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Definitions

• the present invention relates to alpha hydroxy amides including compounds of I and related compounds and their use in the prophylaxis and treatment of inflammatory disorders and diseases.
• the invention relates to the compounds of formula (I):
• R w denotes a group selected from H, Hal, linear or branched alkyl, Ar, Het, Cyc, (CH 2 ) n Ar, -(CH 2 ) n Het, -(CH 2 ) n Cyc, -(CH 2 ) n OAr, -(CH 2 ) n OHet, -(CH 2 ) n OCyc, A,
• R b denotes H or a linear or branched alkyl, or alternatively,
• R b and R w together with the nitrogen atom to which they are linked, form a Het group, preferably a saturated Het group, such as pyrrolidinyl, piperidinyl or morpholinyl, denotes H, Ar, or alkyl
• R a denotes H or a group selected from the following groups:
• Ar denotes one of the following groups optionally substituted with from 1 to 5 groups independently selected from Hal, CN, -CF 3 , -OCF 3 , O-alkyl, S0 2 - alkyl, COOR , -CO-alkyl, O-phenyl, S0 2 -phenyl, S0 2 -Het, O-Het, Het, - (CH 2 ) n -Het, S0 2 -CF 3 , 0-(CH 2 ) n -Het, 0-(CH 2 ) n -alkyl, A denotes a monocyclic 5-8-membered ring being saturated, unsaturated or aromatic, containing 1 to 3 heteroatoms independently selected from N, O and S, and or a group CO, and optionally substituted with from 1 to 5 groups independently selected from Hal, CN, -CF 3 , -OCF 3 , O-alkyl, S0 2 -alkyl, COOR b ,
• Hal denotes F, CI, Br, I and n is 1 , 2 or 3
• the compounds of formula I show activity as vanin inhibitors.
• vanin inhibitor is preferably defined herein as a compound which, in vitro and/or in vivo: (i) inhibits the activity and/or expression of Vanin-1; and/or (ii) blocks processing of pantetheine into cysteamine and pantothenic acid; and/or (iii) blocks intracellular synthesis of cysteamine and/or of cystamine, the oxidized form of cysteamine. Inhibition and blocking may be total or partial.
• Vanin-1 and Vanin-3 preferentially expressed by epithelial and myeloid cells, respectively (Martin, 2001).
• this enzyme is encoded by 3 genes (VNN-1 , VNN-2, VNN-3).
• Vanin-1 and VNN1 are GPI-anchored to cell membranes and are highly expressed at the brush border of various epithelial cells including intestinal enterocytes, kidney tubular cells, hepatocytes, pancreatic acinar cells, thymic medullary epithelial cells (Galland, 1998; Aurrand-Lions, 1996; Pitari, 2000; Martin, 2001).
• drosophila 4 genes homologous to the mammalian Vanin sequences are identified and preliminary studies show that drosophila has a pantetheinase activity (Granjeaud et al, 1999).
• Vanin-1 deficient mice develop normally but have no detectable free cyst(e)amine in kidney and liver, in spite of the presence of Vanin-3 (Pitari, 2000). Inactivation of the Vanin-1 gene prevents acute and chronic inflammation since in both cases intestinal injury was moderate in Vanin-1 deficient mice, as compared to controls. The protection was associated with reduced expression of inflammatory molecules, myeloid cell recruitment and mucosal damage in the intestine. Furthermore, glutathione synthesis and storage were increased in liver and intestine (US
• an inflammatory disorder denotes a condition of sustained or chronic inflammation that occurs when tissues are injured by viruses, bacteria, trauma, chemicals, heat, cold or any other harmful stimulus.
• an inflammatory disorder according to the invention is a gastrointestinal inflammatory disorder that may be selected from the group consisting of an inflammatory bowel disease (IBD) such as Irritable Bowel Syndrome (IBS), ulcerative colitis and Crohn's disease, an ulcer resulting from administration of a non-steroidal anti-inflammatory drug, such as a peptic ulcer (i.e. a sore that forms in the lining of the stomach or the duodenum), and an inflammatory disorder associated with an infection with Schistosoma mansoni parasite.
