Description

FIELD OF INVENTION

[001] The invention relates to a class of fluorinated and/or aminated as well seven carbon sugar derivatives, the process for their preparation, as well as the application of the same in cosmetics and medicine. BACKGROUND OF THE INVENTION

[002] Carbohydrates and glycosides play an utmost important role in a vast range of biological processes. Therefore, modified carbohydrate derivatives may exhibit advantageous properties in terms of efficacy, selectivity and stability. Of particular interest are fluorinated sugars due to their versatile fields of applications in medicine.

[003] Carbohydrates and the derivatives thereof constitute one of the most common class of compounds in nature. Their structural diversity and complexity result from multiple stereogenic centers bearing functional groups, e.g. hydroxy, amino, acylamino and the like. The combination of an increasing number of functional and stereogenic centers in higher carbohydrates thus exponentially creates chemical diversity surpassing the structural diversity of proteins by far.

[004] Based on their structural diversity carbohydrate and carbohydrate derivatives play a key role in a wide variety of biological processes like recognition events, whereby minor structural variations are critical for discrimination and triggering of signal cascades. Stereochemistry refers in this context to the type of glycosidic linkages of either a- or β- configuration, or regiospecific differences of axial vs. equatorial positions, hence determining differences between carbohydrate monomers, such as D-glucopyranose (equatorial OH at C-2) and D-mannopyranose (axial OH at C-2) and their conformation (open, ring, ring size). [005] Therefore, the physiological interaction of e.g. D-glucose vs. D-mannose is distinctively different, and the same is particular true for hexoses vs. seven carbon sugars e.g. D-mannopyranose vs. D-manno-hept-2-ulose. Furthermore, exchange of hydroxy groups vs. amine or fluorine moieties in carbohydrate derivatives may generate novel, unexpected and valuable properties, very different from these of the parent compounds.

[006] The most prominent fluorinated hexose derivative among others is [ 18 F]-2-fluoro-2- deoxy-glucopyranose (FDG), which commonly finds application as contrast agent in 18 F-PET scanning. (Fukuda et al. Eur. J. Nucl. Med. 1982, 7(7), 294-297). In DE 10 2008 045 644 a method is described for the preparation of 18 F-labelled compounds.

[007] It was also observed that 2-deoxy-D-glucose (2DOG) and 2-fluoro-2-deoxy-D- mannose (2F2DOM) inhibited N-glycosylation of asparagine (Asn) sites on the external domain of viral envelope proteins and are therefore attractive candidates for anti-fusogenic drugs to be used against chronic virus diseases and cancers (Parris et al. Medical Hypotheses 2008, 70(4), 776-782; Schwarz et al. Biochemical Society Transactions 1979, 7(2), 322-69).

[008] These are useful agents as non-metabolizable inhibitors or anti-metabolites (Fokt et al. Carbohydrate Research 2009, 344(12), 1464-147) and effective in the treatment of inflammatory disorders as it is disclosed in the WO 2003/090758 Al .

[009] The document WO 2007/100728 A2 describes that fluorination at position C-2 of D- mannose and D-glucose and 2-deoxy-glucose shows the ability to kill tumor cells in human breast, non-small cell lung cancer cells, pancreatic cancer cells, osteosarcoma cancer cells, and glioblastoma cells. Other uses are the preservation of cells, tissues and organs using gem- difluorinated C-glycopeptides, as disclosed in WO 2007125203. Further the use as a potent mimic of artemisinin, a widely used malaria drug, was demonstrated (Magueur et al. Journal of Fluorine Chemistry (2006), 127(4-5), 637-642). [0010] Moreover, geminal difluorinated glycoconjugates as potential antitumor, antiviral, hypoglycemic prodrug agents were dislcosed in FR 2842810 Al. [0011] Seven carbon sugars are far less abundant in nature. Most prominently, D- mannoheptulose, first isolated from avocado (Americana perseana), was studied in diabetes and anticancer therapy, together with D-glucoheptulose (Malaisse et al., Nature Rev. Endocrin. 2009, 5(7): 394-400; Zelent et al. Biochem. J. 2008, 413(2): 269-280; Nelkin W. Acta Phys. Acad. Sci. Hungaricae 1972, 41(2), 177-9).

[0012] The structural resemblance of D-manno- and D-glucohept-2-uloses with D-glucose enables an uptake of the C7 sugar by active cotransport into the cell, by similar or the same pathways as glucose. However their mode of action in vivo differs. [Ramirez et al. Intern. J. Mol. Med. 2001; 7(6), 631-638; Sener et al. Diabetologia 1998, 41(9), 1109-1113, (Cardenas, M. L., et al. Biochim. Biophys. Acta 1998, 1401, 242-264). D-Mannoheptulose shows the ability to induce hyperglycemia (Froesch et al. Diabetologia (1966), 2(4), 265-8), and it was proposed that binding to an alternative-binding site of glucokinase (GK) stabilizes a closed conformation, hence reducing insulin levels (Leshem et al. Can. J. Biochem. 1974, 52(11), 1078-81; Wilson, J. E. in Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front Diabetes. Vol. 16 (eds Matschinsky, F. M. & Magnuson, M. A.) 18-30 (Karger, Basel, 2004).

[0013] Radiolabeled -hept-2-ulose, namely 125

D-manno I-D-manno-hept-2-ulose (Malaisse et al. Diabetes 2001, 50, A527-A527., or [ ³ H]- or D-[l- ¹⁴ C]-D-manno-hept-2-ulose (Ramirez et al. Intern. J. Mol. Med. 2001, 7(6), 631-638; Ladriere et al. Am. J. Physiol. Endocrinol. Metab. 2001, 281, E298-E303) was reported as contrast agents for radio medical imaging.

[0014] The use of radio labelled derivatives of D-mannoheptulose in biochemical imaging of pancreatic islets was also hypothesized in EP 1 090 646 A2. The derivatives claimed were H- or 11 C- -ulose, and in particular 3-deoxy-3- 18

D-manno-hept-2 F-D-mannoheptulose. However, said compound was not prepared. The prophetic synthetic pathway given therein in analogy to the process disclosed by C. Lemaire et al., J. Labelled Comp. Radiopharm. 40, pp. 256-7

(1997) and WO 97/42203 is not applicable for the preparation of 18 F-heptuloses -in particular

18 F-D-mannoheptulose. Other than hexoses, seven carbon sugars contain two primary hydroxyl-groups thus requiring extensive, multi-step protective group chemistry incompatible with the short half life of the 18 F isotope (t m = 109,8 min). [0015] Finally, WO97/42203 refers to an apparatus to perform a [ 18 F] exchange reaction, but does not describe any methodology for the preparation of suitable derivatives and in particular does not describe any procedure for the preparation of selectively trifluoromethane- sulphonyl functionalized C7-derivatives.

[0016] Surprisingly it was found that the seven carbon sugar derivatives disclosed herein, display high and selective intracellular uptake in cells, e.g. GLUT2-expressing cells. Furthermore, said seven carbon sugar derivatives act as enzyme inhibitors. BRIEF DESCRIPTION OF THE INVENTION

[0017] Coming from the state of the art it is an objective of the present invention to provide novel seven carbon sugar derivates with valuable therapeutic and/or diagnostic properties.

[0018] This invention provides seven carbon sugars according to the generic formula (I)

R ⁴ (I) wherein R 1 , R 2", R 3 ^J , R 4", R 5 ^J and R 7' are selected from the group of combinations comprising: R ¹ = F or Y, R ² = R ³ = R ⁴ = R ⁵ = R ⁷ = OH, or optionally substituted Bn, Bz, or -C(=0)Ci_ ₄ alkyl,

R ¹ = F, R ² = R ⁴ = R ⁵ = R ⁷ = OH, or optionally substituted Bn, Bz, or -C(=0)Ci_ ₄ alkyl, R ³ = Y,

R ¹ = R ² = R ⁴ = R ⁵ = R ⁷ = OH, or optionally substituted Bn, Bz, or -C(=0)Ci_ ₄ alkyl, R ³ = F or Y,

R ¹ = Y, R ² = R ⁴ = R ⁵ = R ⁷ = OH, or optionally substituted Bn, Bz, or -C(=0)Ci_ ₄ alkyl, R ³ = F,

R ¹ = R ³ = F or Y, R ² = R ⁴ = R ⁵ = R ⁷ = OH, or optionally substituted Bn, Bz, or -C(=0)Ci_ ₄ alkyl,

R^ R ² = R ³ =R ⁴ = R ⁵ = OH, or optionally substituted Bn, Bz, or -C(=0)Ci_ ₄ alkyl , R ⁷ = F or Y, R ¹ = Y, R ² = R ³ = R ⁴ = R ⁵ = OH, or optionally substituted Bn, Bz, or -C(=0)Ci_ ₄ alkyl, R ⁷ = F,

R^ R ² = R ⁴ = R ⁵ = OH, or optionally substituted Bn, Bz, or -C(=0)Ci_ ₄ alkyl, R ³ = Y, R ⁷ = F, R ² = R ⁴ = R ⁵ = R ⁷ = OH, or optionally substituted Bn, Bz, or -C(=0)Ci_ ₄ alkyl, R ¹ , R ³ = F R ³ = R ² = R ⁴ = R ⁵ = OH, or optionally substituted Bn, Bz, or -C(=0)Ci_ ₄ alkyl, R ¹ , R ⁷ = F R ³ = R ⁴ = R ⁵ = R ⁷ = OH, or optionally substituted Bn, Bz, or -C(=0)Ci_ ₄ alkyl, R ² , R ³ = F R ¹ = R ⁴ = R ⁵ = R ⁷ = OH, or optionally substituted Bn, Bz, or -C(=0)Ci_ ₄ alkyl, R ³ = Y, R ² = F and Y represents OH, or optionally substituted Bn, Bz, or -C(=0)Ci_ ₄ alkyl, H, -NHR ⁶ , - N(R ⁶ ') _2, -N-phthalimido, -NR ⁸ -C(=0)-NHR ⁹ , -NR ⁸ -C(=0)-OR ⁹ , azido -N ₃ and biotinylated derivatives thereof.

[0019] Biotinylation refers hereby to coupled derivatives using commercially available functionalized and activated biotin derivatives (e.g. Pierce and others) such as Biotin-NHS esters for amine coupling and alkyne- Biotin for commonly used mild copper catalyzed click chemistry (as depicted in the example below) or by usage of dibenzylcyclooctyne-fiz ^' oim ( QCO-Biotin) conjugates for copper free click chemistry.

biotinylated 1 -deoxy-1 -ureido-D-mannoheptulose n = 1 -15

Examples of coupled biotinylated-tethered ketoheptose (here for 1 - and 3-linked D-mannoheptulose) targets.

