Field of the invention

The invention relates to phosphate derivatives of a-D-mannopyranosides useful as antagonists of bacterial adhesion, and to their use in preventing and treating bacterial infections. Background of the invention

Urinary tract infection (UTI) is an inflammatory, pathogen-caused disease that occurs in any part of the urinary tract. UTI is characterized by a wide spectrum of symptoms ranging from mild irritative voiding (dysuria), frequent voiding (polakisuria) or suprapubic tenderness to invasion of bacteria into the kidney (acute pyelonephritis) or blood circulation (urosepsis) with potential local and distant bacterial seeding (abscess), multiorgan failure or even death (B. Foxman, Dis. Mon. 2003, 49, 53-70).

UTIs are among the most prevalent infectious diseases in general and of any organ system. Its magnitude can be estimated in the United States by the number of visits to physicians (about 8 million/year) or hospital discharge diagnoses (about 1 .5 million/year).

Particularly affected are women, who face a 40-50% risk experiencing a symptomatic UTI at some time during their life; more than half of them will experience consecutive infection within 6 months. In approximately 3-5% of women, multiple recurrences of UTI develop over the following years. Frequent sexual intercourse, diaphragm use and lack of urinating after sexual intercourse are risk factors for UTI, further increasing the prevalence of UTI in this subpopulation.

The predominant pathogen in UTIs is uropathogenic Escherichia coli (UPEC) causing >80% of all infections in otherwise healthy people with normal urinary tracts and no systemic predisposing factors (uncomplicated UTI). These strains express a number of well-studied virulence factors of UTI (e.g. fimbriae and toxins), which define tropism to and within the urinary tract, bacterial persistence and the degree of inflammation. UTI can be described as an imbalance of "physiological inflammation", where both immune system and antimicrobial factors of the host are no longer able to control bacterial growth. In healthy individuals, most uropathogens originate from the rectal microbiota and enter the normally sterile urinary bladder via the urethra where they can trigger an infection (cystitis). If the bacterial invasion is not controlled by the immune system response or prompt treatment, bacteria may ascend the ureters to reach the kidneys and pyelonephritis occurs. Inadequate or delayed treatment of UTI may result in severe complications like life-threatening urosepsis, renal scarring or, rarely, end-stage renal disease and hypertension.

Once in the urinary tract, pathogens need to constantly avoid host defense mechanisms. Host defense consists mainly of the following three elements: First, the unidirectional flow of urine that supports the clearance of the urinary tract from bacteria. Second, the epithelial cells, which form a physical barrier, and third the local production of

inflammatory mediators and antimicrobial proteins to recognize and trap bacteria or interfere with their ability to attach (P. Chowdhury, S.H. Sacks, N.S. Sheerin, Kidney Int. 2004, 66, 1334-1344). In order to overcome these protective elements, bacteria attach to the urinary tract epithelium via fimbrial adhesion molecules (H. Connell, M. Hedlund, W. Agace, C. Svanborg, Adv. Dent. Res. 1997, 11, 50-58). They are presumably internalized in an active process similar to phagocytosis once they are bound.

All symptomatic UTIs should be treated with antibiotics to prevent potential devastating complications. Uncomplicated UTI can be effectively treated with an oral antibiotic such as fluoroquinolones (e.g. ciprofloxacin or norfloxacin), cotrimoxazol or amoxicillin/clavanulate, depending on the susceptibility of the causing pathogen. However, recurrent infections with subsequent antibiotic exposure can lead to emergence of antimicrobial resistance, which often leads to treatment failure and reduces the range of therapeutic options.

Hence, there is an urgent need for public health to develop an efficient, cost-effective and safe non-antibiotic therapy to both prevent and treat UTIs without facilitating antimicrobial resistance. Inhibition of type 1 fimbriae-mediated bacterial attachment to the bladder epithelium is a very promising approach to achieve this aim.

The lectin FimH on the tip of type 1 fimbriae of E. coli binds to oligomannosides located on epithelial cells of the urinary tract. This specific binding plays an important role in the development of UTIs. E. coli adhere specifically to the terminal mannose moieties of uroplakin receptors on the surface of urinary tract epithelia.

More than two decades ago, Sharon and coworkers have investigated various

mannosides and oligomannosides as antagonists for type 1 fimbriae-mediated specific bacterial adhesion (I. Ofek, D.L. Hasty, N. Sharon, FEMS Immunol Med Microbiol 2003, 38, 181 -191 ). However, when binding affinities for various mannosides were tested in ELISA formats, only weak interactions with IC ₅₀ values in the milli- to micromolar range were observed. Attempts to improve the affinity followed two different approaches: (i) the design of multivalent carbohydrate ligands and (ii) the rational design of ligands guided by information obtained from the crystal structure of FimH (A. Imberty, Y.M. Chabre, R. Roy, Chem. Eur J .2008, 14, 7490-7499).

Anti-adhesive a-D-mannopyranoside derivatives for prevention and treatment of bacterial infections are described in WO 2005/089733. Further anti-adhesive saccharide derivatives such as thio-a-L-fucopyranosides are described in WO 98/21220. A number of methoxycarbonylbiphenylyl mannosides are disclosed by T. Klein et al., J. Med. Chem. 2010, 53, 8627-8641 . Although these compounds show excellent FimH affinities in the nanomolar range, their bioavailabilty on oral application is disappointingly low.

Summary of the invention

The invention relates to compounds of the formula (I)

wherein

n is 0, 1 or 2;

R ¹ is aryl, heteroaryl or heterocyclyl;

R ² and R ³ are, independent of each other, hydrogen, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally substituted alkenyl, optionally substituted alkinyl, cycloalkyi, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, phenoxy, hydroxysulfonyloxy; mercapto, alkylmercapto, hydroxysulfinyl, alkyl- sulfinyl, halo-lower alkylsulfinyl, hydroxysulfonyl, alkylsulfonyl, arylsulfonyl, heteroaryl- sulfonyl, aminosulfonyl, amino optionally substituted by one or two substitutents selected from lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl; lower alkylcarbonylamino, alkoxycarbonylamino, benzoylamino, pyridinylcarbonylamino, carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids; carboxy, lower alkylcarbonyl, benzoyl, pyridinecarbonyl, pyrimidinecarbonyl, lower alkoxycarbonyl, aminocarbonyl, wherein amino is unsubstituted or substituted by one hydroxy or amino group or one or two substitutents selected from lower alkyl, hydroxy-lower alkyl or lower alkoxy-lower alkyl; tetrazolyl, cyano, halogen, or nitro; or wherein two substituents in ortho-position to each other form a 5- or 6-membered heterocyclic ring containing one or two oxygen atoms and/or one or two nitrogen atoms, wherein the nitrogen atoms are optionally substituted by lower alkyl, lower alkoxy-lower alkyl or lower alkylcarbonyl; and one of R ^A , R ^B , R ^c and R ^D is P0 ₂ (OH) ₂ and the other ones are hydrogen;

and salts thereof.

Furthermore the invention relates to pharmaceutical compositions comprising these compounds, to the use of the compounds for the prevention and treatment of bacterial infections, in particular urinary tract infections, and to a method of prevention and treatment of such bacterial infections.

Detailed description of the invention

The invention relates to compounds of the formula (I)

wherein

n is 0, 1 or 2;

R ¹ is aryl, heteroaryl or heterocyclyl; and

R ² and R ³ are, independent of each other, hydrogen, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally substituted alkenyl, optionally substituted alkinyl, cycloalkyi, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, phenoxy, hydroxysulfonyloxy; mercapto, alkylmercapto, hydroxysulfinyl, alkyl- sulfinyl, halo-lower alkylsulfinyl, hydroxysulfonyl, alkylsulfonyl, arylsulfonyl, heteroaryl- sulfonyl, aminosulfonyl, amino optionally substituted by one or two substitutents selected from lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl; lower alkylcarbonylamino, alkoxycarbonylamino, benzoylamino, pyridinylcarbonylamino, carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids; carboxy, lower alkylcarbonyl, benzoyl, pyridinecarbonyl, pyrimidinecarbonyl, lower alkoxycarbonyl, aminocarbonyl, wherein amino is unsubstituted or substituted by one hydroxy or amino group or one or two substitutents selected from lower alkyl, hydroxy-lower alkyl or lower alkoxy-lower alkyl; tetrazolyl, cyano, halogen, or nitro; or wherein two substituents in ortho-position to each other form a 5- or 6-membered heterocyclic ring containing one or two oxygen atoms and/or one or two nitrogen atoms, wherein the nitrogen atoms are optionally substituted by lower alkyl, lower alkoxy-lower alkyl or lower alkylcarbonyl; and one of R ^A , R ^B , R ^c and R ^D is P0 ₂ (OH) ₂ and the other ones are hydrogen;

and salts thereof.

Mannose-specific (type 1 ) fimbriae are among the most commonly found lectins in enterobacteriae. The adhesion of pathogenic organisms to host tissue mediated by such lectins is considered an important initial event in bacterial infection. Soluble carbohydrates recognized by the bacterial surface lectins inhibit the adhesion to complementary tissue resulting in the lack of the ability to initiate infection. The present invention relates to a particularly active group of mannoside derivatives, which can be successfully applied as orally available FimH antagonists (FirmH = receptor binding domain of a fimbrial tip adhesin). The compounds of the invention show the known high activity of some particular mannosides, and are constructed to be highly water soluble and orally available. A further aspect of the invention is the use of the compounds of the invention as oral drugs for the prevention and treatment of infectious diseases, in particular urinary tract infections. The advantage of the mannoside derivatives of the invention over state-of-the- art antibiotics is the fact that formation of resistance to carbohydrates leads to mutated lectins rendering themselves ineffective with respect to adhesion to host tissue.

Since most mannose derivatives, wherein R ^A , R ^B , R ^c and R ^D are hydrogen, are hardly soluble (approx. 10 micrograms per ml), they are not suitable for use as oral

pharmaceutical preparations. Mannose derivatives carrying carboxylic acid functions show reasonable solubility, but are again not orally available. It has now surprisingly been found that the corresponding phosphates in the 2-, 3-, 4- and/or 6-position of the mannose moiety (positions R ^A , R ^B , R ^c and R ^D , respectively) show excellent solubility both as sodium salts or the free acids in a range of above 3 mg/ml, and are orally active. The phosphates are expected to be converted into the free mannosides in the gastrointestinal tract. In experiments with Caco-2 cell monolayers, which contain alkaline phosphatase primarily in the apical membrane, it could be shown that the phosphates are indeed hydrolyzed.

The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:

The prefix "lower" denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching.

Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.

Double bonds in principle can have E- or Z-configuration. The compounds of this invention may therefore exist as isomeric mixtures or single isomers. If not specified both isomeric forms are intended.

Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration. The compounds may thus be present as mixtures of isomers or as pure isomers, preferably as enantiomer-pure diastereomers. The invention relates also to possible tautomers of the compounds of formula (I).

Alkyl has from 1 to 12, preferably from 1 to 7 carbon atoms, and is linear or branched. Alkyl is preferably lower alkyl.

Lower alkyl has 1 to 7, preferably 1 to 4 carbon atoms and is butyl, such as n-butyl, sec- butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl. Preferably lower alkyl is methyl or ethyl. C ₂ -C ₇ -alkyl is lower alkyl with at least two carbon atoms, for example ethyl, propyl or butyl.

Cycloalkyl has preferably 3 to 7 ring carbon atoms, and may be unsubstitued or substituted, e.g. by lower alkyl or lower alkoxy. Cycloalkyl is, for example, cyclohexyl, cyclopentyl, methylcyclopentyl, or cyclopropyl, in particular cyclopropyl. Aryl stands for a mono- or bicyclic fused ring aromatic group with 5 to 10 carbon atoms optionally carrying substituents, such as phenyl, 1-naphthyl or 2-naphthyl, or also a partially saturated bicyclic fused ring comprising a phenyl group, such as indanyl, dihydro- or tetrahydronaphthyl, all optionally substitued. Preferably, aryl is phenyl or indanyl or tetrahydronaphthyl, in particular phenyl.

The term„aryl carrying substituents" stands for aryl substituted by up to four substituents independently selected from lower alkyl, halo-lower alkyl, cycloalkyl-lower alkyl, carboxy- lower alkyl, lower alkoxycarbonyl-lower alkyl; arylalkyl or heteroarylalkyl, wherein aryl or heteroaryl are unsubstituted or substituted by up to three substituents selected from lower alkyl, cyclopropyl, halo-lower alkyl, lower alkoxy, hydroxysulfonyl, aminosulfonyl, tetrazolyl, carboxy, halogen, amino, cyano and nitro; hydroxy-lower alkyl, lower alkoxy- lower alkyl, aryloxy-lower alkyl, heteroaryloxy-lower alkyl, aryl-lower alkoxy-lower alkyl, heteroaryl-lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl; aminoalkyl wherein amino is unsubstituted or substituted by one or two substituents selected from lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl and amino-lower alkyl, or by one substituent alkylcarbonyl, alkoxycarbonyl, amino-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl and aminocarbonyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; optionally substituted alkenyl, optionally substituted alkinyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, lower alkoxy, halo- lower alkoxy, lower alkoxy-lower alkoxy, cycloalkyl-lower alkoxy, aryloxy, aryl-lower alkoxy, aryloxy-lower alkoxy, heteroaryloxy, heteroaryl-lower alkoxy, heteroaryloxy-lower alkoxy, optionally substituted alkenyloxy, optionally substituted alkinyloxy, cycloalkyloxy, heterocyclyloxy, hydroxysulfonyloxy; alkylmercapto, hydroxysulfinyl, alkylsulfinyl, halo- lower alkylsulfinyl, hydroxysulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl;

aminosulfonyl wherein amino is unsubstituted or substituted by one or two substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, cycloalkyi, optionally substituted phenyl, optionally substituted phenyl-lower alkyl, optionally substituted heteroaryl and optionally substituted heteroaryl-lower alkyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; amino optionally substituted by one or two substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, di-lower alkylamino- lower alkyl, cycloalkyi, optionally substituted phenyl-lower alkyl and optionally substituted heteroaryl-lower alkyl, or by one substituent optionally substituted phenyl, optionally substituted heteroaryl, alkylcarbonyl, optionally substituted phenylcarbonyl, optionally substituted pyridylcarbonyl, alkoxycarbonyl or aminocarbonyl, and wherein alkyl or lower alkyl in each case may be substituted by halogen, lower alkoxy, aryl, heteroaryl or optionally substituted amino, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids; lower alkylcarbonyl, halo-lower alkylcarbonyl, optionally substituted phenylcarbonyl, optionally substituted heteroarylcarbonyl, carboxy, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl; aminocarbonyl wherein amino is unsubstituted or substituted by one hydroxy or amino group or one or two substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, cycloalkyi, optionally substituted phenyl-lower alkyl and optionally substituted heteroaryl-lower alkyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; cyano, halogen, and nitro; and wherein two substituents in ortho- position to each other can form a 5-, 6- or 7-membered carbocyclic or heterocyclic ring containing one, two or three oxygen atoms, one or two nitrogen atoms and/or one sulfur atom, wherein the nitrogen atoms are optionally substituted by lower alkyl, lower alkoxy- lower alkyl or lower alkylcarbonyl.

