WO2020025848A1 - Zwitterionic compounds of 2-phosphocholine carboxylic acids and their use as cytotoxic agents - Google Patents
Zwitterionic compounds of 2-phosphocholine carboxylic acids and their use as cytotoxic agents Download PDFInfo
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- WO2020025848A1 WO2020025848A1 PCT/ES2019/070541 ES2019070541W WO2020025848A1 WO 2020025848 A1 WO2020025848 A1 WO 2020025848A1 ES 2019070541 W ES2019070541 W ES 2019070541W WO 2020025848 A1 WO2020025848 A1 WO 2020025848A1
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- 150000001875 compounds Chemical class 0.000 title claims description 78
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- 229940127089 cytotoxic agent Drugs 0.000 title claims description 5
- 231100000599 cytotoxic agent Toxicity 0.000 title claims description 5
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- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 13
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims abstract description 4
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 3
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- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000002633 crown compound Substances 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- OQPSYKGFRJRVSW-WTQDWYTRSA-N ethyl (9Z,11E,13Z)-2-hydroxyoctadeca-9,11,13-trienoate Chemical compound CCCC/C=C\C=C\C=C/CCCCCCC(C(=O)OCC)O OQPSYKGFRJRVSW-WTQDWYTRSA-N 0.000 description 1
- BYMSBCKITCBJQQ-UHFFFAOYSA-N ethyl 2-hydroxyicosa-2,4,6,8,10-pentaenoate Chemical compound C(C)OC(C(=CC=CC=CC=CC=CCCCCCCCCC)O)=O BYMSBCKITCBJQQ-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000021281 monounsaturated fatty acids Nutrition 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention is framed both in the field of pharmaceutical chemistry and in medicine, more specifically it refers to compounds useful as cytotoxic agents, and more specifically, zwitterionic compounds derived from 2-phosphocholine.
- Phospholipids are structures derived from lipids formed by a hydrophobic zone, generally constituting two fatty acid chains, and a hydrophilic zone, formed by a phosphate group. Such structures mainly form cell membranes due to their amphiphilic nature.
- Phosphatidylcholines are a type of phospholipids in which the hydrophilic part is formed by a phosphocholine group, also forming biological membranes. Phosphocholine is formed by a phosphate group that supports a negative charge, linked to a choline unit, which supports a positive charge. Both phosphatidylcholines and sphingomyelins are the only phospholipid derivatives that do not contain glycerol as the main skeleton.
- lysophosphatidylcholines Another derivative of phosphatidylcholine are lysophosphatidylcholines, resulting from the loss of one of the fatty acids through partial hydrolysis, and their alkyl analogs.
- synthetic antitumor lysophospholipids ALPs
- These two products have shown high metabolic stability and anticancer effects, by selective apoptosis of tumor cells, as well as immunomodulatory or antiprotozoal effectiveness (CancerLetters, 2017, 388, 262-268.), (International Journal of AntimicrobialAgents, 2017, 49, 465 -471) (Mollinedo et al., 1997. Cancer Res. 57 ⁇ 1320-1328; Gajate et al., 2004. J Exp. Med. 200 ⁇ 353-365).
- these compounds have drawbacks such as their poor water solubility or their high toxicity.
- US5049552A refers to the use of hexadecylphosphocholine (Miltefosine) in the treatment of cancer.
- EP1079838A1 discloses the use of Edelfosine in the treatment of brain tumors.
- W02012095500A2 describes a pharmaceutical composition of oleyl phosphocholine useful in the treatment of cancer, or parasitic or skin diseases.
- JP55118494 describes phosphocholine derivatives with antitumor activity.
- the present invention relates to compounds with a phosphocholine unit linked to the derivative of a saturated, monounsaturated or polyunsaturated fatty acid through the hydroxyl group located in the alpha position to the carbonyl group.
- these hydroxylated fatty acids in the position a (the position adjacent to the carboxyl), saturated, monounsaturated, or polyunsaturated, regulate the composition and structure of membrane lipids in all cells preventing or reversing diseases such as cancer, cardiovascular pathologies, neurodegenerative processes, obesity, metabolic disorders, inflammations or autoimmune diseases, among others.
- both the double bond and the substituent located in the carbon in alpha to the carbonyl carbon are essential for the proper functioning of the structure, since a greater curative or preventive activity has been observed with respect to structures without these two specific characteristics .
- WO 2010/066931 discloses the starting material of compound MCH-811 partially responsible for the activity.
- phosphatidylcholines has been addressed using different strategies such as the direct addition of phosphocholine or one of its salts or the step formation of phosphocholine on the substrate, among others, and different reagents or catalysts such as 2,4 chloride , 6-triisopropylbenzenesulfonyl or charge transfer complexes.
- Phosphatidic acid has also been used in the synthesis of phosphatidylcholines, using a condensing agent such as 2,4,6-triisopropylbenzenesulfonyl chloride, with the disadvantage of the difficulty in generating iodoform and its subsequent salt elimination of choline, or tetrafen and I choline borate (Journal of LipidResearch ⁇ 984, 25, 1 140-1 142.), used in conjunction with a condensing agent, 2,4,6-triisopropylbenzenesulfonyl chloride.
- a condensing agent such as 2,4,6-triisopropylbenzenesulfonyl chloride
- the synthesis of the product presented consists of two steps with mild reaction conditions, the first of addition of 2-bromoethyl dichlorophosphate (or chloroethyl or iodoethyl) on the hydroxyl group located in alpha position to the carbonyl group and the second step replacement of the bromine, iodine or chlorine atom with a trimethylamino group.
- cancer is, behind cardiovascular diseases, the second leading cause of death in the world, causing 14 million deaths in 2012
- anticancer agents capable of selectively attacking cancer cells are left leaving cells healthy unchanged.
- lipid derivatives of different nature have demonstrated their antitumor efficacy, among other applications, as developed below.
- activity has also been detected against different types of tumor cells.
- the present invention refers to the Zwitterions of saturated, monounsaturated, polyunsaturated carboxylic 2-phosphocholine acids, and their pharmaceutically acceptable derivatives, with a structure as described in the general formula (1) and its derivatives, as detailed below.
- the present invention also refers to the synthesis of the compounds of the general formula (1), a synthesis consisting of 2 reaction steps (Schemes 1 and 2) where the corresponding 2-hydroxy derived from saturated acid is transformed, monounsaturated, polyunsaturated or its derivatives (asters, thioesters, amides, thioamides, nitriles or metal salts among others), in the Zwitterion of saturated, monounsaturated or polyunsaturated carboxylic acid 2-phosphocholine or one of its derivatives (asters, thioesters, amides, thioamides , nitriles or metal salts among others).
- pharmaceutically acceptable derivative refers for example to pharmaceutically acceptable salts, hydrates or polymorphs.
- Both the compounds of formula 1 defined in the first claim and the pharmaceutically acceptable derivatives may be in the crystalline, amorphous or polymorphic state.
- polyunsaturated refers to the compound comprising more than one double bond, or triple bond or more than one triple bond, or mixtures thereof.
- the present invention refers, in a first aspect, to a compound of general formula (1)
- - R can be any atom or group of atoms with a weight between 1 and 200 Da
- R is preferably selected from: COOH, COOMe, COOEt, COOBu 1 , COOBu, COOPH, COOBu ', COOPr, COSEt, COSMe, COSPr, COSBu, COSPH, CN, CSNR2R3, CONR2R3, and COOM, where M is a derived cation alkali metal or alkaline earth metal, such as lithium, sodium, potassium, cesium, magnesium or calcium, R2 and R3 may be the same or different and represent an alkyl radical, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert -butyl, pentyl, hexyl.
- saturated, monounsaturated, polyunsaturated carboxylic 2-phosphocholine acids and their acid derivatives such as salts, hydrates of said salts, thioesters, esters, amides, thioamides, nitriles are generally represented.
- Particular embodiments of the invention refer to a compound of formula (1), in which the hydrocarbon chain of A has a number of between 4 and 19 carbons. Further particular embodiments of the invention refer to a compound of formula (1), in which the hydrocarbon chain of A has a number of between 13 and 19 carbons.
- A is a fragment of fifteen carbon atoms containing a double bond
- C C between the C9-C10 carbons with Z configuration and the group R represents a COOEt ethyl ester (it has been referred to as the MCH-811 molecule).
- the characteristics of the compounds of formula (1) give the molecule a preventive or curative activity in the micromolar range for a wide variety of cancer cell lines (IC 50 to 7.06 ⁇ 1.45 mM, see table 3), a lower degradation in the biological environment which implies a greater therapeutic effect, as well as a greater specificity towards the lipid bilayer of the cells and their action on them.
- the present invention refers to the synthesis of said compounds of formula (1) through 2 reaction steps.
- the synthesis of the molecules of the present invention (1) consists of two simple steps performed under mild reaction conditions.
- a and R have the meanings given for the compound of formula (1), by the addition of the 2-bromoethyl dichlorophosphate of formula (3), or its chlorinated or iodinated analog (previously synthesized on the hydroxyl group located in alpha position to the carbonyl group, of a compound of formula (4)
- the product of the present invention (1) is obtained from the intermediate of the previous step (2) when reacting with trimethylamine dissolved in an alcohol, under mild conditions between 0 ° C and 60 ° C for 1-5 days and subsequent treatment with a mild inorganic base such as sodium acetate, sodium or potassium carbonate, sodium or potassium acid phosphate, and preferably sodium or potassium bicarbonate.
- a mild inorganic base such as sodium acetate, sodium or potassium carbonate, sodium or potassium acid phosphate, and preferably sodium or potassium bicarbonate.
- the first step of the synthesis comprises the addition of 2-bromoethyl dichlorophosphate (3) (or its chlorinated or iodinated analog) on the hydroxyl group located in the alpha position to the carbonyl group of the fatty acid, its derivative - monounsaturated or polyunsaturated (4) in the presence of an apolar solvent, such as toluene, xylene, diethyl ether, tert-butylmethyl ether (MTBE), tetrahydrofuran, heptane, hexane, a base, such as triethylamine, diisopropylethylamine (DIPEA), tributylamine , trimethylamine, N-methylpiperidine, 1,4-dimethylpiperazine, at room temperature (Scheme 1),
- an apolar solvent such as toluene, xylene, diethyl ether, tert-butylmethyl ether (MTBE),
- the second step consists in a substitution of the bromine atom (or chlorine or iodine) with a trimethylamino group, and subsequent formation of the corresponding zwitterion that perform on the product of the previous step (2) (Scheme 2).