[0020] R ⁶ stands for C _1-4 alkyl, optionally halogenated, -C(=0)Ci_ ₄ alkyl, optionally halogenated, an amino protective group, well known to the artisan, as e.g. carbamate, in particular t-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBz), or 9-fluorenyloxycarbonyl (Fmoc) or l,3-dimethyl-2,4,6-(lH,3H,5H)-trioxopyrimidine-5-ylidene)met hyl (DTPM), tetrachlorophthaloyl (TCP), phthalimido, and the like (see: Theodora W. Greene, Peter G. Wuts -Protective Groups in Organic Synthesis, 4 ^th Edition; P. J. Kocienski, Protecting Groups, Thieme 2005). [0021] R ⁶ stands for C _1-4 alkyl, optionally halogenated and R ⁸ stands for -H, -N=0, Boc, Ci_ ₄ ,-alkyl; R ⁹ is azido-C2-ioralkyl, optionally substituted by one or more halogen, e.g. -1-azido- butyl, , l-azido-2,2', 3, 3 '-tetrafluorobutyl, l-azido-2,2' ,3, 3 '-hexafluorobutyl, 1-azido- 2,2',3,3',4,4'-hexafluoropentyl, l-azido-2,2',3,3',4,4',5,5'-hexafluorohexyl, or amido-d-io,- alkyl, optionally substituted by one or more halogen, e.g. 1-amido-butyl, 1-amido- 2,2',3,3',4,4'-tetrafluoropentyl, l-amido-2,2',3,3',4,4',5,5'-hexafluorohexyl, polyethyleneglycol with n = 1-15 repeating units, optionally substituted by halogen, preferably fluorine-, up to perhalogenated, preferably perfluorinated polyethyleneglycols with n = 1-15 repeating units and halogen stands for fluoro, chloro, bromo and iodo, preferably, chloro and fluoro, mostly prefered fluoro. [0022] Herein, the synthesis of novel aminated and fluorinated derivatives of seven carbon sugars and their use in cosmetics and medicine are described. Said derivatives display immuno-stimulating, antiviral, antifungal, anticancer, anti-inflammatory, inhibitory activity for therapy or in the treatment and diagnosis of diseases like cancer, inflammation, hyperglycaemia, obesity, and diabetes and related applications thereof. Said derivatives may also find applications for the treatment of the skin, wherein a topic application of the cosmetic composition is proposed. Furthermore the disclosed fluorinated derivatives are valuable compoundsfor the non-invasive imaging of hepatocytes and insulin secreting cells

[0023] It is intended that a seven-carbon sugar derivate according to the disclosure comprises a fluorinated derivative of formula (I) also as part of a pharmaceutical or cosmetic composition in an effective amount.

[0024] The disclosed sugar derivatives are intended for their use in imaging, labelling and quantification of GLUT-expressing cells, especially GLUT2 expressing cells by a non- invasive procedure.

DETAILED DESCRIPTION OF THE INVENTION

[0025] Novel seven carbon sugar derivatives of the generic formular (I) are provided, the process for their preparation, as well as their application. Compounds in formula (I) refer hereby to seven carbon carbohydrates and thereof, in particular D/L-manno- and gluco- ept- 2-ulose and their derivatives. Derivatives refer to regio specific ally aminated and fluorinated derivatives with application in cosmetics and medicine. In particular applications in the field of medicine and therapy for immunostimulation, antiviral, antifungal, anticancer, anti- inflammatory, inhibitory activity for therapy and in the treatment and diagnostic of e.g. hyperglycaemia, obesity, diabetes and thereof related applications. [0026] Those skilled in the art will be aware of the fact that the composition of the invention can be contacted with an organism, preferably a human or an animal, on various routes. In particular, an artisan will also be familiar with the fact that the pharmaceutical agents can be applied at varying dosages. Application should be effected in such a way that a disease is combated as effectively as possible, or the onset of a disease is prevented by a prophylactic administration. A person skilled in the art using routine tests can determine concentration and type of application. Preferred applications of the compounds of the invention are oral application in the form of powders, tablets, juice, drops, capsules or the like, rectal application in the form of suppositories, solutions and the like, parenteral application in the form of injections, infusions and solutions, and local application in the form of ointments, pads, dressings, lavages and the like. Contacting with the composition according to the invention is preferably effected in a prophylactic or therapeutic fashion.

[0027] For example, the suitability of the selected form of application, of the dose, application regimen, selection of adjuvant and the like can be determined by taking serum aliquots from the patient, i.e., human or animal, and testing for the presence of indicators of a disease in the course of the treatment procedure. Alternatively or concomitantly, the condition of the kidneys, liver and the like, but also, the amount of T cells or other cells of the immune system, can be determined in a conventional manner so as to obtain a general survey on the immunological constitution of the patient and, in particular, the constitution of organs important to the metabolism. Additionally, the clinical condition of the patient can be observed for the desired effects. Where insufficient therapeutic effectiveness results, the patient can be subjected to further treatment using the agents of the invention, optionally modified with other well-known medicaments expected to bring about an improvement of the overall constitution. Obviously, it is also possible to modify the carriers or vehicles of the pharmaceutical agent or to vary the route of administration.

[0028] In addition to oral ingestion, intramuscular or subcutaneous injections, or injections into the blood vessels can be envisaged as another preferred route of therapeutic administration of the composition according to the invention. At the same time, influx via catheters or surgical tubes can also be used, e.g. via catheters directly leading to particular organs such as kidneys, liver, spleen, intestine, lungs, etc. [0029] The invention relates also to a method for treating a physiological disorder, symptom or disease in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of the invention, wherein said physiological disorder, symptom or disease is a respiratory disease, stress related disorder, gastrointestinal disorder, obesity, diabetes, headache, neuropathic pain, bladder disorder, genitourinary disorder, cough, cancer, autoimmune disease, proliferative disease or angiogenic disorder.

[0030] Prior to setting forth this part of the invention it may be helpful to an understanding thereof to set forth definitions of certain terms to be used hereinafter.

[0031] A "patient" for the purposes of the present invention includes both humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In the preferred embodiment the patient is a mammal, and in the most preferred embodiment the patient is human.

[0032] The term "angiogenesis" refers to the generation of new blood vessels into cells, tissue, organs or tumors.

[0033] The term "metastasis" refers to the process by which tumor cells are spread to distant parts of the body. The term is also used herein to refer to a tumor that develops through the metastatic process.

[0034] The term "contacting" is used herein interchangeably with the following: combined with, added to, mixed with, passed over, incubated with, flowed over, etc. Moreover, the compounds of present invention can be "administered" by any conventional method such as, for example, parenteral, oral, topical and inhalation routes as described herein.

[0035] As used herein, the term "safe and effective amount" refers to the quantity of a component that is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. By "therapeutically effective amount" is meant an amount of a compound of the present invention effective to yield the desired therapeutic response. For example, an amount effective to delay the growth of or to cause a cancer, either a sarcoma or lymphoma, to shrink or not metastasize. The specific safe and effective amount or therapeutically effective amount will vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives.

[0036] The terms "treating cancer," "therapy," and the like refer generally to any improvement in the mammal having the cancer wherein the improvement can be ascribed to treatment with the compounds of the present invention. The improvement can be either subjective or objective. For example, if the mammal is human, the patient may note improved vigor or vitality or decreased pain as subjective symptoms of improvement or response to therapy. Alternatively, the clinician may notice decrease in tumor size or tumor burden based on physical exam, laboratory parameters, tumor markers or radiographic findings. Some laboratory signs that the clinician may observe for response to therapy include normalization of tests such as white blood cell count, red blood cell count, platelet count, erythrocyte sedimentation rate, and various enzyme levels. Additionally, the clinician may observe a decrease in a detectable tumor marker. Alternatively, other tests can be used to evaluate objective improvement such as sonograms, nuclear magnetic resonance testing and positron emissions testing.

[0037] "Inhibiting the growth of tumor cells" can be evaluated by any accepted method of measuring whether growth of the tumor cells has been slowed or diminished. This includes direct observation and indirect evaluation such as subjective symptoms or objective signs as discussed above.

[0038] Accordingly, the compositions of the invention are administered to cells. By "administered" herein is meant administration of a therapeutically effective dose of the candidate agents of the invention to a cell either in cell culture or in a patient. By "therapeutically effective dose" herein is meant a dose that produces the effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by those skilled in the art. By "cells" herein is meant almost any cell in which mitosis or meiosis can be altered. [0039] According to a preferred embodiment, the invention provides a method for treating or lessening the severity of a cancer mediated disease or condition in a patient comprising administering to said patient an effective amount of at least one compound of invention.

[0040] Proliferative diseases which may be treated or prevented by the compounds of this invention include, but are not limited to leukemias, lymphomas, sarcomas, carcinomas, neural cell tumors, undifferentiated tumors, sensinomas, melanomas, neuroblastomas, multiple myeloma, mixed cell tumors, metastatic neoplasia and neoplasia due to pathogenic infections. Leukemias include acute myelogenous leukemia, chronic myelogenous leukemia and juvenile myelomonocytic leukemia.

[0041] Therefore, the invention relates to the use of the compounds and/or pharmaceutical agent of the invention in the treatment of diseases associated with metastasis, angiogenesis or autoimmunodeficiency. These can be inflammatory reactions, autoimmune diseases, e.g. diabetes, obesity, and diseases associated with cell division disorders, such as cancer in a patient (human or animal).

[0042] In an embodiment the cancerous disease or tumor being treated or prevented is selected from the group of cancerous diseases or tumor diseases of the ear-nose-throat region, of the lungs, mediastinum, gastrointestinal tract, urogenital system, gynaecological system, breast, endocrine system, skin, bone and soft-tissue sarcomas, mesotheliomas, melanomas, neoplasms of the central nervous system, cancerous diseases or tumor diseases during infancy, lymphomas, leukaemia, paraneoplastic syndromes, metastases with unknown primary tumor (CUP syndrome), peritoneal carcinomatoses, immunosuppression-related malignancies and/or tumor metastases.