In particular, the substituents may be independently selected from lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally substituted alkenyl, optionally substituted alkinyl, cyclohexyl, cyclopropyl, aryl, heteroaryl, heterocyclyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, cycloalkyloxy, phenoxy, hydroxysulfonyloxy; alkylmercapto, hydroxysulfinyl, alkylsulfinyl, halo-lower alkylsulfinyl, hydroxysulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl; aminosulfonyl wherein amino is unsubstituted or substituted by one or two substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl and optionally substituted phenyl-lower alkyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; amino optionally substituted by one or two substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, di-lower alkylamino-lower alkyl, cycloalkyl, or by one substituent optionally substituted phenyl, optionally substituted heteroaryl, alkylcarbonyl, optionally substituted phenylcarbonyl, optionally substituted pyridylcarbonyl, alkoxycarbonyl or aminocarbonyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids; lower alkylcarbonyl, halo-lower alkylcarbonyl, carboxy, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl; aminocarbonyl wherein amino is unsubstituted or substituted by one hydroxy or amino group or one or two substitutents selected from lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally substituted phenyl-lower alkyl and optionally substituted heteroaryl-lower alkyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; cyano, halogen, and nitro; and wherein two substituents in ortho-position to each other can form a 5- or 6-membered heterocyclic ring containing one or two oxygen atoms and/or one or two nitrogen atoms, wherein the nitrogen atoms are optionally substituted by lower alkyl, lower alkoxy-lower alkyl or lower alkylcarbonyl.

In optionally substituted phenyl, substituents are preferably lower alkyl, halo-lower alkyl, lower alkoxy-lower alkyl, cyclopropyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, methylenedioxy, hydroxysulfonyloxy, carboxy, lower alkoxycarbonyl, aminocarbonyl, hydroxylaminocarbonyl, tetrazolyl, hydroxysulfonyl, aminosulfonyl, halo, cyano or nitro, in particular carboxy, lower alkoxycarbonyl, aminocarbonyl, hydroxylaminocarbonyl, tetrazolyl, or aminosulfonyl. Heteroaryl represents an aromatic group containing at least one heteroatom selected from nitrogen, oxygen and sulfur, and is mono- or bicyclic, optionally carrying substituents. Monocyclic heteroaryl includes 5 or 6 membered heteroaryl groups containing 1 , 2, 3 or 4 heteroatoms selected from nitrogen, sulfur and oxygen. Bicyclic heteroaryl includes 9 or 10 membered fused-ring heteroaryl groups. Examples of heteroaryl include pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and benzo or pyridazo fused derivatives of such monocyclic heteroaryl groups, such as indolyl, benzimidazolyl, benzofuryl, quinolinyl, isoquinolinyl, quinazolinyl, pyrrolopyridine, imidazopyridine, or purinyl, all optionally substituted. Preferably, heteroaryl is pyridyl, pyrimdinyl, pyrazinyl, pyridazinyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxadiazolyl, triazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrrolyl, indolyl, pyrrolopyridine or

imidazopyridine; in particular pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, oxadiazolyl, triazolyl, indolyl, pyrrolopyridine or imidazopyridine.

The term "heteroaryl carrying substituents" stands for heteroaryl substituted by up to three substituents independently selected from lower alkyl, halo-lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, aryloxy-lower alkyl, heteroaryloxy- lower alkyl, lower alkoxy-lower alkoxy-lower alkyl; aminoalkyl, wherein amino is unsubstituted or substituted by one or two substituents selected from lower alkyl, hydroxy- lower alkyl, alkoxy-lower alkyl, amino-lower alkyl, alkylcarbonyl, alkoxycarbonyl, amino- lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl and aminocarbonyl; optionally substituted alkenyl, optionally substituted alkinyl, cycloalkyl; aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein aryl or heteroaryl are unsubstituted or substituted by up to three substituents selected from lower alkyl, halo-lower alkyl, lower alkoxy, halogen, amino, cyano and nitro; hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, cycloalkyloxy, cycloalkyl-lower alkoxy, aryloxy, aryl-lower alkoxy, heteroaryloxy, heteroaryl-lower alkoxy, alkenyloxy, alkinyloxy, alkylmercapto, alkylsulfinyl, halo-lower alkylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl wherein amino is unsubstituted or substituted by one or two substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-lower alkyl, optionally substituted heteroaryl and optionally substituted heteroaryl-lower alkyl, or wherein the two

substituents on nitrogen form together with the nitrogen heterocyclyl; amino optionally substituted by one or two substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, di-lower alkylamino-lower alkyl, cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-lower alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-lower alkyl, alkylcarbonyl, alkoxycarbonyl or aminocarbonyl, and wherein alkyl or lower alkyl in each case may be substituted by halogen, lower alkoxy, aryl, heteroaryl or optionally substituted amino, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; lower alkylcarbonyl, halo-lower alkylcarbonyl, optionally substituted phenylcarbonyl, carboxy, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl; aminocarbonyl wherein amino is unsubstituted or substituted by one hydroxy or amino group or one or two substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, cycloalkyl, optionally substituted phenyl, optionally substituted phenyl- lower alkyl, optionally substituted heteroaryl and optionally substituted heteroaryl-lower alkyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; cyano, halogen, and nitro.

In particular, the substituents on heteroaryl may be independently selected from lower alkyl, halo-lower alkyl, cycloalkyl-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, optionally substituted alkenyl, optionally substituted alkinyl, cycloalkyl, aryl, heteroaryl, hydroxy, lower alkoxy, cycloalkyloxy, alkenyloxy, alkinyloxy, alkyl- mercapto, alkylsulfinyl, halo-lower alkylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl wherein amino is unsubstituted or substituted by one or two substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-lower alkyl, optionally substituted heteroaryl and optionally substituted heteroaryl-lower alkyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; amino optionally substituted by one or two substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, di-lower alkylamino-lower alkyl, cycloalkyl, alkylcarbonyl, alkoxycarbonyl or aminocarbonyl, and wherein alkyl or lower alkyl in each case may be substituted by lower alkoxy or optionally substituted amino, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; lower alkylcarbonyl, halo-lower alkylcarbonyl, carboxy, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl; aminocarbonyl wherein amino is unsubstituted or substituted by one hydroxy or amino group or one or two substitutents selected from lower alkyl, cycloalkyl- lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl or cycloalkyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; cyano, halogen, and nitro. In optionally substituted heteroaryl, substituents are preferably lower alkyl, halo-lower alkyl, lower alkoxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy- lower alkoxy, methylenedioxy, carboxy, lower alkoxycarbonyl, aminocarbonyl, hydroxylaminocarbonyl, tetrazolyl, aminosulfonyl, halo, cyano or nitro.

Alkenyl contains one or more, e.g. two or three, double bonds, and is preferably lower alkenyl, such as 1 - or 2-butenyl, 1 -propenyl, allyl or vinyl.

Alkinyl is preferably lower alkinyl, such as propargyl or acetylenyl.

In optionally substituted alkenyl or alkinyl, substituents are preferably lower alkyl, lower alkoxy, halo, optionally substituted aryl or optionally substituted heteroaryl, and are connected with a saturated or unsaturated carbon atom of alkenyl or alkinyl.

Heterocyclyl designates preferably a saturated, partially saturated or unsaturated, mono- or bicyclic ring containg 4-10 atoms comprising one, two or three heteroatoms selected from nitrogen, oxygen and sulfur, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a ring nitrogen atom may optionally be substituted by a group selected from lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl and acyl, and a ring carbon atom may be substituted by lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl, heteroaryl, lower alkoxy, hydroxy or oxo, or which may be fused with an optionally substituted benzo ring. Substituents considered for substituted benzo are those mentioned above for optionally substituted aryl. Examples of heterocyclyl are pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxolanyl, tetrahydro- furanyl and tetrahydropyranyl, and optionally substituted benzo fused derivatives of such monocyclic heterocyclyl, for example indolinyl, benzoxazolidinyl, benzothiazolidinyl, tetrahydroquinolinyl, and benzodihydrofuryl.

Acyl designates, for example, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, aryl-lower alkylcarbonyl, or heteroarylcarbonyl. Lower acyl is preferably lower alkylcarbonyl, in particular propionyl or acetyl.

Hydroxyalkyl is especially hydroxy-lower alkyl, preferably hydroxymethyl, 2-hydroxyethyl or 2-hydroxy-2-propyl.

Cyanoalkyl designates preferably cyanomethyl and cyanoethyl. Haloalkyl is preferably fluoroalkyl, especially trifluoromethyl, 3,3,3-trifluoroethyl or pentafluoroethyl.

Halogen is fluorine, chlorine, bromine, or iodine.

Lower alkoxy is especially methoxy, ethoxy, isopropyloxy, or tert-butyloxy.

ArylalkyI includes aryl and alkyl as defined hereinbefore, and is e.g. benzyl, 1 -phenethyl or 2-phenethyl.

Heteroarylalkyl includes heteroaryl and alkyl as defined hereinbefore, and is e.g. 2-, 3- or 4-pyridylmethyl, 1 - or 2-pyrrolylmethyl, 1 -pyrazolylmethyl, 1 -imidazolylmethyl,

2-(1 -imidazolyl)ethyl or 3-(1 -imidazolyl)propyl. In substituted amino, the substituents are preferably those mentioned as substituents hereinbefore. In particular, substituted amino is alkylamino, dialkylamino, optionally substituted arylamino, optionally substituted arylalkylamino, lower alkylcarbonylamino, benzoylamino, pyridylcarbonylamino, lower alkoxycarbonylamino or optionally substituted aminocarbonylamino.

Salts are especially the pharmaceutically acceptable salts of compounds of formula (I).

Particular salts considered are those replacing one or two hydrogen atoms of the phosphate group, and optionally of a further acidic function, e.g. of a carboxylic acid function. Suitable cations are, e.g., sodium, potassium, calcium, magnesium or ammonium cations, or also cations derived by protonation from primary, secondary or tertiary amines containing, for example, lower alkyl, hydroxy-lower alkyl or hydroxy-lower alkoxy-lower alkyl groups, e.g., 2-hydroxyethylammonium, 2-(2-hydroxyethoxy)ethyl- dimethylammonium, diethylammonium, di(2-hydroxyethyl)ammonium, trimethyl- ammonium, triethylammonium, 2-hydroxyethyldimethylammonium, or di(2-hydroxyethyl)- methylammonium, also from correspondingly substituted cyclic secondary and tertiary amines, e.g., N-methylpyrrolidinium, N-methylpiperidinium, N-methylmorpholinium, N-2- hydroxyethylpyrrolidinium, N-2-hydroxyethylpiperidinium, or N-2-hydroxyethyl- morpholinium, and the like.

If the compounds of formula (I) contain a basic nitrogen atom, zwitter ions may be formed. It may also be possible to prepare pharmaceutically acceptable acid addition salts of such basic compounds. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantane- carboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1 ,2-disulfonic acid, benzenesulfonic acid,

2-naphthalenesulfonic acid, 1 ,5-naphthalene-disulfonic acid, 2-, 3- or 4-methyl- benzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid,

N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.

For isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.

In view of the close relationship between the novel compounds in free form and those in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the novel compounds, any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.

The compounds of formula (I) have valuable pharmacological properties. The invention also relates to compounds of formula (I) and salts as defined hereinbefore for use as medicaments. A compound of formula (I) according to the invention shows prophylactic and therapeutic efficacy especially against bacterial infections, in particular against infective diseases caused by Escherichia coli (£. coli), a Gram negative bacterium commonly found in the lower intestine of warm-blooded organisms. Most E. coli strains are harmless and part of the normal flora of the gut, however, the compounds of the invention are useful in the treatment of infective diseases caused by virulent strains of £. coli, in particular in the treatment of gastroenteritis, diarrhea, food poisoning, urinary tract infections, pyelonephritis, and neonatal meningitis caused by £ coli strains, also in the treatment of unusual infective diseases caused by virulent £ coli strains, in particular in the treatment of haemolytic-uremic syndrome (HUS), peritonitis, mastitis, sepsis, and pneumonia caused by £ coli.

Particularly preferred is the use of a compound of formula (I) or a salt thereof according to the invention as a medicament for the prevention and treatment of urinary infections caused by £. coli. A compound of formula (I) can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations, or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents.

Therapeutic agents for possible combination are especially trimethoprim/sulfamethoxazol (co-trimoxazol), fluoroquinolone (e.g. ciprofloxacin, levofloxacin or norfloxacin), amoxicilin/clavulanic acid, and nitrofurantoin. With the groups of preferred compounds of formula (I) mentioned hereinafter, definitions of substituents from the general definitions mentioned hereinbefore may reasonably be used, for example, to replace more general definitions with more specific definitions or especially with definitions characterized as being preferred. In particular, the invention refers to compounds of formula (I), wherein n is 0 or 1 , preferably 0.

Furthermore, the invention refers preferably to compounds of formula (I), wherein R ¹ is optionally substituted phenyl, optionally substituted 1 -naphthyl, optionally substituted 2- naphthyl, optionally substituted indanyl, or optionally substituted dihydro- or tetrahydro- naphthyl. Preferably, R ¹ is optionally substituted phenyl, optionally substituted indanyl, or optionally substituted tetrahydronaphthyl. In particular R ¹ is optionally substituted phenyl.

More preferred substituents considered for R ¹ with the meaning of the mentioned aryl groups, e.g. phenyl, are lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy- lower alkyl, optionally substituted alkenyl, optionally substituted alkinyl, cyclohexyl, cyclopropyl, aryl, heteroaryl, heterocyclyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, cycloalkyloxy, hydroxysulfonyloxy; mercapto, alkylmercapto, hydroxysulfinyl, alkylsulfinyl, halo-lower alkylsulfinyl, hydroxysulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl wherein amino is unsubstituted or substituted by one or two substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally substituted phenyl-lower alkyl and optionally substituted heteroaryl-lower alkyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; amino optionally substituted by one or two substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl and di-lower alkylamino-lower alkyl, or by one substituent cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, alkylcarbonyl, optionally substituted phenylcarbonyl, optionally substituted pyridylcarbonyl, alkoxycarbonyl or aminocarbonyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids; lower alkylcarbonyl, halo-lower alkylcarbonyl, carboxy, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl; aminocarbonyl wherein amino is unsubstituted or substituted by one hydroxy or amino group or one or two substitutents selected from lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally substituted phenyl-lower alkyl and optionally substituted heteroaryl-lower alkyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; cyano, halogen, and nitro; and wherein two substituents in ortho-position to each other can form a 5- or 6-membered heterocyclic ring containing one or two oxygen atoms and/or one or two nitrogen atoms, wherein the nitrogen atoms are optionally substituted by lower alkyl, lower alkoxy-lower alkyl or lower alkylcarbonyl.

Particularly preferred substituents for R ¹ with the meaning phenyl are lower alkyl, halo- lower alkyl, lower alkoxy-lower alkyl, cyclopropyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, phenoxy, methylenedioxy, hydroxysulfonyloxy, hydroxysulfonyl, aminosulfonyl, lower alkylsulfonyl, amino, lower alkylcarbonylamino, benzoylamino, pyridylcarbonylamino, carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids; carboxy, lower alkoxycarbonyl, aminocarbonyl, hydroxylaminocarbonyl, tetrazolyl, halo, cyano or nitro.

In another particular embodiment, the invention refers to compounds of formula (I), wherein R ¹ is pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzofuryl, pyridopyrrolyl, pyridoimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or purinyl, all optionally substituted. Such groups R ¹ are usually carbon-linked, but, in the case where the nitrogen of the heteroaryl group carries hydrogen, may also be nitrogen-linked. Preferably, R ¹ is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxadiazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, pyridopyrrolyl, or pyridoimidazolyl, all optionally substituted, in particular pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, pyridopyrrolyl, or pyridoimidazolyl, all optionally subtituted. Particularly preferred is pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, benzimidazolyl, pyridopyrrolyl, or pyridoimidazolyl, all optionally substituted.