- the reaction takes place in the presence of an apolar solvent, such as toluene, as a solvent at room temperature using a solution of trimethylamine as an aminating agent, in an alcohol, such as methanol, n-butanol, isopropanol, ethylene glycol, and preferably ethanol, followed of the sodium bicarbonate treatment to form the corresponding zwitterion.
- an apolar solvent such as toluene
- an alcohol such as methanol, n-butanol, isopropanol, ethylene glycol, and preferably ethanol
- the present invention also relates to a pharmaceutically acceptable formulation comprising a compound of formula (1).
- the formulations of the compounds of the invention can be, for example, capsules with the following excipients: colloidal anhydrous silica, microcrystalline cellulose, lactose monohydrate, talc, magnesium stearate, gelatin, titanium dioxide, ferric oxide, purified water. They can also be oral formulations with the following excipients: hydroxypropyl cellulose, propylene glycol and purified water.
- the molecule of general formula (1) shows in vitro activity against different types of carcinogenic cells, for example against tumor cell lines of: lung (non-small cell), pancreas, kidney, central nervous system (CNS) , prostate, colon, breast, melanoma, ovary, acute lymphoblastic leukemia, acute promyelocytic leukemia, chronic myelogenous leukemia, myeloma, immunoblastic large cell lymphoma, burkitt lymphoma, non-Hodgkin B-cell lymphoma, chronic lymphocytic leukemia, cell lymphoma mantle, multiple myeloma and acute T-cell leukemia (Tables 1, 2 and 3).
- the present invention relates to the use of the compounds of formula (1) and their pharmaceutically acceptable derivatives as salts, hydrates or polymorphs, to be used as active species against different types of carcinogenic cells, preferably in the prevention and / or treatment of cancers such as those mentioned in the previous paragraph and in the claims.
- Example 25 In vitro efficacy studies of MCH-811 The cytotoxic activity of the molecule described in the present invention was tested using different human tumor lines to establish its antitumor efficacy. The in vitro activity test was performed as detailed below:
- Cell viability was calculated by comparing the fluorescence values of each concentration with the fluorescence values of the untreated cell culture (100% viability).
- the IC50 values were estimated using GraphPadPrism software (v5).
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Abstract
The present invention relates to zwitterions of saturated, monounsaturated, polyunsaturated and acid derivatives of 2-phosphocholine carboxylic acids with a structure described by general formula (1), and derivatives thereof, in which A is a carbonated chain with a number of carbon atoms between 4 and 19 that is saturated, monounsaturated or polyunsaturated, mono or polyhydroxylated in different positions or non-hydroxylated, and (R) can be any atom or groups of atoms with a weight between 1 and 200 Da, wherein (R) is selected from: COOH, COOMe, COOEt, COOBut, COOBu, COOPri, COOBui, COOPr, COSEt, COSMe, COSPr, COSBu, COSPri,CSNR2R3, CONR2R3, CN and COOM, wherein M is a cation derived from an alkaline metal or alkaline earth metal, such as lithium, sodium, potassium, caesium, magnesium or calcium, R2 and R3 being able to be the same or different and representing an alkyl radical, which are pharmaceutically acceptable. The invention also relates to the use of the zwitterions against different types of carcinogenic cells.
Description
COMPUESTOS ZWITTERIÓNICOS DE ÁCIDOS 2-FOSFOCOLINA CARBOXÍLICOS ZWITTERIONIC COMPOUNDS OF CARBOXYLIC 2-PHOSPHOCOLINE ACIDS
Y SU USO COMO AGENTES CITOTÓXICOS AND ITS USE AS CYTOTOXIC AGENTS
DESCRIPCIÓN DESCRIPTION
Compuestos Zwitteriónicos de ácidos 2-fosfocolina carboxílicos y su uso como agentes citotóxicos Zwitterionic compounds of 2-phosphocholine carboxylic acids and their use as cytotoxic agents
CAMPO DE LA INVENCIÓN FIELD OF THE INVENTION
La presente invención se enmarca tanto en el campo de la química farmacéutica como en el de la medicina, de forma más específica se refiere a compuestos útiles como agentes citotóxicos, y más concretamente, compuestos zwitteriónicos derivados de 2- fosfocolina. The present invention is framed both in the field of pharmaceutical chemistry and in medicine, more specifically it refers to compounds useful as cytotoxic agents, and more specifically, zwitterionic compounds derived from 2-phosphocholine.
ESTADO DE LA TÉCNICA ANTERIOR STATE OF THE PREVIOUS TECHNIQUE
Los fosfolípidos son estructuras derivadas de los lípidos formadas por una zona hidrofóbica, constituyéndola generalmente dos cadenas de ácidos grasos, y una zona hidrofílica, formada por un grupo fosfato. Dichas estructuras forman principalmente las membranas celulares debido a su naturaleza anfifílica. Phospholipids are structures derived from lipids formed by a hydrophobic zone, generally constituting two fatty acid chains, and a hydrophilic zone, formed by a phosphate group. Such structures mainly form cell membranes due to their amphiphilic nature.
Las fosfatidilcolinas son un tipo de fosfolípidos en la que la parte hidrofílica está formada por un grupo fosfocolina, formando también membranas biológicas. La fosfocolina está formada por un grupo fosfato que soporta una carga negativa, enlazado a una unidad de colina, la cual soporta una carga positiva. Tanto las fosfatidilcolinas como las esfingomielinas son los únicos derivados de fosfolípidos que no contienen el glicerol como esqueleto principal. Phosphatidylcholines are a type of phospholipids in which the hydrophilic part is formed by a phosphocholine group, also forming biological membranes. Phosphocholine is formed by a phosphate group that supports a negative charge, linked to a choline unit, which supports a positive charge. Both phosphatidylcholines and sphingomyelins are the only phospholipid derivatives that do not contain glycerol as the main skeleton.
Entre las estructuras de fosfolípidos se han encontrado ejemplos de derivados del éster de fosfocolina (US 2008/0175852 A1) o derivados de fosforilpantoamidas (DE 3728915), entre otros. Examples of phospholipid ester derivatives (US 2008/0175852 A1) or phosphorylpantoamide derivatives (DE 3728915), among others, have been found among the phospholipid structures.
Otro derivado de fosfatidilcolina son las lisofosfatidilcolinas, resultantes de la pérdida de uno de los ácidos grasos a través de una hidrólisis parcial, y sus análogos alquil-
lisofosfolípidos sintéticos antitumorales (ALPs), generados por el intercambio del grupo acilo por el grupo alquilo, tales como la Edelfosina y la Miltefosina. Estos dos productos han mostrado alta estabilidad metabólica y efectos anticancerígenos, por apoptosis selectiva de las células tumorales.así como efectividad inmunomoduladora o antiprotozoaria ( CancerLetters , 2017, 388, 262-268.), ( International Journal of AntimicrobialAgents, 2017, 49, 465-471) (Mollinedo et al., 1997. Cáncer Res.57\ 1320- 1328; Gajate et al., 2004. J Exp. Med.200\ 353-365). Sin embargo, estos compuestos presentan inconvenientes tales como su escasa solubilidad en agua o su elevada toxicidad. Another derivative of phosphatidylcholine are lysophosphatidylcholines, resulting from the loss of one of the fatty acids through partial hydrolysis, and their alkyl analogs. synthetic antitumor lysophospholipids (ALPs), generated by the exchange of the acyl group for the alkyl group, such as Edelfosine and Miltefosine. These two products have shown high metabolic stability and anticancer effects, by selective apoptosis of tumor cells, as well as immunomodulatory or antiprotozoal effectiveness (CancerLetters, 2017, 388, 262-268.), (International Journal of AntimicrobialAgents, 2017, 49, 465 -471) (Mollinedo et al., 1997. Cancer Res. 57 \ 1320-1328; Gajate et al., 2004. J Exp. Med. 200 \ 353-365). However, these compounds have drawbacks such as their poor water solubility or their high toxicity.
US5049552A se refiere al uso de la hexadecilfosfocolina (Miltefosina) en el tratamiento del cáncer. US5049552A refers to the use of hexadecylphosphocholine (Miltefosine) in the treatment of cancer.
EP1079838A1 divulga el uso de Edelfosina en el tratamiento de tumores de cerebro. W02012095500A2 describe una composición farmacéutica de oleil-fosfocolina útil en el tratamiento de cáncer, o enfermedades parasitarias o de piel. EP1079838A1 discloses the use of Edelfosine in the treatment of brain tumors. W02012095500A2 describes a pharmaceutical composition of oleyl phosphocholine useful in the treatment of cancer, or parasitic or skin diseases.
El documento JP55118494 describe derivados de fosfocolina con actividad antitumoral. JP55118494 describes phosphocholine derivatives with antitumor activity.
A diferencia, la presente invención se refiere a compuestos con una unidad de fosfocolina unida al derivado de un ácido graso saturado, monoinsaturado o poliinsaturado a través del grupo hidroxilo situado en la posición alfa al grupo carbonilo. In contrast, the present invention relates to compounds with a phosphocholine unit linked to the derivative of a saturated, monounsaturated or polyunsaturated fatty acid through the hydroxyl group located in the alpha position to the carbonyl group.
Como se describe en WO 2010/066931 estos ácidos grasos hidroxilados en la posición a (la posición adyacente al carboxilo), saturados, monoinsaturados, o poliinsaturados, regulan la composición y estructura de los lípidos de membrana en todas las células previniendo o revirtiendo enfermedades como cáncer, patologías cardiovasculares, procesos neurodegenerativos, obesidad, desórdenes metabólicos, inflamaciones o enfermedades autoinmunes, entre otras. En estos derivados, tanto el doble enlace como el sustituyente situado en el carbono en alfa al carbono carbonílico son esenciales para el correcto funcionamiento de la estructura, puesto que se ha observado una mayor actividad curativa o preventiva con respecto a estructuras sin estas dos características concretas. Además, se ha observado que el sustituyente en la posición en 2 bloquea la degradación del ácido graso o su derivado y le permite permanecer de forma
prolongada, con respecto al ácido graso sin dicho sustituyente, en el medio celular, permitiendo su acción terapéutica. WO 2010/066931 divulga el material de partida del compuesto MCH-811 responsable parcialmente de la actividad. As described in WO 2010/066931 these hydroxylated fatty acids in the position a (the position adjacent to the carboxyl), saturated, monounsaturated, or polyunsaturated, regulate the composition and structure of membrane lipids in all cells preventing or reversing diseases such as cancer, cardiovascular pathologies, neurodegenerative processes, obesity, metabolic disorders, inflammations or autoimmune diseases, among others. In these derivatives, both the double bond and the substituent located in the carbon in alpha to the carbonyl carbon are essential for the proper functioning of the structure, since a greater curative or preventive activity has been observed with respect to structures without these two specific characteristics . In addition, it has been observed that the substituent in the 2-position blocks the degradation of fatty acid or its derivative and allows it to remain prolonged, with respect to fatty acid without said substituent, in the cellular medium, allowing its therapeutic action. WO 2010/066931 discloses the starting material of compound MCH-811 partially responsible for the activity.