• IBD inflammatory bowel disease
• IBS Irritable Bowel Syndrome
• Crohn's disease an ulcer resulting from administration of a non-steroidal anti-inflammatory drug, such as a peptic ulcer (i.e. a sore that forms in the lining of the stomach or the duodenum)
• treating or “treatment” is meant the prophylactic or curative treatment of a disorder, i.e. reversing, alleviating, inhibiting the progress of, or preventing the disorder or ' condition to which such term applies, or one or more symptoms of such disorder or condition.
• the treatment may be associated with another pre-existing treatment in order to improve the efficacy of said pre-existing treatment.
• Alkyl denotes a carbon chain having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms and most preferably 1 to 6 carbon atoms.
• Alkyl very preferably denotes methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1 , 2 or 3 methylbutyl, 1,1 , 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1 ,2,3 or 4 methylpentyl, 1,1 , ,2 , 1,3 , 2,2 , 2,3- or 3,3-dimethylbutyl, 1 or 2 ethylbutyl, 1 ethyl-1-methylpropyl, 1 ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl
• the group Oalkyl preferably denotes methoxy and ethoxy.
• Ar preferably denotes phenyl or biphenyl, which may be unsubstituted or
• Het preferably denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 3 N, O or S atoms which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by a substitutent selected from from a group mentioned under the definition of Het.
• Het is more preferably a 6 to 14 membered ring system and denotes, not withstanding further substitutions, for example, 2 or 3 furyl, 2 or 3 thienyl, 1 ,2 or 3 pyrrolyl, 1 ,2, 4 or 5 imidazolyl, 1 ,3,4 or 5 pyrazoiyi, 2,4 or 5 oxazoiyi, 3,4 or 5 isoxazoiyi, 2 , 4 or 5 thiazolyl, 3,4 or 5 isothiazolyl, 2 , 3 or 4-pyridyl, 2,4,5 or 6 pyrimidinyl, furthermore preferably 1,2,3-triazol-1 , 4- or 5-yl, 1 ,2,4-triazol-1 , 3- or 5yl, 1 or 5 tetrazolyl, 1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3- or 5-yl, 1,3,4-thiadiazol-2- or 5-yl, 1,2,4-thi
• the heterocyclic radicals may also be partially or fully hydrogenated.
• Het can thus also denote, for example, 2,3-dihydro-2 , 3 , 4- or 5-furyl, 2,5-dihydro-2 , 3, 4- or 5 furyl, tetrahydro-2- or 3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1 , 2 , 3, 4- or 5-pyrrolyl, 2,5-dihydro-1 , 2 , 3 , 4- or 5-pyrrolyl, 1 , 2 or 3 pyrrolidinyl, tetrahydro-1 , 2- or 4-imidazolyl, 2,3-dihydro-1 , 2 , 3 , 4- or 5- pyrazolyl, tetrahydro-1 , 3- or 4-pyrazolyl, 1,4-dihydro-1 , 2, 3- or 4-pyridyl, 1,2,3,4- tetrahydro-1 , 2 , 3 , 4 ,
• R w preferably denotes H, alkyl, (CH 2 ) 2 Ar, such as phenyl, and in cases whereT 2 -W is also Hal, more preferably CI and F.
• R a is preferably H, benzyl, (CH 2 ) 2 phenyl, (CH 2 ) 3 phenyl or (CH 2 ) 2 0phenyl, R b is preferably H. R c is preferably H.
• N is preferably 1.
• ammonium ions have Hal or mesylate as a counter ion.
• the compounds according to formula (I) may be prepared from readily available starting materials using the following general methods and procedures. If such starting materials are not commercially available they may be prepared by standard synthetic techniques. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time,
• the compounds according to the general formula (I) may be obtained by several processes using both solution-phase and/or solid-phase chemistry protocols. Examples of synthetic pathways for the preparation of compounds according to the general formula (I) are described herebelow. Optimum reaction conditions may vary with particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures.
