WO2005051891A1 - Utilisation de derives de cyclopropenylesfingosine pour la production d'une composition pharmaceutique modulant l'activite de ceramidases et leurs applications - Google Patents

Utilisation de derives de cyclopropenylesfingosine pour la production d'une composition pharmaceutique modulant l'activite de ceramidases et leurs applications Download PDF

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WO2005051891A1
WO2005051891A1 PCT/ES2004/070101 ES2004070101W WO2005051891A1 WO 2005051891 A1 WO2005051891 A1 WO 2005051891A1 ES 2004070101 W ES2004070101 W ES 2004070101W WO 2005051891 A1 WO2005051891 A1 WO 2005051891A1
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substituents
disease
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pharmaceutical composition
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Gemma Fabrias Domingo
Amadeo Llebaria Soldevila
Josefina Casas Brugulat
Gemma Triola Guillem
Carmen Bedia Girbes
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Consejo Superior De Investigaciones Científicas
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

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  • the present invention is of interest to the pharmaceutical sector. It refers to a new use of compounds derived from cyclopropenylphingosines as modulators of the activity of ceramidases and, therefore, of intracellular levels of ceramide, as well as procedures useful for their preparation and pharmaceutical compositions containing them.
  • ceramide in cellular physiology has also been demonstrated by studies in which the specific activity of some ceramide analogues is examined.
  • D-er / uro- / V-acetylsphingosine exhibits activities similar to those of natural ceramide (Bielawska et al, J. Biol. Chem. 1993, 268, 26226; Fishbein et al, J. Biol. Chem. 268, 9255), while its saturated analog (D-erythro-N-acetylphinganine) lacks the effects of ceramide (Bielawska et al, J. Biol. Chem. 1993, 268, 26226; Tepper et al, Proc.
  • Ceramide is the central molecule in the biosynthesis of sphingolipids and glycosphingolipids. Ceramide originates intracellularly by two metabolic routes: anabolic and catabolic. In the latter, ceramide is generated by hydrolysis of glycosphingolipids catalyzed by hydrolases, or by hydrolysis of sphingomyelin, the latter being known as the "sphingomyelin cycle". Hydrolysis of sphingomyelin is mediated by sphingomyelinases (acidic or neutral), which are activated by a series of natural ligands and also by cellular stress signals, such as ionizing radiation, some drugs, etc.
  • sphingomyelinases acidic or neutral
  • ceramide serves as a precursor to more complex lipids, such as sphingomyelin and glycosphingolipids (Hannun, J. Biol. Chem. 1994, 269, 3125; Merrill and Jones, Biochim. Biophys. Acta 1990, 1044, 1 ; Van Echten and Sandhoff J. Biol. Chem. 1993, 268, 53412; Hakomori, Annu. Rev. Biochem. 1981, 50, 733).
  • ceramide into sphingomyelin involves the transfer of choline phosphate from a molecule of phosphatldylcholine to the C1-OH of ceramide, generating diacylglycerol, which is another very important mediator of cellular signals.
  • ceramide can be transformed, by hydrolysis of the amide function by ceramidases, into sphingosine (Hannun, J. Biol. Chem. 1994, 269, 3125, Spence et al, Biochem. Cell Biol. 1986, 64, 400 ; Slife et al., J. Biol. Chem.
  • ceramidases constitute a way to regulate the ceramide-sphingosine interconversion. At least three different types of ceramidases have been described: a lysosomal ceramidase (Koch et al., J. Biol. Chem.
  • the object of the present invention is the use as modulators of the ceramidases of cyclopropenylphingosine derivatives characterized by the general formula I, their stereoisomers and mixtures thereof, and the pharmaceutically acceptable solvates and addition salts thereof, where:
  • n is an integer that can present any value.
  • R 2 is selected from the group consisting of: i. H, ii.
  • R 3 is selected from the group consisting of: i. H, ii. an alkyl, alkenyl or alkynyl radical, linear, branched or cyclic, or any aryl radical, which may or may not have heteroatoms and contain or not substituents at any position, or any heterocycle, which in turn may contain substituents at any position.
  • R 3 is selected from the group consisting of: i. H, ii. an alkyl, alkenyl or alkynyl radical, linear, branched or cyclic, or any aryl radical, which may or may not have heteroatoms and contain or not substituents in one or more of their positions, or any heterocycle, which in turn may or may not contain Substituents in any position. iii.