La síntesis de fosfatidilcolinas se ha abordado utilizando diferentes estrategias tales como la adición directa de la fosfocolina o una de sus sales o la formación por pasos de la fosfocolina sobre el sustrato, entre otras, y diferentes reactivos o catalizadores como el cloruro de 2,4,6-triisopropilbencenosulfonilo o complejos de transferencia de carga. The synthesis of phosphatidylcholines has been addressed using different strategies such as the direct addition of phosphocholine or one of its salts or the step formation of phosphocholine on the substrate, among others, and different reagents or catalysts such as 2,4 chloride , 6-triisopropylbenzenesulfonyl or charge transfer complexes.
El ácido fosfatídico también ha sido utilizado en la síntesis de fosfatidilcolinas, empleando para ello un agente de condensación como el cloruro de 2,4,6- triisopropilbencenosulfonilo, con el inconveniente de la dificultad en la generación del yodoformo y su posterior eliminación de la sal de colina, o el tetrafen i I borato de colina (Journal of LipidResearch^984, 25, 1 140-1 142.), utilizado conjuntamente con un agente de condensación, el cloruro de 2,4,6-triisopropilbencenosulfonilo. Phosphatidic acid has also been used in the synthesis of phosphatidylcholines, using a condensing agent such as 2,4,6-triisopropylbenzenesulfonyl chloride, with the disadvantage of the difficulty in generating iodoform and its subsequent salt elimination of choline, or tetrafen and I choline borate (Journal of LipidResearch ^ 984, 25, 1 140-1 142.), used in conjunction with a condensing agent, 2,4,6-triisopropylbenzenesulfonyl chloride.
También se han desarrollado derivados de p-nitrofenil-O-fosfocolinhidroxilalquil ésteres (US2008/0175852 A1) a partir de ésteres alquílicos con un buen grupo saliente en el metileno final de la cadena carbonada y fosfocolina de los que resulta el correspondiente alcanoato de fosfocolina tras tratamiento con una amina cuaternaria. Este alcanoato de fosfocolina se esterifica o transesterifica con trifluoroacetato dep-nitrofenilo para obtener el producto deseado. En esta solicitud de patente estadounidense se describe el uso de los compuestos corona y además emplean condiciones de temperatura bastante elevadas, entre 110 y 120°C. Son condiciones de reacción bastante enérgicas que no permiten la síntesis de compuestos sensibles. Cuando hay dobles enlaces la oxidación es muy rápida a esa temperatura, sobre todo cuando en los ácidos grasos poliinsaturados como DHA, EPA o linoléico. Sin embargo, en nuestra metodología se trabaja a temperatura ambiente en todo momento, condiciones suaves. Derivatives of p-nitrophenyl-O-phosphochinohydroxylalkyl esters (US2008 / 0175852 A1) have also been developed from alkyl esters with a good leaving group in the final methylene of the carbon chain and phosphocholine resulting from the corresponding phosphocholine alkanoate after treatment with a quaternary amine. This phosphocholine alkanoate is esterified or transesterified with dep-nitrophenyl trifluoroacetate to obtain the desired product. In this US patent application the use of the crown compounds is described and they also employ quite high temperature conditions, between 110 and 120 ° C. They are quite energetic reaction conditions that do not allow the synthesis of sensitive compounds. When there are double bonds the oxidation is very fast at that temperature, especially when in polyunsaturated fatty acids such as DHA, EPA or linoleic. However, our methodology works at room temperature at all times, mild conditions.
En la presente invención la síntesis del producto presentado consta de dos pasos con condiciones de reacción suaves, el primero de adición del diclorofosfato de 2-bromoetilo (o cloroetilo o yodoetilo) sobre el grupo hidroxilo situado en posición alfa al grupo carbonilo y el segundo paso de sustitución del átomo de bromo, yodo o cloro, por un grupo trimetilamino. Estas condiciones mejoran la operación sintética a escala mayor y los tiempos de ejecución son más cortos con respecto a lo descrito en US 2008/0175852
A1. In the present invention, the synthesis of the product presented consists of two steps with mild reaction conditions, the first of addition of 2-bromoethyl dichlorophosphate (or chloroethyl or iodoethyl) on the hydroxyl group located in alpha position to the carbonyl group and the second step replacement of the bromine, iodine or chlorine atom with a trimethylamino group. These conditions improve synthetic operation on a larger scale and the execution times are shorter compared to that described in US 2008/0175852 A1.
Cabe recalcar que el cáncer es, por detrás de las enfermedades cardiovasculares, la segunda causa de muerte en el mundo, causando 14 millones de fallecidos en el año 2012 Para tratar esta enfermedad se buscan agentes anticancerígenos capaces de atacar selectivamente las células cancerosas dejando las células sanas inalteradas. En este sentido, derivados lipidíeos de distinta naturaleza han demostrado su eficacia antitumoral, entre otras aplicaciones, como se desarrolla a continuación. It should be noted that cancer is, behind cardiovascular diseases, the second leading cause of death in the world, causing 14 million deaths in 2012 To treat this disease, anticancer agents capable of selectively attacking cancer cells are left leaving cells healthy unchanged. In this sense, lipid derivatives of different nature have demonstrated their antitumor efficacy, among other applications, as developed below.
A lo largo de los últimos años se han desarrollado derivados de fosfolípidos que han tenido diferentes aplicaciones tales como transdérmicas y transmembranales (US5,985,292 de Fournerou et al.), ( Journal of Controlled Release, 1998, 51, 259-267), anticancerígenas o para el tratamiento o prevención de la arterioesclerosis y otros trastornos relacionados así como procesos inflamatorios, enfermedades autoinmunes y trastornos proliferativos entre otras. In recent years phospholipid derivatives have been developed that have had different applications such as transdermal and transmembrane (US5,985,292 from Fournerou et al.), (Journal of Controlled Release, 1998, 51, 259-267), anti-cancer or for the treatment or prevention of atherosclerosis and other related disorders as well as inflammatory processes, autoimmune diseases and proliferative disorders among others.
En la presente invención también se ha detectado actividad frente a diferentes tipos de células tumorales. In the present invention activity has also been detected against different types of tumor cells.
Por lo tanto, se hace necesario a la luz de lo anteriormente expuesto, buscar nuevas formulaciones químicas, económicas, sintéticamente sencillas de llevar a cabo y con una alta actividad frente a diferentes líneas de células tumorales. Therefore, it is necessary in the light of the above, to look for new chemical formulations, economical, synthetically simple to carry out and with a high activity against different tumor cell lines.
BREVE DESCRIPCIÓN DE LA INVENCIÓN BRIEF DESCRIPTION OF THE INVENTION
La presente invención hace referencia a los Zwitteriónes de ácidos 2-fosfocolina carboxílicos saturados, monoinsaturados, poliinsaturados, y sus derivados farmacéuticamente aceptables, con una estructura como la descrita en la fórmula general (1) y sus derivados, cómo se detalla a continuación. The present invention refers to the Zwitterions of saturated, monounsaturated, polyunsaturated carboxylic 2-phosphocholine acids, and their pharmaceutically acceptable derivatives, with a structure as described in the general formula (1) and its derivatives, as detailed below.
La presente invención hace referencia, además, a la síntesis de los compuestos de fórmula general (1), una síntesis consistente en 2 pasos de reacción (Esquemas 1 y 2) donde se transforma el correspondiente 2-hidroxi derivado de ácido saturado,
monoinsaturado, poliinsaturado o sus derivados (ásteres, tioésteres, amidas, tioamidas, nitrilos o sales metálicas entre otros), en el Zwitterión de ácido 2-fosfocolina carboxílico saturado, monoinsaturado o poliinsaturado o uno de sus derivados (ásteres, tioésteres, amidas, tioamidas, nitrilos o sales metálicas entre otros). The present invention also refers to the synthesis of the compounds of the general formula (1), a synthesis consisting of 2 reaction steps (Schemes 1 and 2) where the corresponding 2-hydroxy derived from saturated acid is transformed, monounsaturated, polyunsaturated or its derivatives (asters, thioesters, amides, thioamides, nitriles or metal salts among others), in the Zwitterion of saturated, monounsaturated or polyunsaturated carboxylic acid 2-phosphocholine or one of its derivatives (asters, thioesters, amides, thioamides , nitriles or metal salts among others).
DESCRIPCIÓN DETALLADA DE LA INVENCIÓN DETAILED DESCRIPTION OF THE INVENTION
En esta memoria la expresión“derivado farmacéuticamente aceptable” se refiere por ejemplo a sales, hidratos o polimorfos, farmacéuticamente aceptables. Here the term "pharmaceutically acceptable derivative" refers for example to pharmaceutically acceptable salts, hydrates or polymorphs.
Tanto los compuestos de fórmula 1 definidos en la primera reivindicación como los derivados farmacéuticamente aceptables pueden estar en estado cristalino, amorfo o como polimorfos. Both the compounds of formula 1 defined in the first claim and the pharmaceutically acceptable derivatives may be in the crystalline, amorphous or polymorphic state.
En esta memoria el término“poliinsaturado” se refiere a que el compuesto comprenda más de un doble enlace, o triple enlace o más de un triple enlace, o mezclas de ellos. La presente invención hace referencia, en un primer aspecto, a un compuesto de fórmula general (1) Here the term "polyunsaturated" refers to the compound comprising more than one double bond, or triple bond or more than one triple bond, or mixtures thereof. The present invention refers, in a first aspect, to a compound of general formula (1)
en la que: in which:
- R puede ser cualquier átomo o grupo de átomos con un peso entre 1 y 200 Da, - R can be any atom or group of atoms with a weight between 1 and 200 Da,
- y A es una cadena carbonada que puede tener cualquier número de átomos de carbono entre 4 y 19, saturada, monoinsaturada o poliinsaturada, en la que los dobles enlaces C=C pueden tener cualquier tipo de configuración y estar o no conjugados, y en la que la cadena A puede estar sin hidroxilar o hidroxilada (mono o polihidroxilada en distintas posiciones), - and A is a carbon chain that can have any number of carbon atoms between 4 and 19, saturated, monounsaturated or polyunsaturated, in which the double bonds C = C can have any type of configuration and be or not conjugated, and in which chain A may be without hydroxylated or hydroxylated (mono or polyhydroxylated in different positions),
y sus derivados farmacéuticamente aceptables, como pueden ser sales, hidratos correspondientes a dichas sales, o cualquier polimorfo.