Preferred substituents considered for R ¹ with the meaning of the mentioned heteroaryl groups are alkyl, halo-lower alkyl, cycloalkyl-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, optionally substituted alkenyl, optionally substituted alkinyl, cycloalkyl, aryl, heteroaryl, hydroxy, lower alkoxy, cycloalkyloxy, alkenyloxy, alkinyloxy, hydroxysulfonyloxy, lower alkylmercapto, hydroxysulfinyl, lower alkylsulfinyl, halo-lower alkylsulfinyl, hydroxysulfonyl, lower alkylsulfonyl, arylsulfonyl; amino optionally substituted by one or two substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl and di-lower alkylamino-lower alkyl; or one substituent cycloalkyl, lower alkylcarbonyl, phenylcarbonyl, pyrimidinylcarbonyl, alkoxycarbonyl or aminocarbonyl, and wherein alkyl or lower alkyl in each case may be substituted by lower alkoxy or optionally substituted amino; carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, amino- methylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids; or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; lower alkylcarbonyl, halo-lower alkylcarbonyl, carboxy, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl; aminocarbonyl wherein amino is unsubstituted or substituted by one hydroxy or amino group or one or two substitutents selected from lower alkyi, cycloalkyl-lower alkyi, hydroxy-lower alkyi, lower alkoxy-lower alkyi or cycloalkyi, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; cyano, halogen, and nitro. Preferred substituents considered for R ¹ with the meaning of the mentioned preferred heteroaryl groups are lower alkyi, halo-lower alkyi, lower alkoxy-lower alkyi, cyclopropyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, phenoxy, methylene- dioxy, hydroxysulfonyloxy, hydroxysulfonyl, aminosulfonyl, lower alkylsulfonyl, amino, lower alkylcarbonylamino, benzoylamino, pyridylcarbonylamino, carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, amino- methylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids; carboxy, lower alkoxycarbonyl, aminocarbonyl, hydroxylaminocarbonyl, tetrazolyl, halo, cyano or nitro. Most preferred substituents are halo-lower alkyi, lower alkoxy, carboxy, lower alkoxycarbonyl, tetrazolyl, cyano and nitro.

In another particular embodiment, the invention refers to compounds of formula (I), wherein R ¹ is pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, indolinyl, isoindolinyl, benzoxazolidinyl, benzothiazolidinyl, tetrahydroquinolinyl, or benzodihydrofuryl, wherein such group R ¹ may be carbon-linked or, if possible, nitrogen-linked, wherein a ring nitrogen atom may optionally be substituted by a group selected from lower alkyi, amino-lower alkyi, aryl, aryl- lower alkyi and acyl, and a ring carbon atom may be substituted by lower alkyi, amino- lower alkyi, aryl, aryl-lower alkyi, heteroaryl, lower alkoxy, hydroxy or oxo, or wherein the benzo ring, if present, is optionally substituted by lower alkyi, halo-lower alkyi, lower alkoxy-lower alkyi, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, methylenedioxy, carboxy, lower alkoxycarbonyl, aminocarbonyl, hydroxylaminocarbonyl, tetrazolyl, aminosulfonyl, halo, cyano or nitro.

More preferably, R ¹ is pyrrolidinyl, oxazolidinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or benzodihydrofuryl, in particular indolinyl, wherein such group R ¹ may by carbon- or, if possible, nitrogen-linked, wherein a ring nitrogen atom may optionally be substituted by lower alkyi, aryl-lower alkyi or acyl, and a ring carbon atom may be substituted by lower alkyi, amino-lower alkyi, aryl, aryl-lower alkyi, heteroaryl, lower alkoxy, hydroxy or oxo, or wherein the benzo ring, if present, is optionally substituted by lower alkyi, halo-lower alkyi, lower alkoxy-lower alkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, methylenedioxy, carboxy, lower alkoxycarbonyl, aminocarbonyl, hydroxylamino- carbonyl, tetrazolyl, aminosulfonyl, halo, cyano or nitro, more preferably by halo-lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, tetrazolyl, cyano or nitro.

Preferred as R ² and R ³ are, independent of each other, hydrogen, lower alkyl, halo-lower alkyl, lower alkoxy-lower alkyl, cyclopropyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, phenoxy, hydroxysulfonyloxy, methylenedioxy, hydroxysulfinyl, hydroxysulfonyl, lower alkylsulfonyl, arylsulfonyl, aminosulfonyl, amino optionally substituted by one or two substitutents selected from lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl; lower alkylcarbonylamino, alkoxycarbonylamino, benzoylamino, pyridinylcarbonylamino, carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids; carboxy, lower alkoxycarbonyl, aminocarbonyl, hydroxylaminocarbonyl, tetrazolyl, aminosulfonyl, halo, cyano or nitro.

Particularly preferred substituents R ² and R ³ are hydrogen, lower alkyl, halo-lower alkyl, cyclopropyl, lower alkoxy, lower alkoxy-lower alkoxy, phenoxy, hydroxysulfonyl, aminosulfonyl, amino, lower alkylcarbonylamino, benzoylaminoamino, carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids; carboxy, lower alkoxycarbonyl, aminocarbonyl, hydroxylaminocarbonyl, tetrazolyl, halo, cyano or nitro.

Most preferred substituents R ² and R ³ are hydrogen, lower alkoxy, such as methoxy, and halo, such as chloro and fluoro.

One of R ^A , R ^B , R ^c and R ^D is P0 ₂ (OH) ₂ and the other ones are hydrogen. Particularly preferred are compounds wherein R ^A , R ^B and R ^c are hydrogen, and R ^D is P0 ₂ (OH) ₂ .

Preferably, the invention refers to compounds of formula (I), wherein R ¹ is a residue of formula (A)

(A)

wherein R ⁴ is hydrogen, trifluoromethyl, cylcopropyl, hydroxy, lower alkoxy, lower alkoxy- lower alkoxy, phenoxy, hydroxysulfonyl, aminosulfonyl, lower alkylaminosulfonyl, di-lower alkylaminosulfonyl, lower alkylsulfonyl, amino, lower alkylcarbonylamino, benzoylamino, carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids, para-carboxy, lower alkoxycarbonyl, aminocarbonyl, morpholinocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, hydroxylaminocarbonyl, tetrazolyl, nitro, cyano, or halo;

preferably para-hydroxy, aminosulfonyl, lower alkylaminosulfonyl, di-lower alkylaminosulfonyl, lower alkylsulfonyl, amino, lower alkylcarbonylamino, para-carboxy, lower alkoxycarbonyl, aminocarbonyl, morpholinocarbonyl, pyrrolidinocarbonyl, piperidino- carbonyl, tetrazolyl, nitro, cyano, or halo; and wherein the phenyl ring of formula (A) may be further substituted by chloro or fluoro; or of formula (B) or (C)

wherein R ⁵ is hydrogen, trifluoromethyl, cylcopropyl, lower alkoxy, lower alkoxy-lower alkoxy, phenyl-lower-alkoxy, phenoxy, hydroxysulfonyl, aminosulfonyl, lower alkylsulfonyl, amino, lower alkylcarbonylamino, benzoylamino, carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids, carboxy, lower alkoxycarbonyl, aminocarbonyl, hydroxylaminocarbonyl, tetrazolyl, nitro, cyano, or halo; preferably hydrogen, trifluoromethyl, lower alkoxy, such as methoxy, benzyloxy, amino, carboxy, lower alkoxycarbonyl, tetrazolyl, nitro, cyano, or halo; or of formula (D)

wherein R ⁶ is hydrogen, trifluoromethyl, cylcopropyl, lower alkoxy, lower alkoxy-lower alkoxy, phenoxy, hydroxysulfonyl, aminosulfonyl, lower alkylsulfonyl, amino, lower alkylcarbonylamino, benzoylamino, carboxymethylamino or lower alkoxycarbonylmethyl- amino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids, carboxy, lower alkoxycarbonyl, aminocarbonyl, hydroxylaminocarbonyl, tetrazolyl, nitro, cyano, or halo;

preferably hydrogen, trifluoromethyl, lower alkoxy, such as methoxy, carboxy, lower alkoxycarbonyl, tetrazolyl, nitro, cyano, or halo; or of formula (E) or (F)

wherein R ⁷ is hydrogen, lower alkyl, lower alkoxy-lower alkyl, lower alkylcarbonyl, optionally substituted phenylcarbonyl, or aminomethylcarbonyl substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids;

preferably hydrogen or lower alkyl, such as methyl; or of formula (G) wherein R is carboxy or lower alkoxycarbonyl; X or Y or Z, or X and Z, or Y and Z are nitrogen atoms and the other atoms X, Y and Z are carbon atoms; or of formula (H)

wherein R ⁹ is carboxy or lower alkoxycarbonyl;

R ^A , R ^B and R ^c are hydrogen, and R ^D is P0 ₂ (OH) ₂ ; and salts thereof.

Further preferred are compounds of formula (I) wherein

n is 0, 1 or 2; R ¹ is phenyl connected to the phenyl ring of formula (I) in meta- or para-position and substituted by one, two or three substituents selected from the group consisting of lower alkyi, halo-lower alkyi, hydroxy-lower alkyi, lower alkoxy-lower alkyi, optionally substituted alkenyl, optionally substituted alkinyl, cyclohexyl, cyclopropyl, aryl, heteroaryl, heterocyclyl;

para-hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, cycloalkyloxy, hydroxysulfonyloxy;

mercapto, alkylmercapto, hydroxysulfinyl, alkylsulfinyl, halo-lower alkylsulfinyl,

hydroxysulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl wherein amino is unsubstituted or substituted by one or two substitutents selected from lower alkyi, cycloalkyl-lower alkyi, hydroxy-lower alkyi, lower alkoxy-lower alkyi, optionally substituted phenyl-lower alkyi and optionally substituted heteroaryl-lower alkyi, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl;

amino optionally substituted by one or two substitutents selected from lower alkyi, cycloalkyl-lower alkyi, hydroxy-lower alkyi, lower alkoxy-lower alkyi and di-lower alkylamino-lower alkyi, or by one substituent cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, alkylcarbonyl, optionally substituted phenylcarbonyl, optionally substituted pyridylcarbonyl, alkoxycarbonyl or aminocarbonyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids;

lower alkylcarbonyl, halo-lower alkylcarbonyl, para-carboxy, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl; aminocarbonyl wherein amino is unsubstituted or substituted by one hydroxy or amino group or one or two substitutents selected from lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally substituted phenyl-lower alkyl and optionally substituted heteroaryl-lower alkyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl;

cyano, halogen, and nitro;

and wherein two substituents in ortho-position to each other can form a 5- or 6-membered heterocyclic ring containing one or two oxygen atoms and/or one or two nitrogen atoms, wherein the nitrogen atoms are optionally substituted by lower alkyl, lower alkoxy-lower alkyl or lower alkylcarbonyl; or R ¹ is aryl other than optionally substituted phenyl, heteroaryl, heterocyclyl with 5 or more atoms, and

R ² and R ³ are, independent of each other, hydrogen, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally substituted alkenyl, optionally substituted alkinyl, cycloalkyi, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, phenoxy, hydroxysulfonyloxy; mercapto, alkylmercapto, hydroxysulfinyl, alkyl- sulfinyl, halo-lower alkylsulfinyl, hydroxysulfonyl, alkylsulfonyl, arylsulfonyl, heteroaryl- sulfonyl, aminosulfonyl, amino optionally substituted by one or two substitutents selected from lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl; lower alkylcarbonylamino, alkoxycarbonylamino, benzoylamino, pyridinylcarbonylamino, carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids; carboxy, lower alkylcarbonyl, benzoyl, pyridinecarbonyl, pyrimidinecarbonyl, lower alkoxycarbonyl, aminocarbonyl, wherein amino is unsubstituted or substituted by one hydroxy or amino group or one or two substitutents selected from lower alkyl, hydroxy-lower alkyl or lower alkoxy-lower alkyl; tetrazolyl, cyano, halogen, or nitro; or wherein two substituents in ortho-position to each other form a 5- or 6-membered heterocyclic ring containing one or two oxygen atoms and/or one or two nitrogen atoms, wherein the nitrogen atoms are optionally substituted by lower alkyl, lower alkoxy-lower alkyl or lower alkylcarbonyl; R ^A , R ^B and R ^c are hydrogen, and R ^D is P0 ₂ (OH) ₂ ; and salts thereof.

Also preferred are compounds of formula (I), wherein R ¹ is a residue of formula (A)

wherein R ⁴ is hydrogen, trifluoromethyl, cylcopropyl, lower alkoxy, lower alkoxy-lower alkoxy, phenoxy, hydroxysulfonyl, aminosulfonyl, lower alkylsulfonyl, amino, lower alkylcarbonylamino, benzoylamino, carboxymethylamino or lower alkoxycarbonylmethyl- amino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids, carboxy, lower alkoxycarbonyl, aminocarbonyl, hydroxylaminocarbonyl, tetrazolyl, nitro, cyano, or halo; or of formula (B) or (C)

wherein R ⁵ is hydrogen, trifluoromethyl, cylcopropyl, lower alkoxy, lower alkoxy-lower alkoxy, phenoxy, hydroxysulfonyl, aminosulfonyl, lower alkylsulfonyl, amino, lower alkylcarbonylamino, benzoylamino, carboxymethylamino or lower alkoxycarbonylmethyl- amino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids, carboxy, lower alkoxycarbonyl, aminocarbonyl, hydroxylaminocarbonyl, tetrazolyl, nitro, cyano, or halo; or of formula (D)

wherein R ⁶ is hydrogen, trifluoromethyl, cylcopropyl, lower alkoxy, lower alkoxy-lower alkoxy, phenoxy, hydroxysulfonyl, aminosulfonyl, lower alkylsulfonyl, amino, lower alkylcarbonylamino, benzoylamino, carboxymethylamino or lower alkoxycarbonylmethyl- amino substituted at the methyl group such that the resulting substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids, carboxy, lower alkoxycarbonyl, aminocarbonyl, hydroxylaminocarbonyl, tetrazolyl, nitro, cyano, or halo; or of formula (E)

wherein R ⁷ is hydrogen, lower alkyl, lower alkoxy-lower alkyl, lower alkylcarbonyl, optionally substituted phenylcarbonyl, or aminomethylcarbonyl substituted at the methyl group such that the resulting acyl group corresponds to one of the 20 naturally occurring standard amino acids;

R ^A , R ^B and R ^c are hydrogen, and R ^D is P0 ₂ (OH) ₂ ; and salts thereof; and such compounds for use in the prevention and treatment of infectious diseases, such as infectious diseases caused by virulent strains of E.coli, in particular urinary tract infections. Most preferred are the compounds of the examples.

A compound of the invention may be prepared by processes that, though not applied hitherto for the new compounds of the present invention, are known per se, in particular a process, wherein a compound of formula (I), wherein the hydroxy functions of the a-D- mannopyranoside are protected and wherein R ¹ is halogen, is condensed with a reagent replacing halogen by aryl, heteroaryl of heterocyclyl, the protective groups are removed, one of the mannoside hydroxy groups is converted into a phosphate ester and, if so desired, an obtainable compound of formula (I) is converted into another compound of formula (I), a free compound of formula (I) is converted into a salt, an obtainable salt of a compound of formula (I) is converted into the free compound or another salt, and/or a mixture of isomeric compounds of formula (I) is separated into the individual isomers. Suitable reagents for replacing halogen R ¹ by aryl, carbon-linked heteroaryl or carbon- linked heterocyclyl are, e.g., boronic acids in the presence of a palladium catalyst, a reaction known under the name of Suzuki reaction. Other reagents that can be used are described, for example, in M. Rubens, S.L. Buchwald, Accounts Chem. Res. 2008, 41, 1461 -1473.