• the compounds according to formula (I) may be prepared following the synthetic pathways described in the general scheme 1.
• Preferred conditions consist in the treatment of compounds of formula (Ha) with an oxidant such as, but not limited to, Dess Martin Periodinane in a solvent such as dry DCM at room temperature for few hours such as 2h, followed by treatment with preferably a 80% acetic acid solution in water at room temperature for several hours, such as 3h.
• an oxidant such as, but not limited to, Dess Martin Periodinane in a solvent such as dry DCM at room temperature for few hours such as 2h, followed by treatment with preferably a 80% acetic acid solution in water at room temperature
• the corresponding alcohol derivatives can be obtained after protection of compounds of formula (IVa) into an acetonide group by treatment of compounds of formula (IVa) with acetone in the presence of an acid such as, but not limited to, para-toluene sulfonic acid and molecular sieves at room temperature for several days such as 3 days.
• Compounds (IVa) may be prepared by the opening of a pantolactone of formulae (VI) with amines of formulae (Va).
• Preferred conditions consist in the treatment of compounds of formulae (VI) with amines in the presence of a base such as triethylamine, in a suitable solvent such as dry EtOH at a temperature between 100°C and 160°C.
• Compounds of formula (lb), where R w is as described above, may be prepared from compounds of formula (lid) following conditions described above to convert compounds of formulae (la) from compounds of formulae (lla) consisting in the oxidation of the secondary alcohol into a ketone followed by the acetonide deprotection.
• Compounds of formula (lid) can be obtained from compounds of formula (lib) by treatment with classic reagents to run Horner- Wadsworth-Emmons reactions such as phosphonate derivatives of formulae (VII).
• Preferred conditions consist in the treatment of phosphonate of formulae (VII) with NaH, in a suitable solvent such as dry THF at 0°C for few minutes such as 15 minutes followed by the addition of compounds of formula (lib) at 0°C for h then at RT for another hour.
• compounds of general formulae (lc) may be prepared from compounds of formula (lie) following conditions described above to convert compounds of formula (la) from compounds of formulae (Ha) consisting in the oxidation of the secondary alcohol into a ketone followed by the acetonide deprotection.
• Compounds of formula (lie) can be obtained from compounds of formula (llf) by treatment with an allyl derivative of formulae (VIII) where R w is as above defined in the presence of a Grubbs catalyst.
• Preferred conditions consist in the treatment compounds of formula (llf) with allyl derivatives of formula (VIII) in the presence of Grubbs catalyst second generation in a suitable solvent such as dry DCM at reflux overnight such as 16h.
• compounds of general formulae (Id) may be prepared from compounds of formula (llg) following conditions described above to convert compounds of formula (la) from compounds of formula (lla) consisting in the oxidation of the secondary alcohol into a ketone followed by the acetonide deprotection.
• Compounds of formulae (llg) can be obtained from compounds of formula (lib) by treatment with isocyanide derivatives of formulae (IX) where R w is as above defined.
• Preferred conditions consist in the treatment compounds of formula (Mb) with chioroacetic acid and an isocyanide derivative of formulae (IX) in a suitable solvent such as DCM at a temperature such as room temperature. Intermediate is then treated with a base such as K 2 C0 3 in a MeOH: H 2 0 mixture for several hours such as 5h at a temperature such as RT.
• Isocyanide of formula (IX) where R w is as above defined can be obtained from compounds of formula (X) by treatment with ethylformate followed by the dehydration of the formamide intermediate as shown in scheme 4.
• Preferred conditions consist in the treatment of amines of formula (X) with ethylformate at room temperature for few hours such as 12h.
• the intermediate is then dehydrated by addition of trisphosgene in the presence of a base such as triethylamine in a suitable solvent such as DCM at a temperature such as 0°C followed by additional 30 min at RT.
• X 2-Triphosgene ( ⁇
• the compounds according to formula (Id) may be prepared following the synthetic pathway described in the scheme 5.
• compounds of formula (Id) may be prepared from the corresponding derivatives of formula (Xla), by an oxidation step followed by the cleavage of acetal protecting group where W and R w are as above defined.
