##
[0360] To a solution of 1-[3-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 13
Trimethyl[2-(2-methylthiazol-4-yl)ethynyl]silane
[0361] ##STR00115##
[0362] To a solution of 4-bromo-2-methylthiazole (200 mg, 1.12 mmol) and trimethylsilylacetylene (331 mg, 3.37 mmol) in THF (10.0 mL) bis(triphenylphosphine)palladium(II) chloride (39.4 mg, 0.056 mmol), (oxydi-2,1-phenylene)bis(diphenylphosine) (30.2 mg, 0.056 mmol), CuI (10.7 mg, 0.056 mmol) and DIPEA (0.961 mL, 5.62 mmol) were added and the mixture was stirred overnight at 50° C. under a nitrogen atmosphere. The mixture was evaporated and purified by column chromatography (PE/EA=10/1-5/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (120 mg, 55%). ESI-MS m/z calcd for [C.sub.9H.sub.13NSSi] [M+H].sup.+: 196.1; found: 196.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.25 (s, 1H), 2.63 (s, 3H), 0.18 (s, 9H).
6-{5-{4,6-O-Benzylidene-3-deoxy-3-[4-(2-methylthiazol-4-yl)-1H-1,2,3-triazol-1-yl]β-
[0363] ##STR00116##
[0364] To a solution of 6-[5-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 14
Trimethyl(2-thiazol-5-ylethynyl)silane
[0365] ##STR00117##
[0366] To a solution of 5-bromothiazole (328 mg, 2.00 mmol) in THF (10 mL) ethynyl(trimethyl)silane (393 mg, 4.00 mmol), Et.sub.3N (0.836 mL, 6.00 mmol), bis(triphenylphosphine)palladium(II) chloride (73.0 mg, 0.10 mmol) and CuI(38.1 mg, 0.20 mmol) were added at 0° C. and the mixture was stirred under a nitrogen atmosphere overnight at rt. The mixture was poured into water (20 mL) and extracted with EtOAc (2×20 mL). The organic layers were washed with water (20 mL), brine (20 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (PE/EA=20/1-10/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (200 mg, 55%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.71 (s, 1H), 8.01 (s, 1H), 0.26 (s, 9H).
6-{5-{4,6-O-Benzylidene-3-deoxy-3-[4-(5-thiazolyl)-1H-1,2,3-triazol-1-yl]β-
[0367] ##STR00118##
[0368] To a solution of 6-[5-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 15
1-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-β-
[0369] ##STR00119##
[0370] To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
1-{3-{4,6-O-Benzylidene-3-{4-[2-(di-tert-butoxycarbonylamino)thiazol-4-yl]-1H-1,2,3-triazol-1-yl}-3-deoxy-β-
[0371] ##STR00120##
[0372] To a solution of 1-[5-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 16
1-{3-{4,6-O-Benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0373] ##STR00121##
[0374] To a solution of 1-[5-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 17
Methyl 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-3-O-methyl-
[0375] ##STR00122##
[0376] To a solution methyl 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
Methyl 2,6-anhydro-5,7-O-benzylidene-4-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-4-deoxy-3-O-methyl-
[0377] ##STR00123##
[0378] To a solution of methyl 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-3-O-methyl-
2,6-Anhydro-5,7-O-benzylidene-4-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-4-deoxy-3-O-methyl-
[0379] ##STR00124##
[0380] To a solution of methyl 2,6-anhydro-5,7-O-benzylidene-4-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-4-deoxy-3-O-methyl-
1-{3-{4,6-O-Benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-β-
[0381] ##STR00125##
[0382] To a solution of 2,6-anhydro-5,7-O-benzylidene-4-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-4-deoxy-3-O-methyl-
Intermediate 18
5-Chloro-2-cyclopropyl-3-nitropyridine
[0383] ##STR00126##
[0384] To a solution of 2,5-dichloro-3-nitropyridine (6.0 g, 31.1 mmol) in 1,4-dioxane (120 mL) and H.sub.2O (24 mL) potassium cyclopropyltrifluoroborate (7.36 g, 46.6 mmol), K.sub.2CO.sub.3 (12.9 g, 93.3 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.14 g, 1.55 mmol) were added and the mixture was stirred 16 h at 100° C. under nitrogen atmosphere. The mixture was partitioned between water (100 mL) and DCM (100 mL) and the aqueous phase was extracted with DCM (2×100 mL). The combined organic phases were washed with water (100 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4, evaporated and purified by column chromatography (PE/EA=10/1-2/1, Silica-CS 80 g, 40 mL/min, silica gel, UV 254) to afford the product (3.3 g, 53%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.50 (d, J=2.0 Hz, 1H), 8.06 (d, J=2.4 Hz, 1H), 2.67-2.60 (m, 1H), 1.19-1.06 (m, 4H).