[0043] More specifically, the tumors may comprise the following types of cancer: adenocarcinoma of breast, prostate and colon; all forms of lung cancer starting in the bronchial tube; bone marrow cancer, melanoma, hepatoma, neuroblastoma; papilloma; apudoma, choristoma, branchioma; malignant carcinoid syndrome; carcinoid heart disease, carcinoma (for example, Walker carcinoma, basal cell carcinoma, squamobasal carcinoma, Brown-Pearce carcinoma, ductal carcinoma, Ehrlich tumor, in situ carcinoma, cancer-2 carcinoma, Merkel cell carcinoma, mucous cancer, non-parvicellular bronchial carcinoma, oat-cell carcinoma, papillary carcinoma, scirrhus carcinoma, bronchio-alveolar carcinoma, bronchial carcinoma, squamous cell carcinoma and transitional cell carcinoma); histiocytic functional disorder; leukemia (e.g. in connection with B cell leukemia, mixed-cell leukemia, null cell leukemia, T cell leukemia, chronic T cell leukemia, HTLV-II-associated leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, mast cell leukemia, and myeloid leukemia); malignant histiocytosis, Hodgkin disease, non-Hodgkin lymphoma, solitary plasma cell tumor; reticuloendotheliosis, chondroblastoma; chondroma, chondrosarcoma; fibroma; fibrosarcoma; giant cell tumors; histiocytoma; lipoma; liposarcoma; leukosarcoma; mesothelioma; myxoma; myxosarcoma; osteoma; osteosarcoma; Ewing sarcoma; synovioma; adenofibroma; adenolymphoma; carcinosarcoma, chordoma, craniopharyngioma, dysgerminoma, hamartoma; mesenchymoma; mesonephroma, myosarcoma, ameloblastoma, cementoma; odontoma; teratoma; thymoma, chorioblastoma; adenocarcinoma, adenoma; cholangioma; cholesteatoma; cylindroma; cystadenocarcinoma, cystadenoma; granulosa cell tumor; gynadroblastoma; hidradenoma; islet-cell tumor; Leydig cell tumor; papilloma; Sertoli cell tumor, theca cell tumor, leiomyoma; leiomyosarcoma; myoblastoma; myoma; myosarcoma; rhabdomyoma; rhabdomyosarcoma; ependymoma; ganglioneuroma, glioma; medulloblastoma, meningioma; neurilemmoma; neuroblastoma; neuroepithelioma, neurofibroma, neuroma, paraganglioma, non-chromaffin paraganglioma, angiokeratoma, angiolymphoid hyperplasia with eosinophilia; sclerotizing angioma; angiomatosis; glomangioma; hemangioendothelioma; hemangioma; hemangiopericytoma, hemangiosarcoma; lymphangioma, lymphangiomyoma, lymphangiosarcoma; pinealoma; cystosarcoma phylloides; hemangiosarcoma; lymphangiosarcoma; myxosarcoma, ovarial carcinoma; sarcoma (for example, Ewing sarcoma, experimentally, Kaposi sarcoma and mast cell sarcoma); neoplasms (for example, bone neoplasms, breast neoplasms, neoplasms of the digestive system, colorectal neoplasms, liver neoplasms, pancreas neoplasms, hypophysis neoplasms, testicle neoplasms, orbital neoplasms, neoplasms of the head and neck, of the central nervous system, neoplasms of the hearing organ, pelvis, respiratory tract and urogenital tract); neurofibromatosis and cervical squamous cell dysplasia. [0044] In another embodiment the cancerous disease or tumor being treated or prevented is selected from the group of tumors of the ear-nose-throat region, comprising tumors of the inner nose, nasal sinus, nasopharynx, lips, oral cavity, oropharynx, larynx, hypopharynx, ear, salivary glands, and paragangliomas, tumors of the lungs comprising non-parvicellular bronchial carcinomas, parvicellular bronchial carcinomas, tumors of the mediastinum, tumors of the gastrointestinal tract, comprising tumors of the esophagus, stomach, pancreas, liver, gallbladder and biliary tract, small intestine, colon and rectal carcinomas and anal carcinomas, urogenital tumors comprising tumors of the kidneys, ureter, bladder, prostate gland, urethra, penis and testicles, gynecological tumors comprising tumors of the cervix, vagina, vulva, uterine cancer, malignant trophoblast disease, ovarial carcinoma, tumors of the uterine tube (Tuba Faloppii), tumors of the abdominal cavity, mammary carcinomas, tumors of the endocrine organs, comprising tumors of the thyroid, parathyroid, adrenal cortex, endocrine pancreas tumors, carcinoid tumors and carcinoid syndrome, multiple endocrine neoplasias, bone and soft-tissue sarcomas, mesotheliomas, skin tumors, melanomas comprising cutaneous and intraocular melanomas, tumors of the central nervous system, tumors during infancy, comprising retinoblastoma, Wilms tumor, neurofibromatosis, neuroblastoma, Ewing sarcoma tumor family, rhabdomyosarcoma, lymphomas comprising non-Hodgkin lymphomas, cutaneous T cell lymphomas, primary lymphomas of the central nervous system, morbus Hodgkin, leukemias comprising acute leukemias, chronic myeloid and lymphatic leukemias, plasma cell neoplasms, myelodysplasia syndromes, paraneoplastic syndromes, metastases with unknown primary tumor (CUP syndrome), peritoneal carcinomatosis, immunosuppression-related malignancy comprising AIDS-related malignancy such as Kaposi sarcoma, AIDS-associated lymphomas, AIDS-associated lymphomas of the central nervous system, AIDS-associated morbus Hodgkin and AIDS-associated anogenital tumors, transplantation-related malignancy, metastasized tumors comprising brain metastases, lung metastases, liver metastases, bone metastases, pleural and pericardial metastases, and malignant ascites.

[0045] In another embodiment the cancerous disease or tumor being treated or prevented is selected from the group comprising mammary carcinomas, gastrointestinal tumors, including colon carcinomas, stomach carcinomas, pancreas carcinomas, colon cancer, small intestine cancer, ovarial carcinomas, cervical carcinomas, lung cancer, prostate cancer, kidney cell carcinomas and/or liver metastases. Therefore the invention relates also to a method for treating a cancer in a patient or animal in need of such treatment comprising administering to said patient or animal a safe and effective amount of at least one compound of the invention.

[0046] To demonstrate the uptake of F-heptuloses by rat hepatocytes and their inhibitory effect upon glucose-stimulated insulin release from rat isolated pancreatic islets, six F- heptuloses were tested in both rat hepatocytes and islets, namely 1 -deoxy- 1-fluoro-D- mannoheptulose (1FMH), 3-deoxy-3-fluoro-D-mannoheptulose (3FMH), l,3-dideoxy-l,3- difluoro-D-mannoheptulose (1-3-FMH), 1-deoxy-l-fluoro-D-glucoheptulose (1FGH), 3- deoxy-3-fluoro-D-glucoheptulose (3FGH) and l,3-dideoxy-l,3-difluoro-D-glucoheptulose (1- 3FGH). A seventh F-heptulose, namely 7-deoxy-7-fluoro-D-mannoheptulose (7FMH) was so far tested only in islets. The uptake of -heptuloses (25 mM) by isolated rat hepatocytes (3.10 ⁶ cells/0.2 ml) was assessed by ¹⁹ F NMR spectroscopy after 20 min incubation at 37°C. The effects of these F-heptuloses (10 mM) upon insulin release evoked by D-glucose (10 mM) were measured over 90 min incubation in groups of 8 islets each.

[0047] As indicated in Table 1, after 20 min incubation of rat hepatocytes (3xl0 ⁶ cells/0.2 ml) at 37°C in the presence of 25 mM (initial concentration) of each F-heptulose, the extracellular concentration averaged 20 + 1 mM (n = 6). The uptake of the F-heptuloses ranged from 0.50 (1-deoxy-l-fluoro-D-mannoheptulose and 3-deoxy-3-fluoro-D- mannoheptulose) to 0.25 (l,3-dideoxy-l,3-difluoro-D-mannoheptulose) and 0.13 + 0.01 (1- deoxy-l-fluoro-D-glucoheptulose, 3-deoxy-3-fluoro-D-glucoheptulose and l,3-dideoxy-l,3- difluoro-D-glucoheptulose) μιηοΐ per 3xl0 ⁶ cells.

[0048] Table 1. Uptake of F-heptuloses by rat hepatocytes exposed for 90 min at 37°C to 25 mM (initial concentration) of each heptose

F-heptulose Uptake Extracellular concentration

(μιηο1/3χ10 ⁶ cells) (mM at min 20)

1 -deoxy- 1 -fluoro-D-mannoheptulose 0.50 23

3 -deoxy-3 -fluoro-D-mannoheptulose 0.50 20

1 ,3 -dideoxy- 1 ,3 -difluoro-D- 0.25 18

mannoheptulose

1 -deoxy- 1 -fluoro-D-glucoheptulose 0.15 23

3 -deoxy-3 -fluoro-D-glucoheptulose 0.12 20

1 ,3 -dideoxy- 1 ,3 -difluoro-D- 0.12 18

glucoheptulose [0049] As documented in Table 2, the output of insulin was more than doubled (p < 0.001) when the concentration of D-glucose in the incubation medium was raised from 2.8 to 10.0 mM. In the presence of 10.0 mM D-glucose, D-mannoheptulose (also 10.0 mM) decreased (p < 0.001) the increment in insulin output recorded above basal value to about one quarter of that otherwise found in the absence of the heptose. In the presence of both D-glucose and D- mannoheptulose (10.0 mM each), the insulin content remained nevertheless significantly higher (p < 0.002) than the basal value measured in the sole presence of 2.6 mM D-glucose. When compared within the same experiment(s), no significant difference was observed between the output of insulin evoked by D-glucose (10.0 mM) in the presence of D- mannoheptulose, on one hand, and that recorded in the presence of either l£-deoxy-l-fluoro- D-mannoheptulose (p > 0.4), 3-deoxy-3-fluoro-D-mannoheptulose (p > 0.09), 1,3-dideoxy- 1,3-difluoro-D-mannoheptulose (p > 0.35), 7-deoxy-7-fluoro-D-mannoheptulose (p > 0.08) or 1-deoxy-l-fluoro-D-glucoheptulose (p > 0.7), all these heptoses being tested at a 10.0 mM concentration. Both 3-deoxy-3-fluoro-D-glucoheptulose (p < 0.001) also caused a modest but significant decrease of insulin output evoked, within the same experiment(s) by D-glucose, all hexose and heptoses being again tested at a 10.0 mM concentration. However, the output of insulin recorded in the presence of the latter two heptoses remained higher (p < 0.003 or less) than that found, within the same experiments, in the presence of D-mannoheptulose.

[0050] Table 2. Effects of D-mannoheptulose and its analogs on glucose-stimulated insulin release from rat pancreatic islets

D-glucose D-Heptulose Insulin output

(10.0 mM) (μυ/islet per 90 min)

2.8 mM 45.3 + 2.2 (27)

10.0 mM 108.1 + 4.0 (27)

10.0 mM D-mannoheptulose 59.9 + 3.6 (28)

10.0 mM 1 -deoxy- 1 -fluoro-D-mannoheptulose 55.6 + 6.2 (10)

10.0 mM 3-deoxy-3-fluoro-D-mannoheptulose 51.3 + 3.7 (20)

10.0 mM 1 ,3-dideoxy- 1 ,3-difluoro-D- 69.6 + 4.7 (9)

mannoheptulose

10.0 mM 7-deoxy-7-fluoro-D-glucoheptulose 54.0 + 4.4 (6)

10.0 mM 1 -deoxy- 1 -fluoro-D-glucoheptulose 68.4 + 1.7 (11)

10.0 mM 3-deoxy-3-fluoro-D-glucoheptulose 92.1 + 2.3 (10)

10.0 mM 1 ,3-dideoxy- 1 ,3-difluoro-D-glucoheptulose 98.8 + 1.9 (10) [0051] The results reveal that selected F-heptuloses are efficiently taken up by rat hepatocytes. In the same manner as D-mannoheptulose, they also inhibit glucose-stimulated insulin release from isolated rat islets. As a matter of fact, a significant negative correlation (r = - 0.8993; n = 6; p < 0.02) was observed between the uptake by hepatocytes of 1-deoxy- l- fluoro-D-mannoheptulose, 3-deoxy-3-fluoro-D-mannoheptulose, l,3-dideoxy- l,3-difluoro-D- mannoheptulose, 1-deoxy- l-fluoro-D-glucoheptulose, 3-deoxy-3-fluoro-D-glucoheptulose and l,3-dideoxy- l,3-difluoro-D-glucoheptulose and the release of insulin (logarithmic values) by pancreatic islets exposed to the F-heptuloses in the presence of D-glucose. These converging findings support the concept that these F-heptuloses are transported into cells at the intervention of GLUT2.