Preferentemente R es seleccionado de entre: COOH, COOMe, COOEt, COOBu1, COOBu, COOPH, COOBu', COOPr, COSEt, COSMe, COSPr, COSBu, COSPH, CN, CSNR2R3, CONR2R3, y COOM, donde M es un catión derivado de metal alcalino o alcalino-térreo, como litio, sodio, potasio, cesio, magnesio o calcio, R2 y R3 pueden ser iguales o distintos y representan un radical alquílico, tal como metilo, etilo, propilo, isopropilo, butilo, isobutilo, tert-butilo, pentilo, hexilo. and its pharmaceutically acceptable derivatives, such as salts, hydrates corresponding to said salts, or any polymorph. R is preferably selected from: COOH, COOMe, COOEt, COOBu 1 , COOBu, COOPH, COOBu ', COOPr, COSEt, COSMe, COSPr, COSBu, COSPH, CN, CSNR2R3, CONR2R3, and COOM, where M is a derived cation alkali metal or alkaline earth metal, such as lithium, sodium, potassium, cesium, magnesium or calcium, R2 and R3 may be the same or different and represent an alkyl radical, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert -butyl, pentyl, hexyl.
En la anterior fórmula (1) se representan de forma general los ácidos 2-fosfocolina carboxílicos saturados, monoinsaturados, poliinsaturados y sus derivados de ácido tales como sales, hidratos de dichas sales, tioésteres, ásteres, amidas, tioamidas, nitrilos. In the above formula (1), saturated, monounsaturated, polyunsaturated carboxylic 2-phosphocholine acids and their acid derivatives such as salts, hydrates of said salts, thioesters, esters, amides, thioamides, nitriles are generally represented.
Realizaciones particulares de la invención se refieren a un compuesto de fórmula (1), en el que la cadena hidrocarbonada de A tiene un número de entre 4 y 19 carbonos. Realizaciones particulares adicionales de la invención se refieren a un compuesto de fórmula (1), en el que la cadena hidrocarbonada de A tiene un número de entre 13 y 19 carbonos. Particular embodiments of the invention refer to a compound of formula (1), in which the hydrocarbon chain of A has a number of between 4 and 19 carbons. Further particular embodiments of the invention refer to a compound of formula (1), in which the hydrocarbon chain of A has a number of between 13 and 19 carbons.
Realizaciones particulares adicionales de la invención se refieren a un compuesto de fórmula (1), en el que A es una cadena carbonada saturada, monoinsaturada o poliinsaturada, con cualquier tipo de configuración en los dobles enlaces C=C, mono o polihidroxilada en distintas posiciones, o no hidroxilada. Additional particular embodiments of the invention refer to a compound of formula (1), in which A is a saturated, monounsaturated or polyunsaturated carbon chain, with any type of configuration in the double bonds C = C, mono or polyhydroxylated in different positions , or not hydroxylated.
Realizaciones preferentes de la invención se refieren a un compuesto de fórmula (1), en el que A es un fragmento de quince átomos de carbono conteniendo un enlace doble C=C entre los carbonos C9-C10 con configuración Z. Preferred embodiments of the invention refer to a compound of formula (1), in which A is a fragment of fifteen carbon atoms containing a double bond C = C between C9-C10 carbons with Z configuration.
Realizaciones preferentes adicionales de la invención se refieren a un compuesto de fórmula (1), en el que R representa un áster etílico. Further preferred embodiments of the invention refer to a compound of formula (1), in which R represents an ethyl ester.
Una realización especialmente preferente de la invención se refiere a un compuesto de fórmula (1), en el que A es un fragmento de quince átomos de carbono conteniendo un enlace doble C=C entre los carbonos C9-C10 con configuración Z y el grupo R representa un áster etílico COOEt (se ha denominado como la molécula MCH-811). Se
ha estudiado la actividad antitumoral midiendo in vitro el índice IC50 de diferentes líneas celulares tumorales. An especially preferred embodiment of the invention relates to a compound of formula (1), in which A is a fragment of fifteen carbon atoms containing a double bond C = C between the C9-C10 carbons with Z configuration and the group R represents a COOEt ethyl ester (it has been referred to as the MCH-811 molecule). I know He has studied antitumor activity by measuring in vitro the IC 50 index of different tumor cell lines.
Las características de los compuestos de fórmula (1) confieren a la molécula una actividad preventiva o curativa en el rango micromolar para una gran variedad de líneas celulares cancerígenas (IC50 hasta 7.06±1.45 mM, ver tabla 3), una menor degradación en el medio biológico lo que implica un mayor efecto terapéutico, así como una mayor especificidad hacia la bicapa lipídica de las células y su acción sobre ellas. The characteristics of the compounds of formula (1) give the molecule a preventive or curative activity in the micromolar range for a wide variety of cancer cell lines (IC 50 to 7.06 ± 1.45 mM, see table 3), a lower degradation in the biological environment which implies a greater therapeutic effect, as well as a greater specificity towards the lipid bilayer of the cells and their action on them.
De igual modo la presente invención hace referencia a la síntesis de dichos compuestos de fórmula (1) a través de 2 pasos de reacción. Likewise, the present invention refers to the synthesis of said compounds of formula (1) through 2 reaction steps.
Según los Esquemas 1 y 2 se transforma el correspondiente 2-hidroxi derivado de ácido saturado, monoinsaturado o poliinsaturado en el zwitterión de ácido 2-fosfocolina carboxílico saturado, monoinsaturado, poliinsaturado o su derivado. According to Schemes 1 and 2, the corresponding 2-hydroxy derivative of saturated, monounsaturated or polyunsaturated acid is transformed into the zwitterion of saturated, monounsaturated, polyunsaturated 2-phosphocholine carboxylic acid or its derivative.
La síntesis de las moléculas de la presente invención (1) consta de dos sencillos pasos realizados bajo condiciones de reacción suaves. The synthesis of the molecules of the present invention (1) consists of two simple steps performed under mild reaction conditions.
El procedimiento para preparar un compuesto definido en una de las reivindicaciones anteriores, de fórmula (1) comprende: The process for preparing a compound defined in one of the preceding claims, of formula (1) comprises:
- generar un compuesto intermedio de fórmula general (2) - generate an intermediate compound of general formula (2)
2 two
en la que A y R tienen los significados dados para el compuesto de fórmula (1), mediante la adición del 2-bromoetil diclorofosfato de fórmula (3), o su análogo clorado o yodado (sintetizado previamente
sobre el grupo hidroxilo situado en posición alfa al grupo carbonilo, de un compuesto de fórmula (4)
wherein A and R have the meanings given for the compound of formula (1), by the addition of the 2-bromoethyl dichlorophosphate of formula (3), or its chlorinated or iodinated analog (previously synthesized on the hydroxyl group located in alpha position to the carbonyl group, of a compound of formula (4)
4 4
en la que, A y R tienen los significados dados para el compuesto de fórmula (1),wherein, A and R have the meanings given for the compound of formula (1),
- sustitución del átomo de bromo, (cloro o yodo) del compuesto intermedio de fórmula (2) por un grupo trimetilamino y formación de la betaína correspondiente. - substitution of the bromine atom, (chlorine or iodine) of the intermediate compound of formula (2) by a trimethylamino group and formation of the corresponding betaine.
En el segundo paso se obtiene el producto de la presente invención (1) a partir del intermedio del paso anterior (2) al reaccionar con trimetilamina disuelta en un alcohol, en condiciones suaves entre 0°C y 60°C durante 1-5 días y posterior tratamiento con una base inorgánica suave como acetato de sodio, carbonato de sodio o potasio, fosfato ácido de sodio o potasio, y preferentemente bicarbonato de sodio o potasio. In the second step the product of the present invention (1) is obtained from the intermediate of the previous step (2) when reacting with trimethylamine dissolved in an alcohol, under mild conditions between 0 ° C and 60 ° C for 1-5 days and subsequent treatment with a mild inorganic base such as sodium acetate, sodium or potassium carbonate, sodium or potassium acid phosphate, and preferably sodium or potassium bicarbonate.
Según una realización particular del procedimiento, el primer paso de la síntesis comprende la adición del 2-bromoetil diclorofosfato (3) (o su análogo clorado o yodado) sobre el grupo hidroxilo situado en posición alfa al grupo carbonilo del ácido graso, su derivado -monoinsaturado o poliinsaturado (4) en presencia de un disolvente apolar, tal como tolueno, xileno, éter dietílico, tert-butilmetil éter (MTBE), tetrahidrofurano, heptano, hexano, una base, tal como la trietilamina, diisopropiletilamina(DIPEA), tributilamina, trimetilamina, N-metilpiperidina, 1 ,4-dimetilpiperazina, a temperatura ambiente (Esquema 1), According to a particular embodiment of the process, the first step of the synthesis comprises the addition of 2-bromoethyl dichlorophosphate (3) (or its chlorinated or iodinated analog) on the hydroxyl group located in the alpha position to the carbonyl group of the fatty acid, its derivative - monounsaturated or polyunsaturated (4) in the presence of an apolar solvent, such as toluene, xylene, diethyl ether, tert-butylmethyl ether (MTBE), tetrahydrofuran, heptane, hexane, a base, such as triethylamine, diisopropylethylamine (DIPEA), tributylamine , trimethylamine, N-methylpiperidine, 1,4-dimethylpiperazine, at room temperature (Scheme 1),
4 2 4 2
Esquema 1 Scheme 1
donde R y A, tienen los significados dados anteriormente. where R and A, have the meanings given above.