5-Chloro-2-cyclopropylpyridin-3-amine
[0385] ##STR00127##
[0386] To a solution of 5-chloro-2-cyclopropyl-3-nitropyridine (3.3 g, 16.6 mmol) in EtOH (100 mL) iron (4.64 g, 8.31 mmol) and NH.sub.4Cl (4.44 g, 8.31 mmol) were added and the mixture was stirred 16 h at rt under hydrogen atmosphere. The mixture was filtered and evaporated to afford the product (2.00 g, 71%). ESI-MS m/z calcd for [C.sub.8H.sub.9ClN.sub.2][M+H].sup.+: 169.0; found: 169.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.57 (d, J=2.0 Hz, 1H), 6.91 (d, J=2.4 Hz, 1H), 2.06-1.99 (m, 1H), 0.85-0.77 (m, 4H).
(5-Chloro-2-cyclopropyl-3-pyridyl)hydrazine
[0387] ##STR00128##
[0388] To a solution of 5-chloro-2-cyclopropylpyridin-3-amine (450 mg, 2.67 mmol) in water (7 mL) H.sub.2SO.sub.4 (7 mL, 98% w/w) was added. A solution of NaNO.sub.2 (552 mg, 8.01 mmol) in water (2 mL) was added dropwise at −15° C. and the resulting mixture was stirred 2 h under nitrogen atmosphere at −15° C. Then tin(II) chloride dihydrate (3.61 g, 1.60 mmol) was added by small portion at −15° C. and the mixture was stirred 2 h under nitrogen atmosphere at −15° C. NaOH (50 mL, 5 M) was added at −15° C. followed by water (50 mL) and DCM (50 mL). The phases were separated, and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and evaporated to afford the product (230 mg, 47%). ESI-MS m/z calcd for [C.sub.8H.sub.10ClN.sub.3] [M+H].sup.+: 184.1; found: 184.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.61 (d, J=2.4 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.19 (s, 1H), 4.27 (s, 2H), 2.05-1.98 (m, 1H), 0.85-0.81 (m, 4H).
3-[5-(3-Azido-4,6-O-benzylidene-3-deoxy-β-
[0389] ##STR00129##
[0390] To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
3-{5-{4,6-O-Benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0391] ##STR00130##
[0392] To a solution of 3-[5-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 19
1-{3-{4,6-O-Benzylidene-3-{4-[2-(di-tea-butoxycarbonylamino)thiazol-4-yl]-1H-1,2,3-triazol-1-yl}-3-deoxy-β-
[0393] ##STR00131##
[0394] To a solution of 1-[3-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 20
Methyl 3-O-acetyl-2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
[0395] ##STR00132##
[0396] To a solution of methyl 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
Methyl 3-O-acetyl-2,6-anhydro-5,7-O-benzylidene-4-deoxy-4-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]-
[0397] ##STR00133##
[0398] To a solution of methyl 3-O-acetyl-2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
2,6-Anhydro-5,7-O-benzylidene-4-deoxy-4-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]-
[0399] ##STR00134##
[0400] To a solution of methyl 3-O-acetyl-2,6-anhydro-5,7-O-benzylidene-4-deoxy-4-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]-
1-{3-{4,6-O-Benzylidene-3-deoxy-3-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]β-
[0401] ##STR00135##
[0402] To a solution of 2,6-anhydro-5,7-O-benzylidene-4-deoxy-4-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]-
Intermediate 21
6-{3-{4,6-O-Benzylidene-3-deoxy-3-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]β-
[0403] ##STR00136##
[0404] To a solution of 6-[3-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 22
6-{3-{4,6-O-Benzylidene-3-deoxy-3-[4-(2-thiazolyl)-1H-1,2,3-triazol-1-yl]β-
[0405] ##STR00137##
[0406] To a solution of 6-[3-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 23
6-{5-{4,6-O-Benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0407] ##STR00138##
[0408] To a solution of 6-[5-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 24
6-{5-{4,6-O-Benzylidene-3-{4-[2-(di-ta-butoxycarbonylamino)thiazol-4-yl]-1H-1,2,3-triazol-1-yl}-3-deoxy-β-
[0409] ##STR00139##
[0410] To a solution of 6-[5-(3-azido-4,6-O-benzylidene-3-deoxy-β-
Intermediate 25
N-(2-Methyl-1,3-benzothiazol-6-yl)acetamide
[0411] ##STR00140##
[0412] To a solution of 2-methyl-1,3-benzothiazol-6-amine (1.0 g, 6.09 mmol) in DCM (50 mL) acetyl chloride (526 mg, 6.70 mmol) and pyridine (1.48 mL) were added and the mixture was stirred 5 h under nitrogen atmosphere at 0° C. The mixture was partitioned between water (50 mL) and DCM (50 mL) and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with water (50 mL) and brine (3×50 mL), dried over Na.sub.2SO.sub.4, evaporated and purified by column chromatography (PE/EA=10/1-1/2, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (750 mg, 60%). ESI-MS m/z calcd for [C.sub.10H.sub.10N.sub.2OS] [M+H].sup.+: 207.1; found: 207.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.33 (d, J=1.6 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.48 (s, 1H), 7.20-7.15 (m, 1H), 2.75 (s, 3H), 2.15 (s, 3H).