Alternatively, halogen R ¹ may be replaced by cyano and the heteroaryl or heterocyclyl group constructed by addition and further ring elaboration starting by addition reactions to the cyano function, see, for example, N.A. Bokach, V.Y. Kukushkin, Russ. Chem. Bull. 2006, 55, 1869-1882.

Suitable reagents for replacing halogen R ¹ by nitrogen-linked heteroaryl or nitrogen-linked heterocyclyl are, e.g., the corresponding heteroaryl or heterocyclyl compound in the presence of strong base and optionally a catalyst, whereby halogen R ¹ is preferably iodine.

Introduction of a phosphate ester group may be performed by phosphoryl trichloride, which usually leads to the phosphate ester of the 6-hydroxy group (R ^D ). If an excess of reagent is used, mannosides with several phosphate functions are obtained. Selective hydrolysis then leads to phosphate ester functions in other positions, e.g. R ^A , R ^B or R ^c . The protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned. The protection of such functional groups by such protecting groups, the protecting groups themselves, and their removal reactions are described for example in standard reference books for peptide synthesis and in special books on protective groups such as T.W.

Greene & P.G.M. Wuts, "Protective Groups in Organic Synthesis", Wiley, 3 ^rd edition 1999. In the additional process steps, carried out as desired, functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protecting groups mentioned hereinabove under "protecting groups". The protecting groups are then wholly or partly removed according to one of the methods described there.

In the conversion of an obtainable compound of formula (I) into another compound of formula (I), an amino group may be alkylated or acylated to give the correspondingly substituted compounds. Alkylation may be performed with an alkyl halide or an activated alkyl ester. For methylation, diazomethane may be used. Alkylation may also be performed with an aldehyde under reducing conditions. For acylation the corresponding acyl chloride is preferred. Alternatively, an acid anhydride may be used, or acylation may be accomplished with the free acid under conditions used for amide formation known per se in peptide chemistry, e.g. with activating agents for the carboxy group, such as 1 -hydroxybenzotriazole, optionally in the presence of suitable catalysts or co-reagents. Furthermore amine may be transformed into heteroaryl and heterocyclyl under reaction conditions typical for such cyclizations.

A hydroxy group may be alkylated (etherified) or acylated (esterified) to give the correspondingly substituted compounds in a procedure related to the one described for an amino group. Alkylation may be performed with an alkyl halide or an activated alkyl ester. For methylation, diazomethane may be used. For acylation the corresponding acyl chloride or acid anhydride may be used, or acylation may be accomplished with the free acid and a suitable activating agent.

Reduction of a nitro group in a nitro-substituted aryl or heteroaryl group to give the corresponding amino group is done, e.g., with iron powder in alcohol or with other reducing agents.

A carboxy group in a carboxy-substituted aryl or heteroaryl group may be amidated under conditions used for amide formation known per se in peptide chemistry, e.g. with the corresponding amine and an activating agent for the carboxy group, such as 1 -hydroxy- benzotriazole, optionally in the presence of suitable catalysts or co-reagents.

A chloro, bromo or iodo substitutent in an aryl or heteroaryl group may be replaced by phenyl or a phenyl derivative by reaction with a suitable phenylboronic acid in a Suzuki reaction as described above.

Salts of a compound of formula (I) may be prepared in a manner known per se.

Phosphate salts of compounds of formula (I) may thus be obtained by treatment with an inorganic or organic base, for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.

Salts can usually be converted to free compounds, e.g. by treating with suitable acids. It should be emphasized that reactions analogous to the conversions mentioned in this chapter may also take place at the level of appropriate intermediates.

All process steps described here can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably such as are inert to the reagents used and able to dissolve these, in the absence or presence of catalysts, condensing agents or neutralising agents, for example ion exchangers, typically cation exchangers, for example in the H ⁺ form, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from -100°C to about 190°C, preferably from about -80°C to about 150°C, for example at -80 to +60°C, at -20 to +40°C, at room temperature, or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen.

Salts may be present in all starting compounds and transients, if these contain salt- forming groups. Salts may also be present during the reaction of such compounds, provided the reaction is not thereby disturbed.

At all reaction stages, isomeric mixtures that occur can be separated into their individual isomers, e.g. diastereomers or enantiomers, or into any mixtures of isomers, e.g.

racemates or diastereomeric mixtures.

The invention relates also to those forms of the process in which one starts from a compound obtainable at any stage as a transient and carries out the missing steps, or breaks off the process at any stage, or forms a starting material under the reaction conditions, or uses said starting material in the form of a reactive derivative or salt, or produces a compound obtainable by means of the process according to the invention and further processes the said compound in situ. In the preferred embodiment, one starts from those starting materials which lead to the compounds described hereinabove as preferred, particularly as especially preferred, primarily preferred, and/or preferred above all.

In the preferred embodiment, a compound of formula (I) is prepared according to or in analogy to the processes and process steps defined in the Examples.

The compounds of formula (I), including their salts, are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization, i.e. be present as solvates.

New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention. In the preferred embodiment, such starting materials are used and reaction conditions so selected as to enable the preferred compounds to be obtained.

Starting materials of formula (I) are known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art. In particular, compounds of formula (I) wherein R ¹ is halogen are obtained in a reaction of a suitably activated and protected oD-mannopyranoside, for example the corresponding trichloroacetimidate, or also 1 -haloglycosides or thioglycosides, with a phenol, benzyl alcohol or phenylethanol, respectively, bearing the proper substituents R ² and R ³ , and R ¹ as halogen.

The present invention relates also to pharmaceutical compositions that comprise a compound of formula (I) as active ingredient and that can be used especially in the treatment of infective diseases mentioned at the beginning. Compositions for enteral administration, such as nasal, buccal, rectal, uretal or, especially, oral administration to warm-blooded animals, especially humans, are preferred. The compositions comprise the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier. The dosage of the active ingredient depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.

The present invention relates especially to pharmaceutical compositions that comprise a compound of formula (I), a tautomer or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier.

The invention relates also to pharmaceutical compositions for use in a method for the prophylactic or especially therapeutic management of the human or animal body, in particular in a method of treating infective disease, especially those mentioned

hereinabove.

The invention relates also to processes and to the use of compounds of formula (I) thereof for the preparation of pharmaceutical preparations which comprise compounds of formula (I) as active component (active ingredient).

A pharmaceutical composition for the prophylactic or especially therapeutic management of an infective disease, of a warm-blooded animal, especially a human, comprising a novel compound of formula (I) as active ingredient in a quantity that is prophylactically or especially therapeutically active against the said diseases, is likewise preferred. Preferred are pharmaceutical compositions suitable for oral administration.

The pharmaceutical compositions comprise from approximately 1 % to approximately 95% active ingredient, single-dose administration forms comprising in the preferred embodiment from approximately 20% to approximately 90% active ingredient and forms that are not of single-dose type comprising in the preferred embodiment from approximately 5% to approximately 20% active ingredient. Unit dose forms are, for example, coated and uncoated tablets, suppositories, or capsules. Examples are capsules containing from about 0.05 g to about 1 .0 g active ingredient. The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.

Suitable carriers for the preferred orally available pharmaceutical formulations are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.

Tablet cores can be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropyl- methylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient. Pharmaceutical compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. The hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxy- ethylene sorbitan fatty acid ester type, may also be added.

Pharmaceutical compositions suitable for rectal administration are, for example, suppositories that consist of a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

The present invention relates furthermore to a method for the prevention and treatment of an infective disease, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the radicals and symbols have the meanings as defined above for formula (I), in a quantity effective against said disease, to a warm-blooded animal requiring such treatment. The compounds of formula (I) can be administered as such or especially in the form of orally available pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against the said diseases, to a warm-blooded animal, for example a human, requiring such treatment. In the case of an individual having a bodyweight of about 70 kg the daily dose administered is from approximately 0.01 g to approximately 1 g, preferably from

approximately 0.05 g to approximately 0.1 g, of a compound of the present invention.

The following Examples serve to illustrate the invention without limiting the invention in its scope.

Examples

General methods

Commercially available reagents were purchased from Fluka, Aldrich, Merck, AKSci, ASDI or Alfa Aesar. Methanol (MeOH) was dried by distillation from sodium methoxide. Dichloro- methane (DCM) was dried by filtration through Al ₂ 0 ₃ (Fluka, basic; 0.05-0.15 mm).

Toluene was dried by distillation from sodium/benzophenone.

NMR spectra were obtained on a Bruker Avance 500 UltraShield spectrometer at 500.13 MHz ( ¹ H) or 125.76 MHz ( ¹³ C). Chemical shifts are given in ppm and were calibrated on residual solvent peaks or to tetramethylsilane as internal standard. Multiplicities are specified as s (singulet), d (doublet), dd (doublet of a doublet), t (triplet), q (quartet) or m (multiplet). Assignment of the ¹ H and ¹³ C NMR spectra was achieved using 2D methods (COSY, HSQC).

Microanalyses were performed at the Department of Chemistry, University of Basel, Switzerland. ESI mass spectra were recorded on a Waters micromass ZQ instrument. High resolution mass spectra were obtained on an ESI Bruker Daltonics micrOTOF spectrometer equipped with a TOF hexapole detector.

Microwave-assisted reactions were carried out with a CEM Discover and Explorer.

Reactions were monitored by TLC using glass plates coated with silica gel 60 F ₂₅₄ (Fluka) and visualized by using UV light and/or by charring with a molybdate solution (a 0.02 M solution of ammonium cerium sulfate dihydrate and ammonium molybdate tetrahydrate in aqueous 10% H ₂ S0 ₄ ) with heating to 140°C for 5 min. Column chromatography was performed on a CombiFlash Companion (Teledyne-ISCO, Inc.) using RediSep normal phase disposable flash columns (silica gel). Reversed phase chromatography was performed on LiChroprep®RP-18 (Merck, 40-63 μηη). rt = room temperature.

Scheme 1 . Reagents and conditions: (i) 4-Phenylphenol, BF ₃ -Et ₂ 0, DCM, 40°C, overnight, 68%; (ii) NaOMe, MeOH, rt, 4 h, 83%; (iii) POCI ₃ , water, PO(OMe) ₃ , 0°C, 3 h, 40%. Example 1 : Biphenyl-4-yl 2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside (2)

To a solution of penta-O-acetyl-a-D-mannopyranoside (1 ) (1 .0 g, 3.4 mmol) and 4-phenyl- phenol (0.88 g, 5.2 mmol) in dry DCM (20 mL) was added BF ₃ -Et ₂ 0 (1.7 mL, 13.8 mmol) at rt, then the reaction mixture was heated to 40°C and stirred overnight. The reaction was quenched with satd. Na ₂ C0 ₃ (20 mL) and extracted with DCM (50 mL). The organic layer was washed with 0.5 N aq. NaOH (50 mL) and brine (50 mL), dried over Na ₂ S0 ₄ and concentrated. The residue was purified by flash chromatography (petrol ether/EtOAc) to afford 2 (1 .2 g, 68%) as a white solid.

R _f = 0.36 (petrol ether/EtOAc 2:1 ); ¹ H NMR (500 MHz, CDCI ₃ ): δ 2.03, 2.05, 2.06, 2.21 (4s, 12H, 4 OAc), 4.08-4.15 (m, 2H, H-5, H-6a), 4.29 (dd, 1 H, J = 5.2, 12.0 Hz, H-6b), 5.38 (t, 1 H, J = 10.0 Hz, H-4), 5.47 (dd, 1 H, J = 1 .8, 3.5 Hz, H-2), 5.57 (d, 1 H, J = 1.7 Hz, H-1 ), 5.59 (dd, 1 H, J = 3.6, 10.0 Hz, H-3), 7.15-7.18 (m, 2H, Ar), 7.33 (t, 1 H, J = 7.4 Hz, Ar), 7.43 (t, 2H, J = 7.5 Hz, Ar), 7.52-7.55 (m, 4H, Ar).

Example 2: Biphenyl-4-yl g-D-mannopyranoside (3)

To a solution of 2 (0.5 g, 1.0 mmole) in dry MeOH (10 mL) freshly prepared 1 N

NaOMe/MeOH (0.1 mL) was added at rt. After stirring for 4 h, the precipitates were filtered off and washed with cold MeOH, then the precipitates were dissolved in hot methanol and crystallized by cooling down to rt. This procedure was repeated once to give 3 (275 mg, 83%) as a white solid.

1H NMR (500 MHz, CD ₃ OD): δ 3.53 (ddd, 1 H, J = 2.5, 5.1 , 9.7 Hz, H-5), 3.61 -3.68 (m, 3H, H-4, H-6a, H-6b), 3.83 (dd, 1 H, J = 3.4, 9.5 Hz, H-3), 3.93 (dd, 1 H, J = 1.9, 3.4 Hz, H-2), 5.42 (d, 1 H, J = 1 .5 Hz, H-1 ), 7.08-7.1 1 (m, 2H, Ar), 7.18 (t, 1 H, J = 7.4 Hz, Ar), 7.30 (t, 2H, J = 7.5 Hz, Ar), 7.43-7.47 (m, 4H, Ar). Example 3: Disodium (biphenyl-4-yl g-D-mannopyranoside) 6-phosphate (4)

Compound 3 (200 mg, 0.6 mmol) was dissolved in trimethyl phosphate containing water (1 1 μί, 0.6 mmol), then phosphoryl trichloride (170 μί, 1 .8 mmol) was added dropwise at 0°C. The reaction mixture was stirred for 3 h in an ice bath. After addition of crushed ice the yellow solution was neutralized with concentrated aq. ammonia and the solvents were evaporated under diminished pressure. The residue was purified by chromatography as follows: Charcoal (0.5 g) and celite (0.5 g) were mixed together with aq. hydrochloric acid (2 N, 2 mL) and packed into a column. The residue was loaded onto the column and the inorganic salts were eluted with 400 mL of water until no chloride was detectable by observing turbidity on addition of silver nitrate solution. Then the phosphate 4 was eluted with pyridine-water (1 :2, 300 mL) and concentrated. The residue was dissolved in water and passed through a column of Dowex 50X8 (H ⁺ ). After lyophilization, the crude product was purified by RP-18 flash chromatography (H ₂ 0), converted into the sodium salt by passing through a column of Dowex 50X8 (Na ⁺ ), and further purified by P2 size-exclusion chromatography to give 4 (99 mg, 40%) as a white solid after final lyophilization. ¹ H NMR (500 MHz, D ₂ 0): δ 3.72-3.78 (m, 2H), 3.94-4.02 (3H), 4.13 (m, 1 H, H-2), 5.62 (s, 1 H, H-1 ), 7.20-7.21 (m, 2H, Ar), 7.35 (t, 1 H, J = 7.4 Hz, Ar), 7.44-7.47 (m, 2H, Ar), 7.62- 7.64 (m, 4H, Ar).

Scheme 2. Reagents and conditions: (i) 4-Methoxycarbonylphenylboronic acid,

Pd(CI ₂ )dppf-CH ₂ CI ₂ , K ₃ P0 ₄ , DMF, 80°C, overnight, 60%; (ii) NaOMe, MeOH, rt, 4 h, 12%; (iii) POCIs, water, PO(OMe) ₃ , 0°C, 3 h, 35%.