[0052] The possible use of F-heptuloses for the non-invasive imaging of the liver via ¹⁹ F- MRI has several advantages. It avoids the use of a radioactive compound. It indeed deals with compounds labeled with a stable isotope. This considerably simplifies the delivery and storage procedures for the application of this method in relevant institutions. It may also allow MRI over a prolonged period after administration of the ¹⁹ F-heptuloses. For instance, this could permit MRI at a time when the major fraction of the injected ¹⁹ F-heptuloses would be cleared from circulation. In turn, this would minimize the contribution of extracellular material, whilst favouring the intracellular accumulation of the phosphorylated esters of ¹⁹ F- heptuloses generated in reactions catalyzed by either fructokinase (phosphorylation on C I) or hexokinase isoenzymes (phosphorylated on CI). Such phosphorylated esters remain inside cells even after extensive washing [Malaisse, (2001) Diabetologia 44, 393-406; Ramirez et al., (2001) Int. J. Mol. Med. 8, 37-42] . Last, the risk of undesirable side effects seems minimal, taking into account the knowledge that D-mannoheptulose, present in Avocado fruits, is currently ingested in far-from-negligible amounts and was previously already administered to human subjects to document its inhibitory action on insulin secretion [Malaisse et al., (2009) Nat. Rev. Endocrinol. 5, 394-400] . [0053] The seven ¹⁹ F-heptuloses synthesized are depicted in Fig. 1. The net uptake of the ¹⁹ F-heptuloses (25 mM) was measured over 20 min incubation of rat hepatocytes (3xl0 ⁶ cells/0.2 ml) in a Hepes- and bicarbonate-buffered medium [Malaisse et al., (1993) J. Clin. Invest. 91, 432-436.] . For this purpose, freshly isolated viable hepatocytes were prepared from fed female Wistar rats [Berry and Friend, (1969) J. Cell. Biol. 43, 502-520] and, after incubation at 37°C, separated from the incubation medium by centrifugation through an oil layer [Giroix et al., (2006) Biochim. Biophys. Acta 1757, 773-780] CsCl ₂ solution [Jijakli et al., (1996) Arch. Biochem. Biophys. 335, 245-257] . The content of the cells and incubation media in ¹⁹ F-heptuloses was then measured by ¹⁹ F-NMR spectroscopy. The release of insulin by pancreatic islets isolated [Malaisse-Lagae and Malaisse (1984) In Methods in Diabetes Research (Lamer, J. and Pohl, S., eds), pp. 147- 152. John Wiley & Sons, New York] from fed female Wistar rats (8 islets/0.3 ml) was measured by radio-immunoassay [Leclercq-Meyer et al., (1985) Endocrinology 116, 1168-1174] after 90 min incubation at 37°C in the Hepes- and bicarbonate-buffered medium. All results are expressed as mean values (+ SEM) together with the number of individual determinations (n). The statistical significance of differences between mean values was assessed by use of Student' s i-test.

[0054] In conclusion, therefore, the present findings open a novel perspective for the use of the disclosed seven carbon sugar derivatives as selective marker for GLUT2-expressing cells, e.g. for non-invasive imaging of the liver, e.g. in the perspective of the early detection of tumoral hepatic processes involving cells deprived of GLUT2.

[0055] It is also intended to use the disclosed seven carbon sugars in the early diagnostic of tumoral processes in the liver, such as those encountered in patients with hepatic cirrhosis (HCC). There is a need to develop a method for non-invasive imaging of the liver by ¹⁹ F-MRI after administration of selected ¹⁹ F-heptuloses.

[0056] In hepatic tumors as in other tumoral cells, GLUT expression is considerably modified as cellular proliferation is stimulated and an increased uptake of glucose is needed for meeting the metabolic needs of these fast growing cells.

[0057] Although frequently up-regulated in many different tumoral cells, GLUT1 is not over expressed in tumoral hepatocytes (Zimmerman et al. Oncol Rep. 2002, 9, 689-692; Roh et al. Hepatogastroenterology 2004, 51, 1315-1318.). On the other hand and as recently demonstrated, GLUT2 is overexpressed in HCC (Paudyal et al., Int. J. Oncology 2008, 33, 1047- 1054). So the development of ¹⁹ F-mannoheptulose MRI represents a very useful tool for detecting small HCC lesions. This technique could also be of valuable interest for detecting small liver metastasis overexpressing GLUT1 or GLUT2.

Examples

[0058] The invention will be further illustrated by examples without being limited to their content. In detail:

[0059] Example 1: l-Deoxy-l-fluoro-a-D-glycero-D-lyxohept-2-ulopyranose (3)

was prepared in seven steps.

[0060] Step 1 to 5: 2,6-Anhydro-3,4,5,7-tetra-0-benzyl-l-deoxy-D-mannohept-l-eni tol

(1) According to Csuk et al. 1991, starting from D-mannopyranose the 2,6-anhydro-3,4,5,7- tetra-O-benzyl-l-deoxy-D-mannohept-l-enitol (1) was obtained. [R. Csuk, B. I. Glanzer, Tetrahedron 1991, 47, 1655-1664] [0061] Step 6: l-Deoxy-l-fluoro-3,4,5,7-tetra-0-benzyl-a-D-glycero-D-lyxohe pt-2- ulopyranose (2)

[0062] 2,6-Anhydro-3,4,5,7-tetra-0-benzyl-l-deoxy-D-mannohept-l-eni tol (1) (1.78 g; 3.31 mmol, 1 eq.) was dissolved in DMF and Selectfluor ^® (11.7 g, 33.1 mmol, 10 eq.) in DMF/H ₂ 0 (27 mL) (1: 1, v/v) added at room temperature and reacted over night. The reaction mixture was diluted with ethyl acetate and washed twice with distilled water. The combined organic phase was dried with sodium sulphate, then filtered and the solvent removed under vacuum and the crude product purified by flash column chromatography using PE/Et ₂ 0 (2: 1, v/v). 2 was otained as a colorless oil. [E. N. Jacobsen, I. Marko, W. S. Mungall, G. Schroeder, K. B. J. Sharpless, 7. Am. Chem. Soc. 1988, 110, 1968-1970]

[0063] Yield: 1.42 g (2.49 mmol, 75 %), theoret: 1.89 g (3.31 mmol); TLC: (Si0 ₂ , PE/Et ₂ 0 2: 1 v/v): R _f = 0.30 (H ₂ S0 ₄ , UV); specific rotation: = +15.1° (c 2.7, CHC1 ₃ ), C ₃₅ H ₃₇ FO ₆ , mass: 572.66; MALDI-TOF (calcd. for [M+Na] ⁺ ) calc: 611.2206, found 611.2214

[0064] Ή-NMR: (400 MHz, DMSO-d ₆ ): δ/ppm = 7.40-7.37 (m, 2H, CH-arom.), 7.34-7.24 (m, 16H, CH-arom.), 7.20-7.18 (m, 2H, CH-arom.), 6.62 (s, 1H, C ² -OH), 4.84 (d, 7=11.4 Hz, 1H, CH ₂ Ph), 4.80 (d, 7=11.9 Hz, 1H, CH ₂ Ph), 4.79 (d, 7=11.3 Hz, 1H, CH ₂ Ph), 4.65 (d, 7=11.9 Hz, 1H, CH ₂ Ph), 4.60 (d, 7=11.3 Hz, 1H, CH ₂ Ph), 4.52 (d, 7=11.8 Hz, 1H, CH ₂ Ph), 4.50 (d, 7=11.3 Hz, 1H, CH ₂ Ph), 4.49 (dd, 7i _a, i _b =9.0 Hz, 7i _a,F =47.1 Hz, 1H, H-la), 4.43 (d, 7=11.8 Hz, 1H, CH ₂ Ph), 4.19 (dd, 7i _a, i _b =9.0 Hz, 7i _b,F =47.1 Hz, 1H, H-lb), 3.98 (dd, 7 _3,4 =2.9 Hz, 7 ₄ ,5=9.0 Hz, 1H, H-4), 3.97 (d, 7 _3,4 =2.9 Hz, 1H, H-3), 3.84 (ddd, 7 _5,6 =10.0 Hz, 7 _6,7a =4.4 Hz, 7 ₆ , _7b =1.9 Hz, 1H, H-6), 3.79 (dd, 7 ₄ , ₅ =9.0 Hz, 7 ₅ , ₆ =10.0 Hz, 1H, H-5), 3.63 (dd, 7 ₆ , _7a =4.4 Hz, 1H, 7 _7a,7b =10.9 Hz, H-7a), 3.58 (dd, 7 _6,7b =1.9 Hz, 7 _7a,7b =10.9 Hz, 1H, H-7b).

[0065] ¹³ C-NMR: (100.6 MHz, DMSO-d ₆ ): δ/ppm = 138.7, 138.6, 138.5, 138.3, (Cq-arom.), 128.2, 128.2, 128.1, 127.7, 127.6, 127.5, 127.4, (CH-arom.), 96.3 (7 _C,F =22.8 Hz, C-2), 83.6 ( _C,F =169.6 Hz, C-l), 80.3 (C-4), 74.8 (C-3), 74.6 (C-5), 74.1 (2-CH ₂ Ph), 72.2 (CH ₂ Ph), 71.7 (C-6), 71.0 (CH ₂ Ph), 69.0 (C-7).

[0066] ¹⁹ F-NMR: (200 MHz, DMSO-d ₆ ): δ/ppm = -225.9 (t, i, _F =47.1 Hz).

[0067] Step 7: l-Deoxy-l-fluoro-D-g/ cero-D-lyxohept-2-ulopyranose (3)

[0068] Colorless resin, C ₇ Hi ₃ F0 ₆ (212.07 g mol ^"1 ) [0069] Compound 2 (850 mg, 1.49 mmol, 1 eq.) was dissolved in degassed methanol (10 mL, dry) and a catalytic amount of palladium on activated charcoal (Pd/C, 10%) was added. Reduction was performed under a slightly positive pressure of H ₂ at room temperature while stirring for 24 h. The solution was filtered, the solvent was removed under vacuum and the crude product purified by flash column chromatography using silica RP18 with water as eluant.

[0070] Yield: 160 mg (756 μιηο1,51 %), theoret: 316 mg (1.49 mmol), TLC: (Si0 ₂ ; RP-18, H ₂ 0): R ₌ 0.90 (H ₂ S0 ₄ ) , specific rotation: [a] = +25.3° (c 0.97, H ₂ 0), MALDI-TOF (calc. for [M+Na] ⁺ ) calculated: 235.0588, found 235.0589.

[0071] 'H-NMR: (400 MHz, D ₂ 0): δ/ppm = 4.65 (dd, i _a ,ib=9.7 Hz, J _{la F} =46.8 Hz, 1H, H-la),

H, H-4), 87 (ddd, Hz, 1H, H-7b), 3.69 (dd, Hz, 1H, H-5).

