WO2012140300A1 - Composés et composition pour le traitement du myélome multiple - Google Patents

Composés et composition pour le traitement du myélome multiple Download PDF

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WO2012140300A1
WO2012140300A1 PCT/ES2012/070240 ES2012070240W WO2012140300A1 WO 2012140300 A1 WO2012140300 A1 WO 2012140300A1 ES 2012070240 W ES2012070240 W ES 2012070240W WO 2012140300 A1 WO2012140300 A1 WO 2012140300A1
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Prior art keywords
inhibitor
compound
gastric
cpt
group
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PCT/ES2012/070240
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English (en)
Spanish (es)
Inventor
Germán Manuel PERDOMO HERNÁNDEZ
Irene CÓZAR CASTELLANO
José Manuel TIRADO VÉLEZ
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Servicio Andaluz De Salud
Fundación Para La Gestión De La Investigación Biomédica De Cádiz
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Priority claimed from ES201130569A external-priority patent/ES2390306B1/es
Priority claimed from ES201130570A external-priority patent/ES2390303B1/es
Application filed by Servicio Andaluz De Salud, Fundación Para La Gestión De La Investigación Biomédica De Cádiz filed Critical Servicio Andaluz De Salud
Publication of WO2012140300A1 publication Critical patent/WO2012140300A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
    • C07D305/12—Beta-lactones

Definitions

  • the present invention relates to carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compounds, gastric and / or pancreatic lipase inhibitor compounds and their therapeutic use. More specifically, the authors of the invention have used etomoxir, in isolation, in combination with bortezomib, in combination with orlistat and optionally formulated in combination with low density lipoproteins (LDL), in the treatment of a pathology with uncontrolled proliferation of plasma cells, and more specifically, in the treatment of multiple myeloma.
  • CPT I carnitine palmitoyl transferase I
  • LDL low density lipoproteins
  • Plasma cells are producing antibodies, which constitute molecules of great importance in the immune response. Each plasma cell responds specifically to an antigen by producing a specific antibody against said antigen. When a cancer that affects plasma cells occurs, they are generated in large numbers and are called myeloma cells. These myeloma cells are deposited in the bone marrow and bone. Sometimes myeloma cells accumulate in a single bone forming a mass of cells called plasmacytoma. In many cases, however, myeloma cells accumulate in several bones forming tumors and giving rise to what is known as multiple myeloma (MM).
  • MM multiple myeloma
  • MM is an incurable and relatively rare cancer, which represents the
  • MM is characterized by an uncontrolled proliferation of plasma cells in the bone marrow.
  • MM is the second most common in the Western world diagnosed hematologic disease, and involves 14 because of death caused by cancer when considering all types of tumors. Unfortunately, MM is still considered an incurable disease. The average survival of patients with MM is maintained for an average of 3-4 years despite the efforts made in the last three decades to improve the cytotoxic activity of chemotherapy-based therapies for the treatment of MM.
  • MM Current treatment of MM includes radiotherapy, surgery and chemotherapy (Kumar A et al 2011 Acta Haematol 125 (l-2): 8-22).
  • agents used in the treatment of MM there are the following: dexamethasone, melphalan, doxorubicin, lenalidomide, prednisone, carmustine, etoposide, cisplatin, vincristine, cyclophosphamide, thalidomide and bortezomib.
  • Bortezomib (Velcade®) is a recent medication used in the treatment of MM in those patients who are not candidates for bone marrow transplantation or who do not respond to other treatments such as thalidomide or lenalidomide. Its mechanism of action is through a cytotoxic effect, since it acts on the tumor cell by reversible and selective inhibition of the proteasome, interfering with the cellular machinery responsible for controlling cell division.
  • the invention relates to the use of an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compounds for the manufacture of a medicament for the treatment and / or prevention of a proliferating pathology. uncontrolled plasma cells in the bone marrow.
  • CPT I carnitine palmitoyl transferase I
  • the invention relates to the use of an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds for the manufacture of a medicament for the treatment and / or prevention of a pathology that occurs with uncontrolled cell proliferation.
  • Bone marrow plasma a compound or combination of gastric and / or pancreatic lipase inhibitor compounds for the manufacture of a medicament for the treatment and / or prevention of a pathology that occurs with uncontrolled cell proliferation.
  • the invention in another aspect, relates to a composition
  • a composition comprising at least one carnitine palmitoyl transferase I (CPT I) enzyme inhibitor and at least one 26S proteasome inhibitor.
  • CPT I carnitine palmitoyl transferase I
  • the invention in another aspect, relates to a composition
  • a composition comprising at least one gastric and / or pancreatic lipase inhibitor and at least one 26 S proteasome inhibitor.
  • the invention in another aspect, relates to a composition
  • a composition comprising at least one carnitine palmitoyl transferase I (CPT I) enzyme inhibitor and at least one gastric and / or pancreatic lipase inhibitor.
  • CPT I carnitine palmitoyl transferase I
  • the invention in another aspect, relates to a low density lipoprotein (LDL) comprising an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compounds.
  • LDL low density lipoprotein
  • CPT I carnitine palmitoyl transferase I
  • the invention in another aspect, relates to a low density lipoprotein (LDL) comprising an inhibitor compound or combination of gastric and / or intestinal lipase inhibitor compounds.
  • LDL low density lipoprotein
  • the invention in another aspect, relates to a low density lipoprotein (LDL) comprising an inhibitor compound or combination of carnitine palmitoyl transferase enzyme (CPT I) inhibitor compounds and an inhibitor compound or combination of 26S proteasome inhibitor compounds.
  • LDL low density lipoprotein
  • CPT I carnitine palmitoyl transferase enzyme
  • the invention in another aspect, relates to a low density lipoprotein (LDL) comprising an inhibitor compound or combination of compounds.
  • LDL low density lipoprotein
  • the invention in another aspect, relates to a low density lipoprotein (LDL) comprising an inhibitor compound or combination of carnitine palmitoyl transferase enzyme (CPT I) inhibitor compounds and an inhibitor compound or combination of gastric lipase inhibitor compounds and / or pancreatic.
  • LDL low density lipoprotein
  • CPT I carnitine palmitoyl transferase enzyme
  • the invention relates to a composition comprising at least one carnitine palmitoyl transferase I (CPT I) enzyme inhibitor and at least one 26S proteasome inhibitor, a composition comprising at least one gastric lipase inhibitor and / or pancreatic and at least one 26S proteasome inhibitor, a composition comprising at least one carnitine palmitoyl transferase I (CPT I) enzyme inhibitor and at least one gastric and / or pancreatic lipase inhibitor, a low density lipoprotein (LDL) comprising an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compounds, a low density lipoprotein (LDL) comprising an inhibitor compound or combination of gastric and / or intestinal lipase inhibitor compounds, a lipoprotein of low density (LDL) comprising an inhibitor compound or combination of carnitine palmitoyl transferase enzyme (CPT I) inhibitor compounds and an inhibitor compound or combination of 26S
  • the invention relates to the use of a composition comprising at least one carnitine palmitoyl transferase I (CPT I) enzyme inhibitor and at least one 26S proteasome inhibitor, a composition comprising at least one lipase inhibitor gastric and / or pancreatic and at least one 26S proteasome inhibitor, a composition comprising at least one carnitine palmitoyl transferase I (CPT I) enzyme inhibitor and at least one gastric lipase inhibitor and / or pancreatic, a low density lipoprotein (LDL) comprising an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compounds, a low density lipoprotein (LDL) comprising an inhibitor compound or combination of inhibitor compounds Gastric and / or intestinal lipase, a low density lipoprotein (LDL) comprising an inhibitor compound or combination of carnitine palmitoyl transferase enzyme (CPT I) inhibitor compounds and an inhibitor compound or
  • Figure 1 describes that ethomoxir inhibits the oxidation of fatty acids in MM cells.
  • A Fatty acid oxidation rates in cell lines. * p ⁇ 0.05 vs RPMI and U266; # p ⁇ 0.05 NCI vs RPMI.
  • Figure 2 describes that etomoxir and orlistat dose dependently decrease the viability of MM cells.
  • Myeloma cells were pre-incubated in the presence of ethomoxir or orlistat at the indicated doses for 18 and 24 hours respectively. Then the cell viability was determined.
  • Dose dependence of orlistat in RPMI-8226 (D) U-266B 1 (E) and NCI-H929 (F). * / 0.05 vs. Control by ANO VA. N 4-6
  • Figure 3 shows that etomoxir and orlistat prevent the cell cycle progression of MM cells.
  • the cells were preincubated with ethomoxir or orlistat at the indicated doses. Next, the percentage of cells in each phase of the cell cycle using propidium iodide staining.
  • (B) Phases of the cell cycle in the U-266B1 cell line treated with 20 ⁇ Or ⁇ for 24 hours. * p ⁇ 0.05 vs. Control by ANO VA. N 4-6
  • Figure 4 describes that etomoxir and orlistat do not stimulate the apoptosis of MM cells.
  • the cells were preincubated with ethomoxir or orlistat at the indicated doses.
  • the percentage of caspase-3-active cells was analyzed by flow cytometry.
  • A Percentage of caspase-3-active cells in control U-266B1 cells and treated with 50 ⁇ Etx for 18 hours.
  • B Percentage of active caspase-3- cells in control U-266B1 cells and treated with 20 ⁇ Or ⁇ for 24 hours.
  • N 5 in triplicate.
  • Figure 5 shows that etomoxir and orlistat decrease the proliferation of MM cells.
  • the cells were preincubated with ethomoxir or orlistat at the indicated doses. Next, the rate of incorporation of tritiated thymidine was quantified.
  • A Incorporation of tritiated thymidine into control U-266B1 cells and treated with 50 ⁇ Etx for 18 hours.
  • B Incorporation of tritiated thymidine into control U-266B1 cells and treated with Or ⁇ 20 ⁇ for 24 hours.
  • N 5-6 in triplicate. . * /> ⁇ 0.05 vs. Control by t-Student.
  • Figure 6 shows that etomoxir and orlistat decrease the proliferation of the cells of primary cultures of patients with multiple myeloma. From my bone marrow aspirates of patients with multiple myeloma, myeloma cells that were pre-incubated with ethomoxir or orlistat were isolated at the indicated doses. Next, the rate of incorporation of tritiated thymidine was quantified.
  • A Incorporation of tritiated thymidine in primary cultures of human control myeloma cells and treated with 50 ⁇ Etx for 8 hours.
  • B Incorporation of tritiated thymidine in primary cultures of human control myeloma cells and treated with 20 ⁇ Or ⁇ for 8 hours.
  • N 2 in triplicate.
  • Figure 7 describes that ethomoxir potentiates the cytotoxic effect of bortezomib on multiple myeloma cells. Effect of etomoxir on the viability of myeloma cells in combination with bortezomib. Myeloma cells were pre-incubated in the presence of etomoxir, bortezomib or bortezomib + etomoxir at the indicated doses for 18 hours. Then the cell viability was determined. (A) RPMI-8226, (B) U-266B1, (C) NCI-H929. * / 0.05 vs Control by ANO VA; # p ⁇ 0.05 vs. Btz or Etx for ANO VA.
  • the authors of the present invention have identified that compounds capable of inhibiting fatty acid oxidation mediated by the enzyme carnitine palmitoyl transferase I (CPT I), and compounds capable of inhibiting the hydrolysis of fatty acids mediated by gastric and / or pancreatic lipase, They are able to significantly reduce the viability of myeloma cells.
  • CPT I carnitine palmitoyl transferase I
  • pharmacological inhibition of fatty acid oxidation mediated by ethomoxir as well as pharmacological inhibition of hydrolysis of fatty acids mediated by orlistat, prevents cell cycle progression and decreases the proliferation of multiple myeloma cells.
  • the authors of the present invention have shown that fatty acid oxidation inhibitors and gastric and / or pancreatic lipase inhibitors enhance the cytotoxic effect of bortezomib on MM cells.
  • CPT I carnitine palmitoyl transferase I
  • the invention relates to the use of an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compounds for the manufacture of a medicament for the treatment and / or prevention of a pathology that involves uncontrolled proliferation of plasma cells in the bone marrow.
  • CPT I carnitine palmitoyl transferase I
  • the invention relates to an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compounds for use in the treatment and / or prevention of a pathology that occurs with uncontrolled proliferation of plasma cells in the bone marrow .
  • CPT I carnitine palmitoyl transferase I
  • the invention relates to a method of treatment for the treatment and / or prevention of a pathology that occurs with uncontrolled proliferation of plasma cells in the bone marrow comprising the administration of a inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compounds.