Example 4: Methyl 4'-(2,3,4,6-tetra-Q-acetyl- a-D-mannopyranosyloxy)-3'-chlorobiphenyl- 4-carboxylate (6)

A two-neck flask was charged with 5 (200 mg, 0.34 mmol), 4-methoxycarbonyl-phenyl- boronic acid (61 mg, 0.34 mmol), Pd(CI ₂ )dppf-CH ₂ CI ₂ (8 mg, 0.01 mmol) and K ₃ P0 ₄ (108 mg, 0.51 mmol). The vessel was evacuated and flushed with argon, then DMF (2 mL) was added. The reaction mixture was heated to 80°C, monitored by TLC, until compound 5 was almost consumed. The mixture was diluted with EtOAc (50 mL), washed with H ₂ 0 (50 mL) and brine (50 mL), dried over Na ₂ S0 ₄ and concentrated. The residue was purified by chromatography (petrol ether/EtOAc 2:3-1 :4) to afford 6 (120 mg, 60%) as a colorless oil.

¹ H NMR (CDC ): δ 2.03, 2.06, 2.20 (3s, 12H, 4 OAc), 3.92 (s, 3H, OCHs), 4.08 (dd, J = 2.4 Hz, 12.3 Hz, 1 H, H-6a), 4.17 (m, 1 H, H-5), 4.28 (dd, J = 5.4 Hz, 12.3 Hz, 1 H, H-6b), 5.39 (t, J = 10.6 Hz, 1 H, H-4), 5.54 (dd, J = 1.9 Hz, 3.4 Hz, 1 H, H-2), 5.59 (d, J = 1.8 Hz, 1 H, H-1 ), 5.62 (dd, J = 3.5 Hz, 10.1 Hz, 1 H, H-3), 7.24 (s, 1 H, Ar), 7.44 (dd, J = 2.2 Hz, 8.5 Hz, 1 H, Ar), 7.57 (d, J = 8.5 Hz, 2H, Ar), 7.65 (d, J = 2.2 Hz, 1 H, Ar), 8.08 (d, J = 8.5 Hz, 2H, Ar).

Example 5: Methyl 3'-chloro-4'-(a-D-mannopyranosyloxy)-biphenyl-4-carboxylate (7)

According to the procedure described for compound 3, compound 7 was prepared from 6 (764 mg, 1 .29 mmol) and purified by flash chromatography to give 7 (69 mg, 12%) as a white solid. ¹ H NMR (CDsOD): δ 3.64 (m, 1 H, H-5), 3.72 (m, 1 H, H-6a), 3.78 (m, 2, H-4, H-6b), 3.91 (s, 3H, OCHs), 4.00 (dd, J = 3.4 Hz, 9.5 Hz, 1 H, H-3), 4.1 1 (dd, J = 1 .8 Hz, 3.1 Hz, 1 H, H- 2), 5.60 (d, J = 1 .1 Hz, 1 H, H-1 ), 7.46 (d, J = 8.6 Hz, 1 H, Ar), 7.58 (dd, J = 2.2 Hz, 8.6 Hz, 1 H, Ar), 7.69 (d, J = 8.4 Hz, 2H, Ar), 7.72 (d, J = 2.2 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 2H, Ar).

Example 6: Disodium (4'-methoxycarbonyl-3-chloro-biphenyl-4-yl g-D-mannopyranoside) 6-phosphate (8)

According to the procedure described for compound 4, compound 8 was prepared from 7 (100 mg, 0.24 mmol) to give 8 (45 mg, 35%) as a white solid.

1H NMR (D2O): δ 3.84-4.20 (m, 4H, H-4, H-5, H-6a, H-6b), 3.98 (s, 3H, OCHs), 4.20-4.35 (m, 2H, H-2, H-3), 5.80 (s, 1 H, H-1 ), 7.66 (d, J = 8.6 Hz, 1 H, Ar), 7.78 (dd, J = 2.2 Hz, 8.6 Hz, 1 H, Ar), 7.89 (d, J = 8.4 Hz, 2H, Ar), 7.92 (d, J = 2.2 Hz, 1 H, Ar), 8.28 (d, J = 8.4 Hz, 2H, Ar).

Scheme 3. Reagents and conditions: (i) 5-Nitroindoline, Cs ₂ C0 ₃ , Pd ₂ (dba) ₃ , X-Phos, dioxane, Ac ₂ 0, pyridine, 80°C, 53 h, 56%; (ii) NaOMe, MeOH, rt, 23 h, 80%; (iii) POCI ₃ , water, PO(OMe) ₃ , 0°C, 3 h, 40%.

Example 7: 3-lodophenyl 2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside (9)

A dried flask was charged with 1 (2.00 g, 5.15 mmol) and 3-iodophenol (1 .36 g, 6.15 mmol) under argon. The reagents were dissolved in dry toluene under stirring. Then BF ₃ -Et ₂ 0 (125 μΙ_, 1.02 mmol) was added dropwise. The reaction mixture was stirred for 90 h at 40°C. Ice-cold NaOH solution (1 M, 40 mL) and toluene (50 mL) were added to the reaction mixture and the phases were separated. The organic layer was washed with brine (2 x 50 mL) and the aqueous layers were extracted with toluene (2 x 50 mL). The organic layers were combined and dried over Na ₂ S0 ₄ . Removal of the solvent by evaporation under reduced pressure left a residue that was purified by chromatography on silica gel (petrol ether/EtOAc 10:1.5-2:1 ) to give 9 (1 .57 g, 56%).

¹ H NMR (CDCI ₃ ): δ 2.02, 2.16 (2s, 12H, 4 OAc), 4.04 (m, 2H, H-5, H-6a), 4.25 (m, 1 H, H- 6b), 5.32 (t, J = 10.0 Hz, 1 H, H-4), 5.39 (dd, J = 1 .9 Hz, 3.5 Hz, 1 H, H-2), 5.47 (d, J = 1 .8 Hz, 1 H, H-1 ), 5.50 (dd, J = 3.5 Hz, 10.0 Hz, 1 H, H-3), 7.02 (m, 2H, Ar), 7.38 (d, J = 1.4 Hz, 7.3 Hz, 1 H, Ar), 7.47 (s, 1 H, Ar).

Example 8: 3-(5-Nitroindolin-1 -yl)phenyl 2,3,4,6-tetra-O-acetyl-g-D-mannopyranoside (10) A dry Schlenk tube was charged with Cs ₂ C0 ₃ (266 mg, 0.816 mmol). The tube was evacuated for 30 min and then flushed with argon and 9 (150 mg, 0.272 mmol) was added to the tube, followed by Pd ₂ (dba) ₃ (2.8 mg, 0.003 mmol) and X-Phos (6.5 mg, 0.014 mmol). The mixture was dissolved in dry dioxane (5 mL) and the solution was degassed in an ultrasonic bath for 20 min. Then 5-nitroindoline (67.3 mg, 0.41 mmol) was added and the mixture was stirred for 53 h at 80°C. TLC (petrol ether/EtOAc 3:1 ) and mass spectroscopy indicated the formation of partially deacetylated mannoside during the progress of the reaction. Therefore, dry pyridine (2 mL) and dry acetic anhydride (1 mL) were added 50 h after the reaction started to regain fully protected mannoside. Then EtOAc (30 mL) and satd. aq. NaHC0 ₃ solution (50 mL) were added to the reaction mixture. The layers were separated and the organic phase was washed with brine (2 x 50 mL). The aqueous layers were extracted with EtOAc (3 x 30 mL). The combined organic layers were dried with Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified with silica gel chromatography (petrol ether/EtOAc, 10:1 -1 :1 ) to give 10 (128 mg, 80%) as an orange solid.

1H NMR (CDCI ₃ ): δ 2.02, 2.20 (2s, 12H, 4 OAc), 3.21 (t, J = 8.5 Hz, 2H, CH ₂ ), 4.1 1 (m, 4H, CH ₂ , H-6a, H-5), 4.26 (dd, J = 7.3 Hz, 1 H, H-6b), 5.37 (t, J = 9.9 Hz, 1 H, H-4), 5.43 (s, 1 H, H-2), 5.53 (m, 2H, H-1 , H-3), 6.84 (d, J = 8.3 Hz, 1 H, Ar), 6.98 (m, 3H, Ar), 7.30 (t, J = 8.1 Hz, 1 H, Ar), 8.00 (s, 1 H, Ar), 8.05 (d, J = 8.8 Hz, 1 H, Ar). Example 9: 3-(5-Nitroindolin-1 -yl)phenyl g-D-mannopyranoside (11 )

Compound 10 (127 mg, 0.21 mmol) was dissolved in dry MeOH (5 mL), a freshly prepared solution of NaOMe/MeOH (1 M, 0.2 mL) was added and the reaction mixture was stirred at rt for 23 h. The solution was neutralized with glacial acetic acid and concentrated. The residue was purified by RP18 chromatography (H ₂ 0/MeOH) to yield 11 (68 mg, 60%).

¹ H NMR (CD ₃ OD): δ 3.07 (t, J = 8.6 Hz, 2H, CH2), 3.53 (m, 1 H, H-5), 3.66 (m, 3H, H-6a, H-6b, H-4), 3.81 (dd, J = 3.3 Hz, 9.4 Hz, 1 H, H-3), 3.92 (dd, J = 1 .72 Hz, 3.1 Hz, 1 H, H-2), 4.00 (t, J = 8.9 Hz, 2H, CH2), 5.40 (s, 1 H, H-1 ), 6.79 (d, J = 8.2 Hz, 1 H, Ar), 6.88 (m, 2H, Ar), 6.98 (s, 1 H, Ar), 7.22 (t, J = 8.2 Hz, 1 H, Ar), 7.85 (s, 1 H, Ar), 7.89 (d, 1 H, Ar). Example 10: Disodium [3-(5-nitroindolin-1 -yl)phenyl a-D-mannopyranosidel 6-phosphate (12)

According to the procedure described for compound 4, compound 12 was prepared from 11 (100 mg, 0.24 mmol) to give 11 (52 mg, 40%) as a white solid.

1H NMR (D ₂ 0): δ 3.07 (t, J = 8.6 Hz, 2H, CH ₂ ), 3.60-3.86 (m, 4H, H-4, H-5, H-6a, H-6b), 4.01 (m, 1 H, H-3), 4.12 (m, 1 H, H-2), 4.20 (t, J = 8.9 Hz, 2H, CH ₂ ), 5.60 (s, 1 H, H-1 ), 6.79 (d, J = 8.2 Hz, 1 H, Ar), 6.88 (m, 2H, Ar), 6.98 (s, 1 H, Ar), 7.22 (t, J = 8.2 Hz, 1 H, Ar), 7.85 (s, 1 H, Ar), 7.89 (d, 1 H, Ar).

Scheme 4. Reagents and conditions: (i) a. Cul, K ₂ C0 ₃ , L-proline, DMSO, 90°C, overnight; b. Ac ₂ 0/pyridine, DMAP, 4 h, 28%; (ii) NaOMe/MeOH, rt, 70%; (iii) POCI ₃ , water,

PO(OMe) ₃ , 0°C, 3 h, 30%.

Example 1 1 : 2-Chloro-4-(indol-1 -yl)phenyl g-D-mannopyranoside (14)

To a dry Schlenk tube compound 5 (146 mg, 0.25 mmol), Cul (10 mg, 0.05 mmol), indole (35 mg, 0.3 mmol), K ₂ C0 ₃ (86 mg, 0.625 mmol), L-proline (1 1 .5 mg, 0.1 mmol) and a stirring bar were added, and the reaction vessel was fitted with a rubber septum. The vessel was twice evacuated and flushed with argon. Then DMSO (2 mL) was added under a stream of argon. The reaction tube was quickly sealed and the contents were stirred at 90°C overnight. The reaction mixture was cooled to rt, diluted with EtOAc (10 mL), and filtered through a pad of celite. The filtrate was concentrated and the resulting crude mixture acetylated with Ac ₂ 0/pyridine for 4 h. The reaction was quenched by addition of MeOH, the mixture was concentrated and the residue was purified by chromatography on silica (petrol ether/EtOAc 4:1 -1 :1 ) to give 13 (40 mg, 28%). 13 (40 mg, 0.07 mmol) was dissolved in dry MeOH and treated at rt with 0.5 M MeONa/MeOH (14 μί) ίθΓ 5 h. The reaction mixture was neutralized with Amberlyst-15 and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica (DCM/MeOH 10:1 ) to afford 14 (20 mg, 70%) as a white solid.

¹ H NMR (CD ₃ OD): δ 3.69-3.81 (m, 4H, H-6a, H-4, H-6b, H-5), 4.01 (dd, J = 9.0, 2.5 Hz, 1 H, H-3), 4.14 (m, 1 H, H-2), 5.61 (s, 1 H, H-1 ), 6.65 (s, 1 H, Ar), 7.1 1 (t, J = 7.0 Hz, 1 H, Ar), 7.18 (t, J = 7.0 Hz, 1 H, Ar), 7.38-7.45 (m, 3H, Ar), 7.54-7.62 (m, 3H, Ar).

Example 12: Disodium (2-chloro-4-(indol-1 -yl)phenyl a-D-mannopyranoside) 6-phosphate (15)

According to the procedure described for compound 4, compound 15 was prepared from 14 (100 mg, 0.25 mmol) to give 15 (39 mg, 30%) as a white solid.

1H NMR (D ₂ 0): δ 3.89-4.01 (m, 4H, H-6a, H-4, H-6b, H-5), 4.21 (dd, J = 9.0, 2.5 Hz, 1 H), 4.34 (m, 1 H, H-2), 5.81 (s, 1 H, H-1 ), 6.85 (s, 1 H, Ar), 7.1 1 (t, J = 7.0 Hz, 1 H, Ar), 7.28 (t, J = 7.0 Hz, 1 H, Ar), 7.40-7.65 (m, 3H, Ar), 7.74-7.82 (m, 3H, Ar).

Scheme 5. Reagents and conditions: (i) ROH, BF ₃ -Et ₂ 0, DCM, 0°C, 3 h, 40%; (ii) NaOMe, MeOH, rt, 4 h, 36%; (iii) POCI ₃ , water, PO(OMe) ₃ , 0°C, 3 h, 40%.

Example 13: Methyl 5-r4-(2,3,4,6-tetra-0-acetyl-a-D-mannopyranosyloxy)phenyll-2 - pyridinecarboxylate (17)

To an ice-cold solution of methyl 5-(4-hydroxyphenyl)-pyridine-2-carboxylate (100 mg, 0.44 mmol) and 16 (304 mg, 0.87 mmol) in dry DCM (5 mL) was added BF ₃ -Et ₂ 0

(0.33 mL, 2.62 mmol), and the mixture was stirred at 0°C for 3 h. The reaction was quenched with satd. aq. Na ₂ C0 ₃ (50 mL), extracted with DCM (50 mL), and the organic layer was washed with 0.5 N aq. NaOH (50 mL) and brine (50 mL). The organic layer was dried over Na ₂ S0 ₄ and concentrated. The residue was purified by chromatography (petrol ether/EtOAc 4:1 -1 :1 ) to afford 17 (100 mg, 40%) as colorless oil.