N-(2-Methyl-1,3-benzothiazol-6-yl)thioacetamide
[0413] ##STR00141##
[0414] To a solution of N-(2-methyl-1,3-benzothiazol-6-yl)acetamide (640 mg, 3.1 mmol) in THF (30 mL) Lawesson's Reagent (690 mg, 1.71 mmol) was added and the mixture was stirred 2 h under nitrogen atmosphere at 65° C. The mixture was partitioned between water (50 mL) and DCM (50 mL) and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with water (50 mL) and brine (3×50 mL), dried over Na.sub.2SO.sub.4, evaporated and purified by column chromatography (PE/EA=10/1-1/2, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (400 mg, 58%). ESI-MS m/z calcd for [C.sub.10H.sub.10N.sub.2S.sub.2] [M+H].sup.+: 223.0; found: 223.1. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.63 (d, J=2.0 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.66-7.63 (m, 1H), 2.82 (s, 3H), 2.68 (s, 3H).
Methyl N-(2-methyl-1,3-benzothiazol-6-yl)ethanimidothioate
[0415] ##STR00142##
[0416] To a solution of N-(2-methyl-1,3-benzothiazol-6-yl)thioacetamide (400 mg, 1.80 mmol) in DMF (10 mL) iodomethane (766 mg, 5.4 mmol) and cesium carbonate (1170 mg, 3.6 mmol) were added and the mixture was stirred 3 h under nitrogen atmosphere at rt. The mixture was partitioned between water (50 mL) and DCM (50 mL) and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4, evaporated and purified by column chromatography (PE/EA=10/1-1/3, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (300 mg, 71%). ESI-MS m/z calcd for [C.sub.11H.sub.12N.sub.2S.sub.2] [M+H].sup.+: 237.0; found: 237.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.80 (d, J=8.4 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 6.79-6.76 (m, 1H), 2.74 (s, 3H), 2.37 (s, 3H), 1.97 (s, 3H).
6-{3-{4,6-O-Benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-β-
[0417] ##STR00143##
[0418] To a Solution of 2,6-anhydro-5,7-O-benzylidene-4-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-4-deoxy-3-O-methyl-
Intermediate 26
Methyl 2,6-anhydro-5,7-O-benzylidene-4-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-4-deoxy-
[0419] ##STR00144##
[0420] To a solution of methyl 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-D-glycero-L-manno-heptonate (500 mg, 1.49 mmol) in DMF (10 mL) copper(II) sulfate pentahydrate (186 mg, 0.75 mmol), 2-(4-chlorothiazol-2-yl)ethynyltrimethylsilane (483 mg, 2.24 mmol) and (+)-sodium L-ascorbate (148 mg, 0.75 mmol) were added and the mixture was stirred 3 h at rt. The mixture was partitioned between water (50 mL) and DCM (50 mL) and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4, evaporated and purified by column chromatography (PE/EA=10/1-1/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (650 mg, 91%). ESI-MS m/z calcd for [C.sub.20H.sub.19ClN.sub.4O.sub.6S] [M+H].sup.+: 479.1; found: 479.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.31 (s, 1H), 7.33-7.28 (m, 5H), 7.03 (s, 1H), 5.41 (s, 1H), 4.98 (dd, J=10.8, 2.4 Hz, 1H), 4.64 (t, J=10.0 Hz, 1H), 4.47 (d, J=2.8 Hz, 1H), 4.39 (d, J=13.6 Hz, 1H), 4.06-4.02 (m, 2H), 3.81 (s, 3H), 3.72 (s, 1H).