  • CPT I carnitine palmitoyl transferase I
  • CPT I carnitine palmitoyl transferase I
  • CAT1 a mitochondrial enzyme
  • CPT I protein mediates the transport of long chain fatty acids across the membrane, binding them to carnitine molecules.
  • the gene coding for CPT I is conserved in chimpanzee, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito and C. elegans.
  • the invention contemplates the use of inhibitors of functionally equivalent variants of said enzyme.
  • functionally equivalent variant is meant all those polypeptides derived from the sequence of CPT I by modification, insertion and / or deletion of one or more amino acids, provided that the function of the enzyme CPT I is substantially maintained.
  • the variant Functionally equivalent of CPT I retains at least the function related to the transport of long-chain fatty acids through the internal membrane of the carnitine-dependent mitochondria (McGarry & Brown. Eur J Biochem. 1997; 244 (1): 1 -14).
  • Functionally equivalent variants of CPT I include those that show at least 25%, at least 40%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96% , at least 97%, at least 98% or at least 99%) of sequence identity with respect to the CPT I sequences indicated above.
  • the degree of identity between two amino acid sequences can be determined by conventional methods, for example, by standard sequence alignment algorithms known in the state of the art, such as, for example, BLAST (Altschul SF et al. Basic local alignment search tool J Mol Biol. 1990; 215 (3): 403-10).
  • BLAST Altschul SF et al. Basic local alignment search tool J Mol Biol. 1990; 215 (3): 403-10.
  • the person skilled in the art will understand that the amino acid sequences referred to in this description can be chemically modified, for example, by chemical modifications that are physiologically relevant, such as phosphorylations, acetylations, etc.
  • CPT I inhibitor or “combination of CPT I inhibitor compounds”, as used in the present invention, refers to any compound / s that are specifically binds to CPT I (or the functionally equivalent variant thereof) and which, when bound, is capable of causing a decrease in the activity of said enzyme or decreasing levels of mRNA or CPT I protein.
  • CPT I inhibitors for proteins of different species, depending on the species in which it is desired to inhibit CPT I.
  • the invention contemplates inhibitors of CPT I protein of human origin, such as defined in the NCBI database with access number, for liver isoform M_001876, muscle M_152245 and brain M_152359 (March 31, 2011 version).
  • homologues of other mammalian species including, without limitation, CPT I of the common rat (Rattus norvegicus) corresponding to the protein described in NCBI with accession number NP_037332.1 (version March 31, 2011), CPT I of dog (Canis lupus familiaris) corresponding to the protein described in the NCBI database with accession number AF482992.1 (version March 31, 2011), as well as poultry, pigs , cats, horses, rabbits, mice, bovine species and the like, as well as other animals, such as fish or other animals of interest.
  • Suitable methods for the determination of those compounds that are CPT I inhibitors comprise both the methods based on the determination of the levels of CPT I or mRNA encoding CPT I, and those based on the ability of the inhibitors to reduce the enzymatic capacity of CPT I.
  • Suitable methods for determining the ability of the compound to inhibit CPT I activity include, but are not limited to, the method described in Figure 1 of the present invention, in which the oxidation rate of fatty acids is determined by the use of radioisotopes following the protocol described by Perdomo and cois. (Brown NF et al, 2007, Metabolism 56 (11): 1500-1507, Sipula IJ et al, 2006, Metabolism 55 (12): 1637-1644).
  • tritium-labeled palmitate is quantified as a function of time and the number of cells.
  • a compound of the invention is considered to inhibit the activity of CPT I if it inhibits its function, ie if the activity of CPT I is decreased by at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%), at least 70%, at least 80%, at least 90%, or 100%, with respect to the control to which it has not been added the inhibitor compound.
  • treatment means administration of a compound according to the invention to alleviate or eliminate the pathology mentioned above or reduce or eliminate one or more symptoms associated with said pathology.
  • treatment also includes alleviating or eliminating the physiological sequelae of the disease.
  • prevention refers to the ability of a compound of the invention to prevent, minimize or hinder the onset or development of a disease or condition before its onset.
  • a pathology with uncontrolled proliferation of plasma cells in the bone marrow refers to a pathology in which the plasma cells of the bone marrow reproduce uncontrollably.
  • Illustrative examples of pathologies that occur with uncontrolled proliferation of plasma cells in the bone marrow include, but are not limited to, monoclonal gammopathy of undetermined significance (MGUS), multiple quiescent myeloma (SMM), Waldenstrom macroglobulinemia, primary amyloidosis, monoclonal gammopathies , Poems syndrome and multiple myeloma.
  • the pathology that occurs with uncontrolled proliferation of plasma cells in the bone marrow is a multiple myeloma.
  • multiple myeloma can be found in any of the different stages of the disease, from stage I to stage III.
  • the inhibitor is suitable for use in the treatment of MM in any of stages I, II and III.
  • the inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compounds includes, but is not limited to, a compound that is selected from the group consisting of:
  • Ri and R 2 independently are selected from the group consisting of: a hydrogen atom, a halogen atom, C1-C4 alkyl group, a C1-C4, a nitro group and a trifluoromethyl group;
  • R3 is a hydrogen atom or a C1-C4 alkyl group
  • Y is the group -0- (CH 2 ) m , where -m is 0 or an integer between l and 4;
  • n is an integer between 2 and 8
  • Ri and R 2 independently are selected from the group consisting of: a hydrogen atom, a halogen atom, C1-C4 alkyl group, a C1-C4, a nitro group and a trifluoromethyl group;
  • R 3 is a hydrogen atom or a C1-C4 alkyl group
  • Y is the group -0- (CH 2 ) m , where -m is 0 or an integer between l and 4;
  • n is an integer between 2 and 8
  • Ri and R 2 substituents of the phenyl ring are preferably in positions meta or para to the oxyalkylene oxirancarbox ⁇ lico acid.
  • the compound is a compound of formula
  • Ri and R2 are in meta or para position
  • Ri is a Hydrogen, a Chlorine atom, a methyl group, a methoxy group, a nitro group or a trifluoromethyl group;
  • R 2 is a Hydrogen or Chlorine atom
  • R 3 is a hydrogen atom or a Ci-C 4 alkyl group
  • Y is the group -0- (CH 2 ) m , where -m is 0 or 1 and n is an integer between 3 and 7, where the sum of myn is an integer between 3 and 7.
  • the compound is a compound of formula
  • Ri and R2 are in meta or para position
  • Ri is a Hydrogen, a Chlorine atom or a trifluoromethyl group
  • R 2 is a Hydrogen
  • R 3 is a hydrogen atom, a methyl group or an ethyl group
  • halogen refers to a substituent of chlorine, bromine, fluorine or iodine.
  • alkyl refers to a linear or branched hydrocarbon chain consisting of carbon and hydrogen atoms, which does not contain any unsaturation and contains 1 to 6 carbon atoms (Ci-C 6 alkyl), preferably 1 to 4 (C1-C4 alkyl) and which is linked to the rest of the molecule through a single bond.
  • alkyl groups include, without limitation, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.
  • alkoxy or alkoxy group refers to a radical of the formula -OR 'in which R' is an alkyl radical as defined above, for example, methoxy, ethoxy, propoxy, etc.
  • R' is an alkyl radical as defined above, for example, methoxy, ethoxy, propoxy, etc.
  • the alkoxy group contains 1 to 6 carbon atoms and more preferably, between 1 and 4 carbons.
  • the compound is a compound selected from the group: 2- (6- (4-chlorophenoxy) -hexyl) -oxyran-2-carboxylic acid ester, 2- (4- (3-chlorophenoxy) acid ester -butyl) -oxyran-2-carboxylic acid, 2- (4- (3-trifluoromethylphenoxy) -butyl) -oxyran-2-carboxylic acid ester 2- (5- (4-chlorophenoxy) -pentyl) -oxyran-2 - carboxylic acid, 2- (6- (3,4-dichlorophenoxy) -hexyl) -oxirane-2-carboxylic acid ester, 2- (6- (4- fluorophenoxy) -hexyl) -oxyran-2- carboxylic acid and 2- (6-phenoxyhexyl) -oxyran-2-carboxylic.
  • the compound is the ester of 2- [6- (4- chlorophenoxy) hexyl] -oxyran-2-carboxylic acid or ethomoxir, according to the formula:
  • substituents include, for example and in a nonlimiting sense, Ci- 6 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, N0 2, CF 3, -N (R a) (Rb) , -ORc, -SRd, -C (0) Re, -C (0) OR f , -C (0) N (R g ) (R h ), -OC (0) R i; in which R a , R b , R c , 3 ⁇ 4 Re, Rf, Rg, Rh and Ri are independently selected from hydrogen, Ci-C 6 alkyl, aryl, heterocyclyl, heteroaryl and trifluoromethyl.
  • pharmaceutically acceptable salts or solvates refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound that, in its administration, is capable of providing (directly or indirectly) a compound such as those described herein. document.
  • pharmaceutically unacceptable salts also fall within the scope of the invention, since these may be useful for the preparation of pharmaceutically acceptable salts.
  • the preparation of salts, prodrugs and derivatives can be carried out by methods known in the state of the art.
  • salts of the compounds provided herein are synthesized from the compound of the invention, by conventional chemical methods.
  • such salts are prepared, for example, by reacting the free acidic or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • acid addition salts include addition salts of mineral acids such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate , citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
  • mineral acids such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate
  • organic acid addition salts such as, for example, acetate, maleate, fumarate , citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
  • alkaline addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium, and organic alkaline salts such as, for example, ethylenediamine, ethanolamine, N, N-dialkylene ethalamine, glucamine and basic amino acid salts.
  • Especially preferred derivatives or prodrugs are those that increase the bioavailability of the compounds of the invention when these compounds are administered to the subject (for example, allowing an orally administered compound to be absorbed more rapidly into the blood) or that improve the supply of the compound to a biological compartment (for example, the brain or lymphatic system) with respect to the initial compound.
  • the compounds of the invention may be in a crystalline form as free compounds or solvates and it is intended that both forms are within the scope of the present invention.
  • Solvation methods are generally known in the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment the solvate is a hydrate.
  • the compounds of the invention or their salts or solvates are preferably in pharmaceutically acceptable form or in substantially pure form.
  • a pharmaceutically acceptable form it is understood, inter alia, that they have a pharmaceutically acceptable level of purity, excluding normal pharmaceutical additives such as diluents and excipients, and not including any material considered toxic at normal dosage levels.
  • the purity levels for the compound of the invention are preferably above 50%, more preferably above 70%), and even more preferably above 90%. In a preferred embodiment it is above 95% of the compound of the invention, or of its salts, solvates or prodrugs.
  • the compounds of the present invention may include enantiomers depending on the presence of chiral centers or isomers depending on the presence of multiple bonds (eg, Z, E).
  • the individual isomers, enantiomers or diastereomers and mixtures thereof are within the scope of the present invention.
  • a compound is drawn with explicit stereochemistry, it is intended to represent the racemic structure with relative stereochemistry, as well as enantiomers in different degrees of purity.
  • the enantiomers and the shallow diastereoi of the compounds represented with a particular stereochemistry also form part of the compounds of the invention.
  • siRNAs Small interference RNAs or siRNAs (siRNAs in their English name) are agents that are capable of inhibiting the expression of a target gene by RNA interference.
  • An siRNA can be chemically synthesized, can be obtained by in vitro transcription or can be synthesized in vivo in the target cell.
  • siRNAs consist of a double strand of RNA between 15 and 40 nucleotides in length and which may contain a 3 'and / or 5' protruding region of 1 to 6 nucleotides. The length of the protuberant region is independent of the total length of the siRNA molecule.
  • SiRNAs act by degradation or post-transcriptional silencing of the target messenger.
  • the siRNAs can be called shRNA (short hairpin RNA) characterized in that the antiparallel chains that form the siRNA are connected by a loop or hairpin region. These siRNAs are composed of a short antisense sequence (from 19 to 25 nucleotides), followed by a loop of between 5 and 9 nucleotides followed by the sense chain.
  • shRNAs may be encoded by plasmids or viruses, and be under the control of promoters such as the U6 promoter of RNA polymerase III.
  • siRNAs of the invention are substantially homologous to the mRNA of CPT I or the genomic sequence encoding said protein.
  • substantially homologous is meant that they have a sequence that is sufficiently complementary or similar to the target mRNA so that the siRNA is capable of causing degradation of the latter by RNA interference.
