EP2010163A2 - Co-crystals of calixarenes and biologically active molecules - Google Patents
Co-crystals of calixarenes and biologically active moleculesInfo
- Publication number
- EP2010163A2 EP2010163A2 EP07731905A EP07731905A EP2010163A2 EP 2010163 A2 EP2010163 A2 EP 2010163A2 EP 07731905 A EP07731905 A EP 07731905A EP 07731905 A EP07731905 A EP 07731905A EP 2010163 A2 EP2010163 A2 EP 2010163A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- arene
- calix
- diseases
- crystal
- biologically active
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- HDPRHRZFFPXZIL-UHFFFAOYSA-N calix[8]arene Chemical compound OC1=C(CC=2C(=C(CC=3C(=C(CC=4C(=C(CC=5C(=C(CC=6C(=C(CC=7C(=C(C8)C=CC=7)O)C=CC=6)O)C=CC=5)O)C=CC=4)O)C=CC=3)O)C=CC=2)O)C=CC=C1CC1=C(O)C8=CC=C1 HDPRHRZFFPXZIL-UHFFFAOYSA-N 0.000 claims description 2
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 1
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- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 229940005573 sodium fumarate Drugs 0.000 description 1
- 235000019294 sodium fumarate Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/695—Silicon compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
- C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
- C07C279/265—X and Y being nitrogen atoms, i.e. biguanides containing two or more biguanide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/41—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
- C07C309/43—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton having at least one of the sulfo groups bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
-
- 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/54—Ortho- or ortho- and peri-condensed systems containing more than five condensed rings
Definitions
- the present invention relates to the field of organic co-crystals. More specifically, this invention relates to analogous calixarene and macrocycle derivatives for the formation of co-crystals and pharmaceutical compositions comprising such co-crystals. The invention also relates to processes for the preparation of these novel co-crystals and their use, in particular in the preparation of medicaments.
- Biologically active compounds in particular pharmaceutically active compounds (CAPs) can be prepared in various forms. They may be in amorphous form or in crystalline form, especially in drugs.
- CAPs pharmaceutically active compounds
- the subject of the invention is a co-crystal of at least one calix [n] arene molecule or at least one of its derivatives, and at least one biologically active molecule.
- this co-crystal has the physical properties corresponding to the crystalline compounds, for example an X-ray diffraction due to an ordered organization in three dimensions.
- the co-crystal of calix [n] arene or of one of its derivatives, and of a biologically active molecule, in particular a pharmaceutically active compound (CAP), may be defined as the combination of at least one molecule of calix [n] arene or a derivative thereof, and at least one biologically active molecule.
- a biologically active molecule in particular a pharmaceutically active compound (CAP)
- CAP pharmaceutically active compound
- This association can in particular be done via at least one non-covalent interaction.
- non-covalent interactions it may be the same type of non-covalent interactions or several types of non-covalent interactions.
- Non-covalent interactions include ionic, ion-dipole, dipole-dipole, induced dipole-dipole, induced dipole-induced dipole, hydrogen bond, ⁇ - ⁇ interaction, Van der Waals force, and hydrophobic interaction.
- the calix [n] arene or its derivative, and the biologically active molecule are not bound by one or more covalent bond (s).
- Calix [n] arenes and their derivatives, in particular resorcinarenes, are macrocycles that host molecules. They may be available in industrial quantities and in pharmaceutical grade purity.
- These compounds can generally be modified both in terms of aromatic rings, benzyl positions or on phenol functions. Such modifications may make it possible to modulate, and in particular to increase, the interactions with various groups present on host molecules, in particular on biologically active molecules, and in particular on molecules present as active principle in medicaments.
- Calix [n] arenes are cyclic compounds comprising several aromatic units.
- calix [n] arenes can satisfy the following formula (I):
- n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20,
- R1 represents a polar group, in particular chosen from the group comprising the hydroxyl, ether, carboxylic acid, sulphonic acid, phosphonic acid, sulphonamide, amide and ester functions, or an alkyl, alkenyl, alkyne or acyl group, linear, branched or cyclic; , or an aryl, arylalkyl or alkylaryl group, or heterocycle, optionally substituted, in particular with a polar group,
- R 2, R 3, R 4 and R 5 each independently represent a hydrogen atom, an alkyl, alkene or alkyne group, optionally substituted, in particular with a polar group, in particular with a hydroxyl or ether function, especially bearing an alkyl, alkene or alkyne group
- X represents an atom selected from carbon, oxygen, sulfur and nitrogen
- x and y each independently represent 0 or 1
- R6 represents a polar group, in particular selected from the group comprising hydroxyl functions, ether, carboxylic acid, sulfonic acid, phosphonic acid, sulfonamide, amide and ester, or an alkyl group, branched or linear, optionally substituted by a polar group.
- the alkyl, alkenes or alkynes radicals can comprise from 1 to 2 to 18 carbon atoms, especially from 1 to 2 to 12 carbon atoms, and in particular from 1 to 2 to 6 carbon atoms.
- the alkenes may include one or more double bonds.
- the alkyne radicals may comprise one or more triple bonds.
- the aryl, arylalkyl or alkylaryl radicals may comprise from 5 to 20 carbon atoms, especially from 6 to 15 carbon atoms.
- the heterocycles may comprise from 4 to 12 carbon atoms and at least one heteroatom, in particular chosen from oxygen, sulfur and nitrogen.
- polar group means a group whose dipole moment is different from zero.