El segundo paso consiste en una sustitución del átomo de bromo (o de cloro o de yodo) por un grupo trimetilamino, y posterior formación del correspondiente zwitterión que se
realiza sobre el producto del paso anterior (2) (Esquema 2). La reacción tiene lugar en presencia de un disolvente apolar, tal como tolueno, como disolvente a temperatura ambiente utilizando una disolución de trimetilamina como agente de aminación, en un alcohol, como metanol, n-butanol, isopropanol, etilenglicol, y preferentemente etanol, seguida del tratamiento con bicarbonato de sodio para formar el zwitterión correspondiente. The second step consists in a substitution of the bromine atom (or chlorine or iodine) with a trimethylamino group, and subsequent formation of the corresponding zwitterion that perform on the product of the previous step (2) (Scheme 2). The reaction takes place in the presence of an apolar solvent, such as toluene, as a solvent at room temperature using a solution of trimethylamine as an aminating agent, in an alcohol, such as methanol, n-butanol, isopropanol, ethylene glycol, and preferably ethanol, followed of the sodium bicarbonate treatment to form the corresponding zwitterion.
2 1 twenty-one
Esquema 2 Scheme 2
La presente invención se refiere también a una formulación farmacéuticamente aceptable que comprende un compuesto de fórmula (1). The present invention also relates to a pharmaceutically acceptable formulation comprising a compound of formula (1).
Las formulaciones de los compuestos de la invención pueden ser, por ejemplo, cápsulas con los siguientes excipientes: sílice anhidra coloidal, celulosa microcristalina, monohidrato de lactosa, talco, estearato de magnesio, gelatina, dióxido de titanio, óxido férrico, agua purificada. También pueden ser formulaciones orales con los siguientes excipientes: hidroxipropilcelulosa, propilenglicol y agua purificada. The formulations of the compounds of the invention can be, for example, capsules with the following excipients: colloidal anhydrous silica, microcrystalline cellulose, lactose monohydrate, talc, magnesium stearate, gelatin, titanium dioxide, ferric oxide, purified water. They can also be oral formulations with the following excipients: hydroxypropyl cellulose, propylene glycol and purified water.
Se observó que la molécula de fórmula general (1) muestra actividad in vitro frente a diferentes tipos de células carcinogénicas, por ejemplo frente a líneas celulares tumorales de: pulmón (de células no pequeñas), páncreas, riñón, sistema nervioso central (SNC), próstata, colon, mama, melanoma, ovario, leucemia linfoblástica aguda, leucemia promielocítica aguda, leucemia mielógena crónica, mieloma, linfoma inmunoblástico de células grandes, linfoma de burkitt, linfoma de células B no Hodgkin, leucemia linfocítica crónica, linfoma de células del manto, mieloma múltiple y leucemia aguda de células T (Tablas 1 , 2 y 3). It was observed that the molecule of general formula (1) shows in vitro activity against different types of carcinogenic cells, for example against tumor cell lines of: lung (non-small cell), pancreas, kidney, central nervous system (CNS) , prostate, colon, breast, melanoma, ovary, acute lymphoblastic leukemia, acute promyelocytic leukemia, chronic myelogenous leukemia, myeloma, immunoblastic large cell lymphoma, burkitt lymphoma, non-Hodgkin B-cell lymphoma, chronic lymphocytic leukemia, cell lymphoma mantle, multiple myeloma and acute T-cell leukemia (Tables 1, 2 and 3).
Además, la presente invención se refiere al uso de los compuestos de fórmula (1) y sus derivados farmacéuticamente aceptables como sales, hidratos o polimorfos, para ser usados como especies activas frente a diferentes tipos de células carcinogénicas,
preferentemente en la prevención y/o tratamiento de cánceres tales como los mencionados en el párrafo anterior y en las reivindicaciones. In addition, the present invention relates to the use of the compounds of formula (1) and their pharmaceutically acceptable derivatives as salts, hydrates or polymorphs, to be used as active species against different types of carcinogenic cells, preferably in the prevention and / or treatment of cancers such as those mentioned in the previous paragraph and in the claims.
DESCRIPCIÓN DETALLADA DE EJEMPLOS DE PREPARACIÓN DETAILED DESCRIPTION OF PREPARATION EXAMPLES
Ejemplo 1 : Preparación del compuesto (2a) [(A = (CH2)5-(Z)-CH=CH(CH2)7CH3,(R) = COOEt] (MCH-811 ) Example 1: Preparation of compound (2a) [(A = (CH2) 5- (Z) -CH = CH (CH2) 7CH3, (R) = COOEt] (MCH-811)
En un balón de 1 I se añaden el 2-hidroxi oleato de etilo (37 g, 1 13 mmol), tolueno (420 mi) y trietilamina (22 mi, 125 mmol) y se agita hasta homogeneidad. Seguidamente sobre esta disolución se añade, gota a gota, el 2-bromoetil diclorofosfato (35,61 mi, 136 mmol) y se agita toda la noche (~16 h) a temperatura ambiente (~25 °C). Transcurrido este tiempo el crudo de reacción se lava con salmuera (2 X 250 mi) en un embudo de decantación. Se añade acetato de etilo (100 mi) a la fase acuosa para extraer, y las dos fases orgánicas se juntan, se secan con MgSCL, se filtran y se concentra a vacío. Se obtienen 57.1 g (98% de rendimiento) de producto en forma de aceite de color marrón. In a 1 I balloon, ethyl 2-hydroxy oleate (37 g, 1,13 mmol), toluene (420 mL) and triethylamine (22 mL, 125 mmol) are added and stirred until homogeneous. Then 2-bromoethyl dichlorophosphate (35.61 ml, 136 mmol) is added dropwise onto this solution and stirred overnight (~ 16 h) at room temperature (~ 25 ° C). After this time, the reaction crude is washed with brine (2 X 250 ml) in a separatory funnel. Ethyl acetate (100 ml) is added to the aqueous phase to extract, and the two organic phases are combined, dried with MgSCL, filtered and concentrated in vacuo. 57.1 g (98% yield) of product are obtained in the form of brown oil.
Ejemplo 1 B: Preparación del compuesto (2a) [A = (CH2)5-(Z)-CH=CH(CH2)7CH3, (R) = COOEt] (MCH-811 ). Preparación in situ de 2-bromoetilclorofosfato Example 1 B: Preparation of compound (2a) [A = (CH2) 5- (Z) -CH = CH (CH2) 7CH3, (R) = COOEt] (MCH-811). In situ preparation of 2-bromoethylchlorophosphate
En un balón de 1 I se añaden oxicloruro de fósforo (136 mmol), bromoetanol (136 mmol) y trietilamina (44 mi, 250 mmol) en tolueno. (420 mL) y se agita hasta homogeneidad. Seguidamente sobre esta disolución se añade el 2-hidroxi oleato de etilo (37 g, 113 mmol), y se agita toda la noche (~16 h) a temperatura ambiente (~25 °C). Transcurrido este tiempo el crudo de reacción se lava con salmuera (2 X 250 mi) en un embudo de decantación. Se añade acetato de etilo (100 mi) a la fase acuosa para extraer, y las dos fases orgánicas se juntan, se secan con MgSCL, se filtran y se concentra a vacío. Se obtienen 57.1 g (98% de rendimiento) de producto en forma de aceite de color marrón. In a 1 I balloon, phosphorus oxychloride (136 mmol), bromoethanol (136 mmol) and triethylamine (44 mL, 250 mmol) in toluene are added. (420 mL) and stir until homogeneous. Then over this solution, add the ethyl 2-hydroxy oleate (37 g, 113 mmol), and stir overnight (~ 16 h) at room temperature (~ 25 ° C). After this time, the reaction crude is washed with brine (2 X 250 ml) in a separatory funnel. Ethyl acetate (100 ml) is added to the aqueous phase to extract, and the two organic phases are combined, dried with MgSCL, filtered and concentrated in vacuo. 57.1 g (98% yield) of product are obtained in the form of brown oil.
Ejemplo 2: Preparación del compuesto (1a) [A = (CH2)5-(Z)-CH=CH(CH2)7CH3, (R) = COOEt] (MCH-811 ) Example 2: Preparation of compound (1a) [A = (CH2) 5- (Z) -CH = CH (CH2) 7CH3, (R) = COOEt] (MCH-811)
El producto de la reacción anterior (2a, 57.1 g, 1 11 mmol) se disuelve con tolueno (180 mi) en un balón de 500 mi. Sobre esta disolución se añade una disolución de
trimetilamina en etanol 4.2M (150 ml, 628 mmol) y se agita a temperatura ambiente (~25 °C) durante 3 días. Pasado este tiempo se añaden NaHCC>3 (10 g, 1 19 mmol) y agua (10 ml) y se agita durante 2 horas. El crudo se concentra a vacío y se purifica por columna cromatográfica (DCM/MeOH/NHs). Se obtienen 32 g (59% de rendimiento) del producto puro. The product of the previous reaction (2a, 57.1 g, 11 mmol) is dissolved with toluene (180 ml) in a 500 ml balloon. A solution of Trimethylamine in 4.2M ethanol (150 ml, 628 mmol) and stirred at room temperature (~ 25 ° C) for 3 days. After this time, NaHCC> 3 (10 g, 11 mmol) and water (10 ml) are added and stirred for 2 hours. The crude is concentrated in vacuo and purified by chromatographic column (DCM / MeOH / NHs). 32 g (59% yield) of the pure product are obtained.
Ejemplo 3: Preparación del compuesto (2b) [A = (CH2)5-(Z)-Example 3: Preparation of compound (2b) [A = (CH 2 ) 5- (Z) -
CH=CHCH2CH(OH)(CH2)5CH3, (R) = COOEt] CH = CHCH 2 CH (OH) (CH2) 5 CH3, (R) = COOEt]
En un balón de 1 I se añaden el 12-((Terc-butildimetilsilil)oxi)2-hidroxi oleato de etilo (51.62 g, 113 mmol). Se continúa como en el ejemplo 1. In a 1 I balloon are added 12 - ((Terc-butyldimethylsilyl) oxy) 2-hydroxy ethyl oleate (51.62 g, 113 mmol). Continue as in example 1.
Ejemplo 4: Preparación del compuesto (1 b) [A = (CH2)5-(Z)-Example 4: Preparation of compound (1 b) [A = (CH 2 ) 5- (Z) -
CH=CHCH2CH(OH)(CH2)5CH3,(R) = COOEt] CH = CHCH 2 CH (OH) (CH2) 5 CH3, (R) = COOEt]
Con el producto del ejemplo anterior 2b, se procede como en el ejemplo 2. Además en este caso habría que continuar y realizar la desprotección del grupo TBDMS empleando un compuesto fluorado, como por ejemplo, fluoruro de tetrabutilamonio. With the product of the previous example 2b, we proceed as in example 2. Furthermore, in this case the protection of the TBDMS group should be continued and carried out using a fluorinated compound, such as tetrabutylammonium fluoride.