  • X can be O, S or N
  • Y can be O, S, NH or -CHOH
  • R 5 can be iii . i H, iii.ii a radica! alkyl, alkenyl or alkynyl, linear, branched or cyclic, or any aryl radical, which may or may not have heteroatoms and contain or not substituents in one or more of their positions, or any heterocycle, which in turn may or may not contain substituents in any position.
  • Another object of the present invention is also a process for obtaining said compounds of general formula I which includes a reaction step of Garner aldehyde, its enantiomer or any of these with a cyclopropenillitium in tetrahydrofuran to obtain a mixture of alcohols. Erythro / threo diastereomerics in a proportion between (70:30) and (85:15).
  • Such derivatives can be used in the preparation of a composition for the diagnosis of Farber's disease and in the preparation of pharmaceutical compositions for the treatment and / or prophylaxis of human or animal diseases such as Farber's disease, cancer, cardiovascular diseases. or inflammatory diseases.
  • BRIEF DESCRIPTION OF THE FIGURES Figure 1. Scheme of synthesis of the compounds la. a) 1. n-Butyllithium, tetrahydrofuran, -23 ° C, 2 hours; 2. (ft) - (+) - i, tetrahydrofuran / hexamethylphosphorotriamide; 3. Column chromatography; b) 1.
  • Figure 4 Effect of stereoisomers 1 2S, 1 2f? and 1 S, 2S of the compound on neutral ceramidase.
  • the assays are carried out by incubation with microsomes of the inhibitor (500 ⁇ M) and the enzyme substrate (/ V- (12- (4- nitrobenzo-2-oxa-1, 3-diazolo) dodecyl) sphingosine) (25 ⁇ M).
  • the amounts of 12 (4-nitrobenzo-2-oxa-1, 3-diazolo) dodecanoic acid formed is measured by HPLC, after proceeding as indicated in example 13.
  • Figure 5 Relationship concentration-inhibitory activity of the compound (1 S, 2S) -la on the neutral ceramidase.
  • the assays are carried out by incubation with microsomes of the inhibitor, at the indicated doses, and the enzyme substrate ( ⁇ / - (12- (4-nitrobenzo-2-oxa-1, 3-diazolo) dodecyl) sphingosine).
  • the amounts of 12 (4-nitrobenzo-2-oxa-1,3-diazolo) dodecanoic acid formed are measured by HPLC, after proceeding as indicated in example 13.
  • FIG. 7 Hydrolysis of compound (1 S, 2f?) - lb by acid ceramidase in Farber lymphoblasts. The tests are carried out by incubation of the GM12497 (control) and GM05748 (derived from a Farber patient) cell lines with the compound (1S, 2f?) - lb (10 ⁇ M). The amounts of 12 (4- nitrobenzo-2-oxa-1,3-diazolo) dodecanoic acid formed are measured by fluorescence, after proceeding as indicated in example 15.
  • the present invention describes compounds of general formula I, their stereoisomers and mixtures thereof, and the pharmaceutically acceptable solvates and addition salts thereof, where n, W, R 1 , R 2 and R 3 are specified in the claims.
  • Pharmaceutically acceptable salts include acid addition salts, such as mesylates, smokers, hydrochlorides, citrates, maleates and Tartrates
  • Physiologically acceptable salts can also be formed with sulfuric and phosphoric acids.
  • basic type salts of an alkali metal, such as sodium, or an alkaline earth metal, for example calcium or magnesium can be formed. There may be more than one cation or anion depending on the number of functions with charge and the valence of the cations and anions.
  • Some of the compounds of formula I of the present invention may have one or more chiral centers.
  • the present invention encompasses all possible stereoisomers, not only their racemic mixtures but also their optically active isomers. Obtaining a single enantiomer can be achieved by any of the procedures commonly used, for example, by resolution of the racemic mixture by recrystallization techniques, chiral synthesis, enzymatic resolution, biotransformation or chromatographic resolution.
  • Some of the compounds of formula I of the present invention may exist as non-solvated forms or as solvates, for example as hydrates.
  • the present invention comprises all the aforementioned forms that are pharmaceutically active.
  • Some of the compounds of general formula I may have polymorphism, this invention comprising all possible polymorphic forms.
  • the compounds of the present invention can be prepared following the general methods presented in Figures 1-3.
  • a method for the synthesis of the compounds (1f?, 2f?) -, (1 S.2S) - and (1R, 2S) -la ( Figure 1), (1 S, 2f) is described in Figures 1 and 2 ?) - lb y (1 S, 2R) -lc ( Figure 2).