  • Suitable siRNAs to cause such interference include siRNAs formed by RNA, as well as siRNAs containing different chemical modifications, such as:
  • RNA chain conjugates with a functional reagent such as a fluorophore.
  • Nucleotides with modified sugars such as O-alkylated moieties in 2 'position such as 2'-0-methylribose-p-2'-0-fluorosibose.
  • Nucleotides with modified bases such as halogenated bases (for example 5-bromouracil and 5-iodouracil), alkylated bases (for example 7- methylguanosine).
  • halogenated bases for example 5-bromouracil and 5-iodouracil
  • alkylated bases for example 7- methylguanosine
  • siRNAs and siRNAs of the invention can be obtained using a series of techniques known to the person skilled in the art.
  • the siRNA can be chemically synthesized from ribonucleosides protected with forsforami dites in a conventional DNA / RNA synthesizer.
  • siRNAs can be produced recombinantly from plasmid and viral vectors in which In this case, the region that encodes the chain, or chains, that form the siRNAs are under operational control of RNA polymerase III promoters.
  • Dicer RNase processes shRNAs in functional siRNAs.
  • the region of CPT I that is taken as the basis for designing the siRNAs is not limiting and may contain a region of the coding sequence (between the initiation codon and the termination codon) or, alternatively, may contain sequences from the non-translated region 5 'or 3', is preferably between 25 and 50 nucleotides in length and in any position in 3 'position with respect to the initiation codon.
  • One way to design an siRNA involves the identification of the AA (N19) TT motifs where N can be any nucleotide in the CPT I sequence and selecting those that have a high G / C content. If this motif is not found, it is possible to identify the motif NA (N21), where N can be any nucleotide.
  • CPT I specific siRNAs that can be used include any siRNA specifically targeting the CPT I protein of the species to be inhibited.
  • Examples of siRNA include, but are not limited to, RNA si sc-40376 for human CPT I, siRNA sc-40377 for mouse CPT I and siRNA se-156134 for rat CPT I, all of them from Santa Cruz Biotechnology , etc.
  • a further aspect of the invention relates to the use of nucleic acids.
  • Antisense to inhibit expression, for example by inhibiting the transcription and / or translation of a nucleic acid encoding CPT I and whose activity it is desired to inhibit.
  • Antisense nucleic acids can be linked to the potential target of the drug by conventional base complementarity, or, for example, in the case of binding to double stranded DNA, through specific interactions in the major groove of the double helix. In general, these methods refer to the range of techniques generally employed in the art and include any method that is based on specific binding to oligonucleotide sequences.
  • An antisense construct of the present invention can be distributed, for example, as an expression plasmid which, when transcribed in the cell, produces RNA that is complementary to at least a single part of the cellular mRNA encoding CPT I.
  • the antisense construction is a probe of oligonucleotides that are generated ex vivo and that, when introduced into the cell, produce inhibition of gene expression by hybridizing with the mRNA and / or genomic sequences of a target nucleic acid.
  • oligonucleotide probes are preferably modified oligonucleotides, which are resistant to endogenous nucleases, for example, exonucleases and / or endonucleases, and which are therefore stable in vivo.
  • exemplary nucleic acid molecules for use as antisense oligonucleotides are DNA analogs of phosphoramidate, phosphothionate and methylphosphonate (see also U.S. Patent Nos. 5176996; 5264564; and 5256775).
  • oligodeoxyribonucleotide regions derived from the translation initiation site are preferred, for example, between -10 and +10 of the target gene.
  • Antisense approaches involve the design of oligonucleotides (either DNA, or RNA) that are complementary to the mRNA encoding the target polypeptide. Antisense oligonucleotides will bind to mRNA transcripts and prevent translation.
  • the antisense oligonucleotides can be DNA or RNA or chimeric mixtures or derivatives or modified versions thereof, single chain or double chain.
  • the oligonucleotide can be modified in the base group, the sugar group or the phosphate skeleton, for example, to improve the stability of the molecule, its hybridization capacity etc.
  • the oligonucleotide may include other bound groups, such as peptides (for example, to direct them to host cell receptors) or agents to facilitate transport across the cell membrane (see, for example, Letsinger et al, Proc. Nati. Acad Sci. USA 86: 6553-6556, 1989; Lemaitre et al, Proc. Nati. Acad. Sci.
  • the oligonucleotide may be conjugated to another molecule, for example, a peptide, a transport agent, hybridization triggered cutting agent, etc.
  • antisense oligonucleotides complementary to the coding region of the target mRNA sequence of CPT I can be used, as well as those complementary to the untranslated transcribed region.
  • Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cut of APvN (Rossi, Current Biology 4: 469-471, 1994).
  • the mechanism of action of ribozyme involves sequence-specific hybridization of the ribozyme molecule to a complementary target RNA, followed by an endonucleolytic sheath event.
  • the composition of the ribozyme molecules preferably includes one or more sequences complementary to the target mRNA, and to the well-known sequence responsible for mRNA cutting or a functionally equivalent sequence (US Patent No. 5093246).
  • Ribozymes used in the compositions of the present invention include hammerhead ribozymes, endoribonuclease RNAs (Cech type) (Zaug et al, Science 224: 574-578, 1984). Ribozymes may be composed of modified oligonucleotides (for example to improve stability, targeting, etc.) and should be distributed to cells expressing the target gene in vivo. A preferred method of distribution involves using a DNA construct that "encodes" the ribozyme under the control of a strong constitutive promoter of pol III or pol II, so that the transfected cells will produce sufficient amounts of the ribozyme to destroy the endogenous target messengers. and inhibit translation. Since ribozymes, contrary to other antisense molecules, are catalytic, a lower intracellular concentration is required for their effectiveness.
  • anti-CPT I antibody is understood in the context of the present invention any antibody that is capable of binding to CPT I specifically causing the inhibition of CPT I activity.
  • Anti-CPT I antibodies are specifically directed against essential protein epitopes to perform their function or against the complete protein.
  • Antibodies can be prepared using any of the methods that are known to the person skilled in the art. Thus, polyclonal antibodies are prepared by immunization of an animal with the protein that is You want to inhibit. Monoclonal antibodies are prepared using the method described by Kohler, Milstein et al. (Nature, 1975, 256: 495).
  • Suitable antibodies in the context of the present invention include intact antibodies comprising a variable region of antigen binding and a constant region, "Fab", “F (ab ' ) 2" and “Fab “ "fragments, Fv, scFv, diabodies and bispecific antibodies.
  • Antibodies capable of inhibiting the activity of CPT I include, without limitation, the antibody directed to residues 428-441 of rat CPT I used in Broadway NM et al 2003 Biochem. J. 370: 223-231, the antibody for rat liver CPT I employed by Sebastián D et al. J Lipid Res. 50: 1789-1799, etc.
  • Specific anti-CPT I antibodies also include commercial antibodies such as those of Santa Cruz Biotechnology (A-14, H-40 and N-17), which are polyclonal antibodies directed to rat, mouse and human CPT I and generated in goat or rabbit ; GeneTex GTX110253 antibody directed to rat, mouse and human and generated in rabbit; Novus Biologicals antibodies, which include goat-generated and human-directed polyclonal antibodies NB 100-53791, NBP1-50401, and H00001374-M02 monoclonal antibody also directed to human and mouse-generated; the human-directed polyclonal antibodies of Sigma-Aldrich SAB2500270 (generated in goat) and SAB2100476 (generated in rabbit) for CPT IA, C6623 (generated in rabbit), C6748 (generated in rabbit), SAB1300662 (generated in rabbit), SAB2501134 ( generated in goat) SAB1300298 (generated in rabbit) and HPA029583 for CPT IB, and HPA014529 for CPT IC, etc.
  • SAB2500270
  • the invention relates to the use of an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds for the manufacture of a medicament for the treatment and / or prevention of a pathology that occurs with uncontrolled proliferation of plasma cells in the bone marrow.
  • the invention relates to an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds for use in the treatment and / or prevention of a pathology that occurs with uncontrolled proliferation of plasma cells in the bone marrow.
  • the invention relates to a method of treatment for the treatment and / or prevention of a pathology that occurs with uncontrolled proliferation of plasma cells in the bone marrow comprising the administration of an inhibitor compound or combination of gastric lipase inhibitor compounds and / or pancreatic.
  • lipase refers to an enzyme that is capable of hydrolyzing ester bonds present in lipid substrates insoluble in aqueous solvents.
  • gastric lipase As used in the present invention, the term “gastric lipase” is used to refer to an acidic lipase secreted in the gastric mucosa.
  • pancreatic lipase and “pancreatic triacylglycerol lipase” are used interchangeably to refer to a lipase produced by the pancreas and which is the primary enzyme that hydrolyses dietary fat molecules in the apparatus. digestive, converting triglycerides into monoglycerides and fatty acids.
  • the invention contemplates the use of inhibitors of functionally equivalent variants of said enzyme.
  • “Functionally equivalent variant” means all those polypeptides derived from the gastric and / or pancreatic lipase sequence by modification, insertion and / or deletion of one or more amino acids, as long as the function of said enzyme is substantially maintained.
  • Functionally equivalent variants of gastric and / or pancreatic lipase include those that show at least 25%, at least 40%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% , at least 96%, at least 97%), at least 98% or at least 99% sequence identity with respect to gastric and / or pancreatic lipase sequences.
  • the degree of identity between two amino acid sequences can be determined by conventional methods, for example, by standard sequence alignment algorithms known in the state of the art, such as, for example, BLAST (Altschul SF et al. Basic local alignment search tool J Mol Biol. 1990; 215 (3): 403-10).
  • BLAST Altschul SF et al. Basic local alignment search tool J Mol Biol. 1990; 215 (3): 403-10.
  • the person skilled in the art will understand that the amino acid sequences referred to in this description can be chemically modified, for example, by chemical modifications that are physiologically relevant, such as, phosphorylations,
  • gastric and / or pancreatic lipase inhibitor or “combination of gastric and / or pancreatic lipase inhibitor compounds”, as used in the present invention, refers to any compound / s that is capable of causing a decrease. of the activity of said enzyme or of decreasing levels of mRNA or protein.
  • gastric and / or pancreatic lipase inhibitors specific for proteins of different species, depending on the species in which it is desired to inhibit gastric and / or pancreatic lipase.
  • the invention contemplates pancreatic lipase protein inhibitors of human origin, as defined in the NCBI database with accession number P 16233 for the protein of human origin, Q6P8U6 for the protein of murine origin, P00591 for the protein of porcine origin, P27657 for rat protein, as well as birds, pigs, cats, horses, rabbits, mice, bovine species and the like, as well as other animals, such as fish or other animals of interest.
  • Suitable methods for the determination of those compounds that are gastric and / or pancreatic lipase inhibitors comprise both methods based on the determination of the levels of gastric and / or pancreatic lipase or mRNA encoding gastric and / or pancreatic lipase, such as those based on the inhibition of the enzymatic activity of gastric and / or pancreatic lipase.
  • Suitable methods for determining the ability of the compound to inhibit the activity of gastric and / or pancreatic lipase include, but are not limited to, methods based on the measurement of trioleoylglycerol hydrolysis to give oleic acid as described, for example, in Tsujita et al. (J.Lipid Res., 2006, 47: 1852-1858).
  • a compound is considered to inhibit gastric and / or pancreatic lipase activity if it inhibits its function, that is, if gastric and / or pancreatic lipase activity is decreased by at least 15%, at least 20%, at least one 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%), at least 90%, or 100%, with respect to control over that the inhibitor compound has not been added.
  • the inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds includes, but is not limited to, a compound that is selected from the group consisting of:
  • RNAip for gastric, gastric and / or pancreatic lipase
  • antisense oligonucleotide specific for gastric and / or pancreatic lipase iii) an antisense oligonucleotide specific for gastric and / or pancreatic lipase
  • the compound is the acid lactone (2S, 3S, 5S, 7Z, 10Z) -5 - [(S) -2-formamido-4-methyl-varyloxy] -2-hexyl-3-hydroxy- 7,10- hexadecadienoic or lipstatin, according to the formula:
  • the gastric and / or pancreatic lipase inhibitor is acid lactone (2S, 3S, 5S) -5 - [(S) -2-fomamido-4-methyl-varyloxy] -2-hexyl- 3- hydroxy-hexadecanoic acid, or tetrahydrolipstatin or orlistat according to the formula:
  • substituents include, for example and in a nonlimiting sense, Ci- 6 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, N0 2, CF 3, -N (R a) (Rb) , -ORc, -SRd, -C (0) Re, -C (0) OR f , -C (0) N (R g ) (R h ), -OC (0) R i; in which R a , R b , R c , 3 ⁇ 4 Re, R f , R g , R h and Ri are independently selected from hydrogen, Ci-C 6 alkyl, aryl, heterocyclyl, heteroaryl and trifluoro
  • pharmaceutically acceptable salts or solvates refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound that, in its administration, is capable of providing (directly or indirectly) a compound such as those described herein. document.