Ejemplo 5: Preparación del compuesto (2c) [A = (CH2)I2CH3, (R) = COOEt] Example 5: Preparation of compound (2c) [A = (CH 2 ) I2 CH3, (R) = COOEt]
En un balón de 1 I se añaden el 2-hidroxi palmitato de etilo (34. Og, 113 mmol), se continúa como en el ejemplo 1. In a 1 I balloon the ethyl 2-hydroxy palmitate (34. Og, 113 mmol) is added, continued as in example 1.
Ejemplo 6: Preparación del compuesto (1c) [A = (CH2)I2CH3, (R) = COOEt] Example 6: Preparation of compound (1c) [A = (CH 2 ) I2 CH3, (R) = COOEt]
Con el producto del ejemplo anterior 2c, se procede como en el ejemplo 2. With the product of the previous example 2c, proceed as in example 2.
Ejemplo 7: Preparación del compuesto (2d) [A =(CH2)i4CH3, (R) = COOEt] Example 7: Preparation of compound (2d) [A = (CH 2 ) i4CH3, (R) = COOEt]
En un balón de 1 I se añaden el 2-hidroxi estearato de etilo (37.1 g, 113 mmol), tolueno (420 ml) y trietilamina (22 ml, 125 mmol) y se agita hasta homogeneidad. Se continúa como en el ejemplo 1.
Ejemplo 8: Preparación del compuesto (1 d) [A = (CH2)i4CH3, (R) = COOEt] In a 1 I balloon, ethyl 2-hydroxy stearate (37.1 g, 113 mmol), toluene (420 ml) and triethylamine (22 ml, 125 mmol) are added and stirred until homogeneous. Continue as in example 1. Example 8: Preparation of compound (1 d) [A = (CH2) i4CH3, (R) = COOEt]
Con el producto del ejemplo anterior 2d, se procede como en el ejemplo 2. With the product of the previous example 2d, proceed as in example 2.
Ejemplo 9: Preparación del compuesto (2e) [A =(CH2)9-(Z)-CH=CH(CH2)7CH3, (R) = COOEt] Example 9: Preparation of compound (2e) [A = (CH2) 9- (Z) -CH = CH (CH2) 7CH3, (R) = COOEt]
En un balón de 1 I se añaden el 2-hidroxieuricato de etilo (43.23g, 1 13 mmol), tolueno (420 mi) y trietilamina (22 mi, 125 mmol) y se agita hasta homogeneidad. Se continúa como en el ejemplo 1. In a 1 I balloon, ethyl 2-hydroxyeuricate (43.23g, 13 mmol), toluene (420 mL) and triethylamine (22 mL, 125 mmol) are added and stirred until homogeneous. Continue as in example 1.
Ejemplo 10: Preparación del compuesto (1e) [A = (CH2)9-(Z)-CH=CH(CH2)7CH3, (R) = COOEt] Example 10: Preparation of compound (1e) [A = (CH2) 9- (Z) -CH = CH (CH2) 7CH3, (R) = COOEt]
Con el producto del ejemplo anterior 2e, se procede como en el ejemplo 2. With the product of the previous example 2e, proceed as in example 2.
Ejemplo 11 : Preparación del compuesto (2f) [A =(CH2)4-(Z,Z)-Example 11: Preparation of compound (2f) [A = (CH2) 4- (Z, Z) -
CH=CHCH2CH=CH(CH2)5CH3, (R) = COOEt] CH = CHCH 2 CH = CH (CH 2 ) 5 CH3, (R) = COOEt]
En un balón de 1 I se añaden el 2-hidroxilinoleato de etilo (36.67 g, 113 mmol), tolueno (420 mi) y trietilamina (22 mi, 125 mmol) y se agita hasta homogeneidad. Se continúa como en el ejemplo 1. In a 1 I balloon, ethyl 2-hydroxylininoleate (36.67 g, 113 mmol), toluene (420 mL) and triethylamine (22 mL, 125 mmol) are added and stirred until homogeneous. Continue as in example 1.
Ejemplo 12: Preparación del compuesto (1f) [A = (OHS Z,Z)-Example 12: Preparation of compound (1f) [A = (OHS Z, Z) -
CH=CHCH2CH=CH(CH2)5CH3, (R) = COOEt] CH = CHCH 2 CH = CH (CH 2 ) 5 CH3, (R) = COOEt]
Con el producto del ejemplo anterior 2f, se procede como en el ejemplo 2. With the product of the previous example 2f, proceed as in example 2.
Ejemplo 13: Preparación del compuesto (2g) [A =(CH2)2-(Z,Z,Z)-Example 13: Preparation of compound (2g) [A = (CH2) 2- (Z, Z, Z) -
CH=CHCH2CH=CHCH2CH=CH(CH2)4CH3, (R) = COOEt] CH = CHCH 2 CH = CHCH 2 CH = CH (CH2) 4CH3, (R) = COOEt]
En un balón de 1 I se añaden el 2-hidroxi-gamma-linolenato de etilo (36.44g, 113 mmol), tolueno (420 mi) y trietilamina (22 mi, 125 mmol) y se agita hasta homogeneidad. Se continúa como en el ejemplo 1.
Ejemplo 14: Preparación del compuesto (1 g) [A = (CH2)2-(Z,Z,Z)-In a 1 I balloon, ethyl 2-hydroxy-gamma-linoleate (36.44g, 113 mmol), toluene (420 mL) and triethylamine (22 mL, 125 mmol) are added and stirred until homogeneous. Continue as in example 1. Example 14: Preparation of the compound (1 g) [A = (CH 2 ) 2 - (Z, Z, Z) -
CH=CHCH2CH=CHCH2CH=CH(CH2)4CH3, (R) = COOEt] CH = CHCH 2 CH = CHCH 2 CH = CH (CH2) 4CH3, (R) = COOEt]
Con el producto del ejemplo anterior 2g, se procede como en el ejemplo 2. With the product of the previous example 2g, proceed as in example 2.
Ejemplo 15: Preparación del compuesto (2h) [A =(CH2)5-(Z,Z,Z)- CH=CHCH2CH=CHCH2CH=CHCH2CH3, (R) = COOEt] Example 15: Preparation of compound (2h) [A = (CH 2 ) 5- (Z, Z, Z) - CH = CHCH 2 CH = CHCH 2 CH = CHCH 2 CH 3 , (R) = COOEt]
En un balón de 1 I se añaden el 2-hidroxi-alfa-linolenato de etilo (36.44 g, 113 mmol), tolueno (420 mi) y trietilamina (22 mi, 125 mmol) y se agita hasta homogeneidad. Se continúa como en el ejemplo 1. In a 1 I balloon, ethyl 2-hydroxy-alpha-linoleate (36.44 g, 113 mmol), toluene (420 mL) and triethylamine (22 mL, 125 mmol) are added and stirred until homogeneous. Continue as in example 1.
Ejemplo 16: Preparación del compuesto (1 h) [A = (CH2)5-(Z,Z,Z)-Example 16: Preparation of the compound (1 h) [A = (CH 2 ) 5- (Z, Z, Z) -
CH=CHCH2CH=CHCH2CH=CHCH2CH3, (R) = COOEt] CH = CHCH 2 CH = CHCH 2 CH = CHCH 2 CH 3 , (R) = COOEt]
Con el producto del ejemplo anterior 2h, se procede como en el ejemplo 2. With the product of the previous example 2h, proceed as in example 2.
Ejemplo 17: Preparación del compuesto (2i) [A =(CH2)5-(Z,E,Z)-Example 17: Preparation of compound (2i) [A = (CH 2 ) 5- (Z, E, Z) -
CH=CHCH=CHCH=CH(CH2)3CH3,(R) = COOEt] CH = CHCH = CHCH = CH (CH 2 ) 3 CH 3 , (R) = COOEt]
En un balón de 1 I se añaden el 2-hidroxipunicato de etilo (36.44 g, 113 mmol), tolueno (420 mi) y trietilamina (22 mi, 125 mmol) y se agita hasta homogeneidad. Se continúa como en el ejemplo 1. In a 1 I balloon, ethyl 2-hydroxypunicate (36.44 g, 113 mmol), toluene (420 mL) and triethylamine (22 mL, 125 mmol) are added and stirred until homogeneous. Continue as in example 1.
Ejemplo 18: Preparación del compuesto (1 i) [A = (CH2)5-(Z,E,Z)-Example 18: Preparation of compound (1 i) [A = (CH 2 ) 5- (Z, E, Z) -
CH=CHCH=CHCH=CH(CH2)3CH3, (R) = COOEt] CH = CHCH = CHCH = CH (CH 2 ) 3 CH 3 , (R) = COOEt]
Con el producto del ejemplo anterior 2i, se procede como en el ejemplo 2. With the product of the previous example 2i, proceed as in example 2.
Ejemplo 19: Preparación del compuesto (2j) [A =CH2-(Z,Z,Z,Z)-Example 19: Preparation of compound (2j) [A = CH 2 - (Z, Z, Z, Z) -
[CH=CHCH2]4(CH2)4CH3, (R) = COOEt] [CH = CHCH 2 ] 4 (CH 2 ) 4 CH 3 , (R) = COOEt]
En un balón de 1 I se añaden el 2-hidroxiaraquidonato de etilo (39.38g, 113 mmol),
tolueno (420 mi) y trietilamina (22 mi, 125 mmol) y se agita hasta homogeneidad. Se continúa como en el ejemplo 1. In a 1 I balloon, the ethyl 2-hydroxyaraquidonate (39.38g, 113 mmol) is added, toluene (420 ml) and triethylamine (22 ml, 125 mmol) and stir until homogeneous. Continue as in example 1.
Ejemplo 20: Preparación del compuesto (1j) [A = CH2-(Z,Z,Z,Z)-[CH=CHCH2]4CH3, (R) = COOEt] Example 20: Preparation of compound (1j) [A = CH2- (Z, Z, Z, Z) - [CH = CHCH2] 4CH3, (R) = COOEt]
Con el producto del ejemplo anterior 2j, se procede como en el ejemplo 2. With the product of the previous example 2j, proceed as in example 2.