[0072] C-NMR: (100.6 MHz, D ₂ 0): δ/ppm = 96.6 ( _c,F =20.6 HZ, C-2), 84.2 ( _c,F =168.9 HZ, C-l), 73.3 (C-6), 70.7 (C-3), 69.7 (C-4), 66.8 (C-5), 60.9 (C-7) [0073] F-NMR: (200 MHz, D ₂ 0): δ/ppm = -232.7 (t, / _liF =46.8 Hz)

[0074] Example 2: 3-Deoxy-3-fluoro-D-glycero-D-lyxohept-2-ulopyranose (8)

was prepared in nine steps. Steps 1 to 5 were as for 1

[0076] Colorless solid, C ₂₇ H ₂₇ F0 ₅ (450.18 g mol ^"1 )

[0077] 2-Deoxy-2-fluoro-3,4,6-tri-0-benzyl-a-D-mannopyranose (4) (2.10 g, 4.64 mmol, 1 eq.) was dissolved in DMF (dry, 12 mL) at 30 °C and suspended with acetic anhydride (9.60 mL, 102 mmol, 22 eq.) and stirred for 24 h at 30 °C. The reaction mixture was diluted with water (50 mL) and diethyl ether (30 mL). The aqueous phase was washed a three times with Et ₂ 0 (20 mL) and the combined organic phase dried over sodium sulphate, filtered and the solvent removed under vacuum. Purification was by flash column chromatography (PE/Et ₂ 0 1: 1, v/v) and colorless solid 5 was obtained.

[0078] Yield: 2.05 g (4.55 mmol, 98%), theoret: 2.09 g (4.64 mmol), TLC: (Si0 ₂ , PE/Et ₂ 0 1: 1 v/v): R _f = 0.50 (H ₂ S0 ₄ , UV), specific rotation: [af° = +31.5° (c 1.0, CHCI ₃ ), m.p.: 57.0 °C, mass: C ₂₇ H ₂₇ F0 ₅ , MALDI-TOF (calcd. for [M+Na] ⁺ ) calculated: 473.1753, found 473.1755. [0079] Ή-NMR: (500 MHz, DMSO-d ₆ ): δ/ppm = 7.37-7.26 (m, 15H, CH-arom.), 5.78 (dd, 7 ₂ ,3=3.2 Hz, 7 _2, F=45.4 Hz, 1H, H-2), 4.65 (s, 2H, CH ₂ Ph), 4.61 (d, 7=11.0 Hz, 1H, CH ₂ Ph), 4.51 (d, 7=11.8 Hz, 1H, CH ₂ Ph), 4.47 (ddd, 7 _4,5 =8.5 Hz, 7 _5,6a =1.9 Hz, 7 _5,6b =5.4 Hz, 1H, H-5), 4.44 (d, 7=11.8 Hz, 1H, CH ₂ Ph), 4.42-4.37 (m, 2H, H-3, CH ₂ Ph), 3.87-3.82 (m, 1H, H-4), 3.65 (dd, 7 ₅ ,6a=1.9 Hz, Hz, 1H, H-6a), 3.59 (dd, 7 ₅ , ₆ b=5.4 Hz, Hz, 1H, H-6b).

[0080] ¹³ C-NMR: (125.6 MHz, DMSO-d ₆ ): δ/ppm = 166.9 (7 _C,F =21.8 Hz, C-l), 137.8, 137.5, 137.1 (Cq-arom.), 128.3, 128.3, 128.1, 127.9, 127.8, 127.7, 127.6, 127.6 (CH-arom.), 86.6 (7C,F=192.7 Hz, C-2), 76.7 (C-5), 76.2 (7 _C,F =15.3 Hz, C-3), 74.5 (7 _C,F =7.5 Hz, C-4), 72.1, 71.7, 70.9 (CH ₂ Ph), 68.3 (C-6).

[0081] ¹⁹ F-NMR: (200 MHz, DMSO-d ₆ ): δ/ppm = -202.1 (dt, 7 ₂ , _F =45.4 Hz, 7 ₃ , _F =6.7 Hz).

[0082] Step 7: 2,6-Anhydro-l,3-dideoxy-3-fluoro-4,5,7-tri-0-benzyl-D-mannoh ept- 1-enitol (6)

[0083] Yellowish oil, C ₂ 8H ₂₉ F0 ₄ (480.20 g mol ^"1 ) [0084] Using brown glassware under Schlenck conditions by excluding air, moisture and UV light 5 (1.75 g, 3.89 mmol, 1 eq.) and dimethyl titanocene (1.78 g, 8.56 mmol, 2.2 eq.) were reacted in anhydrous toluene (20 mL) and heated to 60 °C. The reaction mixture was stirred for 24 h. The solvent was removed under vacuum and the crude product purified by flash column chromatography (PE/Et ₂ 0 4: 1 + 0.5% Et ₃ N, v/v) and yellowish oil was obtained.

[0085] Yield: 1.30 g (2.90 mmol; 75%), theoret: 1.74 g (3.89 mmol), TLC: (Si0 ₂ , PE/Et ₂ 0 5: 1 v/v): R _f = 0.50 (H ₂ S0 ₄ , UV), specific rotation: [af° = +76.1° (c 0.85, CHC1 ₃ ), mass: C ₂₈ H ₂₉ F0 ₄ , MALDI-TOF (calcd. for [M+Na] ⁺ ) calculated: 449.2123, found: 449.2126.

[0086] Ή-NMR: (400 MHz, DMSO-d ₆ ): δ/ppm = 7.39-7.27 (m, 13H, CH-arom.), 7.21-7.18 (m, 2H, CH-arom.), 5.44 (dd, 7 _3,4 =2.5 Hz, 7 _3,F =50.4 Hz, 1H, H-3), 4.78 (d, 7=11.9 Hz, 1H, CH ₂ Ph), 4.76 (d, 7=11.4 Hz, 1H, CH ₂ Ph), 4.73 (s, 2H, H-l), 4.65 (d, 7=11.9 Hz, 1H, CH ₂ Ph), 4.55(d, 7=12.2 Hz, 1H, CH ₂ Ph), 4.52 (d, 7=11.4 Hz, 1H, CH ₂ Ph), 4.49 (d, 7=12.2 Hz, 1H, CH ₂ Ph), 3.88 (ddd, 7 _4,5 =9.0 Hz, 7 _5,6 =9.1 Hz, 7 _5,F =4.6 Hz, 1H, H-5), 3.77 (ddd, 7 _3,4 =2.5 Hz, 7 _4, 5=9.0 Hz, 7 _4, F=26.4 Hz, 1H, H-4), 3.71-3.66 (m, 2H, H-7), 3.63 (ddd, 7 _5,6 =9.1 Hz, 7 _6,7a =3.1 Hz, 7 ₆ , _7b =6.3 Hz, 1H, H-6).

[0087] ¹³ C-NMR: (100.6 MHz, DMSO-d ₆ ): δ/ppm = 154.0 (7 _C,F =15.3 Hz, C-2), 138.1, 138.0, 138.0 (Cq-arom.), 128.2, 128.1, 127.8, 127.6, 127.5, 127.4 (CH-arom.), 100.0 (7 _C,F =7.7 Hz, C-l), 86.4 (7C _, F=174.3 Hz, C-3), 79.5 (7 _C , _F =19.0 Hz, C-4), 79.0 (C-6), 73.9 (CH ₂ Ph), 73.2 (7C _, F=2.3 Hz, C-5), 72.3, 70.5 (CH ₂ Ph), 68.6 (C-7).

[0088] F-NMR: (200 MHz, DMSO-d ₆ ): δ/ppm = -183.4 (ddd, 7 _3,F =50.4 Hz, 7 _4,F =26.4 Hz, 7 ₅ , _F =4.6 Hz).

3-Deoxy-3-fluoro-4,5,7-tri-0-benzyl-a-D-g ycero-D-lyxohept-2-

[0091] 6 (259 mg, 578 μιηοΐ, 1.0 eq.) was taken up in a mixture of ie/t-butanol and water (16 mL, 1: 1, v/v) and suspended with potassium carbonate 260 mg, 1.88 mmol, 3.3 eq.), followed by addition of potassium hexacyanoferrat(III) (600 mg, 1.82 mmol, 3.1 eq.) and a catalytic amount of potassium osmate-dihydrate. The suspension was stirred at room temperature for the 24h. Once the reaction was completed, the solution was diluted with ethyl acetate and washed twice with distilled water. The combined organic phase was dried with sodium sulfate, then filtered and the solvent removed under vacuum. Purification was done by flash column chromatography using diethyl ether.

[0092] Yield: 270 mg (560 μηοΐ, 97%), theoret: 279 mg (578 μηοΐ), TLC: (Si0 ₂ , Et ₂ 0): R _f = 0.47 (H ₂ S0 ₄ , UV), specific rotation: [a] = +44.2° (c 0.48, CHCI ₃ ), mass: C ₂₈ H ₃ iF0 ₆ , MALDI-TOF (calcd. for [M+Na] ⁺ ) calculated: 521.1736, found 521.1735..

[0093] Ή-NMR: (500 MHz, DMSO-d ₆ ): δ/ppm = 7.38-7.25 (m, 13H, CH-arom.), 7.21-7.18 (m, 2H, CH-arom.), 6.34 (d, 7 _oh,F =3.5 HZ, C ² -OH), 4.93 (dd, 7 _ΟΗ =5.9 Hz, J _lh =5.6 Hz, 1H, C^OH), 4.85 (dd, 7 _3,4 =1.5 Hz, 7 _3,F =50.8 Hz, 1H, H-3), 4.78 (d, 7=11.0 Hz, 1H, CH ₂ Ph), 4.72 (d, 7=11.9 Hz, 1H, CH ₂ Ph), 4.61 (d, 7=11.9 Hz, 1H, CH ₂ Ph), 4.52 (d, 7=12.1 Hz, 1H, CH ₂ Ph), 4.49 (d, 7=11.0 Hz, 1H, CH ₂ Ph), 4.45 (d, 7=12.1 Hz, 1H, CH ₂ Ph), 3.92-3.81 (m, 2H, H-4, H-6), 3.68 (dd, 7 _4,5 =9.7 Hz, 7 _5,6 =10.2 Hz, 1H, H-5), 3.64 (dd, 7 _6,7a =4.6 Hz, 7 _7a,7b =10.7 Hz, 1H, H-7a), 3.58 (dd, 7 _6,7b =1.6 Hz, 7 _7a,7b =10.7 Hz, 1H, H-7b), 3.52 (ddd, 7 _la,lb =l l. l Hz, 7i _a , _OH =5.9 Hz,7i _a , _F =1.9 Hz, 1H, H-la), 3.34-3.30 (m, 1H, H-lb). [0094] ¹³ C-NMR: (125.8 MHz, DMSO-d ₆ ): δ/ppm = 138.4, 138.3, 138.2 (Cq-arom.), 128.2, 128.2, 127.8, 127.7, 127.6, 127.5, 127.5 (CH-arom.), 96.5 (C-2), 85.5 (/ _c,F =176.0 HZ, C-3), 78.2 ( _C,F =17.1 Hz, C-4), 74.4 (C-5), 74.1, 72.2 (CH ₂ Ph), 71.1 (C-6), 70.4 (CH ₂ Ph), 68.9 (C- 7), 63.1 (/ _C,F =2.8 Hz, C-l).