¹ H NMR (500 MHz, CDCI ₃ ): δ 2.05, 2.06, 2.07, 2.23 (4s, 12H, 4 OAc), 4.04 (s, 3H, OCH ₃ ), 4.08-4.1 1 (m, 2H, H-5, H-6a), 4.30 (dd, J = 5.0, 12.4 Hz, 1 H, H-6b), 5.41 (t, J = 10.1 Hz, 1 H, H-4), 5.48 (dd, J = 1 .9, 3.5 Hz, 1 H, H-2), 5.59 (dd, J = 3.6, 10.1 Hz, 1 H, H-3), 5.60 (d, J = 1.8 Hz, 1 H, H-1 ), 7.23-7.25 (m, 2H, Ar), 7.58-7.61 (m, 2H, Ar), 7.99 (dd, J = 2.4, 8.2 Hz, 1 H, Ar), 8.20 (dd, J = 0.6, 8.2 Hz, 1 H, Ar), 8.93 (dd, J = 0.5, 2.2 Hz, 1 H, Ar). Example 14: Methyl 5-r4-(a-D-mannopyranosyloxy)phenyll-2-pyridinecarboxylate (18) Compound 18 was synthesized in a similar procedure as 3. Starting from 17 (60 mg, 0.1 1 mmol) 18 (15 mg, 36%) was obtained as a white solid.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 3.40 (m, 1 H, H-5), 3.45-3.53 (m, 2H, H-4, H-6a), 3.61 (dd, J = 6.1 , 10.3 Hz, 1 H, H-6b), 3.71 (m, 1 H, H-3), 3.86 (bs, 1 H, H-2), 3.91 (s, 3H, OCH ₃ ), 4.49 (t, J = 6.0 Hz, 1 H, OH-6), 4.82 (d, J = 5.8 Hz, 1 H, OH-3), 4.88 (d, J = 5.8 Hz, 1 H, OH- 4), 5.09 (m, 1 H, OH-2), 5.47 (d, J = 1 .4 Hz, 1 H, H-1 ), 7.24-7.26 (m, 2H, Ar), 7.78-7.80 (m, 2H, Ar), 8.1 1 (d, J = 8.2 Hz, 1 H, Ar), 8.25 (dd, J = 2.3, 8.3 Hz, 1 H, Ar), 9.03 (d, J = 2.2 Hz, 1 H, Ar).

Example 15: Disodium (2'-methoxycarbonyl-5'-pyridinyl-4-phenyl g-D-mannopyranoside) 6-phosphate (19)

According to the procedure described for compound 4, compound 19 was prepared from 18 (100 mg, 0.26 mmol) to give 19 (53 mg, 40%) as a white solid.

1H NMR (D ₂ 0): δ 3.30-3.81 (m, 4H, H-4, H-5, H-6a, H-6b), 3.72 (m, 1 H, H-3), 3.94 (m, 1 H, H-2), 3.91 (s, 3H, OCH ₃ ), 5.67 (d, J = 1 .4 Hz, 1 H, H-1 ), 7.24-7.26 (m, 2H, Ar), 7.78-7.80 (m, 2H, Ar), 8.1 1 (d, J = 8.2 Hz, 1 H, Ar), 8.25 (dd, J = 2.3, 8.3 Hz, 1 H, Ar), 9.03 (d, J = 2.2 Hz, 1 H, Ar).

Scheme 6. Reagents and conditions: (i) benzaldehyde dimethylacetal, p-TsOH,

MeCN/DMF (10:1 ), 50°C, overnight, 70%; (ii) a. dibutyltin oxide, toluene, reflux, 3 h; b. BnBr, toluene, 1 15°C overnight, 80%; (iii) 1 ,2,4-triazole, dibenzyl N,N- diisopropylphosphoramidite (90%), ί-BuOOH, CH ₃ CN, 62%; (iv) a. Pd(OH) ₂ /C, EtOAc, cat. HOAc, H ₂ (4 bar); b. 25% aq. NH ₃ /MeOH, 45%.

Example 16: Biphenyl-4yl 4,6-O-benzylidene-a-D-mannopyranoside (20)

To a mixture of 3 (1 .16 g, 3.51 mmol) and benzaldehyde dimethylacetal (1 .58 mL, 10.5 mmoL) in dry acetonitrile/DMF (10 mL/1 mL) was added p-toluenesulfonic acid (40 mg). The reaction mixture was stirred at 80°C overnight and then neutralized with aq. NaHC0 ₃ . The reaction mixture was diluted with DCM, washed with water (3 x) and brine. The organic layer was dried over Na ₂ S0 ₄ and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM/MeOH 20:1 -9:1 ) to afford 20 (1 .03 g, 70%) as a white solid.

[a] _D ²⁰ +163.1 (C 1.09, CHCI ₃ /MeOH 1 :1 ); ¹ H NMR (CDCI ₃ , 500 MHz): δ 3.83 (t, J = 10.0 Hz, 1 H, H-6a), 3.99 (td, J = 4.5, 9.5 Hz, 1 H, H-5), 4.04 (t, J = 9.5 Hz, 1 H, H-4), 4.22 (dd, J = 5.0, 10.0 Hz, 1 H, H-6b), 4.28 (m, 1 H, H-2), 4.33 (dd, J = 3.5, 9.5 Hz, 1 H, H-3), 5.60 (s, 1 H, PhCH), 5.66 (m, 1 H, H-1 ), 7.13 (m, 2H, Ar-H), 7.31 -7.50 (m, 8H, Ar-H), 7.55 (m, 4H, Ar-H); ¹³ C NMR (CDCI ₃ , 125 MHz) δ 63.77 (C-5), 68.56 (C-3), 68.66 (C-6), 70.85 (C-2), 78.71 (C-4), 98.06 (C-1 ), 102.34 (PhCH), 1 16.62, 126.27, 126.84, 126.95, 128.29, 128.36, 128.75, 128.99, 129.31 , 129.74, 134.45, 135.69, 137.12, 140.52, 155.35 (Ar-C); ESI-MS calcd for C ₂₅ H ₂₄ Na0 ₆ [M+Na] ⁺ : 443.15, found: 443.12.

Example 17: Biphenyl-4-yl 3-0-benzyl-4,6-0-benzylidene-a-D-mannopyranoside (21 ) A suspension of 20 (380 mg, 0.9 mmol) and dibutyltin oxide (247 mg, 0.99 mmol) in dry toluene (6 mL) was refluxed at 135°C for 3 h. The mixture was concentrated to dryness, then TBAB (320 mg, 0.99 mmol), BnBr (0.13 mL, 1.08 mmol) and dry toluene (6 mL) were added. The reaction mixture was stirred at 1 15°C overnight, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (petrol ether/EtOAc 6:1 -4:1 ) to afford 21 (370 mg, 80%) as a white solid.

[a] _D ²⁰ +139.6 (C 2.66, CHCI ₃ ); ¹ H NMR (CDCI ₃ , 500 MHz): δ 3.87 (t, J = 10.5 Hz, 1 H, H- 6a), 4.01 (td, J = 5.0, 10.0 Hz, 1 H, H-5), 4.17 (dd, J = 3.0, 9.5 Hz, 1 H, H-3), 4.20-4.26 (m, 2H, H-6b, H-4), 4.31 (dd, J = 1.5, 3.0 Hz, 1 H, H-2), 4.82, 4.97 (2 d, J = 12.0 Hz, 2H,

OCH ₂ Ph), 5.66 (s, 1 H, PhCH), 5.69 (d, J = 1.0 Hz, 1 H, H-1 ), 7.13 (m, 2H, Ar-H), 7.37-7.46 (m, 10H, Ar-H), 7.51 -7.58 (m, 7H, Ar-H); ¹³ C NMR (CDCI ₃ , 125 MHz) δ 64.01 (C-5), 68.71 (C-6), 69.97 (C-2), 73.26 (OCH ₂ Ph), 75.43 (C-3), 78.73 (C-4), 97.91 (C-1 ), 101.68

(PhCH), 126.07, 126.84, 126.95, 126.99, 127.85, 127.95, 128.01 , 128.23, 128.28, 128.54, 128.75, 128.82, 128.96, 129.00, 129.75, 134.45, 135.68, 137.44, 137.94, 140.53, 155.29 (Ar-C); ESI-MS calcd for C ₃₂ H ₃₀ NaO ₆ [M+Na] ⁺ : 533.19, found: 533.17. Example 18: Dibenzyl (biphenyl-4-yl 3-0-benzyl-4,6-0-benzylidene-a-D- mannopyranoside) 2-phosphate (22)

To a mixture of 21 (194 mg, 0.25 mmol) and 1 ,2,4-triazole (69.5 mg, 1.0 mmol) in dry acetonitrile (3.0 mL) was added dibenzyl Λ/,/V-diisopropylphosphoramidite (90%) (187 μΙ_, 0.5 mmol) at 0°C. The reaction mixture was stirred at 0°C for 20 minutes and further stirred at rt under argon for 29 h. Then ie f-butylhydroperoxide (150 μΙ_) was added to the reaction mixture at 0°C and the mixture was stirred vigorously at rt for 1 h. The mixture was quenched with 1 M aq. Na ₂ S ₂ 0 ₃ and 1 M aq. NaHC0 ₃ , and extracted with DCM. The combined organic phases were washed with brine and dried over Na ₂ S0 ₄ . The solvent was removed under reduced pressure and the residue was purified by flash

chromatography on silica gel (toluene/EtOAc 24:1-15:1 ) to afford 22 (120 mg, 62%) as a white solid.

¹ H NMR (CDCIs, 500 MHz): δ 3.81 (t, J = 10.5 Hz, 1 H, H-6a), 3.99 (td, J = 5.0, 10.0 Hz, 1 H, H-5), 4.1 1 (t, J = 10.0 Hz, 1 H, H-4), 4.22 (m, 2H, H-3, H-6b), 4.85 (m, 2H, OCH ₂ Ph), 5.30 (m, 1 H, H-2), 5.08-5.12 (m, 4H, OCH ₂ Ph), 5.62 (m, 2H, H-1 , PhCH), 7.03 (m, 2H, Ar- H), 7.26-7.58 (m, 27H, Ar-H); ¹³ C NMR (CDCI ₃ , 125 MHz) δ 64.63 (C-5), 68.51 (C-6), 69.52 (d, J = 5.5 Hz, OCH ₂ Ph), 69.60 (d, J = 5.5 Hz, OCH ₂ Ph), 72.81 (OCH ₂ Ph), 73.88 (d, J = 4.75 Hz, C-3), 74.61 (d, J = 5.5 Hz, C-2), 78.19 (C-4), 97.24 (d, J = 2.88 Hz, C-1 ), 101 .58 (PhCH), 1 16.78, 126.04, 126.84, 126.94, 126.98, 127.59, 127.68, 127.74, 127.85, 127.92, 128.19, 128.22, 128.32, 128.45, 128.52, 128.56, 128.74, 128.94, 135.66, 135.71 , 135.76, 135.82, 135.93, 137.35, 137.51 , 137.95, 140.46, 155.01 (Ar-C); ESI-MS calcd for C ₄₆ H ₄₄ 0 ₉ P [M+H] ⁺ : 771.27, found: 771 .37. Example 19: Diammonium (biphenyl-4-yl g-D-mannopyranoside) 2-phosphate (23)

A solution of 22 (100 mg, 0.129 mmol) in EtOAc (6.0 mL) in the presence of 10% Pd(OH) ₂ (12 mg) and HOAc (50 μί) was hydrogenated (4 bar H ₂ ) at rt overnight. Then the suspension was filtered through celite, and the filtrate was concentrated in vacuo. The residue was stirred in 25% aq. NH ₃ /MeOH overnight, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (DCM/MeOH/H ₂ 0 6:4:0.6) to provide 23 (26 mg, 45%) as white solid.

[a] _D ²⁰ +66.7 (c 0.12, H ₂ 0); ¹ H NMR (D ₂ 0, 500 MHz): δ 3.77-3.82 (m, 3H, H-5, H-6a, H-6b), 3.87 (t, J = 10.0 Hz, 1 H, H-4), 4.14 (ddd, J = 2.0, 3.0, 10.0 Hz, 1 H, H-3), 4.62 (ddd, J = 2.0, 3.0, 8.5 Hz, 1 H, H-2), 5.89 (d, J = 1.5 Hz, 1 H, H-1 ), 7.31 (m, 2H, Ar-H), 7.44 (m, 1 H, Ar-H), 7.55 (t, J = 7.5 Hz, 2H, Ar-H), 7.71 (m, 4H, Ar-H); ¹³ C NMR (D ₂ 0, 125 MHz) δ 60.46 (C-6), 66.60 (C-4), 70.06 (d, J = 4.88 Hz, C-3), 73.53 (C-5), 73.59 (d, J = 5.13 Hz, C-2), 96.96 (d, J = 2.5 Hz, C-1 ), 1 17.27, 1 17.56, 126.67, 127.36, 128.01 , 128.21 , 129.1 1 , 135.29, 139.95, 155.03 (Ar-C); ESI-MS calcd for Ci ₈ H ₂ o0 ₉ P [M-H]-: 41 1 .08, found: 41 1.06.

Scheme 7. Reagents and conditions: (i) a. dibutyltin oxide, MeOH, reflux, 5 h; b. BnBr, toluene, 1 15°C overnight, 36%; (ii) Pyr/BzCI, DMAP, 99%; (iii) Pd(OH) ₂ /C, dioxane/EtOAc, cat. HOAc, H ₂ , 4 bar, 73%; (iv) 1 ,2,4-triazole, dibenzyl Λ/,/V-diisopropylphosphoramidite (90%), CH ₃ CN, 80% (mixture of 2-and 3-phosphate); (v) Pd(OH) ₂ /C, EtOH/EtOAc, 5 h, H ₂ , quant.; (vi) 25% aq. NH ₃ /MeOH (1 :4), overnight, 85%.

Example 20: Biphenyl-4-yl 3-O-benzyl-a-D-mannopyranoside (24)

A mixture of 3 (665 mg, 2.0 mmol) and dibutyltin oxide (548 mg, 2.2 mmol) was dissolved in dry MeOH (10 mL). The reaction mixture was refluxed for 5 h and concentrated to dryness under reduced pressure. To a solution of the residue in dry toluene (10 mL) were added tetrabutylammonium bromide (TBAB, 709 mg, 2.2 mmol) and benzyl bromide (285 μΙ_, 2.4 mmol). The mixture was stirred at 1 15°C overnight, concentrated to dryness, and purified by chromatography on silica gel (petrol ether/EtOAc 4:1 -1 :3) to give 24 (306 mg, 36%) as white solid.

[a] _D ²⁰ +99.8 (c 1.38, CHCI ₃ ); ¹ H NMR (CDCI ₃ , 500 MHz): δ 3.00 (s, 3H, 2,4,6-OH), 3.71 (m, 2H, H-5, H-6a), 3.81 (m, 1 H, H-6b), 3.96 (dd, J = 3.0, 9.5 Hz, 1 H, H-3), 4.17 (m, 2H, H-2, H-4), 4.70 (d, J = 1 1 .5 Hz, 1 H, OCH ₂ Ph), 4.79 (d, J = 1 1 .5 Hz, 1 H, OCH ₂ Ph), 5.65 (d, J = 1.5 Hz, 1 H, H-1 ), 7.10 (m, 2H, Ar-H), 7.31 -7.44 (m, 8H, Ar-H), 7.50-7.52 (m, 1 1 H, Ar- H); ¹³ C NMR (CDCI ₃ , 125 MHz) δ 61 .47 (C-6), 65.52 (C-4), 67.87 (C-2), 72.32 (OCH ₂ Ph), 72.76 (C-5), 79.42 (C-3), 97.69 (C-1 ), 1 16.62, 126.81 , 126.93, 128.26, 128.29, 128.34, 128.70, 128.75, 135.60, 137.39, 140.49, 155.42 (Ar-C); ESI-MS calcd for C ₂₅ H ₂₆ Na0 ₆ [M+Na] ⁺ : 445.16, found: 445.14.

Example 21 : Biphenyl-4-yl 2,4,6-tri-0-benzoyl-3-0-benzyl-a-D-mannopyranoside (25) To a solution of 24 (290 mg, 0.686 mmol) in pyridine (5.0 mL) were added benzoyl chloride (0.40 mL, 3.43 mmol) and DMAP (4.19 mg) at rt. The reaction mixture was stirred at rt overnight, then the reaction was quenched with MeOH and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petrol ether/EtOAc 4:1 -3:1 ) to give 25 (499 mg, 99%) as white solid.