• Preferred conditions consist in the treatment of compounds of formula (Xla) with an oxidant such as, but not limited to, Dess Martin
• Compounds of formula (Xla) may be prepared from the corresponding acid derivatives of formula (Xlb) by coupling with amine derivatives of formula (XII) wherein W and R w are as above defined with W preferably representing a single bond.
• compounds of formula (Xla) can be obtained using usual conditions for the formation of an amide starting from a carboxylic acid and an amine by using coupling agents such as DCC, DIC, EDC, HATU or via the formation of an acid chloride or an activated ester.
• Preferred conditions consist in the treatment of compounds of formula (Xlb) with HATU in the presence of a base such as, but not limited to, N-methyl morpholine in a solvent such as DMF at a temperature such as 100°C.
• a base such as, but not limited to, N-methyl morpholine in a solvent such as DMF at a temperature such as 100°C.
• the corresponding carboxylic acid of formula (Xlb) can be obtained by hydrolysis of the corresponding esters of formula (Xlc) using reagents such as, but not limited to, LiOH, NaOH or KOH in solvents such water, alcohol, THF, dioxane, or mixture thereof.
• Compounds of formulae (If) where Ra is as above defined may be prepared from compounds of formula (Vb) following conditions described above to synthesize compounds of formulae (IVa) from compounds of formula (VI) and amines of formula (Va) consisting in the opening of a pantolactone by an amine.
• Compounds of formula (Vb) can be obtained by treatment of compounds of formula (XV) with a sulfonyl chloride such as methane sulfonyl chloride followed by the reaction with ethylene diamine.
• Preferred conditions consist in the treatment of alcohol derivatives (XV) with methane sulfonyl chloride in the presence of a base such as, but not limited to, triethylamine in a suitable solvent such as dry DCM at a temperature such as 0°C. ethanesulfonic acid derivatives are then treated with ethylene diamine in a suitable solvent such as eOH at a temperature such as RT for few hours such as 16h.
• a base such as, but not limited to, triethylamine in a suitable solvent such as dry DCM at a temperature such as 0°C.
• ethanesulfonic acid derivatives are then treated with ethylene diamine in a suitable solvent such as eOH at a temperature such as RT for few hours such as 16h.
• the compounds according to formula (I) can be prepared from readily available starting materials by several synthetic approaches, using both solution-phase and solid-phase chemistry protocols or mixed solution and solid phase protocols. Examples of synthetic pathways are described below in the examples.
• Step 1
• Step 1 (R)-2, 4-Dihydroxy-N-(3-hydroxy-propyl)-3, 3-dimethyl-butyramide
• Step 2 (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-hydroxy-propyl)- amide
• 1-lsocyanomethyl-3-trifluoromethoxy-benzene was prepared following the general procedure C from 3-trifluoromethoxy-benzylamine (382 mg, 2 mmol) as a pale yellow liquid.
• 1-lsocyanomethyl-4-methanesulfonyl-benzene was prepared following the general procedure C from 4-methyl sulfonyl benzylamine (2 mmol) as a pale yellow liquid.
• Phenylisocyanate (1 3 mg, 1.1 mmol) as a colorless liquid (212 mg, 58%).
• Step 2 2 ⁇ ydroxy-4- ⁇ [(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxa
• A/-(3-Phenyl-propyl)-ethane-1 ,2-diamine was prepared following the general proced F from methanesulfonic acid 3-phenyl-propyl ester (1.92 g, 9 mmol) as a colorless liquid (1. 5 g, 72%).
• ⁇ /'-Phenethyl-ethane-l , 2-diamine was prepared following the general procedure F from methanesulfonic acid phenethyi ester (2.5g, 12.5 mmol) as a colorless liquid (1.65 g, 80%).
• A/'-(2-Phenoxy-ethyl)-ethane-1 , 2-diamine was prepared following the general procedure F from methanesulfonic acid 2-phenoxy-ethyl ester (1.56 g, 7.2 mmol) as a colorless liquid (820 mg, 63%).