  • pharmaceutically unacceptable salts also fall within the scope of the invention, since these may be useful for the preparation of pharmaceutically acceptable salts.
  • the preparation of salts, prodrugs and derivatives can be carried out by methods known in the state of the art.
  • salts of the compounds provided herein are synthesized from the compound of the invention, by conventional chemical methods.
  • such salts are prepared, for example, by reacting the free acidic or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • acid addition salts include addition salts of mineral acids such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate , citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
  • mineral acids such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate
  • organic acid addition salts such as, for example, acetate, maleate, fumarate , citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
  • alkaline addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium, and organic alkaline salts such as, for example, ethylenediamine, ethanolamine, N, N-dialkylene ethalamine, glucamine and basic amino acid salts.
  • Especially preferred derivatives or prodrugs are those that increase the bioavailability of the compounds of the invention when these compounds are administered to the subject (for example, allowing an orally administered compound to be absorbed more rapidly into the blood) or that improve the supply of the compound to a biological compartment (for example, the brain or lymphatic system) with respect to the initial compound.
  • the compounds of the invention may be in a crystalline form as free compounds or solvates and both forms are intended to be within the scope of the present invention.
  • Solvation methods are generally known in the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment the solvate is a hydrate.
  • the compounds of the invention or their salts or solvates are preferably in pharmaceutically acceptable form or in substantially pure form.
  • a pharmaceutically acceptable form it is understood, inter alia, that they have a pharmaceutically acceptable level of purity, excluding normal pharmaceutical additives such as diluents and excipients, and not including any material considered toxic at normal dosage levels.
  • the purity levels for the compound of the invention are preferably above 50%, more preferably above 70%), and even more preferably above 90%. In a preferred embodiment it is above 95% of the compound of the invention, or of its salts, solvates or prodrugs.
  • the compounds of the present invention may include enantiomers depending on the presence of chiral centers or isomers depending on the presence of multiple bonds (eg, Z, E).
  • the individual isomers, enantiomers or diastereomers and mixtures thereof are within the scope of the present invention.
  • a compound is drawn with explicit stereochemistry, it is intended to represent the racemic structure with relative stereochemistry, as well as enantiomers in different degrees of purity.
  • the enantiomers and the shallow diastereoi of the compounds represented with a particular stereochemistry also form part of the compounds of the invention.
  • siRNAs Small interference RNAs or siRNAs (siRNAs in their English name) are agents that are capable of inhibiting the expression of a target gene by RNA interference.
  • An siRNA can be chemically synthesized, can be obtained by in vitro transcription or can be synthesized in vivo in the target cell.
  • siRNAs consist of a double strand of RNA between 15 and 40 nucleotides in length and may contain a 3 'and / or 5' protruding region from 1 to 6 nucleotides The length of the protuberant region is independent of the total length of the siRNA molecule.
  • SiRNAs act by degradation or post-transcriptional silencing of the target messenger.
  • siRNAs of the invention are substantially homologous to the mRNA of the gastric and / or pancreatic lipase to the genomic sequence encoding said protein.
  • substantially homologous is meant that they have a sequence that is sufficiently complementary or similar to the target mRNA so that the siRNA is capable of causing degradation of the latter by RNA interference.
  • Suitable siRNAs to cause such interference include siRNAs formed by RNA, as well as siRNAs containing different chemical modifications, such as:
  • RNA chain conjugates with a functional reagent such as a fluorophore.
  • Nucleotides with modified sugars such as O-alkylated moieties in 2 'position such as 2'-0-methylribose-p-2'-0-fluorosibose.
  • Nucleotides with modified bases such as halogenated bases (for example 5-bromouracil and 5-iodouracil), alkylated bases (for example 7- methylguanosine).
  • halogenated bases for example 5-bromouracil and 5-iodouracil
  • alkylated bases for example 7- methylguanosine
  • siRNAs and siRNAs of the invention can be obtained using a series of techniques known to the person skilled in the art.
  • the siRNA can be chemically synthesized from ribonucleosides protected with forsforami dites in a conventional DNA / RNA synthesizer.
  • siRNAs can be produced recombinantly from plasmid and viral vectors in which case the region encoding the chain, or chains, that form the siRNAs are under operational control of RNA polymerase III promoters.
  • Dicer RNase processes shRNAs in functional siRNAs.
  • the region of gastric and / or pancreatic lipase mRNA that is taken as the basis for designing the siRNAs is not limiting and may contain a region of the sequence coding (between the initiation codon and the termination codon) or, alternatively, may contain sequences from the 5 'or 3' untranslated region, is preferably between 25 and 50 nucleotides in length and at any position in 3 'position with with respect to the initiation codon.
  • One way to design an siRNA involves the identification of the AA (N19) TT motifs where N can be any nucleotide in the gastric and / or pancreatic lipase sequence and selecting those that have a high G / C content. If this motif is not found, it is possible to identify the motif NA (N21), where N can be any nucleotide.
  • siRNAs for gastric and / or pancreatic lipase that can be used include any siRNA specifically directed to the gastric and / or pancreatic lipase protein of the species to be inhibited.
  • siRNA for gastric lipase include, but are limited to, siRNA sc-60673 and sc-60674 from Santa Cruz Biotechnology, etc.
  • siRNA for pancreatic lipase include, but are not limited to, the siRNA sc-61285 and sc-61286 of Santa Cruz Biotechnology, etc.
  • a further aspect of the invention relates to the use of "antisense" nucleic acids to inhibit expression, for example by inhibiting the transcription and / or translation of a nucleic acid encoding gastric and / or pancreatic lipase and whose activity it is desired to inhibit.
  • Antisense nucleic acids can be linked to the potential target of the drug by conventional base complementarity, or, for example, in the case of binding to double stranded DNA, through specific interactions in the major groove of the double helix. In general, these methods refer to the range of techniques generally employed in the art and include any method that is based on specific binding to oligonucleotide sequences.
  • An antisense construct of the present invention can be distributed, for example, as an expression plasmid which, when transcribed in the cell, produces RNA that is complementary to at least a single part of the cellular mRNA encoding gastric lipase and / or pancreatic
  • the antisense construct is an oligonucleotide probe that is generated ex vivo and that, when introduced into the cell, produces inhibition of gene expression by hybridizing with mRNA and / or genomic sequences of a target nucleic acid.
  • oligonucleotide probes are preferably modified oligonucleotides, which are resistant to endogenous nucleases, for example, exonucleases and / or endonucleases, and which are therefore stable in vivo.
  • exemplary nucleic acid molecules for use as antisense oligonucleotides are DNA analogs of phosphoramidate, phosphothionate and methylphosphonate (see also U.S. Patent Nos. 5176996; 5264564; and 5256775).
  • oligodeoxyribonucleotide regions derived from the translation initiation site are preferred, for example, between -10 and +10 of the target gene.
  • Antisense approaches involve the design of oligonucleotides (either DNA, or RNA) that are complementary to the mRNA encoding the target polypeptide. Antisense oligonucleotides will bind to mRNA transcripts and prevent translation.
  • the antisense oligonucleotides can be DNA or RNA or chimeric mixtures or derivatives or modified versions thereof, single chain or double chain.
  • the oligonucleotide can be modified in the base group, the sugar group or the phosphate skeleton, for example, to improve the stability of the molecule, its hybridization capacity etc.
  • the oligonucleotide may include other bound groups, such as peptides (for example, to direct them to host cell receptors) or agents to facilitate transport across the cell membrane (see, for example, Letsinger et al, Proc. Nati. Acad Sci. USA 86: 6553-6556, 1989; Lemaitre et al, Proc. Nati. Acad. Sci.
  • the oligonucleotide may be conjugated to another molecule, for example, a peptide, a transport agent, hybridization triggered cutting agent, etc.
  • antisense oligonucleotides complementary to the coding region of the mRNA target sequence of the gastric and / or pancreatic lipase can be used, as well as those complementary to the untranslated transcribed region.
  • Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cut of RNA (Rossi, Current Biology 4: 469-471, 1994).
  • the mechanism of action of ribozyme involves sequence-specific hybridization of the ribozyme molecule to a complementary target RNA, followed by an endonucleolytic sheath event.
  • the composition of the ribozyme molecules preferably includes one or more sequences complementary to the target mRNA, and to the well-known sequence responsible for mRNA cutting or a functionally equivalent sequence (US Patent No. 5093246).
  • Ribozymes used in the compositions of the present invention include hammerhead ribozymes, endoribonuclease RNAs (Cech type) (Zaug et al, Science 224: 574-578, 1984). Ribozymes may be composed of modified oligonucleotides (for example to improve stability, targeting, etc.) and should be distributed to cells expressing the target gene in vivo. A preferred method of distribution involves using a DNA construct that "encodes" the ribozyme under the control of a strong constitutive promoter of pol III or pol II, so that the transfected cells will produce sufficient amounts of the ribozyme to destroy the endogenous target messengers. and inhibit translation. Since ribozymes, contrary to other antisense molecules, are catalytic, a lower intracellular concentration is required for their effectiveness.
  • gastric anti-lipase antibody intestinal anti-lipase, anti-pancreatic lipase means in the context of the present invention any antibody that is capable of binding to gastric lipase, intestinal lipase or pancreatic lipase in a specific manner causing inhibition of lipase activity.
  • Gastric anti-lipase, intestinal anti-lipase and pancreatic lipase antibodies are specifically directed against essential protein epitopes to perform their function or against the whole protein.
  • Antibodies can be prepared using any of the methods that are known to the person skilled in the art. So, the antibodies Polyclonal are prepared by immunization of an animal with the protein that it is desired to inhibit.
  • Monoclonal antibodies are prepared using the method described by Kohler, Milstein et al. (Nature, 1975, 256: 495). Suitable antibodies in the context of the present invention include intact antibodies comprising a variable region of antigen binding and a constant region, "Fab", “F (ab ' ) 2" and “Fab “ "fragments, Fv, scFv, diabodies and bispecific antibodies.
  • Antibodies capable of inhibiting gastric lipase activity include, but are not limited to, antibodies directed to human D-17, G-16 and S-15 (generated in goat) and H-70 (generated in rabbit), all they from Santa Cruz Biotechnology, the rabbit-generated polyclonal antibody directed to human and mouse NB 110-60930, from Novus Biologicals, etc.
  • Antibodies capable of inhibiting the activity of pancreatic lipase include, without limitation, clone LIP10-143.3 directed to human and mouse generated by Pierce Antibodies, polyclonal antibodies directed to human H-41, Z-24 (generated in rabbit) , 302, 1.BB.985, 13301, 13302 (mouse generated), A-12, N-17 and R-14 (generated in goat), all of them from Santa Cruz Biotechnology, the human-directed ab30746 monoclonal antibody generated in Abcam mouse, polyclonal antibodies generated in mouse and directed to human H00005406-B01 and NB 100-62716 from Novus Biologicals, etc.
  • Compositions of the invention include, without limitation, clone LIP10-143.3 directed to human and mouse generated by Pierce Antibodies, polyclonal antibodies directed to human H-41, Z-24 (generated in rabbit) , 302, 1.BB.985, 13301, 13302 (mouse generated), A-12, N-17 and R-14 (generated in goat), all of them from Santa Cruz Biotechnology
  • composition A of the invention comprising at least one inhibitor of the carnitine palmitoyl transferase I enzyme (CPT I) and at least one 26S proteasome inhibitor.
  • CPT I carnitine palmitoyl transferase I enzyme
  • composition A of the invention comprises an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) inhibitor compounds that includes, but is not limited to, a compound that is selected from the group consisting of:
  • Ri and R 2 independently are selected from the group consisting of: a hydrogen atom, a halogen atom, C1-C4 alkyl group, a C1-C4, a nitro group and a trifluoromethyl group;
  • R3 is a hydrogen atom or a C1-C4 alkyl group
  • Y is the group -0- (CH 2 ) m , where -m is 0 or an integer between l and 4;
  • n is an integer between 2 and 8
  • the carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compound of composition A is ethomoxir.