[0095] ¹⁹ F-NMR: (200 MHz, DMSO-d ₆ ): δ/ppm = -206.2 (dd, / _3,F =50.8 HZ, / _4iF =28.5 HZ).

[0098] 7 (300 mg, 622 μιτιοΐ, 1.0 eq.) was dissolved in methanol (10 mL, dry) and a catalytic amount of palladium on activated charcoal (Pd/C, 10%) was added. Reduction was performed under a slight positive pressure of H ₂ at room temperature. After 72 h the reaction was stopped, the mixture was filtered, and the solvent removed under vacuum. The crude product was purified by flash column chromatography (silica RP-18) using water.

[0099] Yield: 127 mg (599 μιηοΐ, 96%),(theoret: 132 mg (622 μιηοΐ); TLC: (Si0 ₂ ;RP-18, H ₂ 0): R _f = 0.91 (H ₂ S0 ₄ ), specific rotation: [a » = +36.7° (c 0.39, H ₂ 0), mass: C ₇ Hi ₃ F0 ₆ , MALDI-TOF (calcd. for [M+Na] ⁺ ) calculated: 235.0588, found 235.0589.

[00100] Ή-NMR: (500 MHz, DMSO-d ₆ ): δ/ppm = 4.78 (dd, ₃ , ₄ =2.6 Hz, / ₃ , _F =50.0 Hz, 1H, H-3), 4.02 (ddd, _3,4 =2.6 Hz, _4,5 =9.7 Hz, / _4,F =30.7 Hz, 1H, H-4), 3.92-3.84 (m, 2H, H-6, H-7a), 3.83-3.7 (m, 2H, H-la, H-7b), 3.73 (dd, _4,5 =9.7 Hz, _5,6 =9.8 Hz, 1H, H-5), 3.60 (dd, i _a, i _b =12.0 Hz, i _b,F =3.4 Hz, 1H, H-lb) [00101] ¹³ C-NMR: (100.6 MHz, D ₂ 0): δ/ppm = 96.4 (/ _c,F =24.3 HZ, C-2), 89.4 ( _C,F =175.5 Hz, C-3), 73.1 (C-6), 70.1 (/ _c,F =17.5 HZ, C-4), 66.8 (C-5), 63.4 (/ _c,F =3.5 HZ, C- 1), 60.7 (C-7). [00102] ¹⁹ F-NMR: (200 MHz, D ₂ 0): δ/ppm = -209.6 (dd, / _3,F =50.0 HZ, _4iF =30.7 HZ) .

[00103] Example 3: l,3-Dideoxy-l,3-difluoro-D-g/j>cero-D-lyxohept-2- ulopyranose (10)

Starting from compound 6, as described in Example 2, 10 was prepared in two steps.

[00104] Step 1: l,3-Dideoxy-l,3-difluoro-4,5,7-tri-0-benzyl-a-D-g ycero- yjcohept-2-ulopyranose (9)

[00106] Compound 6 (300 mg, 669 μιηοΐ, 1 eq.) was dissolved in DMF (5 mL) and suspended with water (5 mL) (10 mL DMF/H ₂ 0 1: 1 v/v). Selectfluor ^® (2.37 g (6.69 mmol, 10 eq.) was added at room temperature stirred reacted overnight until full conversion was confirmed by tic. The reaction mixture was diluted with ethyl acetate and washed twice with distilled water. The combined organic phase was dried with sodium sulphate, then filtered and the solvent removed under vacuum and the crude product purified by flash column chromatography with von PE/Et ₂ 0 (1: 1, v/v) and colorless oil was obtained. [00107] Yield: 238 mg (492 μηιο1,74%), theoret: 324 mg (669 μηιοΐ); TLC: (Si0 ₂ , PE/Et ₂ 0 2: 1 v/v): R _f = 0.24 (H ₂ S0 ₄ , UV), specific rotation: [af° = +37.0° (c 0.71, CHCI ₃ ), mass: C ₂₈ H ₃ 0F ₂ O ₅ , MALDI-TOF (calcd for [M+Na] ⁺ ) calculated: 507.1954, found 507.1983. [00108] Ή-NMR: (500 MHz, DMSO-d ₆ ): δ/ppm = 7.39-7.26 (m, 13H, CH-arom.), 7.21-7.18 (m, 2H, CH-arom.), 7.06 (d, 7 _oh, F=3.9 HZ, IH, C ² -OH), 4.85 (dd, 7 _3,4 =1.5 Hz, 7 _3,F =51.5 Hz, IH, H-3), 4.78 (d, 7=11.5 Hz, IH, CH ₂ Ph), 4.76 (d, 7=11.9 Hz, IH, CH ₂ Ph), 4.63 (d, 7=11.9 Hz, IH, CH ₂ Ph), 4.52 (d, 7=11.8 Hz, IH, CH ₂ Ph), 4.50 (d, 7=11.5 Hz, IH, CH ₂ Ph), 4.46 (d, 7=11.8 Hz, IH, CH ₂ Ph), 4.45 (ddd, J _la,lb =9.6 Hz, 7i _a,F =1.3 Hz, 7i _a,F =46.7 Hz, IH, H-la), 4.26 (ddd, 7i _a, i _b =9.6 Hz, 7i _b,F =2.6 Hz, 7i _b,F =46.7 Hz, IH, H-lb), 3.89 (ddd, 7 _3,4 =1.5 Hz, 7 _4,5 =9.7 Hz, 7 _4,F =28.9 Hz, IH, H-4), 3.87 (ddd, 7 _5,6 =9.8 Hz, 7 _6,7a =4.8 Hz, 7 _6,7b =1.6 Hz, IH, H-6), 3.69 (dd, 7 _4,5 =9.7 Hz, 7 _5,6 =9.8 Hz, IH, H-5), 3.65 (dd, 7 _6,7a =4.8 Hz, 7 _7a,7b =11.0 Hz, IH, H-7a), 3.60 (dd, 7 _6,7b =1.6 Hz, 7 _7a,7b =11.0 Hz, IH, H-7b) . [00109] ¹³ C-NMR: (125.3 MHz, DMSO-d ₆ ): δ/ppm = 138.3, 138.2, 138.1 (Cq-arom.), 128.2, 128.2, 127.8, 127.7, 127.5, 127.5 (CH-arom.), 94.7 (7 _C,F =25.1, 47.8 Hz, C-2), 85.4 (7c _,F =178.1 Hz, C-3), 82.7 (7 _C,F =170.1 Hz, C- l), 77.8 (7 _C,F =17.1 Hz, C-4), 74.2 (CH ₂ Ph), 74.0 (C-5), 72.2 (CH ₂ Ph), 71.2 (C-6), 70.5 (CH ₂ Ph), 68.7 (C-7). [00110] ¹⁹ F-NMR: (200 MHz, DMSO-d ₆ ): δ/ppm = -206.5 (ddd, 7 _3,F =51.5 Hz, 7 _4,F =28.9 Hz, 7 _5,F =6.7 Hz, C ³ -F), -232.4 (t, 7i _,F =46.7 Hz, C^F).

[00111] Step 2: l,3-Dideoxy-l,3-difluoro-D-g ycero-D-lyxohept-2- ulopyranose (10)

[00112] Colorless solid, C ₇ Hi ₂ F ₂ 0 ₅ (214.07 g moP) [00113] Compound 9 (220 mg, 454 μιηοΐ, 1 eq.) was dissolved in methanol (10 mL, dry) and a catalytic amount of palladium on activated charcoal (Pd/C, 10%) was added. Reduction was performed under a slight positive pressure of H ₂ while stirring at room temperature. After 7 d, the mixture was filtered, and the solvent was removed under vacuum. The crude product was purified by flash column chromatography (silica RP- 18) using water.

[00114] Yield: 91.7 mg (428 μηοΐ, 94%), theoret: 97.2 mg ( 454 μηοΐ); TLC: (Si0 ₂ ;RP-18, H ₂ 0): R _f = 0.90 (H ₂ S0 ₄ ), specific rotation: [a] = +43.3° (c 0.27, H ₂ 0), m.p.: 156.1, mass: C ₇ Hi ₂ F ₂ 0 ₅ , MALDI-TOF (calcd. for [M+Na] ⁺ ) calculated: 237.0545, found: 237.0545

[00115] Ή-NMR: (500 MHz, D ₂ 0): δ/ppm = 4.80 (dd, / _3,4 =2.4 Hz, / _3,F =50.3 HZ, lH, H-3), 4.62 (ddd, J _la

Hz, ib _,F =3.2 Hz, ib _iF =46.3 Hz, 1H, H-lb), 4.03 (ddd, _3,4 =2.4 Hz, _4,5 =9.7 Hz, _4,F =30.6 Hz, 1H, H-4), 3.90-3.85 (m, 2H, H-6, H-7a), 3.82 (dd, Hz, 1H, H-7b), 3.75 (dd, Hz, 1H, H-5).

[00116] ¹³ C-NMR: (100.6 MHz, D ₂ Hz, C-3), 83.4 4.6 Hz, C-l), 73.3 (C-6), 69.9 HZ, C-5), 60.5 (C-7).

[00117] ¹⁹ F-NMR: (200 MHz, D ₂ 0): δ/ppm = -209.1 (dd, / _3,F =50.3 Hz, _4,F =30.6 Hz, C ³ -F), -235.4 (t, Hz, C^F).

Example 4: 7-Deoxy-7-fluoro-D-g ycero-D-lyxohept-2-ulopyranose (16)

(Example 4)

[00119] Step 1: 11 (Phenyl-6-deoxy-6-fluoro-2, 3, 4-tri-O-benzyl-l-thio-a-D- mannopyranoside) was prepared starting from D-mannose according to Crich et al. 2007. [Crich D., Vinogradova O., J. Am. Chem. Soc. 2007, 129, 11756-11765]

[00120] Step 2: 6-Deoxy-6-fluoro-2,3,4-tri-0-benzyl-a-D-mannopyranose (12) was prepared according to Motawia et al. 1995. [Motawia M. S., Marcussen J., M0ller B. L., J. Carboh dr. Chem. 1995, 14, 1279-1294]

[00121] Colorless solid, C ₂₇ H ₂ 9FO ₅ (452.20 g mol ^"1 ) [00122] Phenyl-6-deoxy-6-fluoro-2,3,4-tri-C ⁾ -benzyl- l-thio-a-D-mannopyranoside (11) (250 mg, 460 μιηοΐ, 1 eq.) was dissolved in a mixture of acetone water (10 mL) (9: 1, v/v). At room temperature N-bromo succinimide (258 mg, 1.45 mmol, 3.2 eq.) was added and for another 30 min stirred at r.t. The reaction mixture was diluted and extracted three times using diethyl ether. The combined organic phase were neutralized and washed with saturated sodium hydrogen carbonate solution, then dried with sodium sulphate and filtered. The solvent was removed under vacuum and the product purified using flash column chromatography (PE/Et ₂ 0 1 : 1, v/v). A colorless solid was obtained. [00123] Yield: 183 mg (406 μιηοΐ, 89%), theoret: 208 mg (460 μιηοΐ); TLC: (Si0 ₂ , PE/Et ₂ 0 1: 1 v/v): R _f = 0.42 (H ₂ S0 ₄ , UV), specific rotation: [af° = +22.2° (c 0.45, CHCI ₃ ), m.p

122.0 °C, mass: C ₂₇ H ₂₉ F05, MALDI-TOF (calcd. for [M+Na] ⁺ ) calculated: 475.1891, found: 475.1915; [M+K] ⁺ 491.1631, found: 491.1637. [00124] Ή-NMR: (500 MHz, DMSO-d ₆ ): δ/ppm = 7.39-7.26 (m, 15H, CH-arom.), 6.72 (d, Hz, 7i _,OH =4.0 HZ, lH, H- 1), 4.83 (d, 7=11.1 Hz, 1H, CH ₂ Ph), 4.67 (b, 2H, CH ₂ Ph), 4.65 (d, 7=11.9 Hz, 1H, CH ₂ Ph), 4.63-4.44 (m, 4H, CH ₂ Ph, H-6), 3.86 (dd, 7 _2,3 =3.0 Hz, 7 _3,4 =9.1 Hz, 1H, H-3), 3.82 (dd, 7 =1.8 Hz, 7 _2,3 =2.4 Hz, 1H, H-2), 3.81 (dddd, 7 _4,5 =9.9 Hz, 7 _5,6a =1.5 Hz, 7 _5,6b =3.5 Hz, 7 _5,F =24.7 Hz, 1H, H-5), 3.72 (dd, 7 _3,4 =9.1 Hz, 7 _4,5 =9.6 Hz, H-4).