• Example 1 (R)-2.4-Dihvdroxy-3,3-dimethyl-N-(3-oxo-butyl)-butyramide (R)-2,4-Dihydroxy-3,3-dimethyl-A/-(3-oxo-butyl)-butyramide was synthesised following general procedure B from (R)-2,2,5,5-tetramethyl-[1 ,3]dioxane-4-carboxylic acid (3- hydroxy-butyl)-amide (180 mg, 0.7 mmo! as colorless gummy liquid (8 mg, 4%).
• Step 1 (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid ((E)-3-hydroxy-6- phenyl-hex-4-enyl)-amide
• Step 2 (R)-2, 4-Dihydroxy-3, 3-dimethyl-N-((E)-3-oxo ⁇ 6-phenyl-hex-4-enyl)-butyramide
• Step 1 (R)-2, 2, 5, 5-Tetramethyl-[1 , 3]dioxane-4-carboxylic acid ((E)-5-oxo-hex-3-enyl)- amide
• Step 2 (R)-2, 4-Dihydroxy-3, 3-dimethyl-N-((E)-5-oxo-hex-3-enyl)-butyramide
• Step 1 (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid ((E)-5-oxo-7-phenyl- ept-3-enyl)-amide
• Step 2 (R)-2 -Dihydroxy-3,3-dimethyl-N-(E)-5-oxo-7-phenyl-hept ⁇
• Step 1 (R)-2,2,5,5-Tetramethyl-[1,3]dioxane-4-carboxylic acid (3-carbamoyl-3- hydroxy-propyl)-amide
• Step 2 (R)-N-(3-Carbamoyl-3-oxo-propyl)-2, 4-dihydroxy-3, 3-dimethyl-butyramide
• Example 18 (R)-N-(3-Cvclohexylcarbamoyl-3-oxo-propyl)-2,4-dihvdroxy-3.3- dimethyl butyramide
• Chiral (R)-/V-(3-Cyclohexylcarbamoyl-3-oxo-propyl)-2,4-dihydroxy-3,3-dimethyl butyramide was synthesized following general procedure B starting from (R)-2,2,5,5-tetramethyl- [1 ,3]dioxane-4-carboxylic acid (3-cyclohexylcarbamoyl-3-hydroxy-propyl)-amide (61 mg, 0.17 mmol) as a white solid (17 mg, 31%).
• Example 19 ⁇ R)-2.4-Dihvdroxy-3.3-dimethyl-N- ⁇ 3-r(naDhthalen-1-ylmethvn- carbamoyll-3-oxo-Dropyl ⁇ -butyramide
• Example 23 fR)-2.4-Dihvdroxy-3.3-dimethyl-N-i3-oxo-3-(2-tnfluoromethyl- benzylcarbamovO-propyll-butyramide
• butyramide was synthesized following general procedure B starting from (R)-2-(4- methoxy-phenyl)-5,5-dimethyl-[1 ,3]dioxane-4-carboxylic acid ⁇ 3-[(biphenyl-4-lmethyl)- carbamoyl]-3-hydroxy-propyl ⁇ -amide (75 mg, 0.14 mmol) as a pale yellow solid (9 mg, 16%).
• 3,3-dimethyl-butyramide was synthesized following general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1 ,3]dioxane-4-carboxylic acid ⁇ 3-hydroxy-3-2-4- methanesulfonyl-phenyl)-ethylcarbamoyl]-propyl ⁇ -amide (64 mg, 0.12 mmol) as a colorless gum (11 mg, 22%).
• Example 35 fR)-2.4-Dihvdroxy-3.3-dimethvi-N-f3-oxo-3-f3 4-fpiDeridine-1- sulfon vD-phen yll-prop ylcarbamoyl prop vD-butyramide
• Example 40 (R)-2.4-Dihvdroxy-3.3-dimethyl-N- ⁇ 3-oxo'3-r3-(3-oxo-morDholin-4-Yl)- prop ylcarbamoyll-prop vD-butyramide
• 2,4-dihydroxy-3,3-dimethy ) -butyramide was synthesized following general procedure B starting from (R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1 ,3]dioxane-4-carboxylic acid ⁇ 3- hydroxy-4-oxo-4-[4-(3-trifluoromethanesulfonyl-phenylamino)-piperidin-1-yl]-butyl ⁇ - amide (143 mg, 0.26 mmol) as a off-white solid (77 mg, 66%).