  • 26S proteasome refers to the most common form of the proteasome, 26S, defined by its svedberg sedimentation coefficient (S), which includes a 20S core and two 19S regulatory subunits.
  • S svedberg sedimentation coefficient
  • the nucleus which is hollow, has a closed cavity where proteins are degraded. The openings at the ends of the nucleus serve as input to the proteins.
  • the 19S regulatory subunits located at the ends of the barrel have multiple sites with ATPase activity and ubiquitin binding sites, thus forming the structure that is responsible both for recognizing polyubiquitinated proteins, and for transferring them to the catalytic core.
  • 26S proteasome inhibitor or “combination of 26S proteasome inhibitor compounds”, as used in the present invention, refers to any compound / s that specifically binds to those proteins that constitute the 26S proteasome (or the variant functionally equivalent of them) and that when united it is capable of causing a decrease in the activity of the proteasome or of decreasing the levels of mRNA or proteins that constitute the 26S proteasome.
  • the invention contemplates the use of inhibitors of functionally equivalent variants of the 26S proteasome.
  • functionally equivalent variant is meant all those polypeptides derived from the 26S proteasome sequence by modification, insertion and / or deletion of one or more amino acids, as long as the function of the 26S proteasome is substantially maintained.
  • the functionally equivalent variant of the 26S proteasome retains at least the function related to protein degradation.
  • Functionally equivalent variants of the 26S proteasome include those that show at least 25%, at least 40%, at least 60%, at least 70%, at least 80%), at least 90%, at least 95%, at least 96 %, at least 97%, at least 98% or at least 99% sequence identity with respect to the 26 S proteasome sequences.
  • the degree of identity between two amino acid sequences can be determined by conventional methods, for example, by algorithms. sequence alignment standard known in the state of the art, such as, for example, BLAST (Altschul SF et al. Basic local alignment search tool. J Mol Biol. 1990; 215 (3): 403-10).
  • sequence alignment standard known in the state of the art such as, for example, BLAST (Altschul SF et al. Basic local alignment search tool. J Mol Biol. 1990; 215 (3): 403-10).
  • the person skilled in the art will understand that the amino acid sequences referred to in this description can be chemically modified, for example, by chemical modifications that are physiologically relevant, such
  • the invention contemplates inhibitors of the 26 S proteasome components in human, as defined in the NCBI database of the April 3, 2011 version with access number, such as regulatory subunit 1 (M_002807) (version April 3, 2011 from NCBI), Regulatory Subunit 2 (NM_002808), Regulatory Subunit 3 (NM_002804), Regulatory Subunit 4 (NM_002810), Regulatory Subunit 5 (NM_005047), Regulatory Subunit 6 (NM_014814), Regulatory Subunit 7 (NM_002811), Subunit Regulatory 8 (NM_002812), Regulatory Subunit 9 (NM_002813), Regulatory Subunit 10 (NM_002814 and NM_170750), Regulatory Subunit 11 (NM_002815), Regulatory Subunit 12 (NM_002816), Regulatory Subunit 13 (NM_175932 and NM_002817) regulatory subunit 14 (NM_005805).
  • M_002807 version April 3, 2011 from NCBI
  • Regulatory Subunit 2 NM_002808
  • Suitable methods for the determination of those compounds that are inhibitors of the 26S proteasome comprise both the methods based on the determination of the levels of the 26S proteasome or mRNA encoding the 26S proteasome.
  • 26S proteasome inhibitors include, but are not limited to, carfilzomib (PR-171), salinosporamide A (NPI-0052), beta-lactones such as lactacystin, TMC-95, belactosin A and C, disulfiramo, MG-132, and Bortezomib (PS-341).
  • composition A of the invention comprises an inhibitor compound or combination of 26S proteasome inhibitor compounds that includes, but is not limited to, a compound according to the formula: where
  • Y is R 8 -C (0), R 8 -S0 2 -, R 8 -NH-C (0) - or R 8 -0-C (0) -, where R 8 is alkyl, aryl, alkaryl or aralkyl; any of them being optionally substituted or if Y is R 8 -C (0) or R 8 -S0 2 -, then R 8 may also be a saturated, partially unsaturated or aromatic 5-10 membered heterocycle, optionally substituted;
  • X 3 is a covalent bond or -C (0) -CH 2 -;
  • R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, a heterocycle of 5-10 atoms saturated, partially saturated or unsaturated and -CH 2 -R 5 , where R 5 is aryl, aralkyl, alloadlo, cycloalkyl, heterocycle or chalcogen-to the chyl; Y
  • Z 1 and Z 2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together they form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms such as chain or ring, said chain or ring comprising carbon atoms and, optionally, a heteroatom or heteroatoms that may / n be N, S or O,
  • the proteasome inhibitor compound in a preferred embodiment, is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • 26S is bortezomib, of formula
  • aryl refers to an aromatic group having between 6 and 18, preferably between 6 and 10, more preferably 6 or 10, carbon atoms, comprising 1, 2 or 3 aromatic nuclei linked through a carbon bond -carbon or fused.
  • aryl groups include phenyl, naphthyl, diphenyl, indenyl, phenanthryl, etc.
  • alkaryl or alkylaryl refers to an alkyl group, as previously defined, attached to the rest of the molecule through an aryl group, as previously defined.
  • aralkyl or arylalkyl refers to an aryl group, as previously defined, attached to the rest of the molecule through an alkyl group, as previously defined; for example benzyl, phenylethyl, etc.
  • heterocycle refers to a stable cyclic radical of 3 to 10 members, preferably a 5 or 6 member cycle, consisting of carbon atoms and 1 to 5, preferably 1 to 3, heteroatoms selected from nitrogen, oxygen and sulfur, and which may be totally or partially saturated or aromatic ("heteroaryl").
  • heteroaryl a stable cyclic radical of 3 to 10 members, preferably a 5 or 6 member cycle, consisting of carbon atoms and 1 to 5, preferably 1 to 3, heteroatoms selected from nitrogen, oxygen and sulfur, and which may be totally or partially saturated or aromatic
  • heterocyclyl can be a mono-, bi- or tricyclic system, which can include fused ring systems.
  • heterocyclyl groups include, for example, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, benzimidazole, benzothiazole, furan, pyrrole, pyridine, pyrimidine, thiazole, thiophene, imidazole, indole, etc.
  • ci el oal quilo refers to a radical derived from cycloalkane containing from 3 to 7 (“C 3 -C 7 cycloalkyl”), preferably from 3 to 6 (“C3-C 6 cycloalkyl”) carbon atoms .
  • Illustrative examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • substituents include, for example and in a nonlimiting sense, Ci- 6 alkyl, C3-7 cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, N0 2, CF 3, -N (R a) (Rb) , -ORc, -SRd, -C (0) Re, -C (0) OR f , -C (0) N (R g ) (R h ), -OC (0) R i; wherein R a , R b , R c , 3 ⁇ 4 Re, Rf, Rg, Rh and Ri are independently selected from hydrogen, Ci-C 6 alkyl, aryl, heterocyclyl, heteroaryl and trifluoromethyl.
  • composition B of the invention comprising at least one gastric and / or pancreatic lipase inhibitor and at least one 26S proteasome inhibitor.
  • pancreatic lipase gastric lipase
  • pancreatic or gastic lipase inhibitor combination of pancreatic or gastic lipase inhibitors
  • 26S proteasome 26S proteasome inhibitor
  • composition B of the invention comprises an inhibitor compound or combination of lipase inhibitor compounds Gastric / pancreatic that includes, but is not limited to, a compound that is selected from the group consisting of:
  • RNAip for gastric, gastric and / or pancreatic lipase
  • antisense oligonucleotide specific for gastric and / or pancreatic lipase ii) a specific RNAip for gastric, gastric and / or pancreatic lipase, iii) an antisense oligonucleotide specific for gastric and / or pancreatic lipase
  • the gastric and / or pancreatic lipase inhibitor of composition B is orlistat according to the formula
  • composition B of the invention comprises an inhibitor compound or combination of 26S proteasome inhibitor compounds that includes, but is not limited to, a compound according to the formula: where
  • Y is R 8 -C (0), R 8 -S0 2 -, R 8 - HC (0) - or R 8 -0-C (0) -, where R 8 is alkyl, aryl, alkaryl or aralkyl; any of them being optionally substituted or if Y is R 8 -C (0) or R 8 -S0 2 -, then R 8 may also be a saturated, partially unsaturated or aromatic 5-10 membered heterocycle, optionally substituted;
  • X 3 is a covalent bond or -C (0) -CH 2 -;
  • R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, a saturated 5-10 atom heterocycle, partially saturated or unsaturated and -CH 2 -R 5 , where R 5 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle or chalcogen-alkyl; Y
  • Z 1 and Z 2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together they form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms such as chain or ring, said chain or ring comprising carbon atoms and, optionally, a heteroatom or heteroatoms that may / n be N, S or O,
  • the 26S proteasome inhibitor compound is bortezomib, of formula
  • alkyl alkoxy or alkoxy group
  • halogen aryl
  • aryl aleadlo or alkylaryl
  • aralkyl or arylalkyl heterocycle
  • cycloalkyl cycloalkyl
  • composition C of the invention comprising at least one inhibitor of the carnitine palmitoyl transferase I enzyme (CPT I) and at least one gastric and / or pancreatic lipase inhibitor.
  • CPT I carnitine palmitoyl transferase I enzyme
  • composition C of the invention comprises an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) inhibitor compounds that includes, but is not limited to, a compound that is selected from the group consisting of:
  • Ri and R 2 independently are selected from the group consisting of: a hydrogen atom, a halogen atom, C1-C4 alkyl group, a C1-C4, a nitro group and a trifluoromethyl group;
  • R3 is a hydrogen atom or a C1-C4 alkyl group
  • Y is the group -0- (CH 2 ) m , where -m is 0 or an integer between l and 4;
  • n is an integer between 2 and 8
  • the carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compound of composition C is ethomoxir.
  • composition C of the invention comprises an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds that includes, but is not limited to, a compound that is selected from the group consisting of:
  • RNAip for gastric, gastric and / or pancreatic lipase
  • an antisense oligonucleotide specific for pancreatic gastric lipase an antisense oligonucleotide specific for pancreatic gastric lipase
  • the gastric and / or pancreatic lipase inhibitor compound of composition C is orlistat.
  • composition D of the invention comprising at least one inhibitor of the carnitine palmitoyl transferase I (CPT I) enzyme, at least one 26S proteasome inhibitor and in addition at least one gastric and / or pancreatic lipase inhibitor.
  • CPT I carnitine palmitoyl transferase I
  • composition D of the invention comprises an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) inhibitor compounds that includes, but is not limited to, a compound that is selected from the group consisting of:
  • Ri and R 2 independently are selected from the group consisting of: a hydrogen atom, a halogen atom, an alkyl group C 1 -C 4 alkoxy group C1 - C4, a nitro group and a trifluoromethyl group;
  • R3 is a hydrogen atom or a group C1 - C4 alkyl
  • Y is the group -0- (CH 2 ) m , where -m is 0 or an integer between l and 4;
  • n is an integer between 2 and 8
  • the carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compound of composition D is ethomoxir.
  • composition D of the invention comprises an inhibitor compound or combination of 26S proteasome inhibitor compounds that includes, but is not limited to, a compound according to the formula:
  • Y is R 8 -C (0), R 8 -S0 2 -, R 8 - HC (0) - or R 8 -0-C (0) -, where R 8 is alkyl, aryl, alkaryl or aralkyl; any of them being optionally substituted or if Y is R 8 -C (0) or R 8 -S0 2 -, then R 8 may also be a saturated, partially unsaturated or aromatic 5-10 membered heterocycle, optionally substituted;
  • X 3 is a covalent bond or -C (0) -CH 2 -;
  • R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, a saturated 5-10 atom heterocycle, partially saturated or unsaturated and -CH 2 -R 5 , where R 5 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle or chalcogen-to chyl; Y
  • Z 1 and Z 2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together they form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms such as chain or ring, said chain or ring comprising carbon atoms and, optionally, a heteroatom or heteroatoms that may / n be N, S or O,
  • the 26 S proteasome inhibitor compound of composition D is bortezomib.
  • composition D of the invention comprises an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds that includes, but is not limited to, a compound that is selected from the group consisting of:
  • RNAip for gastric, gastric and / or pancreatic lipase
  • antisense oligonucleotide specific for gastric and / or pancreatic lipase ii) a specific RNAip for gastric, gastric and / or pancreatic lipase, iii) an antisense oligonucleotide specific for gastric and / or pancreatic lipase
  • the gastric and / or pancreatic lipase inhibitor compound of composition D is orlistat.