[a] _D ²⁰ +7.1 (c 1.52, CHCI ₃ ); ¹ H NMR (CDCI ₃ , 500 MHz): δ 4.40-4.46 (m, 3H, H-6a, H-3, H- 5), 4.62-4.65 (m, 2H, OCH ₂ Ph, H-6b), 4.79 (d, J = 12.4 Hz, 1 H, OCH ₂ Ph), 5.80 (d, J = 2.0 Hz, 1 H, H-1 ), 5.91 (dd, J = 2.0, 3.0 Hz, 1 H, H-2), 5.97 (t, J = 10.0 Hz, 1 H, H-4), 7.12-7.23 (m, 7H, Ar-H), 7.34 (m, 3H, Ar-H), 7.42-7.54 (m, 1 1 H, Ar-H), 7.61 (m, 2H, Ar-H), 8.03 (m, 4H, Ar-H), 8.16 (m, 2H, Ar-H); ¹³ C NMR (CDCI ₃ , 125 MHz) δ 63.04 (C-6), 68.01 (C-4), 68.51 (C-5), 69.60 (C-2), 71 .27 (OCH ₂ Ph), 74.14 (C-3), 96.25 (C-1 ), 1 16.85, 126.77, 126.99, 127.69, 127.87, 128.21 , 128.27, 128.28, 128.34, 128.50, 128.72, 129.36, 129.39, 129.70, 129.80, 129.92, 129.99, 132.91 , 133.32, 133.42, 135.93, 137.33, 140.32, 155.18 (Ar-C), 165.38, 165.68, 166.08 (3 CO); ESI-MS calcd for C ₄ 6H ₃₈ Na0 ₉ [M+Na] ⁺ : 757.24, found: 757.29. Example 22: Biphenyl-4-yl 2,4,6-tri-O-benzoyl-a-D-mannopyranoside (26)

A solution of 25 (499 mg, 0.679 mmol) in dioxane/EtOAc (5 mL/1 mL) in the presence of 10% Pd(OH) ₂ (50 mg) and HOAc (50 μΐ) was hydrogenated (4 bar H ₂ ) at rt overnight. The reaction suspension was filtered through celite, the filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (petrol ether/EtOAc 9:1 -4:1 ) to give 26 (314 mg, 73%) as colorless syrup. [a] _D ²⁰ +56.5 (c 1.02, CHCI ₃ ); ¹ H NMR (CDCI ₃ , 500 MHz): δ 2.58 (d, J = 8.0 Hz, 1 H, 3-OH), 4.48 (m, 2H, H-5, H-6a), 4.64 (m, 2H, H-3, H-6b), 5.66 (dd, J = 2.0, 3.5 Hz, 1 H, H-2), 5.77 (t, J = 9.5 Hz, 1 H, H-4), 5.82 (d, J = 2.0 Hz, 1 H, H-1 ), 7.22 (m, 2H, Ar-H), 7.31 -7.35 (m, 3H, Ar-H), 7.42-7.53 (m, 1 1 H, Ar-H), 7.61 (m, 2H, Ar-H), 7.97 (dd, J = 1 .0, 8.0 Hz, 2H, Ar- H), 8.10 (m, 4H, Ar-H); ¹³ C NMR (CDCI ₃ , 125 MHz) δ 62.95 (C-6), 69.21 , 69.01 (C-5, C-3), 70.21 (C-4), 72.58 (C-2), 95.73 (C-1 ), 1 16.83, 126.82, 127.02, 128.28, 128.36, 128.58, 128.76, 129.70, 129.93, 129.96, 133.06, 133.69, 133.73, 136.01 , 140.38, 155.25 (Ar-C), 165.86, 166.07, 166.85 (3 CO); ESI-MS calcd for [M+Na] ⁺ : 667.29, found: 667.19.

Example 23: Dibenzyl (biphenyl-4-yl 2,4,6-O-tribenzoyl-a-D-mannopyranoside) 3- phosphate (27)

To a mixture of 26 (21 1 mg, 0.335 mmol) and 1 ,2,4-triazole (92.5 mg, 1 .34 mmol) in dry acetonitrile (5.0 mL) was added dibenzyl Λ/,/V-diisopropylphosphoramidite (90%) (0.25 mL, 0.67 mmol) at 0°C. The reaction mixture was stirred at 0°C for 20 min and further stirred at rt under argon for 24 h. Then ie f-butylhydroperoxide (190 μί, 1.34 mmol) was added to the reaction mixture at 0°C and the solution was stirred vigorously at rt for 1 h. The mixture was quenched with 1 M aq. Na ₂ S ₂ 0 ₃ and 1 M aq. NaHC0 ₃ , and then extracted with DCM. The combined organic phases were washed with brine and dried over Na ₂ S0 ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (petrol ether/EtOAc 6:1 -4:1 ) to afford a mixture of 2- dibenzylphosphate and 27 (3:2, by NMR) (245 mg, 80%) as white solid.

1H NMR (CDCI ₃ , 500 MHz): δ 4.62 (m, 2H, H-5, H-6a), 4.76 (dd, J = 12.0, 7.5 Hz, 1 H, H- 6b), 4.85-5.1 1 (m, 4H, OCH ₂ Ph), 5.55 (td, J = 3.5, 9.0 Hz, 1 H, H-3), 5.81 (d, J = 1 .5 Hz, 1 H, H-1 ), 5.87 {dd, J = 1 .9, 3.4 Hz, 1 H, H-2), 6.04 (m, 1 H, H-4), 6.92-8.1 1 (m, 34 H, Ar-H); ¹³ C NMR (CDCI ₃ , 125 MHz) δ 62.76 (C-5), 67.58 (d, J = 5.63 Hz, C-4), 69.51 (C-6), 69.75 (d, J = 5.63 Hz, OCH ₂ Ph), 69.81 (d, J = 6.0 Hz, OCH ₂ Ph), 70.95 (d, J = 2.0 Hz, C-2), 73.69 (d, J = 5.13 Hz, C-3), 95.69 (C-1 ), 1 16.82, 126.82, 127.55, 127.67, 127.85, 127.96, 128.20, 128.23, 128.27, 128.32, 128.41 , 128.50, 128.54, 128.57, 128.62, 129.71 , 129.85, 129.99, 132.99, 133.48, 133.64, 136.09, 140.35, 155.08 (Ar-C), 165.35, 165.46, 166.01 (3 CO); ESI-MS calcd for C ₅₃ H ₄₅ NaOi ₂ P [M+Na] ⁺ : 927.25, found: 927.23.

Example 24: Diammonium (biphenyl-4-yl-a-D-mannopyranoside) 3-phosphate (29)

A solution of 27 (130 mg, mixture with 2-dibenzylphosphate) in EtOAc (6 mL) containing 10% Pd(OH) ₂ (15 mg) was hydrogenated (1 atm H ₂ ) at rt for 5 h. Then the reaction suspension was filtered through celite and the filtrate was concentrated under vacuo. The intermediate 28 was dissolved in 25% aq. NH ₃ /MeOH (4:1 ) and the mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (DCM/MeOH/H ₂ 0 6:4:0.6) to give 29 (4.5 mg) as white solid and a mixture of 29 and 23 (42 mg).

1H NMR (D ₂ 0, 500 MHz): δ 3.75-3.83 (m, 3H, H-5, H-6a, H-6b), 3.92 (t, J = 9.5 Hz, 1 H, H- 4), 4.39 (m, 1 H, H-2), 4.55 (dt, J = 3.0, 9.0 Hz, 1 H, H-3), 5.72 (s, 1 H, H-1 ), 7.32 (m, 2H, Ar-H), 7.45 (m, 1 H, Ar-H), 7.54 (t, J = 7.5 Hz, 2H, Ar-H), 7.71 (m, 4H, Ar-H); ¹³ C NMR (D ₂ 0, 125 MHz) δ 61 .38 (C-6), 66.92 (d, J = 3.0 Hz, C-4), 70.02 (d, J = 2.88 Hz, C-2), 73.96 (C-5), 75.03 (d, J = 5.0 Hz, C-3), 98.52 (C-1 ), 1 18.13, 1 18.25, 127.31 , 127.34, 128.00, 128.83, 129.76, 135.82, 140.62, 155.73 (Ar-C); ESI-MS calcd for Ci ₈ H ₂ o0 ₉ P [M- H] ^" : 41 1.08, found: 41 1 .06.

Scheme 8. Reagents and conditions: (i) Pyr/BzCI, DMAP, 60%; (ii) Me ₃ N ^« BH ₃ , AICI ₃ , THF/H ₂ 0, rt, 67%; (iii) 1 ,2,4-triazole, dibenzyl Λ/,/V-diisopropylphosphoramidite (90%), CH ₃ CN, 53%; (iv) Pd(OH) ₂ /C, EtOAc, 5 h, H ₂ , quant.; (v) 25% aq. NH ₃ /MeOH (1 :4), overnight, 56%. Example 25: Biphenyl-4-yl 4,6-0-benzylidene-2,3-0-dibenzoyl-a-D-mannopyranoside (30) To a solution of 20 (300 mg, 0.71 mmol) in pyridine (5 mL) were added BzCI (0.33 mL, 2.85 mmol) and DMAP (4.35 mg) at rt. The reaction mixture was stirred at rt overnight, quenched with MeOH and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with (petrol ether/EtOAc 6:1 -4:1 ) to give 30 (270 mg, 60%) as white solid.

[a] _D ²⁰ +21.8 (c 1 .08, CHCI ₃ ); ¹ H NMR (CDCI ₃ , 500 MHz): δ 4.00 (t, J = 9.5 Hz, 1 H, H-6a), 4.32-4.38 (m, 2H, H-6b, H-5), 4.48 (t, J = 9.5 Hz, 1 H, H-4), 5.73 (s, 1 H, PhCH), 5.82 (d, J = 1 .5 Hz, 1 H, H-1 ), 5.97 (dd, J = 1 .5, 3.5 Hz, 1 H, H-2), 6.10 (dd, J = 3.5, 10.5 Hz, 1 H, H- 3), 7.25 (m, 2H, Ar-H), 7.35-7.39 (m, 6H, Ar-H), 7.45-7.61 (m, 1 1 H, Ar-H), 7.68 (t, J = 7.5 Hz, 1 H, Ar-H), 7.99 (m, 2H, Ar-H), 8.17 (m, 2H, Ar-H); ¹³ C NMR (CDCI ₃ , 125 MHz) δ 64.60 (C-5), 68.67 (C-6), 68.80 (C-3), 70.78 (C-2), 76.64 (C-4), 96.69 (C-1 ), 101 .97 (PhCH), 1 16.79, 126.14, 126.85, 126.97, 128.18, 128.25, 128.32, 128.43, 128.62, 128.73, 129.04, 129.30, 129.57, 129.76, 129.87, 130.14, 133.09, 133.63, 136.03, 136.95, 140.45, 155.14 (Ar-C), 165.36, 165.45 (2 CO); ESI-MS calcd for C ₃₉ H ₃₂ Na0 ₈ [M+Na] ⁺ : 651.20, found: 651 .17.

Example 26: Biphenyl-4-yl 2,3-0-dibenzoyl-6-0-benzyl-a-D-mannopyranoside (31 )

To a solution of 30 (270 mg, 0.429 mmol) in dry THF (4.0 mL) was added Me ₃ N ^« BH ₃ (125 mg, 1.72 mmol) at rt followed by AICI ₃ (340.8 mg, 2.56 mmoL). After 15 min, water (15.5 μΙ_) was added and the reaction mixture was stirred at rt for another 45 min. The reaction was quenched with 1 N aq. HCI, diluted with DCM, the organic layer was washed with water and brine, and dried over Na ₂ S0 ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (petrol ether/EtOAc 6:1 -3:1 ) to afford 31 (178 mg, 67%) as a white solid.

[a] _D ²⁰ +10.8 (c 1 .21 , CHCI ₃ ); ¹ H NMR (CDCI ₃ , 500 MHz): δ 4.00 (t, J = 9.5 Hz, 1 H, H-6a), 4.32-4.38 (m, 2H, H-6b, H-5), 4.48 (t, J = 9.5 Hz, 1 H, H-4), 5.73 (s, 1 H, PhCH), 5.82 (d, J = 1 .5 Hz, 1 H, H-1 ), 5.97 (dd, J = 1 .5, 3.5 Hz, 1 H, H-2), 6.10 (dd, J = 3.5, 10.5 Hz, 1 H, H- 3), 7.25 (m, 2H, Ar-H), 7.35-7.39 (m, 6H, Ar-H), 7.45-7.61 (m, 1 1 H, Ar-H), 7.68 (t, J = 7.5 Hz, 1 H, Ar-H), 7.99 (m, 2H, Ar-H), 8.17 (m, 2H, Ar-H); ¹³ C NMR (CDCI ₃ , 125 MHz) δ 67.35 (C-4), 69.78 (C-6), 70.33 (C-2), 72.03 (C-5), 72.61 (C-3), 73.75 (OCH ₂ Ph), 95.99 (C-1 ), 1 16.82, 126.86, 126.95, 127.56, 127.70, 128.29, 128.40, 128.58, 128.74, 129.88, 129.92, 133.37, 133.53, 135.86, 137.93, 140.52, 155.43 (Ar-C), 165.46, 166.66 (2 CO); ESI-MS calcd for C ₃₉ H ₃₄ Na0 ₈ [M+Na] ⁺ : 653.22, found: 653.25.

Example 27: Dibenzyl (biphenyl-4-yl 2,3-0-dibenzoyl-6-0-benzyl-a-D-mannopyranoside) 4-phosphate (32)

To a mixture of 31 (160 mg, 0.253 mmol) and 1 ,2,4-triazole (70 mg, 1 .01 mmol) in dry acetonitrile (2.0 mL) was added dibenzyl Λ/,/V-diisopropylphosphoramidite (90%) (190 μΐ, 0.51 mmol) at 0°C. The reaction mixture was stirred at 0°C for 20 min and further stirred at rt under argon for 16 h. Then ie f-butylhydroperoxide (200 μΙ_) was added to the reaction mixture at 0°C and the mixture was stirred vigorously at rt for 1 h. The reaction was quenched with 1 M aq Na ₂ S ₂ 0 ₃ and 1 M aq NaHC0 ₃ , and then extracted with DCM. The combined organic phases were washed with brine and dried over Na ₂ S0 ₄ . The solvent was removed under reduced pressure and th e resi d u e was pu rifi ed by fl ash chromatography on silica gel (petrol ether/EtOAc 6:1 -4:1 ) to afford 32 (120 mg, 53%) as a glassy solid.