• Example 45 4- i4-((R)-2,4-Dihvdroxy-3.3-dimethyl-butyrylamino)-2-oxo- butyrylaminoJ-methvD-benzoic acid ethyl ester
• benzoic acid ethyl ester was synthesized following general procedure B starting from 4- [(2-hydroxy-4- ⁇ [(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1 ,3]dioxane-4-carbonyl]-amino ⁇ - butyrylamino)-methyl]-benzoic acid ethyl ester (49 mg, 0.1 mmol) as a white solid (17 mg, 45%).
• Example 46 fR)-2.4-Dihvdroxy-3.3-dimethyl-N-r3-oxo-3-(f1-r4-(2-oxo-pyrrolidin-1- vn-benzenesulfonyll-piperidin-4-ylmethyl ⁇ -carbamoyl)-propyl1-butyramide
• Example 47 fR)-2.4-Dihvdroxy-N- 3-ri1-methanesulfonyl-piperidin-4-ylmethyl)- carbamo ⁇ -3-oxo-prop yl ⁇ -3, 3-dimeth yl-butyramide
• Example 48 (R)-N-f3-f(1-Acetyl-pipe din-4-ylmethyl)-carbamoyll-3-oxo-propyl)- 2.4-dih ydroxy-3, 3-dimeth yl-butyramide
• Example 51 (R)-N-(3-ff 1-(3-Fluoro-benzenesulfonyl)-piperidin-4-ylmethyll- carbamo yl)-3-oxo-prop yl)-2, 4-dihydroxy-3, 3-dimeth yl-b utyr amide
• Example 53 fR)-2 ⁇ 4-Dihydroxy--N- 3-if4'-methanesulfonyl-biphenyl-4-ylmethyl)- carbamoyll-3"OXO-propyl ⁇ -3,3-dimethyl-butyramide
• Example 54 4- ⁇ [4-((R)-2,4-Dihvdroxy-3,3-dimethyl-butyrylamino)-2-oxo- butyrylaminol-methvD-benzoic acid
• bipheny)-4-carboxylic acid methyl ester was synthesized following general procedure E starting from 4'-[(2-hydroxy-4- ⁇ [(R)-2-(4-methoxy-phenyl)-5,5-dimethyl-[1 ,3]dioxane-4- carbonyl]-amino ⁇ -butyrylamino)-methyl]-biphenyl-4-carboxylic acid methyl ester as a white solid (14 mg, 32%).
• Example 60 iR ⁇ -N' ⁇ 2-rBenzyl-(2-chloro-acetyl)-aminol-ethyl)-2.4-dihvdroxy-3.3- dimethyl-butyramide
• Eyamp/e 64 ffl)-A/ 2- ⁇ 2-C 7/oro-acefW)- 2-r -mef/7anesi /fon -p ienoxy)-efh 7- amino ⁇ -ethyl) ⁇ 2,4-dihydroxy-3,3-dimethvt-butyramide
• ethoxy-benzoic acid methyl ester was synthesized following general procedure H starting from 4- ⁇ 2-[2-((R)-2,4-dihydroxy-3,3-dimethyl-butyrylamino)-ethylamino]- ethoxy ⁇ -benzoic acid methyl ester (33 mg, 0.09 mmol) as a yellow gum (4 mg, 10%).
• VNN1 Human recombinant Vanin-1 (VNN1) was purchased from Sino Biological Inc. (Catalog Number: 11662-H08H).
• Measurement of VNN1 inhibition is performed in 384 well format based on
• the cellular activity of the examples was measured in 96 well format based on fluorescence intensity assay using SUIT-S2 cell line (ATCC # CRL1596)

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