  • Garner aldehyde or its enantiomer is treated with a solution of 2-alkyl-1-cyclopropenyl lithium, which can be prepared, for example, by the procedure described in Al-Dulayymi et al., Tetrahedron 1996, 52, 12509, in a mixture of tetrahydrofuran and hexamethylphosphorotriamide, obtaining a mixture of erythroltrean diastereomeric alcohols in a proportion (90:10). Following this same procedure, but carrying out the condensation of the organolytic with the aldehyde in the presence of ZnBr 2 , a mixture of erythroltreo alcohols is obtained in a proportion (9:91).
  • Pure enantiomers can be isolated, for example, by column chromatography on silica gel.
  • hydrolysis of the protecting groups for example by reaction with trimethylsilyl triflate in the presence of 2,6-lutidine, and ⁇ / -acylation of the resulting product with an activated acid (for example, acid chloride or anhydride) in pyridine, the desired final compound.
  • an activated acid for example, acid chloride or anhydride
  • This method consists of the transformation of intermediate (1'R, 4S) -iii in the bicyclic system (1'f?, 4S) -iv by treatment with NaH. Hydrolysis in a mild acid medium of said bicycles leads to hydroxycarbamate (1S, 2f?) - v.
  • This is a very versatile synthetic intermediate, since it can be transformed into the amine (1S, 2R) -v ⁇ by treatment with an ethanolic solution of NaOH, or, after changing the hydroxyl group for the desired substituent, into other various amines.
  • ⁇ / -acylation of these different modified analogs can be obtained in the primary hydroxyl group, such as, for example, the compounds (1 S, 2R) -ld, (1 S, 2R) -le and (1S, 2R) -lf described in example 12.
  • the compounds of the present invention are modulators of the activity of ceramidases.
  • Some of the compounds of the present invention (for example, (1 S, 2R) -lb) are very good substrates of ceramidases, so, when they compete very effectively with their natural substrate, ceramide, they cause an increase in intracellular levels of it.
  • other compounds of the present invention for example; (1 R, 2) -la, (1 R, 2S) -la and (1S, 2S) -la
  • the compounds of the present invention may be useful for the modulation and treatment in humans and animals of pathologies caused by or associated with alterations in the structure and / or activity of ceramidases.
  • cancer cells have lost the ability to apoptosis, which is due in many cases to a decrease in intracellular ceramide levels, which can be increased by inhibition of ceramidases (Selzner et al. Cancer Res., 2001, 61, 1233).
  • ceramidases hydrolyse the ceramide to sphingosine and this is then transformed into sphingosine-1-phosphate, which mediates proliferative signals, it is expected that the compounds of the The present invention is useful for the treatment, prevention and / or diagnosis of other pathologies associated with cellular hyperproliferation.
  • diseases include, in addition to cancer, some cardiovascular disorders and some inflammatory diseases.
  • Patents WO9744019 and WO03005965 describe the use of ceramidase inhibitors for the treatment and / or prevention of various pathologies, although all the compounds described in these two patents are outside the scope of the present invention.
  • Farber's disease is a hereditary pathology caused by various mutations in the acid ceramidase (Sugita et al., Science 1972, 178, 1100) that cause a decrease in this enzymatic activity, which can become void
  • This defect causes an accumulation of ceramide in the tissues that originates the serious symptoms typical of the disease, which manifests towards four months of life and usually causes death before the year.
  • the compound (1f?, 2S) -la is synthesized by condensation of (-R) - (+) - 4- formyl-2,2-dimethyl-3-oxazolidinecarboxylate of butyl-((R) - (+) - H ) with 2- tridecyl-1-cyclopropenillitium, obtained from 1-pentadecine following the sequence of reactions described in Al Dulayymi et al., Tetrahedron 1996, 52, 12509.
  • the product is extracted with CH 2 CI 2 and the organic phases are washed successively with phosphate buffer, saturated NaHC03 solution and saturated NaCl solution. Dried over MgS0 4l is the solvent and the resulting residue was evaporated dissolved in chloroform / methanol (2: 1) (2.5 mL) and pyridine (2.5 mL) and treated at 0 ° C, with 0.7 mmol of octanoyl chloride. Stir for 18 hours at 25 ° C. The product is extracted with CHCI 3 (10 mL) and the combined organic phases are washed with saturated NaCl solution. The solvent of the organic solution is evaporated and the residue is purified by column chromatography on silica gel.