[00125] ¹³ C-NMR: (125.3 MHz, DMSO-d ₆ ): δ/ppm = 138.7, 138.5, 138.7 (Cq-arom.), 128.2, 128.2, 127.7, 127.6, 127.5, 127.4, 127.4 (CH-arom.), 91.4 (C-l), 82.8 (7 _C,F =169.5 Hz, C-6), 78.9 (C-3), 75.3 (C-2), 74.1 (CH ₂ Ph), 73.6 (7 _C,F =6.9 Hz, C-4), 71.8, 70.5 (CH ₂ Ph), 70.0

[00126] F-NMR: (200 MHz, DMSO-d ₆ ): δ/ppm = -229.7 (dt, 7 _5,F =24.7 Hz, 7 _6,F =48.6

Hz). [00127] Step 3: 6-Deoxy-6-fluoro-2,3,4-tri-0-benzyl-D-mannono-l,5- lacton (13)

[00128] Colorless solid, C ₂₇ H ₂₇ FO ₅ (450.18 g mol ^"1 )

[00129] At 30 °C compound 12 (155 mg (343 μηοΐ, 1 eq.) was taken up in DMSO (dry, 2mL) and suspended with acetic anhydride (715 μΐ _^ (7.60 mmol, 22 eq.). The mixture was stirred for 24 h at 30 °C, and then diluted with water and diethylether. The aqueous phase was extracted by washing 3 times with diethylether. The combined organic phase was dried by sodium sulfate, filtered and the solvent was removed under vacuum. Purification was by flash column chromatography using PE/Et ₂ 0 (1: 1, v/v). A colorless solid was obtained.

[00130] Yield: 147 mg (327 μηοΐ, 95%), theoret: 154 mg (343 μηοΐ); TLC: (Si0 ₂ , PE/Et ₂ 0 1: 1 v/v): R _f = 0.46 (H ₂ S0 ₄ , UV), specific rotation: [a] = -3.9° (c 0.67, CHC1 ₃ ), m.p: 85.5 °C, mass: C ₂₇ H ₂₇ F0 ₅ , MALDI-TOF (calcd for [M+Na] ⁺ ) calculated: 473.1735, found: 473.1752; [M+K] ⁺ 489.1474, found 489.1471.

[00131] Ή-NMR: (400 MHz, DMSO-d ₆ ): δ/ppm = 7.27-7.43 (m, 15H, CH-arom.), 4.86 (d, 7=11.9 Hz, 1H, CH ₂ Ph), 4.74 (d, 7 ₂ , ₃ =2.3 Hz, 1H, H-3), 4.71-4.51 (m, 7H, H-5, H-6, CH ₂ Ph), 4.48 (d, 7=11.7 Hz, 1H, CH ₂ Ph), 4.22 (d, 7 _2,3 =2.3 Hz, 1H, H-2), 3.76 (d, 7 _4,5 =8.1 Hz, 1H, H-4).

[00132] ¹³ C-NMR: (100.6 MHz, DMSO-d ₆ ): 169.1 (C-l), 137.9, 137.8, 137.2 (Cq- arom.), 128.3, 128.2, 128.2, 128.0, 127.9, 127.7, 127.6, 127.5, 127.4, (CH-arom.), 81.6 (7C _, F=172.6 Hz, C-6), 76.8 (C-2), 76.0 (7 _C,F =17.8 Hz, C-5), 75.6 (C-3), 74.5 (7 _C,F =6.8 Hz, C- 4), 70.9, 70.7, 70.7 (CH ₂ Ph). [00133] ¹⁹ F-NMR: (200 MHz, DMSO-d ₆ ): δ/ppm = -228.3 (dt, 7 ₅ , _F =23.6 HZ, 7 ₆ , _F =50.2 Hz).

[00134] Step 4: 2,6-Anhydro-l,7-dideoxy-7-fluoro-3,4,5-tri-0-benzyl-D- mannohe t-l-enitol (14)

[00136] Method according to Csuk and Glanzer 1991. [R. Csuk, B. I. Glanzer, Tetrahedron 1991, 47, 1655-1664]

[00137] To exclude air and moisture from the reaction mixture, the reaction was carried out under an argon atmosphere and by exclusion UV-light.

[00138] 13 (115 mg, 255 μιηοΐ, 1.0 eq.) and dimethyl titanocene (117 mg (561 μιηοΐ,

2.2 eq.) were dissolved in toluene (3 mL, dry) and heated to 60 °C. The reaction mixture was allowed to react while stirring for 24 h. The solvent was removed under vacuum. Purification was by flash column chromatography using PE/Et ₂ 0 (5: 1 + 0.5% Et ₃ N, v/v) to give 14 as yellowish oil.

[00139] Yield: 88.0 mg (196 μηοΐ, 77 %), theoret: 122 mg ( 255 μηοΐ); TLC: (Si0 ₂ , PE/Et ₂ 0 5: 1 v/v): R _f = 0.51 (H ₂ S0 ₄ , UV), specific rotation: = +8.8° (c 0.25, CHC1 ₃ ), mass: C ₂₈ H ₂₉ F0 ₄ , MALDI-TOF (calcd. for [M+Na] ⁺ ) calculated : 471.1942, found: 471.1939.

[00140] 1H-NMR: (400 MHz, DMSO-d ₆ ): δ/ppm = 7.38-7.27 (m, 15H, CH-arom.), 4.81

(d, 7=11.1 Hz, IH, CH ₂ Ph), 4.72 (s, IH, H-la), 4.68-4.53 (m, 7H, H-lb, H-7, CH ₂ Ph), 4.40 (d, 7=12.2 Hz, IH, CH ₂ Ph), 4.32 (d, 7 _3,4 =3.1 Hz, IH, H-3), 3.93 (dd, 7 _4,5 =8.6 Hz, 7 _5,6 =9.0 Hz, IH, H-5), 3.76 (dd, 7 _3,4 =3.1 Hz, 7 _4,5 =8.6 Hz, IH, H-4), 3.69 (dddd, 7 _5,6 =9.0 Hz, 7 _6,7a =2.5 Hz, 7 _6,7b =5.0 Hz, 7 _6,F =26.7 Hz, IH, H-6). [00141] ^B C-NMR: (100.6 MHz, DMSO-d ₆ ): δ/ppm = 154.6 (C-2), 138.3, 138.2, 138.1 (Cq-arom.), 128.2, 127.8, 127.5, 127.4, 127.4 (CH-arom.), 98.3 (C-l), 82.2 (/ _c,F =170.5 HZ, C-7), 80.0 (C-4), 78.1 ( _c,F =18.0 HZ, C-6), 73.9 (C-3), 73.8 (CH ₂ Ph), 72.6 (/ _c,F =7.1 HZ, C-5), 70.2, 69.3 (CH ₂ Ph).

[00142] ¹⁹ F-NMR: (200 MHz, DMSO-d ₆ ): δ/ppm = -229.7 (dt, / _6,F =26.7 HZ, _7,F =47.6 Hz).

[00143 ] Step 5: 7-Deoxy-7-fluoro-3,4,5-tri-0-benzyl-a-D-g ycero -Ό-lyxo -hept- 2-ulopyranose (15)

[00144] Preparation method according to Jacobsen et al. 1988 (J. Am. Chem. Soc. 1988, 110, 1968-1970).

[00145] Colorless oil, C ₂₈ H ₃ iF0 ₆ (482.21 g mol ^-1 )

[00146] Compound 14 (80.0 mg, 178 μιηοΐ, 1 eq.) was taken up in a mixture of tert- butanol and water (2.5 ml, 1: 1, v/v) and suspended with potassium carbonate (XX mg, XX mmol, 3.0 eq.), followed by addition of potassium hexacyanoferrat(III) (80.0 mg, 564 μιηοΐ, 3.2 eq.) and a catalytic amount of potassium osmate-dihydrate. The suspension was stirred at room temperature for 7 d until conversion completed. The solution was diluted with ethyl acetate and washed twice with distilled water. The combined organic phase was dried with sodium sulphate, then filtered and the solvent removed under vacuum. The crude product was purified by flash column chromatography using diethylether to give pure 15 as colorless oil.

[00147] Yield: 82.0 mg (170 μιηοΐ, 96%), theoret: 85.8 mg (178 μιηοΐ) , colorless oil, C ₂₈ H ₃ iF0 ₆ (482.21 g mol ^"1 ); TLC: (Si0 ₂ , Et ₂ 0): R _f = 0.59 (H ₂ S0 ₄ , UV) , specific rotation: [a] = -39.1° (c 0.57, CHC1 ₃ ), mass: C ₂₈ H ₃ iF0 ₆ , MALDI-TOF (calcd. for [M+Na] ⁺ ) calculated: 505.1997, found: 505.2012

[00148] Ή-NMR: (400 MHz, DMSO-d ₆ ): δ/ppm = 7.40-7.24 (m, 15H, CH-arom.), 6.02 (s, IH, C ² -OH), 4.84 (dd, 7i _a,OH =6.7 Hz, 7 _¾ΟΗ =4.2 Hz, IH, C^OH), 4.83 (d, 7=11.1 Hz, IH, CH ₂ Ph), 4.79 (d, 7=11.5 Hz, IH, CH ₂ Ph), 4.76 (d, 7=12.3 Hz, IH, CH ₂ Ph), 4.67 (d, 7=11.5 Hz, IH, CH ₂ Ph), 4.63 (d, 7=12.3 Hz, IH, CH ₂ Ph), 4.56 (d, 7=11.1 Hz, IH, CH ₂ Ph), 4.54 (ddd, 7 ₆ , _7a =4.3 Hz, Hz, 7 _7B ,F=48.2 Hz, IH, H-7b), 4.02-3.97 (m, 2H, H-3, H-4), 3.81 (dddd, 7 _5,6 =9.6 Hz, 7 _6,7a =4.3 Hz, 7 _6,7b =1.3 Hz, 7 _6, F=28.3 Hz, IH, H-6), 3.72 (dd, 7 _4,5 =9.4 Hz, 7 _5,6 =9.6 Hz, IH, H-5), 3.58 (dd, 7 _laJb =10.7 Hz, 7i _a,OH =6.7 Hz, IH, H-la), 3.32 (dd, J _{la lb} =10.7 Hz, 7i _b,OH =4.2 Hz, IH, H-lb).