Methyl 2,6-anhydro-5,7-O-benzylidene-4-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-4-deoxy-
[0421] ##STR00145##
[0422] To a solution of methyl methyl 2,6-anhydro-5,7-O-benzylidene-4-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-4-deoxy-
6-{3-{4,6-O-Benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0423] ##STR00146##
[0424] To a solution of 2,6-anhydro-5,7-O-benzylidene-4-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-4-deoxy-
Intermediate 27
N-(3-Methylbenzimidazol-5-yl)acetamide
[0425] ##STR00147##
[0426] To a solution of 3-methylbenzimidazol-5-amine (750 g, 5.1 mmol) in DCM (50 mL) and pyridine (5 mL) acetyl chloride (800 mg, 10.0 mmol) was added at 0° C. and the mixture was stirred 12 h at rt under a nitrogen atmosphere. The mixture was partitioned between water (50 mL) and DCM (50 mL) and the aqueous phase was extracted with DCM (2×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (DCM/MeOH=I/0˜0/1, Silica-CS 40 g, 40 mL/min, silica gel, UV 254) to afford the product (400 mg, 41%). ESI-MS m/z calcd for [C.sub.10H.sub.11N.sub.3O] [M+H].sup.+: 190.1; found: 190.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.01 (s, 1H), 8.09 (s, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.54 (d, J=4.8 Hz, 1H), 7.18 (dd, J=8.4, 1.6 Hz, 1H), 3.77 (s, 3H), 2.07 (s, 3H).
N-(3-Methylbenzimidazol-5-yl)thioacetamide
[0427] ##STR00148##
[0428] To a solution of N-(3-methylbenzimidazol-5-yl)acetamide (320 mg, 1.7 mmol) in THF (30 mL) Lawesson's reagent (1.37 g, 3.40 mmol) was added and the mixture was stirred 12 h at 65° C. The mixture was partitioned between water (50 mL) and DCM (50 mL) and the aqueous phase was extracted with DCM (2×50 mL). The combined organic layers were washed with water (50 mL) and brine (3×50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (DCM/MeOH=I/0˜1/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (200 mg, 58%). ESI-MS m/z calcd for [C.sub.10H.sub.11N.sub.3S] [M+H].sup.+: 206.1; found: 206.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.68 (s, 1H), 8.25 (d, J=1.6 Hz, 1H), 8.21 (s, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.36 (dd, J=8.8, 2.0 Hz, 1H), 3.81 (s, 3H), 2.63 (s, 3H).
Methyl N-(3-methylbenzimidazol-5-yl)ethanimidothioate
[0429] ##STR00149##
[0430] To a solution of N-(3-methylbenzimidazol-5-yl)thioacetamide (65 mg, 0.32 mmol) in MeCN (5 mL) K.sub.2CO.sub.3 (88 mg, 0.63 mmol) and iodomethane (0.06 mL, 0.95 mmol) were added and the mixture was stirred 3 h at rt under a nitrogen atmosphere. The mixture was partitioned between water (50 mL) and DCM (50 mL) and the aqueous phase was extracted with DCM (2×50 mL). The combined organic layers were washed with water (50 mL) and brine (3×50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (DCM/MeOH=10/1˜1/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (48 mg, 69%). ESI-MS m/z calcd for [C.sub.11H.sub.13N.sub.3S][M+H].sup.+: 220.1; found: 220.1. .sup.1H NMR (400 MHz, Methanol-d4) δ 8.04 (d, J=6.8 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 6.91 (d, J=1.2 Hz, 1H), 6.71 (dd, J=8.4, 2.0 Hz, 1H), 3.85 (s, 3H), 2.43 (s, 3H), 2.03 (s, 3H).
5-{3-{4,6-O-Benzylidene-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-β-
[0431] ##STR00150##
[0432] To a solution of 2,6-anhydro-5,7-O-benzylidene-4-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-4-deoxy-
Intermediate 28
2,6-Anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
[0433] ##STR00151##
[0434] To a solution of methyl 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
2,6-Anhydro-4-azido-5,7-O-benzylidene-4-deoxy-1-C—(N-methoxy-N-methyl)-aldehydo-
[0435] ##STR00152##
[0436] To a stirred solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-
2,6-Anhydro-4-azido-5,7-O-benzylidene-4-deoxy-3-O-methoxymethyl-1-C—(N-methoxy-N-methyl)-aldehydo-
[0437] ##STR00153##
[0438] To a solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-1-C—(N-methoxy-N-methyl)-aldehydo-
3,7-Anhydro-5-azido-6,8-O-benzylidene-5-deoxy-4-O-methoxymethyl-
[0439] ##STR00154##
[0440] To a stirred solution of 2,6-anhydro-4-azido-5,7-O-benzylidene-4-deoxy-3-O-methoxymethyl-1-C—(N-methoxy-N-methyl)-aldehydo-
3,7-Anhydro-6,8-O-benzylidene-5-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-5-deoxy-4-O-methoxymethyl-
[0441] ##STR00155##
[0442] To a solution of 3,7-anhydro-5-azido-6,8-O-benzylidene-5-deoxy-4-O-methoxymethyl-
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