[a] _D ²⁰ +29.2 (c 1.18, CHCI ₃ ); ¹ H NMR (CDCI ₃ , 500 MHz): δ 3.85 (dd, J = 1.5, 1 1 .0 Hz, 1 H, H-6a), 3.94 (dd, J = 4.0, 1 1 .5 Hz, 1 H, H-6b), 4.24 (m, 1 H, H-5), 4.56 (s, 2H, OCH ₂ Ph), 4.63 (dd, J = 8.5, 12.0 Hz, 1 H, OCH ₂ Ph), 4.74 (dd, J = 7.0, 12.0 Hz, 1 H, OCH ₂ Ph), 4.81 (dd, J = 8.5, 12.0 Hz, 1 H, OCH ₂ Ph), 4.88 (dd, J = 7.5, 12.0 Hz, 1 H, OCH ₂ Ph), 5.43 (q, J = 9.5 Hz, 1 H, H-4), 5.79 (d, J = 2.0 Hz, 1 H, H-1 ), 5.85 (dd, J = 2.0, 3.0 Hz, 1 H, H-2), 6.04 (dd, J = 3.5, 10.0 Hz, 1 H, H-3), 7.1 1 - 7.61 (m, 28H, Ar-H), 7.99 (dd, J = 8.5, 1 .0 Hz, 2H, Ar-H), 8.04 (dd, J = 8.0, 1 .0 Hz, 2H, Ar-H); ¹³ C NMR (CDCI ₃ , 125 MHz) δ 68.35 (C-6), 69.23 (d, J = 5.38 Hz, OCH ₂ Ph), 69.34 (d, J = 5.88 Hz, OCH ₂ Ph), 70.27 (C-2), 70.50 (d, J = 2.38 Hz, C-3), 71.38 (d, J = 5.75 Hz, C-5), 71.63 (d, J = 5.88 Hz, C-4), 73.38 (OCH ₂ Ph), 95.80 (C-1 ), 126.86, 126.98, 127.39, 127.43, 127.45, 127.69, 127.90, 128.23, 128.27, 128.32, 128.36, 128.40, 128.45, 128.61 , 128.74, 129.35, 130.02, 133.23, 133.51 , 135.30, 135.35, 135.50, 135.56, 136.02, 138.31 , 140.48, 155.38 (Ar-C), 165.37, 165.54 (2 CO); ESI-MS calcd for C ₅₃ H ₄₇ NaOnP [M+Na] ⁺ : 913.28, found: 913.31 .

Example 28: (Biphenyl-4-yl 2,3-O-dibenzoyl-a-D-mannopyranoside) 4-phosphate (33) A solution of 32 (80 mg, 0.09 mmol) in EtOAc (4.0 mL) was hydrogenated (1 atm H ₂ ) in the presence of 10% Pd(OH) ₂ (12 mg) at rt overnight. The reaction suspension was filtered through celite and the filtrate was concentrated under vacuo to provide 33 (quant.), which was used in the next step without further purification.

¹ H NMR (CD ₃ OD, 500 MHz): δ 3.75 (m, 1 H, H-6a), 3.98 (m, 1 H, H-5), 4.12 (m, 1 H, H-6b), 5.43 (q, J = 10.0 Hz, 1 H, H-4), 5.80 (m, 1 H, H-3), 5.82 (s, 1 H, H-1 ), 5.86 (m, 1 H, H-2), 6.04 (dd, J = 3.5, 10.0 Hz, 1 H, H-3), 7.28-7.65 (m, 15H, Ar-H), 8.07 (m, 4H, Ar-H); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 61 .72 (C-6), 69.53 (d, J = 5.0 Hz, C-4), 71 .54 (C-2), 72.77 (d, J = 3.5 Hz, C-3), 74.40 (d, J = 3.25 Hz, C-5), 97.59 (C-1 ), 1 18.16, 127.74, 127.98, 129.22, 129.25, 129.66, 129.83, 130.69, 131 .05, 131 .12, 131.22, 134.1 1 , 134.71 , 137.22, 141 .89, 156.81 (Ar-C), 166.96, 167.52 (2 CO); ESI-MS calcd for C ₃₂ H ₂₉ NaOnP [M+Na] ⁺ : 643.13, found: 643.06. Example 29: Diammonium (biphenyl-4-yl g-D-mannopyranoside) 4-phosphate (34)

Compound 33 (52 mg) was stirred in 25% aq. N H ₃ /MeOH (4 mL/1 mL) overnight. The solvents were removed under reduced pressure and the residue was purified by flash chromatography on silica gel (DCM/MeOH/H ₂ 0 4:1 :0.1 ) to yield 34 (18 mg, 56%) as white solid.

[a] _D ²⁰ +104.8 (c 0.20, H ₂ 0); ¹ H NMR (D ₂ 0, 500 MHz): δ 3.75-3.87 (m, 3H, H-6a, H-5, H- 6b), 4.24 (m, 3H, H-2, H-3, H-4), 5.70 (s, 1 H, H-1 ), 7.30 (d, J = 8.5 Hz, 2H), 7.43 (t, J = 7.5 Hz, 1 H, Ar-H), 7.54 (t, J = 8.0 Hz, 2H, Ar-H), 7.70 (d, J = 8.0 Hz, 4H, Ar-H); ¹³ C NMR (D ₂ 0, 125 MHz) δ 60.58 (C-6), 69.58 (C-2), 69.74 (d, J = 4.63 Hz, C-4), 70.66 (C-3), 72.61 (d, J = 6.88 Hz, C-5), 97.87 (C-1 ), 1 17.55, 126.69, 127.38, 128.22, 129.13, 135.26, 139.98, 155.06 (Ar-C); ESI-MS calcd for Ci ₈ H ₂ o0 ₉ P [M-H] ^" : 41 1.08, found: 41 1 .1 1 .

Scheme 9. Reagents and conditions: (i) Trityl chloride, BzCI, pyr, (two steps in one pot); (ii) FeCIs, DCM, 61 %; (iii) Ac ₂ 0, DMSO, HOAc, rt, 24 h, 35%; (iv) H ₃ P0 ₄ , NIS, THF, 58%; (v) 25% aq. NH ₃ /MeOH (1 :4), overnight, 50%.

Example 30: Biphenyl-4-yl 2,3,4-tri-0-benzoyl-6-0-trityl-a-D-mannopyranoside (35)

To a solution of 3 (650 mg, 1 .956 mmol) in pyridine (6 mL) were added trityl chloride (655 mg, 2.45 mmol) and DMAP (12 mg) at rt. The reaction mixture was stirred at 80 °C overnight, then cooled to rt. A solution of BzCI (0.9 mL) in pyridine (1.5mL) was added to the reaction mixture at rt and stirring was continued at 50°C overnight. The reaction was quenched with MeOH at 0 °C, then diluted with DCM, washed carefully with satd. aq. NaHC0 ₃ , brine and dried over Na ₂ S0 ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (petrol ether/EtOAc 6:1 -4:1 ) to afford crude 35 (1 .52 g, 88%) as a glassy solid, which was used in the next step without further purification.

Example 31 : Biphenyl-4-yl 2,3,4-tri-O-benzoyl-a-D-mannopyranoside (36)

To a solution of 35 (1.00 g, 1 .13 mmol) in dry DCM (10 mL) were added water (0.121 mL) and FeCI ₃ (549 mg, 3.38 mmol) at rt. The reaction mixture was stirred at rt overnight, diluted with DCM, washed with water and brine, and the organic layer was dried over Na ₂ S0 ₄ . The solvent was removed and the residue was purified by flash chromatography on silica gel (petrol ether/EtOAc 6:1 -7:3) to give 36 (443 mg, 61 %) as white foam.

1H NMR (CDCIs, 500 MHz): δ 2.70 (dd, J = 6.0, 8.4 Hz, 1 H, 6-OH), 3.76 (ddd, J = 3.3, 5.9, 13.0 Hz, 1 H, H-6a), 3.85 (ddd, J = 2.0, 8.5, 12.8 Hz, 1 H, H-6b), 4.21 (dt, J = 2.6, 10.1 Hz, 1 H, H-5), 5.90 (d, J = 1 .7 Hz, 1 H, H-1 ), 5.91 (dd, J = 1.9, 3.3 Hz, 1 H, H-2), 5.98 (t, J = 10.1 Hz, 1 H, H-4), 6.25 (dd, J = 3.4, 10.1 Hz, 1 H, H-3), 7.26-7.35 (m, 5H, Ar-H), 7.39-7.48 (m, 5H, Ar-H), 7.51 -7.59 (m, 7H, Ar-H), 7.65 (m, 1 H, Ar-H), 7.88 (m, 2H, Ar-H), 8.01 (m, 2H, Ar-H), 8.15 (m, 2H, Ar-H); ¹³ C NMR (CDCI ₃ , 125 MHz) δ 61 .16 (C-6), 67.13 (C-4), 69.50 (C-3), 70.49 (C-2), 71 .79 (C-5), 96.1 1 (C-1 ), 126.95, 127.1 1 , 128.45, 128.48, 128.64, 128.79, 128.86, 129.12, 129.20, 129.83, 130.04, 130.08, 133.19, 133.40, 133.86, 136.18, 140.53 (Ar-C), 165.59, 165.65, 166.74 (3 CO).

Example 32: Biphenyl-4-yl 2,3,4-tri-0-benzoyl-6-0-(methylthiomethyl)-a-D- mannopyranoside (37)

To a solution of 36 (469 mg, 0.726 mmol) in Ac ₂ 0/HOAc (2.5 mL/0.25 mL) was added DMSO (2.5 mL) at rt under argon. The reaction mixture was stirred at rt for 24 h, diluted with DCM, washed with satd. aq. NaHC0 ₃ and brine, and dried over Na ₂ S0 ₄ . The solvents were removed under reduced pressure and the residue was purified by flash chromatography on silica gel (petrol ether/EtOAc 9:1 -6:1 ) to give crude 37 (171 mg, 35%) as white foam, which was used in the next step without further purification.

Example 33: Biphenyl 2,3,4-tri-0-benzoyl-6-0-(phosphonooxymethyl)-a-D- mannopyranoside (38)

To a mixture of 37 (170 mg, 0.25 mmol) and H ₃ PO4 (1 M in THF) in dry THF (1 .5 mL) was added NIS (84 mg, 0.375 mmol) at 0°C under argon. The reaction mixture was stirred at 0°C for 15 min, then the ice-bath was removed and stirring was continued at rt for 1 h. The reaction mixture was diluted with DCM/MeOH (4:1 ) and washed with 1 M aq. Na ₂ S ₂ 0 ₃ . The organic layer was dried over Na ₂ S0 ₄ and the solvents were removed under reduced pressure below 20°C. The residue was purified by flash chromatography on silica gel (DCM/MeOH 9:1 -3:1 ) to yield 38 (1 10 mg, 58%) as white foam.

¹ H NMR (CD ₃ OD, 500 MHz): δ 3.90 (dd, J = 4.5, 1 1.5 Hz, 1 H, H-6a), 4.01 (m, 1 H, H-6b), 4.47 (m, 1 H, H-5), 5.06 (dd, J = 5.5, 9.5 Hz, 1 H, OCH ₂ 0), 5.16 (dd, J = 5.5, 9.5 Hz, 1 H, OCH ₂ 0), 5.89 (s, 1 H, H-1 ), 5.93 (s, 1 H, H-2), 6.06 (m, 2H, H-4, H-3), 7.26-7.69 (m, 18H, Ar-H), 7.79 (d, J = 7.5 Hz, 2H, Ar-H), 7.96 (d, J = 8.0 Hz, 2H, Ar-H), 8.13 (d, J = 7.5 Hz, 2H, Ar-H); ¹³ C NMR (CD ₃ OD, 125 MHz) δ 68.23 (C-4), 68.70 (C-6), 71 .46 (C-2), 71 .86 (C- 3), 71 .93 (C-5), 92.82 (d, J = 4.25 Hz, OCH ₂ 0), 97.56 (C-1 ), 1 18.37, 127.74, 128.03, 129.30, 129.45, 129.62, 129.83, 129.86, 130.30, 130.42, 130.52, 130.57, 130.73, 130.92, 134.54, 134.64, 134.91 , 137.45, 141.78, 156.79 (Ar-C), 166.82, 167.01 (3C, 3 CO).

Example 34: Biphenyl-4-yl 6-Q-(diammonium phosphonooxymethyQ-g-D- mannopyranoside (39)

Aqueous ammonia (4 mL) was added to a solution of 38 (1 10 mg, 0.146 mmol) in methanol (1 mL). The reaction mixture was stirred at rt overnight, then the solvent was removed under reduced pressure. The residue was dissolved in water and washed with diethyl ether (4x). The aqueous layer was collected and concentrated under reduced pressure, the residue was purifed by reversed-phase chromatography (RP-18, H ₂ 0/MeOH 1 :0-6:1 ) to yield 39 (32 mg, 50%) as white solid.

¹ H NMR (D ₂ 0, 500 MHz): δ 3.85 (dd, J = 2.0, 1 1.5 Hz, 1 H, H-6a), 3.88 (m, 1 H, H-5), 3.93 (t, J = 9.5 Hz, 1 H, H-4), 3.97 (dd, J = 4.0, 1 1 .5 Hz, 1 H, H-6b), 4.10 (dd, J = 3.5, 9.5 Hz, 1 H, H-3), 4.22 (dd, J = 2.0, 3.5 Hz, 1 H, H-2), 4.94 (dd, J = 5.5, 1 1 .0 Hz, 1 H, OCH ₂ 0), 5.04 (dd, J = 5.5, 8.5 Hz, 1 H, OCH ₂ 0), 5.69 (d, J = 1 .5 Hz, 1 H, H-1 ), 7.28 (m, 2H, Ar-H), 7.44 (m, 1 H, Ar-H), 7.54 (m, 2H, Ar-H), 7.69-7.72 (m, 4H, Ar-H); ¹³ C NMR (D ₂ 0, 125 MHz) δ 66.14 (C-4), 66.58 (C-6), 69.91 (C-2), 70.27 (C-3), 72.16 (C-5), 90.38 (d, J = 4.25 Hz, OCH ₂ 0), 98.26 (C-1 ), 1 17.52, 126.70, 127.39, 128.26, 128.76, 129.12, 132.54, 135.35, 139.96, 154.96 (Ar-C). Example 35: Bioconversion of phosphates in Caco-2 cells

Following the procedure described by Haodan Yuan, Na Li, and Yurong Lai, Drug Metabolism and Disposition 37:1443-1447, 2009, Caco-2 cells (American Type Culture Collection, Rockville, MD) were maintained in DMEM high glucose medium, containing 1 % L-glutamine solution, 1 % MEM-NEAA solution, 10% FBS, 1 U/ml penicillin, 1 μg/ml streptomycin. At passage numbers between 60 and 65, the cells were seeded at a density of 5.3 x 10 ⁵ cells per well to Transwell ^® 6-well plates (Corning Inc., Corning NY, USA). Bioconversion and transport experiments were performed between days 19 and 21 post- seeding. Previous to the experiment, the integrity of the Caco-2 monolayers was evaluated by measuring the transepithelial electrical resistance (TEER) with an Endohm tissue resistance instrument (World Precision Instrumentes Inc., Sarasota FL, USA). Each prodrug was applied to the apical side to inititate the bioconversion and subsequent transport across the Caco-2 monolayer. The incubation was maintained at 37°C for 1 h under gentle shaking. A 40 μΙ aliquot was collected from both the apical (A) and basal (B) sides after 5, 10, 20, 30, 45, and 60 min. The concentrations of the prodrugs and the parental compounds were monitored by LC/MS/MS.

When compound 4, 23, 29, 34, and 39 were tested, dephosphorylation and accumulation of the parental compound in the apical and basolateral compartments were confirmed.

Table 1 : Metabolic half life (t _1/2 ) of FimH antagonists when given on the apical side of a Caco-2 cell monolayer

Example 36: Thermodynamic Solubility

Microanalysis tubes were charged with 1 mg of solid substance and 100 μΙ_ of phosphate buffer (50 mM, pH 6.5). The samples were briefly shaken by hand and then sonicated for 15 min and vigorously shaken (600 rpm, 25°C, 2 h) on an Eppendorf Thermomixer Comfort. Afterwards, the samples were left undisturbed for 24 h. After measuring the pH, the saturated solutions were filtered through a filtration plate (Multiscreen HTS, Millipore, Billerica MA, USA) by centrifugation (1500 rpm, 25°C, 3 min). Prior to concentration determination by LC/MS/MS, the filtrates were diluted (1 :1 , 1 :10, and 1 :100 or, if the results were outside of the calibration range, 1 :1000 and 1 :10000). The calibration was based on six values ranging from 0.1 to 10 μg mL.

Table 2: Solubility of FimH antagonists