[00149] ¹³ C-NMR: (100.6 MHz, DMSO-d ₆ ): δ/ppm = 139.1, 138.6, 138.4 (Cq-arom.), 128.1, 128.1, 128.0, 127.6, 127.5, 127.4, 127.4, 127.3, 127.2 (CH-arom.), 98.3 (C-2), 80.7 (7C,F=170.3 Hz, C-7), 80.5 (C-4), 75.1 (C-3), 73.9 (2-CH ₂ Ph), 73.7 (7 _C,F =6.7 Hz, C-5), 70.8 (CH ₂ Ph), 70.7 (7C,F=18.9 Hz, C-6), 63.7 (C-l).

[00150] F-NMR: (200 MHz, DMSO-d ₆ ): δ/ppm = -229.9 (dt, 7 _6,F =28.3 Hz, 7 _7,F =48.2

Hz).

[00151] Step 5: 7-Deoxy-7-fluoro-D-g ycero-D- yjco-hept-2-ulopyranose (16)

[00152] Colorless resin, C ₇ Hi ₃ F0 ₆ (212.07 g mol ^"1 )

[00153] Compound 15 (66.8 mg, 139 μιηοΐ, 1.0 eq.) was dissolved in methanol (10 mL, dry) and a catalytic amount of palladium on activated charcoal (Pd/C, 10%) was added. Reduction was performed under a slight positive pressure of H ₂ at room temperature. After 48 h, the mixture was filtered and the solvent removed under vacuum. The crude product was purified by flash column chromatography (silica RP-18) using water as eluant. Colorless oil, C ₂₈ H3iF0 ₆ (482.21 g mol ^"1 ) [00154] Yield: 28.5 mg, (134 μιηοΐ, 96%), theoret: 29.5 mg (139 μιηοΐ); TLC: (Si0 ₂ ; RP-18, H ₂ 0): R _f = 0.93 (H ₂ S0 ₄ ), specific rotation: [a] = +20.8° (c 0.13, H ₂ 0), mass: C ₇ H ₁₃ FO ₆ , MALDI-TOF (calcd. for [M+Na] ⁺ ) calculated: 235.0588, found 235.0590.

[00155] 'H-NMR: (500 MHz, D ₂ 0): δ/ppm = 4.74 (ddd, Hz, Hz, 1H, H-7b), 3.96 (dd, ₃ ,4=2.9 Hz, ₄ , ₅ =9.6 Hz, 1H, H-4), 3.93 (d, ₃ , ₄ =2.9 Hz, 1H, H-3), 3.93 (dddd, Hz, 1H, H- la), 3.75 (dd, Hz, 1H, H-lb). [00156] C-NMR: (125.3 MHz, D ₂ 0): δ/ppm = = 98.2 (C-2), 82.4 ( _c,F =167.6 HZ, C-

7), 71.8 ( _C,F =17.5 Hz, C-6), 70.8 (C-4), 69.7 (C-3), 65.6 ( _c,F =7.0 HZ, C-5), 63.8 (C-l).

[00157] 'F-NMR: (200 MHz, D ₂ 0): δ/ppm = -233.7 (dt, ² =48.0 Hz, ³ =26.0 Hz).

[00158] Example 5: l,7-Dideoxy-l,7-difluoro-a-D-g ycero-D- yjco-hept-2- ulopyranose (18)

D-Mannose

step 5

[00159] Starting from D-Mannose Steps 1 - 3 as for Example 4.

[00160] Step 4: l,7-dideoxy-l,7-difluoro-3,4,5-tri-0-benzyl-a-D-g ycero-D- yjco-hept-2-ulopyranose (17)

[00161] For fluorination compound 14 (160 mg, 357 μιηοΐ) and Selectfluor (5, 1.10 g, 3.11 mmol) in DMF/H ₂ 0 (3 mL) were used according to Stepl (Example 2). After stirring over night and work-up, the crude residue was purified by column chromatography (PE/Et ₂ 0 2: 1) to obtain pure 37 (135 mg, 279 μιηοΐ) as a colourless oil in 78% yield.

[00162] Yield: 135 mg, (279 μηοΐ, 78%), specific rotation: [a] = +21.1° (c 0.55, CHC1 ₃ ), mass: C ₂₈ H ₃ oF ₂ 0 ₅ , MALDI-TOF (calcd. for [M+Na] ⁺ ) calculated: 523.1693, found 523.1699. [00163] Ή-NMR: (500 MHz, DMSO-d ₆ ): δ/ppm = 7.42-7.25 (m, 15H, CH-arom.), 6.75 (s, 1H, C ² -OH), 4.85-4.79 (m, 3H, CH ₂ Ph), 4.66 (d, 7=11.9 Hz, 1H, CH ₂ Ph), 4.60 (d, 7=11.2 Hz, 1H, CH ₂ Ph), 4.58 (d, 7=10.9 Hz, 1H, CH ₂ Ph), 4.55 (ddd, 7 ₆ , _7a =4.1 Hz, 7 _7a , _7b =10.7 Hz, 7 _7a , _F =47.9 Hz, 1H, H-7a), 4.49 (ddd, 7 ₆ , _7b =1.3 Hz, 7 _7a , _7b =10.7 Hz, 7 _7b , _F =47.9 Hz, 1H, H-7b), 4.48 (dd, 7i _a, i _b =9.1 Hz, 7i _a,F =47.0 Hz, 1H, H-la), 4.20 (dd, J _la, i _b =9.1 Hz, 7i _b,F =47.0 Hz, 1H, H-lb), 4.01 (dd, 7 _3,4 =2.3 Hz, 7 _4,5 =9.5 Hz, 1H, H-4), 4.00 (d, 7 _3,4 =2.3 Hz, 1H, H-3), 3.85 (dddd, 7 ₅ ,6=9.5 Hz, 7 _6,7a =4.1 Hz, 7 _6,7b =1.3 Hz, 7 _6,F =28.2 Hz, 1H, H-6), 3.75 (dd, 7 _4,5 =9.5 Hz, [00164] ¹³ C-NMR: (125.8 MHz, DMSO-d ₆ ): δ/ppm = 138.5, 138.5, 138.3 (Cq-arom.), 128.3, 128.2, 128.2, 127.7, 127.7, 127.6, 127.5, 127.5, 127.5 (CH-arom.), 96.5 (7 _C,F =22.7 Hz, C-2), 83.4 (7c _,F =169.4, C-l), 82.5 (7 _C,F =169.9 Hz, C-7), 80.1 (C-4), 74.8 (C-3), 74.2, 74.1 (CH ₂ Ph), 73.4 (7c _,F =6.8 Hz, C-5), 71.0 (CH ₂ Ph), 70.9 (7 _C,F =17.7 Hz, C-6). [00165] ¹⁹ F-NMR: (200 MHz, DMSO-d ₆ ): δ/ppm = -230.1 (dt, 7 ₆ , _F =28.2 Hz, 7 ₇ , _F =47.9

Hz, C ⁷ -F), -231.9 (t, 7i _,F =47.0 Hz, C^F).

[00166] Step 5 1 ,7-Dideoxy- 1 ,7-difluoro- a -glycero -lyxo -hept-2- ulopyranose (18)

[00167] Compound 17 (100 mg, 207 μιηοΐ) and methanol (10 mL) was dissolved in anhydrous methanol (3.1 mL). Then a catalytic amount of 10% Pd/C was added and the reaction mixture was stirred under a hydrogen atmosphere for 48 hours and after completion, it was filtered, concentrated in vacuo. The residue was subjected to column chromatography (RP-18, H ₂ 0) to obtain pure 18 as a colourless solid.

[00168] Yield: 43.1 mg, (201 μιηοΐ, 97%), specific rotation: [a » = +22.2° (c 0.23,

H ₂ 0), mass: C ₇ Hi ₂ F ₂ 0 ₅ , MALDI-TOF (calcd. for [M+H] ⁺ ) calculated: 215.0726, found 215.0720. [00169] ¹ H-NMR (400 MHz, D ₂ 0): δ/ρρηι = 4.76 (ddd, 7 _6,7a =4.1 Hz, / _7aJb =10.7 Hz, 7 _{a F} =48.0 Hz, IH, H-7a), 4.67 (ddd, Hz, IH, H-7b), 4.61 (dd, i _a ,ib=9.7 Hz, J _{la F} =46.8 Hz, IH, H-la), 4.39 (dd, J _la4b =9.7 Hz, J _{lb F} =46.8 Hz, IH,

Hz, Hz,

[00170] ¹³ C-NMR (100.6 MHz, D ₂ 0): δ/ρρηι = 97.0 (/ _c,F =20.6 HZ, C-2), 84.1 ( _C,F =176.6, C-l), 82.4 ( _c,F =175.7 HZ, C-7), 72.1 ( _c,F =17.4 HZ, C-6), 70.5 (C-4), 69.6 (C-3), 65.5 ( _C,F =7.0 Hz, C-5).

[00171] ¹⁹ F-NMR (200 MHz, D ₂ 0): δ/ρρηι = -234.4 (dt, _6,F =28.1 Hz, _7,F =48.0 Hz, C ⁷ - F), -236.5 (t, _liF =46.8 Hz, C^F).

6— *-9 see [3] (Method, new substance)

[4] D. Crich, 0. Vinogradova, J. Am. Chem. Soc. 2007, 129, 11756-11765. _A c ₂ o, DMSO DMSO,

RT, U.N.

95%

11— ^ 12 ^M ' ^S ' ^Motawia ' ^J - Marcussen, B. L. M0ller, J. Carbohydr. Chem. 1995, ,

14 1279-1294. Method new substance

12—

13—

14

14-_»-17 see [3] (Method, new substance)

— »-18 see [3] (Method, new substance)

17: R\R ⁵ = F, R ² =OH, R ³ , R ⁴ = OBn 3: R ¹ = F; R ² , R ³ , R ⁴ , R ⁵ = OH 18: R\R ⁵ = F, R ² , R ³ , R ⁴ = OH 8: R ¹ = OH; R ² = F; R ³ , R ⁴ , R ⁵ = OH

10: R ¹ , R ² = F; R ³ , R ⁴ , R ⁵ = OH 16: R ¹ , R ² , R ³ , R ⁴ = OH; R ⁵ = F

[7] A. Popelova, K. Kefurt, M. HIavackova, J. Moravcova, Carbohydr. Res. 2005, 340, 161-166.

[8] R. E. J. N. Litjens, M. A. Leeuwenburgh, G. A. van der Marel, J. H. van Boom, Tetrahedron Lett. 2001, 42, 8693-8696.