  • compositions A, B, C and D of the present invention contain therapeutically effective amounts of the compounds indicated above.
  • therapeutically effective amount is understood as the amount of compound of the invention necessary for achieve the desired effect which, in this specific case, is the inhibition of CPT I, 26S proteasome and gastric and / or pancreatic lipase.
  • therapeutically effective amount of the compound according to the present invention to be administered will depend, among other factors, on the individual to be treated, on the severity of the disease suffered by said individual, on the chosen form of administration, etc. For this reason, the doses to be administered will be adjusted by a person skilled in the art, depending on the specific circumstances.
  • composition refers to a composition of matter comprising the indicated components, that is, the carnitine palmitoyl transferase I (CPT I) enzyme inhibitor, a 26S proteasome inhibitor and / or a gastric and / or pancreatic lipase inhibitor as well as any product resulting, directly or indirectly, from the combination of the various components in any quantity thereof.
  • CPT I carnitine palmitoyl transferase I
  • 26S proteasome inhibitor a 26S proteasome inhibitor
  • gastric and / or pancreatic lipase inhibitor as well as any product resulting, directly or indirectly, from the combination of the various components in any quantity thereof.
  • the person skilled in the art will appreciate that the composition may be formulated as a single formulation or may be presented as formulations of each of the components separately that may be combined for joint use as a combined preparation.
  • the composition can be a kit of parts where each of the components is formulated and packaged separately.
  • compositions A, B, C and D of the invention may additionally comprise a pharmaceutically acceptable carrier, together with the inhibitors.
  • pharmaceutically acceptable vehicle refers to a vehicle that must be approved by a federal government regulatory agency or a state government or listed in the United States Pharmacopoeia or the European Pharmacopoeia, or other pharmacopoeia generally recognized for use in animals, and more specifically in humans.
  • vehicle refers to a diluent, adjuvant, excipient or carrier with which the compounds of the invention should be administered; obviously, said vehicle must be compatible with said compounds.
  • Such pharmaceutical vehicles may be liquids, such as water, solvents, oils or surfactants, including those of petroleum, animal, vegetable or synthetic origin, for example, and without limitation, peanut oil, soybean oil, mineral oil, oil sesame, castor oils, polysorbates, sorbitan esters, ether sulfates, sulfates, betaines, glycosides, maltósidos, fatty alcohols, nonoxinoles, poloxamers, polyoxyethylene, polyethylene glycols, dextrose, glycerol, digitonin and the like.
  • solvents oils or surfactants
  • suitable carriers for example, and without limitation, peanut oil, soybean oil, mineral oil, oil sesame, castor oils, polysorbates, sorbitan esters, ether sulfates, sulfates, betaines, glycosides, maltósidos, fatty alcohols, nonoxinoles, poloxamers, polyoxyethylene, polyethylene glycols, dextrose, glyce
  • compositions A, B, C and D of the invention can be administered together with a sustained release vehicle.
  • sustained release is used in the conventional sense referring to a system of vehiculization of a compound that provides for the gradual release of said compound over a period of time and preferably, but not necessarily, with relatively constant levels of compound release at over a period of time.
  • sustained release vehicles or systems include, but are not limited to, liposomes, mixed liposomes, oleosomes, niosomes, ethosomes, milicocapsules, microcapsules, nanocapsules, sponges, cyclodextrins, vesicles, micelles, mixed surfactant micelles, phospholipid mixed micelles - surfactant, microspheres, microspheres, nanospheres, lipospheres, microemulsions, nanoemulsions, miniparticles, miliparticles, microparticles, nanoparticles, solid lipid nanoparticles and nanostructured lipid supports.
  • composition A of the invention comprises one or more CPT I inhibitors and one or more 26S proteasome inhibitors.
  • Such inhibitors could be combined in equal or different proportions, and could be part of the same formulation or could be formulated in different formulations for sequential, joint or simultaneous administration.
  • composition B of the invention comprises one or more gastric and / or pancreatic lipase inhibitors and one or more 26S proteasome inhibitors.
  • Such inhibitors could be combined in equal or different proportions, and could be part of the same formulation or could be formulated in different formulations for sequential, joint or simultaneous administration.
  • composition C of the invention comprises one or more CPT I inhibitors and one or more 26S proteasome inhibitors. Such inhibitors could be combined in equal or different proportions, and could be part of the same formulation or could be formulated in different formulations for sequential, joint or simultaneous administration.
  • the composition D of the invention comprises one or more CPT I inhibitors, one or more 26S proteasome inhibitors and one or more gastric and / or pancreatic lipase inhibitors. Such inhibitors could be combined in equal or different proportions, and could be part of the same formulation or could be formulated in different formulations for sequential, joint or simultaneous administration.
  • compositions of the invention are administered topically, transdermally, orally, nasally, intramuscularly, intravenously, intraperitoneally, subcutaneously, enterally or parenterally.
  • topical or transdermal administration include, but are not limited to, iontophoresis, sonophoresis, electroporation, mechanical pressure, osmotic pressure gradient, occlusive cure, microinjections, needleless injections by pressure, microelectric patches and any combination thereof.
  • Illustrative examples of pharmaceutical forms of oral administration include tablets, capsules, granules, solutions, suspensions, etc., and may contain conventional excipients, such as binders, diluents, disintegrants, lubricants, humectants, etc., and may be prepared by conventional methods.
  • the pharmaceutical compositions may also be adapted for parenteral administration, in the form of, for example, sterile lyophilized solutions, suspensions or products, in the appropriate dosage form; in this case, said pharmaceutical compositions will include suitable excipients, such as buffers, surfactants, etc. In any case, the excipients will be chosen based on the pharmaceutical form of administration selected.
  • a review of the different pharmaceutical forms of drug administration and their preparation can be found in the book "Treaty of Pharmacy Galenica", by C. Faul ⁇ i Trillo, 10 Edition, 1993, Luzán 5, S.A. of Editions.
  • said medicament comprises one or more CPT I inhibitors, one or more 26S proteasome inhibitors and one or more gastric and / or pancreatic lipase inhibitors.
  • said inhibitors could be combined in equal or different proportions, and could be part of the same formulation or could be formulated in different formulations for sequential or simultaneous administration.
  • Pharmaceutical compositions containing one or more CPT I inhibitors, one or more 26S proteasome inhibitors and one or more gastric and / or pancreatic lipase inhibitors may be presented in any pharmaceutical form of administration deemed appropriate for the route of administration chosen. , for example, systemically, orally, parenterally or topically, for which they will include the pharmaceutically acceptable excipients necessary for the formulation of the desired administration form.
  • the effective amount of one or more CPT I inhibitors, one or more 26S proteasome inhibitors and one or more gastric and / or pancreatic lipase inhibitors may vary within a wide range and, in general, will vary depending on particular circumstances. of application, the duration of exposure and considerations of this type.
  • Solid dosage forms for oral administration may include conventional capsules, sustained-release capsules, conventional tablets, sustained-release tablets, chewable tablets, sublingual tablets, effervescent tablets, pills, suspensions, powders, granules and gels.
  • the active compounds may be mixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, for example, lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents.
  • the tablets and pills can be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • injectable preparations for example, injectable and sterile aqueous or oleaginous suspensions may be formulated according to the known technique using suitable dispersing agents, wetting agents and / or suspending agents. Between Acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Sterile oils are also conventionally used as solvents or suspending media.
  • CPT I, 26S proteasome and gastric and / or pancreatic lipase inhibitors can be formulated in the form of creams, gels, lotions, liquids, ointments, spray solutions, dispersions, solid bars, emulsions, microemulsions and the like, which can be formulated according to conventional methods using suitable excipients, such as, for example, emulsifiers, surfactants, thickening agents, colorants and combinations of two or more thereof.
  • CPT I, 26S proteasome and gastric and / or pancreatic lipase inhibitors can be administered transdermally in the form of transdermal patches or iontophoresis devices.
  • the CPT I inhibitor or inhibitors of 26S proteasome and gastric and / or pancreatic lipase are administered in the form of a transdermal patch, for example, in the form of a transdermal sustained-release patch.
  • Suitable transdermal patches are described in more detail in, for example, US5262165, US5948433, US6010715 and US6071531.
  • compositions containing CPT I inhibitors, 26S proteasome and gastric and / or pancreatic lipase may additionally include conventional excipients, that is, pharmaceutically acceptable carriers suitable for parenteral application that do not react harmfully with the active compounds.
  • suitable pharmaceutically acceptable carriers include, for example, water, saline solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talcum, surfactants, silicic acid, viscous paraffin, perfuming oil, monoglycerides and acid diglycerides.
  • Suitable sustained release forms as well as materials and methods for their preparation are described in, for example, "Modified-Release Drug Delivery Technology", Rathbone, MJ Hadgraft, J. and Roberts, MS (eds.), Marcel Dekker, Inc., New York (2002); "Handbook of Pharmaceutical Controlled Relay Technology”, Wise, DL (ed.), Marcel Dekker, Inc.
  • the orally administrable form of CPT I inhibitors, 26S proteasome and gastric and / or pancreatic lipase is in a sustained release form that additionally comprises at least one coating or matrix.
  • the sustained release coating or matrix includes, but is not limited to, natural, semi-synthetic or synthetic water-insoluble, modified polymers, waxes, fats, fatty alcohols, fatty acids, semi-synthetic or synthetic natural plasticizers, or a combination of two or more of the same.
  • Enteric coatings can be applied using conventional processes known to those skilled in the art, as described in, for example, Johnson, JL, "Pharmaceutical tablet coating", Coatings Technology Handbook (Second Edition), Satas, D. and Tracton, AA (eds), Marcel Dekker, Inc. New York, (2001); Carstensen, T., “Coating Tablets in Advanced Pharmaceutical Solids", Swarbrick, J. (ed.), Marcel Dekker, Inc. New York (2001), 455-468;
  • the determination of optimal ranges for effective amounts of CPT I inhibitors, 26S proteasome and gastric and / or pancreatic lipase belongs to the usual experience of those skilled in the art.
  • the dosage necessary to provide an effective amount of said CPT I, 26S proteasome and gastric and / or pancreatic lipase inhibitors which can be adjusted by a person skilled in the art, will vary depending on age, health, physical condition, sex, diet, weight, degree of the alteration of the recipient, frequency of treatment and the nature and extent of the alteration or disease, medical condition of the patient, the route of administration, pharmacological considerations such as activity, efficacy, profile Pharmacokinetic and toxicology of the particular compound used, if a drug delivery system is used, and if the compound is administered as part of a combination of drugs.
  • the amount of CPT I inhibitor, 26S proteasome and gastric and / or pancreatic lipase that will be effective in treating a particular disorder or condition it will depend on the nature of the disorder or condition, and can be determined by conventional clinical techniques, including the reference to Goodman and Gilman, supra; The Physician's Desk Reference, Medical Economics Company, Inc., Oradell, NJ, 1995; and Drug Facts and Comparisons, Inc., St. Louis, MO, 1993.
  • the exact dose to be used in the formulation will also depend on the route of administration, and the severity of the disease or disorder, and should be decided at the discretion of the physician and of the patient's circumstances.
  • Low density lipoproteins and compositions comprising LDLs
  • the invention relates to a low density lipoprotein
  • LDL low density lipoprotein 1
  • CPT I carnitine palmitoyl transferase I
  • low density lipoprotein is meant a lipoprotein of greater density than chylomicron, very low density lipoprotein (VLDL) and intermediate density lipoprotein (TDL), and of density less than that of high density lipoprotein (HDL), with a density value of 1,019-1,063 g / ml and a diameter of 19-23 nm in human.
  • Low density lipoprotein is formed by a nucleus formed by cholesterol esters surrounded by a monolayer of phospholipids comprising free cholesterol and Apoprotein B as the main apoprotein. In the bloodstream, LDLs are responsible for transporting cholesterol to peripheral tissues.
  • the LDLs according to the present invention are obtained from a mixture of phosphatidylcholine, cholesterol, cholesterol esters, triglycerides, at least one polypeptide capable of binding to an ApoB receptor and the active ingredient (s). using a molar relationship of the different components previously determined by routine experimentation such as that which allows to generate synthetic LDLs with the appropriate characteristics.