  • Example 6 D ⁇ h ⁇ drooxazolo (3.4,0) oxazol-3-one (1'R 4S) -iv. To 355 mg (0.78 mmol) of (1'R, 4S) -ii ⁇ dissolved in anhydrous tetrahydrofuran (10 mL) are added, at 0 ° C under argon, 63 mg (1.57 mmol) of NaH. Stir for 18 h at 25 ° C, saturated NaHC0 3 solution is added and the product is extracted with diethyl ether. The organic extracts are washed with saturated NaCl solution and dried.
  • Example 7 Oxazolidin-2-one (1 S, 2f?) - v.
  • a solution of the crude from the previous reaction 250 mg, 0.66 mmol) and TsOH (12 mg, 0.06 mmol) in MeOH (10 mL) is stirred at 25 ° C for 6 h. After this time, the solvent is removed and the resulting residue is dissolved in ethyl acetate. The organic solution is washed with saturated NaHC0 3 and NaCI solution and dried. The solvent is removed to obtain an oil that is purified by column chromatography on silica gel (CHCI 3 / MeOH (97: 3)). 150 mg (0.44 mmol, 67%) of (1 S, 2R) -v are obtained. IR: 3315, 1726, 2858.
  • Example 8 Oxazolidin-2-one (1 S, 2?) - viii. A solution of (1 S, 2f?) - v (90 mg, 0.278 mmol) and 2,6-di- ⁇ erc-butylpyridine (0.92 mL, 4.12 mmol) in 10 mL of anhydrous CH 2 CI 2 is added over 411 mg (2.78 mmol) of trimethyloxonium tetrafluoroborate. After 24 h of stirring at 25 ° C, saturated NaCl solution is added and the product is extracted with ethyl acetate.
  • Example 9 Oxazolidin-2-one (1 S, 2R) -vii. To a solution of (1 S, 2f?) - v (123 mg, 0.38 mmol), trletylamine (106 ⁇ L, 0.76 mmol) and dimethylaminopyridine (catalytic amount) in anhydrous CH 2 CI 2 (10 mL) are added at 0 ° C, 59 ⁇ L (0.76 mmol) of MsCI. Stir at 25 ° C for 15 minutes, pour over a solution of 1N HCI and extract with CH2CI2. The organic phase is washed with saturated NaHC0 3 and NaCI solution and dried.
  • Example 10 Oxazolidin-2-one (1 S, 2R) -ix.
  • a solution of (1 S, 2R) -v (86 mg, 0.26 mmol) in anhydrous CH 2 CI 2 (10 mL) is treated, at -78 ° C and under argon, with DAST (68 ⁇ L, 0.52 mmol ). It is heated to 25 ° C for 9 h and stirred at this temperature for 12 h. It is cooled to 0 ° C and a few drops of MeOH are added. The product is extracted with diethyl ether and the organic phase of lava successively with saturated NaHCC » 3 solution and saturated NaCl solution, and dried.
  • Example 11 Aminodiol (1 S. 2R) -vi.
  • a solution of (1 S, 2f?) -V (13 mg, 0.038 mmol) in a 2N solution of NaOH in EtOH (1.3 mL) is stirred at 80 ° C for 3 h. After this period of time, a 1 N solution of HCI is added until neutral pH and the product is extracted with chloroform, obtaining 11 mg (0.035 mmol, 93%) of the aminodiol (1 S, 2) -v ⁇ .
  • Example 12 Deprotection v N-acylation of intermediates (1 S, 2) -vü. (1. 2?) - viii and (1 S, 2f?) - ix.
  • the hydrolysis step of the carbamate group is carried out following the procedure described in example 11 and the resulting crude oils are acylated as described in example 5.
  • Example 14 Neutral ceramidase activity on (1 S, 2R) -lb. This activity is determined following the procedure described in example 13, using rat liver microsomes and concentrations of 25, 50, 100, 150 and 200 ⁇ M (Fig. 6), of compound (1 S, 2R) -lb as inhibitor . The released 12 (4-nitrobenzo-2- oxa-1,3-diazolo) dodecanoic acid is quantified by HPLC.
  • Example 15 Use of compound (1 S.2R) -lb for the diagnosis of Farber's disease.
  • the lymphoblast lines, GM 12497 (control) and GM05748 (derived from a Farber patient), both obtained from the "Human Genetic Mutant Cell Repository”, are incubated at 37 ° C and 5% C0 2 in supplemented RPMI 1640 medium with Glutamax (2 mmol / l), penicillin (100 U / ml), streptomycin (100 ⁇ g / ml) and heat-inactivated bovine fetal serum (10%).
  • the cells are kept in an incubator at 37 ° C and 5% C0 2 for 2 days, the compound (1 S, 2R) -lb (10 ⁇ M) is added and incubated for a further 24 hours. After this time the cells are separated from the medium and the lipids are extracted with a mixture of chloroform / methanol (2: 1). The lipid extract is filtered through a 0.5 x 3 cm HighQ TM column. The stationary phase is washed with 10 ml of methanol and then with 2 ml of a 1 M solution of acetic acid in methanol.
  • the fluorescence of this acid fraction is measured in a fluorimeter and, by comparison with the fluorescence values of different known concentrations of 12 (4-nitrobenzo-2-oxa-1,3-diazolo) dodecanoic acid, the amount of acid formed is quantified by the ceramidase activity of the cells used.
  • the use of the compounds of the present invention for the treatment and / or diagnosis of human or animal diseases will be carried out through pharmaceutical compositions comprising at least a therapeutically effective amount of the compounds defined by the general formula as active ingredient and excipients or pharmaceutically acceptable solvents.