Ejemplo 21 : Preparación del compuesto (2k) [A =CH2-(Z,Z,Z,Z,Z)-[CH=CHCH2]5CH3, (R) = COOEt] Example 21: Preparation of compound (2k) [A = CH2- (Z, Z, Z, Z, Z) - [CH = CHCH2] 5CH3, (R) = COOEt]
En un balón de 1 I se añaden el 2-hidroxieicosapentaenoato de etilo (39.16g, 113 mmol), tolueno (420 mi) y trietilamina (22 mi, 125 mmol) y se agita hasta homogeneidad. Se continúa como en el ejemplo 1. In a 1 I balloon, ethyl 2-hydroxyeicosapentaenoate (39.16g, 113 mmol), toluene (420 mL) and triethylamine (22 mL, 125 mmol) are added and stirred until homogeneous. Continue as in example 1.
Ejemplo 22: Preparación del compuesto (1 k) [A = CH2-(Z,Z,Z,Z,Z)-Example 22: Preparation of compound (1 k) [A = CH2- (Z, Z, Z, Z, Z) -
[CH=CHCH2]5CH3,(R) = COOEt] [CH = CHCH 2 ] 5 CH 3 , (R) = COOEt]
Con el producto del ejemplo anterior 2k, se procede como en el ejemplo 2. With the product of the previous example 2k, proceed as in example 2.
Ejemplo 23: Preparación del compuesto (2I) [A =(Z,Z,Z,Z,Z,Z)-[CH=CHCH2]6CH3, (R) = COOEt] Example 23: Preparation of compound (2I) [A = (Z, Z, Z, Z, Z, Z) - [CH = CHCH 2 ] 6 CH3, (R) = COOEt]
En un balón de 1 I se añaden el 2-hidroxidocosahexaenoato de etilo (42.10g, 113 mmol), tolueno (420 mi) y trietilamina (22 mi, 125 mmol) y se agita hasta homogeneidad. Se continúa como en el ejemplo 1. In a 1 I balloon, add the ethyl 2-hydroxidecosahexaenoate (42.10g, 113 mmol), toluene (420 mL) and triethylamine (22 mL, 125 mmol) and stir until homogeneous. Continue as in example 1.
Ejemplo 24: Preparación del compuesto (11) [A = (Z,Z,Z,Z,Z,Z)-[CH=CHCH2]6CH3, (R) = COOEt] Example 24: Preparation of compound (11) [A = (Z, Z, Z, Z, Z, Z) - [CH = CHCH2] 6CH3, (R) = COOEt]
Con el producto del ejemplo anterior 21, se procede como en el ejemplo 2. With the product of the previous example 21, we proceed as in example 2.
Esquema 3. Representación de los productos de fórmula (1).
Scheme 3. Representation of the products of formula (1).
Ejemplo 25: Estudios de eficacia in vitro de MCH-811 La actividad citotóxica de la molécula que describe la presente invención fue probada utilizando distintas líneas tumorales humanas para establecer su eficacia antitumoral. El ensayo in vitro de actividad se realizó como se detalla a continuación: Example 25: In vitro efficacy studies of MCH-811 The cytotoxic activity of the molecule described in the present invention was tested using different human tumor lines to establish its antitumor efficacy. The in vitro activity test was performed as detailed below:
Las células de los distintos tipos tumorales fueron tratadas con el compuesto MCH-811 con concentraciones conocidas, entre 0,1 y 200 mM, durante 72 horas. Al final del
periodo de incubación, se añadió el reactivo alamarBIue® (1/10 del volumen) directamente a las células en medio de cultivo y 4 horas más tarde se procedió a la lectura de la fluorescencia, usando una longitud de onda de excitación de 485 nm y una longitud de onda de emisión de 595 nm. Cells of the different tumor types were treated with compound MCH-811 with known concentrations, between 0.1 and 200 mM, for 72 hours. At the end of incubation period, the alamarBIue® reagent (1/10 of the volume) was added directly to the cells in culture medium and 4 hours later the fluorescence was read, using an excitation wavelength of 485 nm and an emission wavelength of 595 nm.
La viabilidad celular se calculó comparando los valores de fluorescencia de cada concentración con los valores de fluorescencia del cultivo celular no tratado (viabilidad 100%). Los valores de IC50 fueron estimados utilizando el software GraphPadPrism (v5). Cell viability was calculated by comparing the fluorescence values of each concentration with the fluorescence values of the untreated cell culture (100% viability). The IC50 values were estimated using GraphPadPrism software (v5).
3.1.- Estudios in vitro con líneas celulares tumorales humanas de páncreas (MiaPaca-2, PANC-1 , BxPC-3) 3.1.- In vitro studies with human tumor cell lines of the pancreas (MiaPaca-2, PANC-1, BxPC-3)
Se llevaron a cabo ensayos de proliferación celular con alamarBIue® a 72 h con distintas líneas tumorales de páncreas. Se sembraron 750 células MiaPaca-2, 3500 células PANC-1 y 3500 células BxPC-3 por pocilio en placas de 96 pocilios y se obtuvieron los siguientes valores de IC50 (concentración inhibitoria 50%, Media ± D.E.), calculada como la concentración de compuesto que causa un 50% de inhibición en la proliferación celular (Tabla 1): Cell proliferation assays were carried out with alamarBIue® at 72 h with different tumor lines of the pancreas. 750 MiaPaca-2 cells, 3,500 PANC-1 cells and 3,500 BxPC-3 cells were seeded per well in 96-well plates and the following IC50 values (50% inhibitory concentration, Mean ± SD) were obtained, calculated as the concentration of compound that causes 50% inhibition in cell proliferation (Table 1):
Tabla 1. Eficacia de MCH-811 en distintas líneas celulares tumorales de páncreas. Table 1. Efficacy of MCH-811 in different tumor cell lines of the pancreas.
3.2.- Estudios in vitro con líneas celulares tumorales humanas de linfoma (SR, NAMALWA, DAUDI, DOHH2, JVM-2, KARPAS422) 3.2.- In vitro studies with human tumor cell lines of lymphoma (SR, NAMALWA, DAUDI, DOHH2, JVM-2, KARPAS422)
Se llevaron a cabo ensayos de proliferación celular con alamarBIue® a 72 h con distintas líneas tumorales humanas de diversos tipos de linfomas. En placas de 96 pocilios, se sembraron 6000 células SR, 5000 células NAMALWA y DAUDI y 10000 células DOHH2,
JVM-2 y KARPAS422 por pocilio y se obtuvieron los siguientes valores de concentración inhibitoria 50% (IC50, Media ± D.E.), calculada como la concentración de compuesto que causa un 50% de inhibición en la proliferación celular (Tabla 2): Cell proliferation assays were conducted with alamarBIue® at 72 h with different human tumor lines of various types of lymphomas. In 96-well plates, 6000 SR cells, 5000 NAMALWA and DAUDI cells and 10,000 DOHH2 cells were seeded, JVM-2 and KARPAS422 per well and the following 50% inhibitory concentration values (IC50, Mean ± SD) were obtained, calculated as the concentration of compound that causes 50% inhibition in cell proliferation (Table 2):
Tabla 2. Eficacia de MCH-811 en distintas líneas celulares tumorales de linfoma. Entre paréntesis se indica el número de determinaciones cuando hay más de 2. Table 2. Efficacy of MCH-811 in different tumor cell lines of lymphoma. In brackets, the number of determinations is indicated when there are more than 2.
3.3.- Estudios in vitro con otras líneas celulares tumorales humanas 3.3.- In vitro studies with other human tumor cell lines
Los ensayos in vitro de actividad se realizaron como se ha detallado anteriormente, ajustando la densidad de siembra de las distintas líneas celulares tumorales. En la siguiente tabla (Tabla 3) se representan los valores de IC50 (concentración de producto capaz de inhibir el 50% del cultivo celular tumoral) expresados como Media ± D.E. que se obtuvieron para las diferentes líneas tumorales estudiadas. In vitro activity tests were performed as detailed above, adjusting the seeding density of the different tumor cell lines. The following table (Table 3) shows the IC50 values (concentration of product capable of inhibiting 50% of tumor cell culture) expressed as Mean ± D.E. which were obtained for the different tumor lines studied.
Tabla 3. Eficacia de MCH-811 en distintas líneas celulares humanas correspondientes a otros tipos de tumores.
Table 3. Efficacy of MCH-811 in different human cell lines corresponding to other types of tumors.
Claims
1. Un compuesto zwitteriónico de ácido 2-fosfocolina carboxílico de fórmula general (1 ) 1. A 2-phosphocholine carboxylic acid zwitterionic compound of general formula (1)
en la que: in which:
- A es una cadena carbonada que puede tener puede tener cualquier número de átomos de carbono entre 4 y 19, saturada, monoinsaturada o poliinsaturada, con cualquier tipo de configuración en los dobles enlaces C=C, mono o polihidroxilada en distintas posiciones, o no hidroxilada, - A is a carbon chain that can have any number of carbon atoms between 4 and 19, saturated, monounsaturated or polyunsaturated, with any type of configuration in the double bonds C = C, mono or polyhydroxylated in different positions, or not hydroxylated,
- R es un átomo o grupo de átomos con un peso entre 1 y 200 Da, - R is an atom or group of atoms with a weight between 1 and 200 Da,
y sus derivados farmacéuticamente aceptables. and its pharmaceutically acceptable derivatives.
2. El compuesto según la reivindicación 1 , en el que A tiene un número de átomos de carbono entre 13 y 19. 2. The compound according to claim 1, wherein A has a number of carbon atoms between 13 and 19.
3. El compuesto según una de las reivindicaciones anteriores, en el que R es seleccionado de entre: COOH, COOMe, COOEt, COOBu1, COOBu', COOPr', COOBu, COOPr, COOPr', COSEt, COSMe, COSPr, COSBu, COSPH, CN, CSNR2R3, CONR2R3, y COOM, donde M es un catión derivado de metal alcalino o alcalino-térreo, como litio, sodio, potasio, cesio, magnesio o calcio, R2 y R3 pueden ser iguales o distintos y representan un radical alquílico, preferentemente, metilo, etilo, propilo, isopropilo, butilo, isobutilo, tert-butilo, pentilo o hexilo. 3. The compound according to one of the preceding claims, wherein R is selected from: COOH, COOMe, COOEt, COOBu 1 , COOBu ', COOPr', COOBu, COOPr, COOPr ', COSEt, COSMe, COSPr, COSBu, COSPH, CN, CSNR 2 R 3 , CONR 2 R 3 , and COOM, where M is a cation derived from alkali or alkaline earth metal, such as lithium, sodium, potassium, cesium, magnesium or calcium, R 2 and R 3 can be the same or different and represent an alkyl radical, preferably, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl.
4. El compuesto según una de las reivindicaciones anteriores, en el que A es una cadena carbonada saturada, monoinsaturada o poliinsaturada, con cualquier tipo de configuración en los dobles enlaces C=C, mono o polihidroxilada en distintas posiciones, o no hidroxilada.