  • the LDL1 of the invention comprises an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) inhibitor compounds that includes, but is not limited to, a compound that is selected from the group consisting of:
  • Ri and R 2 independently are selected from the group consisting of: a hydrogen atom, a halogen atom, C1-C4 alkyl group, a C1-C4, a nitro group and a trifluoromethyl group;
  • R3 is a hydrogen atom or a C1-C4 alkyl group
  • Y is the group -0- (CH 2 ) m , where -m is 0 or an integer between l and 4;
  • n is an integer between 2 and 8
  • the carnitine palmitoyl transferase I (CPT I) inhibitor compound of the LDL1 of the invention is ethomoxir.
  • the invention relates to a low density lipoprotein (LDL), hereinafter low density lipoprotein 2 (LDL2) of the invention, which It comprises an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds.
  • LDL low density lipoprotein
  • LDL2 low density lipoprotein 2
  • pancreatic lipase pancreatic or gastic lipase inhibitor
  • pancreatic or gastic lipase inhibitor pancreatic or gastic lipase inhibitor compounds
  • low density lipoprotein low density lipoprotein
  • the LDL2 of the invention comprises an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds that includes, but is not limited to, a compound that is selected from the group consisting of:
  • RNAip for gastric, gastric and / or pancreatic lipase
  • antisense oligonucleotide specific for gastric and / or pancreatic lipase ii) a specific RNAip for gastric, gastric and / or pancreatic lipase, iii) an antisense oligonucleotide specific for gastric and / or pancreatic lipase
  • the LDL2 gastric and / or pancreatic lipase inhibitor compound is orlistat.
  • the invention relates to a low density lipoprotein (LDL), hereinafter low density lipoprotein 3 of the invention (LDL3), which comprises an inhibitor compound or combination of inhibitors compounds of the transferase carnitine carnitine enzyme (CPT I ) and an inhibitor compound or combination of 26S proteasome inhibitor compounds.
  • LDL low density lipoprotein
  • CPT I transferase carnitine carnitine enzyme
  • the LDL3 of the invention comprises an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) inhibitor compounds that includes, but is not limited to, a compound that is selected from the group consisting of:
  • Ri and R 2 independently are selected from the group consisting of: a hydrogen atom, a halogen atom, an alkyl group C 1 -C 4 alkoxy group C1 - C4, a nitro group and a trifluoromethyl group;
  • R3 is a hydrogen atom or a group C1 - C4 alkyl
  • Y is the group -0- (CH 2 ) m , where -m is 0 or an integer between l and 4;
  • n is an integer between 2 and 8
  • the carnitine palmitoyl transferase I (CPT I) inhibitor compound of the LDL3 of the invention is ethomoxir.
  • the LDL3 of the invention comprises an inhibitor compound or combination of 26S proteasome inhibitor compounds that includes, but is not limited to, a compound according to the formula:
  • Y is R 8 -C (0), R 8 -S0 2 -, R 8 - HC (0) - or R 8 -0-C (0) -, where R 8 is alkyl, aryl, alkaryl or aralkyl; any of them being optionally substituted or if Y is R 8 -C (0) or R 8 -S0 2 -, then R 8 may also be a saturated, partially unsaturated or aromatic 5-10 membered heterocycle, optionally substituted;
  • X 3 is a covalent bond or -C (0) -CH 2 -;
  • R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, a saturated 5-10 atom heterocycle, partially saturated or unsaturated and -CH 2 -R 5 , where R 5 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle or chalcogen-to chyl; Y
  • Z 1 and Z 2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together they form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms such as chain or ring, said chain or ring comprising carbon atoms and, optionally, a heteroatom or heteroatoms that may / n be N, S or O,
  • the 26 S proteasome inhibitor compound of the LDL3 of the invention is bortezomib.
  • the LDL3 carnitine palmitoyl transferase I (CPT I) inhibitor compound of the invention is ethomoxir and the 26S proteasome inhibitor compound of the LDL3 of the invention is bortezomib.
  • the invention in another aspect, relates to a low density lipoprotein (LDL), hereinafter low density lipoprotein 4 of the invention (LDL4), which comprises an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds and an inhibitor compound or combination of 26S proteasome inhibitor compounds.
  • LDL low density lipoprotein
  • LDL4 low density lipoprotein 4 of the invention
  • low density lipoprotein gastric and / or pancreatic lipase inhibitor
  • 26S proteasome 26S proteasome inhibitor
  • combination of 26S proteasome inhibitor compounds refer to the terms defined above.
  • the LDL4 of the invention comprises an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds that includes, but is not limited to, a compound that is selected from the group consisting of:
  • RNAip for gastric, gastric and / or pancreatic lipase
  • antisense oligonucleotide specific for gastric and / or pancreatic lipase ii) a specific RNAip for gastric, gastric and / or pancreatic lipase, iii) an antisense oligonucleotide specific for gastric and / or pancreatic lipase
  • the gastric and / or pancreatic lipase inhibitor compound of LDL4 is orlistat.
  • the LDL4 of the invention comprises an inhibitor compound or combination of 26S proteasome inhibitor compounds that includes, but is not limited to, a compound according to the formula: where
  • Y is R 8 -C (0), R 8 -S0 2 -, R 8 - HC (0) - or R 8 -0-C (0) -, where R 8 is alkyl, aryl, alkaryl or aralkyl; any of them being optionally substituted or if Y is R 8 -C (0) or R 8 -S0 2 -, then R 8 may also be a saturated, partially unsaturated or aromatic 5-10 membered heterocycle, optionally substituted;
  • X 3 is a covalent bond or -C (0) -CH 2 -;
  • R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, a saturated 5-10 atom heterocycle, partially saturated or unsaturated and -CH 2 -R 5 , where R 5 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle or chalcogen-alkyl; Y
  • Z 1 and Z 2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together they form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms such as chain or ring, said chain or ring comprising carbon atoms and, optionally, a heteroatom or heteroatoms that may / n be N, S or O,
  • the LDL4 26S proteasome inhibitor compound of the invention is bortezomib.
  • the gastric and / or pancreatic lipase inhibitor compound of LDL4 is orlistat and the 26S proteasome inhibitor compound of LDL4 of the invention is bortezomib.
  • the invention in another aspect, relates to a low density lipoprotein (LDL), hereinafter low density lipoprotein 5 of the invention (LDL5), which comprises an inhibitor compound or combination of inhibitors of the enzyme carnitine palmitoyl transferase (CPT I) ) and an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds.
  • LDL low density lipoprotein
  • CPT I carnitine palmitoyl transferase
  • the LDL5 of the invention comprises an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) inhibitor compounds that includes, but is not limited to, a compound that is selected from the group consisting of:
  • Ri and R 2 independently are selected from the group consisting of: a hydrogen atom, a halogen atom, C1-C4 alkyl group, a C1-C4, a nitro group and a trifluoromethyl group;
  • R3 is a hydrogen atom or a C1-C4 alkyl group
  • Y is the group -0- (CH 2 ) m , where -m is 0 or an integer between l and 4;
  • n is an integer between 2 and 8, or any pharmaceutically acceptable salts, solvates and prodrugs of said compound,
  • the carnitine palmitoyl transferase I (CPT I) inhibitor compound of the LDL5 of the invention is ethomoxir.
  • the LDL5 of the invention comprises an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds that includes, but is not limited to, a compound that is selected from the group consisting of:
  • RNAip for gastric, gastric and / or pancreatic lipase
  • antisense oligonucleotide specific for gastric and / or pancreatic lipase ii) a specific RNAip for gastric, gastric and / or pancreatic lipase, iii) an antisense oligonucleotide specific for gastric and / or pancreatic lipase
  • the LDL5 gastric and / or pancreatic lipase inhibitor compound is orlistat.
  • the LDL5 carnitine palmitoyl transferase I (CPT I) inhibitor compound of the invention is ethomoxir and the LDL5 gastric and / or pancreatic lipase inhibitor compound is orlistat.
  • the invention relates to a low density lipoprotein (LDL), hereinafter low density lipoprotein 6 (LDL6) of the invention, which comprises an inhibitor compound or combination of inhibitors of the enzyme carnitine palmitoyl transferase (CPT) I), an inhibitor compound or combination of 26S proteasome inhibitor compounds (LDL3) and also an inhibitor compound or gastric and / or pancreatic lipase inhibitor compounds.
  • LDL low density lipoprotein
  • CPT carnitine palmitoyl transferase
  • 26S proteasome inhibitor compounds LDL3
  • an inhibitor compound or gastric and / or pancreatic lipase inhibitor compounds also an inhibitor compound or gastric and / or pancreatic lipase inhibitor compounds.
  • the LDL6 of the invention comprises an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) inhibitor compounds that includes, but is not limited to, a compound that is selected from the group consisting of:
  • Ri and R 2 independently are selected from the group consisting of: a hydrogen atom, a halogen atom, an alkyl group C 1 -C 4 alkoxy group C1 - C4, a nitro group and a trifluoromethyl group;
  • R3 is a hydrogen atom or a group C1 - C4 alkyl
  • Y is the group -0- (CH 2 ) m , where -m is 0 or an integer between l and 4;
  • n is an integer between 2 and 8
  • the carnitine palmitoyl transferase I (CPT I) inhibitor compound of LDL6 is ethomoxir.
  • the LDL6 of the invention comprises an inhibitor compound or combination of 26S proteasome inhibitor compounds that includes, but is not limited to, a compound according to the formula: where
  • Y is R 8 -C (0), R 8 -S0 2 -, R 8 - HC (0) - or R 8 -0-C (0) -, where R 8 is alkyl, aryl, alkaryl or aralkyl; any of them being optionally substituted or if Y is R 8 -C (0) or R 8 -S0 2 -, then R 8 may also be a saturated, partially unsaturated or aromatic 5-10 membered heterocycle, optionally substituted;
  • X 3 is a covalent bond or -C (0) -CH 2 -;
  • R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, a saturated 5-10 atom heterocycle, partially saturated or unsaturated and -CH 2 -R 5 , where R 5 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle or chalcogen-to chyl; Y
  • Z 1 and Z 2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together they form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms such as chain or ring, said chain or ring comprising carbon atoms and, optionally, a heteroatom or heteroatoms that may / n be N, S or O,
  • the LDL6 of the invention comprises a 26S proteasome inhibitor compound that is bortezomib.
  • the LDL6 of the invention comprises an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds that includes, but is not limited to, a compound that is selected from the group consisting of:
  • RNAip for gastric, gastric and / or pancreatic lipase
  • antisense oligonucleotide specific for gastric and / or pancreatic lipase ii) a specific RNAip for gastric, gastric and / or pancreatic lipase, iii) an antisense oligonucleotide specific for gastric and / or pancreatic lipase
  • the LDL6 gastric and / or pancreatic lipase inhibitor compound is orlistat.
  • the carnitine palmitoyl transferase I (CPT I) inhibitor compound of LDL6 is ethomoxir
  • the 26S proteasome inhibitor compound is bortezomib
  • the gastric and / or pancreatic lipase inhibitor compound of LDL6 is orlistat.
  • the present invention also includes compositions formed by different types of LDLs and, in particular, compositions comprising at least two LDLs selected from the group:
  • LDLs comprising an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compounds
  • LDLs comprising an inhibitor compound or combination of 26S proteasome inhibitor compounds
  • LDLs comprising an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds
  • the invention relates to compositions comprising LDLs comprising an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compounds and LDLs comprising an inhibitor compound or combination of 26S proteasome inhibitor compounds.
  • CPT I carnitine palmitoyl transferase I
  • the invention relates to compositions comprising LDLs comprising an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds and LDLs comprising an inhibitor compound or combination of 26S proteasome inhibitor compounds.
  • the invention relates to compositions comprising LDLs comprising an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compounds and LDLs comprising an inhibitor compound or combination of gastric lipase inhibitor compounds and / or pancreatic Alternatively, the invention relates to compositions comprising LDLs comprising an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compounds, LDLs comprising an inhibitor compound or combination of 26S proteasome inhibitor compounds and LDLs comprising an inhibitor compound or combination of gastric and / or pancreatic lipase inhibitor compounds.
  • CPT I carnitine palmitoyl transferase I
  • compositions and lipoproteins of the invention relates to a composition comprising at least one carnitine palmitoyl transferase I (CPT I) enzyme inhibitor and at least one 26S proteasome inhibitor ( composition A of the invention), with a composition comprising at least one gastric and / or pancreatic lipase inhibitor and at least one 26S proteasome inhibitor (composition B of the invention), with a composition comprising at least one carnitine palmitoyl transferase I (CPT I) enzyme inhibitor and at least one gastric and / or pancreatic lipase inhibitor (composition C of the invention), with a composition comprising at least one carnitine palmitoyl transferase I (CPT I) enzyme inhibitor, at least one 26S proteasome inhibitor and at least a gastric and / or pancreatic lipase inhibitor (composition D of the invention), with a lipoprotein comprising an inhibitor compound or combination of carnitine palm
  • compositions and lipoproteins of the invention are provided.