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Abstract

La présente invention concerne l'activité modulatrice des dérivés de cyclopropénylsfingosine sur les enzymes céramidases. Plus particulièrement, l'invention a pour objet l'utilisation desdits composés dans la fabrication d'une composition pharmaceutique utile dans le traitement de diverses maladies (la maladie de Faber, les maladies cardio-vasculaires, inflammatoires et le cancer). De plus, l'invention concerne également l'utilisation desdites compositions pharmaceutiques dans le traitement des maladies précitées.
PCT/ES2004/070101 2003-11-25 2004-11-24 Utilisation de derives de cyclopropenylesfingosine pour la production d'une composition pharmaceutique modulant l'activite de ceramidases et leurs applications WO2005051891A1 (fr)

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ES200302767A ES2233204B1 (es) 2003-11-25 2003-11-25 Utilizacion de derivados de ciclopropenilesfingosina para la elaboracion de una composicion farmaceutica moduladora de la actividad de ceramidasa, y sus aplicaciones.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013178545A1 (fr) 2012-05-28 2013-12-05 Fondazione Istituto Italiano Di Tecnologia Inhibiteurs de la céramidase acide et leur utilisation comme médicaments
WO2013178576A1 (fr) 2012-05-28 2013-12-05 Fondazione Istituto Italiano Di Tecnologia Inhibiteurs de la céramidase acide et leur utilisation comme médicaments
WO2015173169A1 (fr) 2014-05-12 2015-11-19 Fondazione Istituto Italiano Di Tecnologia Dérivés de benzoxazolone substitués comme inhibiteurs de la céramidase acide, et leur utilisation comme médicaments
WO2015173168A1 (fr) 2014-05-12 2015-11-19 Fondazione Istituto Italiano Di Tecnologia Dérivés de benzoxazolone en tant qu'inhibiteurs de la céramidase acide, et leur utilisation comme médicaments
US20210244827A1 (en) * 2018-06-29 2021-08-12 Icahn School Of Medicine At Mount Sinai Anc80 encoding sphingolipid-metabolizing proteins

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WO2001079152A1 (fr) * 2000-04-19 2001-10-25 Yissum Research Development Company Of The Hebrew University Of Jerusalem Sphingolipides
ES2170030A1 (es) * 2000-12-19 2002-07-16 Consejo Superior Investigacion Inhibidores de la dihidroceramida desaturasa.
WO2003005965A2 (fr) * 2001-07-11 2003-01-23 Musc Foundation For Research Development Modulateurs de ceramidase et procedes d'utilisation associes

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013178545A1 (fr) 2012-05-28 2013-12-05 Fondazione Istituto Italiano Di Tecnologia Inhibiteurs de la céramidase acide et leur utilisation comme médicaments
WO2013178576A1 (fr) 2012-05-28 2013-12-05 Fondazione Istituto Italiano Di Tecnologia Inhibiteurs de la céramidase acide et leur utilisation comme médicaments
WO2015173169A1 (fr) 2014-05-12 2015-11-19 Fondazione Istituto Italiano Di Tecnologia Dérivés de benzoxazolone substitués comme inhibiteurs de la céramidase acide, et leur utilisation comme médicaments
WO2015173168A1 (fr) 2014-05-12 2015-11-19 Fondazione Istituto Italiano Di Tecnologia Dérivés de benzoxazolone en tant qu'inhibiteurs de la céramidase acide, et leur utilisation comme médicaments
US10213416B2 (en) 2014-05-12 2019-02-26 The Regents of the University of Chicago Substituted benzoxazolone derivatives as acid ceramidase inhibitors, and their use as medicaments
US10226452B2 (en) 2014-05-12 2019-03-12 The Regents Of The University Of California Benzoxazolone derivatives as acid ceramidase inhibitors, and their use as medicaments
US20210244827A1 (en) * 2018-06-29 2021-08-12 Icahn School Of Medicine At Mount Sinai Anc80 encoding sphingolipid-metabolizing proteins

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