4. The compound according to one of the preceding claims, wherein A is a saturated, monounsaturated or polyunsaturated carbon chain, with any type of configuration in the double bonds C = C, mono or polyhydroxylated in different positions, or not hydroxylated.
5. El compuesto según una de las reivindicaciones anteriores, en el que R es un átomo o grupo de átomos con un peso entre 1 y 200 Da. 5. The compound according to one of the preceding claims, wherein R is an atom or group of atoms with a weight between 1 and 200 Da.
6. El compuesto según una de las reivindicaciones anteriores, en el que: 6. The compound according to one of the preceding claims, wherein:
-“A” es una cadena hidrocarbonada monoinsaturada. - "A" is a monounsaturated hydrocarbon chain.
7. El compuesto según una de las reivindicaciones anteriores, en el que A es un fragmento de quince átomos de carbono conteniendo un enlace doble C=C entre los átomos de carbonos C9-C10 y con configuración Z. 7. The compound according to one of the preceding claims, wherein A is a fragment of fifteen carbon atoms containing a double bond C = C between the carbon atoms C9-C10 and with Z configuration.
8. El compuesto según una de las reivindicaciones anteriores, en el que R representa un áster etílico, R=COO-CH2-CH3. 8. The compound according to one of the preceding claims, wherein R represents an ethyl ester, R = COO-CH 2 -CH 3 .
9. El compuesto según la reivindicación 1 , en el que: 9. The compound according to claim 1, wherein:
-A es un fragmento de quince átomos de carbono conteniendo un enlace doble C=C entre los átomos de carbonos C9-C10 con configuración Z. -A is a fragment of fifteen carbon atoms containing a double bond C = C between C9-C10 carbon atoms with Z configuration.
- R representa un áster etílico, R=COO-CH2-CH3. - R represents an ethyl ester, R = COO-CH2-CH3.
10. El compuesto según la reivindicación 1 , en el que el derivado farmacéuticamente aceptable es una sal, un hidrato de dicha sal o un polimorfo. 10. The compound according to claim 1, wherein the pharmaceutically acceptable derivative is a salt, a hydrate of said salt or a polymorph.
11. Un procedimiento para preparar un compuesto definido en una de las reivindicaciones anteriores, de fórmula (1) que comprende: 11. A process for preparing a compound defined in one of the preceding claims, of formula (1) comprising:
- la adición del 2-bromoetil diclorofosfato de fórmula (3), o su análogo clorado o yodado
- the addition of 2-bromoethyl dichlorophosphate of formula (3), or its chlorinated or iodinated analog
sobre el grupo hidroxilo situado en posición alfa al grupo carbonilo.de un compuesto de fórmula (4)
on the hydroxyl group located in alpha position to the carbonyl group of a compound of formula (4)
4 4
en la que:
- A es una cadena carbonada con un número de átomos de carbono entre 4 y 19, saturada, monoinsaturada o poliinsaturada, en la que la configuración en los dobles enlaces C=C es Z o E, mono o polihidroxilada en distintas posiciones, o no hidroxilada,in which: - A is a carbon chain with a number of carbon atoms between 4 and 19, saturated, monounsaturated or polyunsaturated, in which the configuration in the double bonds C = C is Z or E, mono or polyhydroxylated in different positions, or not hydroxylated,
- R es un átomo o grupo de átomos con un peso entre 1 y 200 Da, generando un compuesto intermedio de fórmula general (2)
- R is an atom or group of atoms with a weight between 1 and 200 Da, generating an intermediate compound of general formula (2)
OH OH
2 two
- sustitución del átomo de bromo, cloro o yodo) del compuesto intermedio de fórmula (2) por un grupo trimetilamino, y formación de la betaína correspondiente. - substitution of the bromine, chlorine or iodine atom) of the intermediate compound of formula (2) by a trimethylamino group, and formation of the corresponding betaine.
12. El procedimiento según la reivindicación 11 , en el que después de la sustitución sobre el átomo de bromo, cloro o yodo por un grupo trimetilamino, se forma la correspondiente betaína mediante tratamiento con una base. 12. The method according to claim 11, wherein after substitution on the bromine, chlorine or iodine atom by a trimethylamino group, the corresponding betaine is formed by treatment with a base.
13. El procedimiento según la reivindicación 11 , en el que la base es bicarbonato de sodio. 13. The process according to claim 11, wherein the base is sodium bicarbonate.
14. El procedimiento según la reivindicación 11 , en el que la adición del diclorofosfato de 2-bromoetil, 2-cloroetilo o 2-yodoetilo,de fórmula (2) se realiza en presencia un disolvente apolar, y una base a temperatura ambiente. 14. The process according to claim 11, wherein the addition of 2-bromoethyl, 2-chloroethyl or 2-iodoethyl dichlorophosphate, of formula (2) is carried out in the presence of an apolar solvent, and a base at room temperature.
15. El procedimiento según la reivindicación 14, en el que el disolvente apolar es tolueno, la base es trietilamina y R es COOEt. 15. The process according to claim 14, wherein the apolar solvent is toluene, the base is triethylamine and R is COOEt.
16. El procedimiento según la reivindicación 11 en el que el compuesto de fórmula (2):16. The process according to claim 11 wherein the compound of formula (2):
- A es un fragmento de quince átomos de carbono conteniendo un enlace doble C=C entre los átomos de Carbono C9-C10 con configuración Z, y - A is a fragment of fifteen carbon atoms containing a double bond C = C between C9-C10 Carbon atoms with Z configuration, and
- R representa un grupo COOEt. - R represents a COOEt group.
17. Una formulación farmacéuticamente aceptable que comprende un compuesto de fórmula (1) definido en la reivindicación 1.
17. A pharmaceutically acceptable formulation comprising a compound of formula (1) defined in claim 1.
18. Uso de un compuesto de fórmula (1 ) definido en la reivindicación 1 en terapia o prevención de enfermedades. 18. Use of a compound of formula (1) defined in claim 1 in therapy or disease prevention.
19. Uso de un compuesto de fórmula (1 ) según la reivindicación 18 como agente citotóxico. 19. Use of a compound of formula (1) according to claim 18 as a cytotoxic agent.
20. Uso de un compuesto de fórmula (1 ) según la reivindicación 19, en la prevención o tratamiento de cáncer. 20. Use of a compound of formula (1) according to claim 19, in the prevention or treatment of cancer.
21. Uso según la reivindicación 20, en el que el cáncer es cáncer seleccionado entre cáncer de pulmón de células no pequeñas, páncreas, riñón, sistema nervioso central (SNC), próstata, colon, mama, melanoma, ovario, leucemia linfoblástica aguda, leucemia promielocítica aguda, leucemia mielógena crónica, mieloma, linfoma inmunoblástico de células grandes, linfoma de Burkitt, linfoma de células B no Hodgkin, leucemia linfocítica crónica, linfoma de células del manto, mieloma múltiple y leucemia aguda de células T. 21. Use according to claim 20, wherein the cancer is cancer selected from non-small cell lung cancer, pancreas, kidney, central nervous system (CNS), prostate, colon, breast, melanoma, ovary, acute lymphoblastic leukemia, acute promyelocytic leukemia, chronic myelogenous leukemia, myeloma, immunoblastic large cell lymphoma, Burkitt lymphoma, non-Hodgkin B-cell lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, multiple myeloma and acute T-cell leukemia.
22. Uso según la reivindicación 21 , en el que el cáncer es cáncer de páncreas o linfoma.
22. Use according to claim 21, wherein the cancer is pancreatic cancer or lymphoma.
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| ES201830802A ES2739773B2 (en) | 2018-08-02 | 2018-08-02 | ZWITTERIONIC COMPOUNDS OF 2-PHOSPHOCOLINE CARBOXYL ACIDS AND THEIR USE AS CYTOTOXIC AGENTS |
| ESP201830802 | 2018-08-02 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0121088A1 (en) * | 1983-03-05 | 1984-10-10 | A. Nattermann & Cie. GmbH | New o-acyl-alkanediol-phospholipids, processes for their preparation and pharmaceutical preparations containing them |
| AT393505B (en) * | 1987-04-27 | 1991-11-11 | Max Planck Gesellschaft | Medicinal products which contain alkylphosphoamines in combination with an alkylglycerol |
| WO2007071658A2 (en) * | 2005-12-19 | 2007-06-28 | Æterna Zentaris Gmbh | Alkyl phospholipid derivatives with reduced cytotoxicity and uses thereof |
| WO2010050918A1 (en) * | 2008-10-31 | 2010-05-06 | Qinghai Zhang | Branched chain detergents for membrane protein structural biology |
| WO2012095500A2 (en) * | 2011-01-14 | 2012-07-19 | Dafra Pharma Research&Development Bvba | Pharmaceutical compositions for the treatment of parasitic diseases, cancer, or skin diseases by topical administration |
-
2018
- 2018-08-02 ES ES201830802A patent/ES2739773B2/en active Active
-
2019
- 2019-07-30 WO PCT/ES2019/070541 patent/WO2020025848A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0121088A1 (en) * | 1983-03-05 | 1984-10-10 | A. Nattermann & Cie. GmbH | New o-acyl-alkanediol-phospholipids, processes for their preparation and pharmaceutical preparations containing them |
| AT393505B (en) * | 1987-04-27 | 1991-11-11 | Max Planck Gesellschaft | Medicinal products which contain alkylphosphoamines in combination with an alkylglycerol |
| WO2007071658A2 (en) * | 2005-12-19 | 2007-06-28 | Æterna Zentaris Gmbh | Alkyl phospholipid derivatives with reduced cytotoxicity and uses thereof |
| WO2010050918A1 (en) * | 2008-10-31 | 2010-05-06 | Qinghai Zhang | Branched chain detergents for membrane protein structural biology |
| WO2012095500A2 (en) * | 2011-01-14 | 2012-07-19 | Dafra Pharma Research&Development Bvba | Pharmaceutical compositions for the treatment of parasitic diseases, cancer, or skin diseases by topical administration |
Non-Patent Citations (1)
| Title |
|---|
| BROQUET; C. ET AL.: "Structural Analogs of PAF-Acether. Part 1. rac-Acetyloxydocosyl Phosphorylcholines", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY , vol. 19, no. 3, 1984, pages 229 - 233, XP009521385, ISSN: 0223-5234 * |
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| ES2739773A1 (en) | 2020-02-03 |
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