  • the invention relates to a composition comprising at least one carnitine palmitoyl transferase I (CPT I) enzyme inhibitor and at least one 26S proteasome inhibitor (composition A of the invention), with a composition comprising at least one gastric and / or pancreatic lipase inhibitor and at least one 26S proteasome inhibitor (composition B of the invention), with a composition comprising at least one inhibitor of carnitine palmitoyl transferase I (CPT I) enzyme and at less a gastric and / or pancreatic lipase inhibitor (composition C of the invention), with a composition comprising at least one palmityl palmitoyl transferase I (CPT I) enzyme inhibitor, at least one 26S proteasome inhibitor and at least one gastric and / or pancreatic lipase inhibitor (composition D of the invention), with a lipoprotein comprising an inhibitor compound or combination of carnitine palmitoyl transferase I (CPT I) enzyme inhibitor
  • the invention relates to the use of a composition comprising at least one carnitine palmitoyl transferase I (CPT I) enzyme inhibitor and at least one 26S proteasome inhibitor (composition A of the invention), with a composition comprising at least one gastric and / or pancreatic lipase inhibitor and at least one 26S proteasome inhibitor (composition B of the invention), with a composition comprising at least one inhibitor of the carnitine palmitoyl transferase I enzyme (CPT I) and at least one gastric and / or pancreatic lipase inhibitor (composition C of the invention), with a composition comprising at least an inhibitor of the carnitine palmitoyl transferase I enzyme (CPT I), at least one 26S proteasome inhibitor and at least one gastric and / or pancreatic lipase inhibitor (composition D of the invention), with a lipoprotein comprising an inhibitor compound or combination of carnitine palmitoyl transferase I
  • the invention relates to a composition comprising at least one carnitine palmitoyl transferase I (CPT I) enzyme inhibitor and at least one 26S proteasome inhibitor (composition A of the invention), with a composition comprising at least one inhibitor of gastric and / or pancreatic lipase and at least one 26S proteasome inhibitor (composition B of the invention), with a composition comprising at least one carnitine palmitoyl transferase I (CPT I) enzyme inhibitor and at least one gastric and / or pancreatic lipase inhibitor (composition C of the invention), with a composition comprising at least one carnitine enzyme inhibitor palmitoyl transferase I (CPT I), at least one 26S proteasome inhibitor and at least one gastric and / or pancreatic lipase inhibitor (composition D of the invention), with a lipoprotein comprising an inhibitor compound or combination of inhibitor compounds of the Carnitine palmitoyl transferase I (CPT I) enzyme
  • the invention relates to a method of treatment and / or prevention of a pathology that involves uncontrolled proliferation of plasma cells in the bone marrow comprising the administration of a composition comprising at least one inhibitor of the carnitine palmitoyl transferase I enzyme (CPT I) and at least one 26S proteasome inhibitor (composition A of the invention), with a composition comprising at least one gastric lipase inhibitor and / or pancreatic and at least one 26S proteasome inhibitor (composition B of the invention), with a composition comprising at least one carnitine palmitoyl transferase I (CPT I) inhibitor and at least one gastric and / or pancreatic lipase inhibitor ( composition C of the invention), with a composition comprising at least one carnitine palmitoyl transferase I (CPT I) enzyme inhibitor, at least one 26S proteasome inhibitor and at least one gastric and / or pancreatic lipase inhibitor (composition D of the invention), with a composition compris
  • compositions of the invention can be co-administered as separate pharmaceutical formulations or as part of the same unit dosage form.
  • the different components of the compositions of the invention can be administered separately but as part of a therapeutic regimen.
  • the components do not need to be administered essentially at once, although it is possible if desired.
  • the carnitine palmitoyl transferase I (CPT I) enzyme inhibitor compound, the 26S proteasome inhibitor and the gastric and / or pancreatic lipase inhibitor can be administered simultaneously but by different routes of administration.
  • separate administration of the carnitine palmitoyl transferase I (CPT I) enzyme inhibitor, 26S proteasome inhibitor and gastric and / or pancreatic lipase inhibitor can be performed at different times and in any order.
  • the invention contemplates products comprising;
  • CPT I carnitine palmitoyl transferase I
  • CPT I carnitine palmitoyl transferase I
  • CPT I carnitine palmitoyl transferase I
  • an LDL comprising a gastric and / or pancreatic lipase inhibitor and an LDL comprising a 26S proteasome inhibitor
  • an LDL comprising a carnitine palmitoyl transferase I (CPT I) enzyme inhibitor and an LDL comprising a gastric and / or pancreatic lipase inhibitor
  • an LDL comprising a carnitine palmitoyl transferase I (CPT I) enzyme inhibitor, an LDL comprising a 26S proteasome inhibitor and an LDL comprising a gastric and / or pancreatic lipase inhibitor
  • CPT I carnitine palmitoyl transferase I
  • a combination of the inhibitor compounds that are part of the composition of the invention or of the lipoprotein of the invention can be used for the manufacture of a medicament for the treatment and / or prevention of a pathology that involves a uncontrolled proliferation of plasma cells.
  • the compounds of the invention can be combined with other compounds that are used in a conventional manner for the same purpose, that is, for the treatment and / or prevention of a pathology that involves uncontrolled proliferation of plasma cells.
  • the pathology that occurs with an uncontrolled proliferation of plasma cells is multiple myeloma.
  • RPMI-8226 NCI-H929 and U-266B1.
  • the cells were grown in RPMI-1640 culture medium supplemented with fetal bovine serum (10%), glutamine (1%) and antibiotics (100 U / mL penicillin, 100 ⁇ g / mL streptomycin).
  • the cells were grown under standard conditions of oxygen, humidity and temperature in an incubator.
  • ethomoxir was used (CAS: 828934-
  • the fatty acid oxidation rate was evaluated by the use of radioisotopes as described in Brown NF et al. (2007) (Metabolism 56 (11): 1500-1507) and in Sipula IJ et al. (2006) (Metabolism 55 (12): 1637-1644).
  • the method of incorporating [ 3 H] -thymidine was used to quantify the rate of cell proliferation.
  • Flow cytometry was used for apoptosis and cell cycle assays.
  • a flow cytometer FACScalibur (Becton Dickinson) was used.
  • caspase-3 -active was used followed by an analysis of the percentage of cells expressing caspase-3 -active by means of the flow cytometer.
  • Active caspase-3- is the main protease involved in apoptosis-mediated cell death.
  • propidium iodide staining was used followed by a cell analysis in the flow cytometer. This technique is based on the binding of Propidium Iodide to DNA, allowing quantifying the percentage of cells in the SubGO, G0 / G1, S and G2 phases.
  • the statistical analysis of the data was carried out with the SPSS software for Windows and the Microsoft Excel spreadsheet. Data are expressed as the mean and the standard error of the mean. After determining whether the samples were parametric or non-parametric, a statistical analysis was performed using a t-Student or an ANO VA. It was considered significant p ⁇ 0.05.
  • EXAMPLE 1 Effect of ethomoxir on the oxidation rate of fatty acids in multiple myeloma cells
  • MM myeloma cells
  • RPMI-8226, NCI-H929 and U-266B1 three MM cell lines
  • Etx ethomoxir
  • EXAMPLE 2 Impact of etomoxir and orlistat on the viability of MM cells.
  • EXAMPLE 3 Mechanisms of action of etomoxir and orlistat in MM cells.
  • Etx and Or ⁇ decrease the viability of MM cells, we study the molecular mechanisms involved. The effect of Etx and Or ⁇ on the viability may be due to an increase in cell apoptosis and / or a decrease in cell proliferation.
  • the cell cycle phases of cells treated with Etx (50 ⁇ ) or Or ⁇ (20 ⁇ ) were studied for 18-24 hours on the U-266B1 cell line. As indicated in Figure 3, Etx and Or ⁇ prevent cell cycle progression. Etx arrests cells in the G0 / G1 phase and the Or ⁇ in the synthesis phase (S phase).
  • the apoptotic capacity of Etx and Or ⁇ in MM cells was analyzed.
  • the U-266B1 cell line was treated with Or ⁇ (20 ⁇ ) and Etx (50 ⁇ ) for 18-24 hours.
  • the percentage of caspase-active positive cells was analyzed by flow cytometry. As indicated in Figure 4, the apoptosis rate did not change significantly between treated and untreated cells, indicating that these compounds do not have an effect on the apoptosis of MM cells.
  • the rate of cell proliferation was analyzed by a tritiated thymidine incorporation assay. As indicated in Figure 5, the rate of incorporation of tritiated thymidine decreased significantly in the cells treated with Etx or Or ⁇ with respect to the control cells.
  • EXAMPLE 5 Effects of etomoxir and orlistat on the regulation of cell cycle protein levels in MM cells.
  • p21 cyclin 1A-dependent kinase inhibitor
  • cyclin D2 Gl / S specific cyclin D2
  • cyclin 6-dependent kinase Cdk6
  • pRb retinoblastoma protein

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Abstract

La présente invention concerne des composés inhibiteurs de l'enzyme carnitine palmitoyltransférase I (CPT I) ainsi que des composés inhibiteurs de la lipase gastrique et/ou pancréatique et concerne également les utilisations thérapeutiques de ces composés et des compositions et des lipoprotéines de basse densité (LDL) qui comprennent un ou plusieurs composés inhibiteurs de l'enzyme carnitine palmitoyltransférase I (CPT I), un ou plusieurs inhibiteurs de la lipase gastrique ou un ou plusieurs inhibiteurs du protéasome 26S. La présente invention porte également sur l'utilisation desdites compositions et desdites LDL dans le traitement d'une pathologie qui présente une prolifération incontrôlée de cellules plasmatiques et plus concrètement dans le traitement du myélome multiple.
PCT/ES2012/070240 2011-04-11 2012-04-10 Composés et composition pour le traitement du myélome multiple WO2012140300A1 (fr)

Applications Claiming Priority (4)

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ES201130569A ES2390306B1 (es) 2011-04-11 2011-04-11 Compuestos y composiciones para el tratamiento de mieloma múltiple.
ES201130570A ES2390303B1 (es) 2011-04-11 2011-04-11 Compuestos y composiciones para el tratamiento de mieloma múltiple.
ESP201130569 2011-04-11
ESP201130570 2011-04-11

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004110368A2 (fr) * 2003-06-06 2004-12-23 Merck & Co., Inc. Polytherapie pour le traitement de l'hypertension
EP1815865A1 (fr) * 2004-11-08 2007-08-08 Ono Pharmaceutical Co., Ltd. Agent thérapeutique contre le diabète comprenant un composé inhibiteur de protéase
WO2008109727A1 (fr) * 2007-03-07 2008-09-12 Janssen Pharmaceutica N.V. Phénoxy thiazolidinediones substituées comme modulateurs de récepteur alpha d'œstrogène

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004110368A2 (fr) * 2003-06-06 2004-12-23 Merck & Co., Inc. Polytherapie pour le traitement de l'hypertension
EP1815865A1 (fr) * 2004-11-08 2007-08-08 Ono Pharmaceutical Co., Ltd. Agent thérapeutique contre le diabète comprenant un composé inhibiteur de protéase
WO2008109727A1 (fr) * 2007-03-07 2008-09-12 Janssen Pharmaceutica N.V. Phénoxy thiazolidinediones substituées comme modulateurs de récepteur alpha d'œstrogène

Non-Patent Citations (3)

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Title
ARKO, L. ET AL.: "Experimental approaches for the treatment of Malignant gliomas", PHARMACOLOGY & THERAPEUTICS, vol. 128, 2010, pages 1 - 36, XP027278601 *
SAMUDIO, I. ET AL.: "Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction", THE JOURNAL OF CLINICAL INVESTIGATION, vol. 120, no. 1, 2010, pages 142 - 156, XP002639772, DOI: doi:10.1172/JCI38942 *
TIRADO VELEZ, J.M. ET AL.: "La inhibicion farmacologica del metabolismo intracelular de los acidos grasos arresta en fase de sintesis a las celulas de mieloma multiple", JORNADAS ANDALUZAS SALUD INVESTIGA., 20 October 2010 (2010-10-20), CADIZ (ESPANA). *

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