- functions comprising at least one heteroatom, for example the hydroxyl, amine (primary, secondary and tertiary) functions, ether, carboxylic acid, hydroxysulfate, sulphonic acid, hydroxyphosphate, phosphonic acid, sulfonamide, amide and ester.
- the groups R4 and R5 are identical, and in particular represent a hydrogen atom.
- X is a carbon atom
- the carbon atoms bearing the groups R2 and R3 may all have the same configuration, and in particular be all (S) or all (R).
- Said at least one calix [n] arene or said at least one of its derivatives may be chosen from the group comprising dihydrophosphonic acid calix [4] arene (25,27-bis (dihydroxyphosphoriloxy) -26,28-dihydroxycalix [4] arene), para-sulphonic acid calix [4] arene (5, 11, 17, 23-tetrakis (p-sulphonic acid) -25,26,27, 28-tetrahydroxycalix [4] arene), dimethoxycarboxy calix [4] arene (25,27-bis (methoxycarboxy) -26,28-dihydroxycalix [4] arene), tetramethoxycarboxy calix [4] arene (25,26,27,28-tetra (methoxycarboxy) calix [4] arene), tetrapropioxycarboxy calix [4] arene (25,26,27,28-t
- biologically active molecule is meant in the sense of the present invention a molecule having a activity with respect to biological processes, in particular a pharmaceutically active principle, in particular a molecule used or known as an active ingredient in a medicament.
- the at least one biologically active molecule may comprise at least one unit capable of forming at least one non-covalent interaction with at least one unit complementary to the at least one calix [n] arene or at least one of its derivatives.
- Said at least one biologically active molecule may comprise at least one aromatic ring, an amine function, more or less long alkyl chains, etc., so as to form an interaction with the calixarene.
- This biologically active molecule may be selected from the group consisting of N, N'-bis (4-chlorophenyl) -3,12-diimino-2, 4,11,13-tetraazatetradecanediimidamide (chlorhexidine), A- (butylamino) benzoate 2- (dimethylamino) ethyl (tetracaine ®), (Z) -2- [4- (1, 2-diphenyl-l- butenyl) phenoxy] -N, N-dimethylethanamine (Tamoxifen E), the (3S- cis) -3-éthyldihydro-4- [(l-methyl-lH-imidazol-5- yl) methyl] -2 (3H) -furanone (Pilocarpine ®) and 2- [4- (1,3-benzyl) -3,12-diimino-2, 4,11,13-tetraazatetradecanedi
- the co-crystal according to the invention may have a solubility in water, in mol.l "1 , at 25 ° C greater than or equal to 10%, especially 20%, or even 30% relative to the solubility of biologically active molecule, in particular in neutral form and / or salt form, in particular potassium salt or ammonium salt.
- a solubility in water in mol.l "1 , at 25 ° C greater than or equal to 10%, especially 20%, or even 30% relative to the solubility of biologically active molecule, in particular in neutral form and / or salt form, in particular potassium salt or ammonium salt.
- neutral or pharmaceutically acceptable salt having the best solubilization in water, or even in physiological fluids.
- the co-crystal according to the invention may have a stability greater than 30% or even 40% relative to the stability of the biologically active molecule, especially in neutral form and / or in salt form, in particular potassium salt. or ammonium.
- the co-crystals according to the invention may also allow an improvement in other properties of the biologically active molecules, such as an improvement in the passage of biological barriers, such as the membrane barrier, in particular cells.
- the subject of the invention is a pharmaceutical composition
- a pharmaceutical composition comprising at least one co-crystal of at least one calix [n] arene, or at least one of its derivatives, and at least one molecule.
- biologically active in a pharmaceutically or physiologically acceptable carrier is a pharmaceutical composition comprising at least one co-crystal of at least one calix [n] arene, or at least one of its derivatives, and at least one molecule.
- said at least one calix [n] arene corresponds to formula (I) in which the variables R1, R2, R3, R4, R6, R6, X, n, x and are as previously defined in this document.
- the co-crystal may be present in the composition in a content ranging from 0.01 to 100% by weight, especially from 0.1 to 50% by weight, in particular from 1 to 25% by weight relative to the total weight of the composition.
- composition comprises at least one pharmaceutically acceptable carrier, in particular chosen from group comprising lactose, optionally modified starch, cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, mannitol, sorbitol, xylitol, dextrose, calcium sulfate, calcium phosphate, lactate calcium, dextrates, inositol, calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, and mixtures thereof.
- pharmaceutically acceptable carrier in particular chosen from group comprising lactose, optionally modified starch, cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, mannitol, sorbitol, xylitol, dextrose, calcium sulfate, calcium phosphate, lactate calcium, dextrates, inositol, calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, and mixtures thereof.
- the composition may comprise a content of pharmaceutically or physiologically acceptable support ranging from 5% to 99.99% by weight, in particular from 10% to 90% by weight, and in particular from 20% to 75% by weight relative to the total weight of the composition. .
- the composition may also comprise at least one binder and / or pharmaceutically or physiologically acceptable adhesive.
- binder may be selected from the group consisting of sucrose, gelatin, glucose, starches, alginic acid, aluminum magnesium silicate, celluloses, PEGs, guar gum, polysaccharide acids, bentonites , polymethacrylates, hydroxypropylcellulose, and mixtures thereof.
- the composition according to the invention may also comprise at least one pharmaceutically or physiologically acceptable lubricant.
- This may be chosen from the group comprising glyceryl beheptate, stearic acid and its salts, in particular magnesium, calcium, and sodium salts, hydrogenated vegetable oils, colloidal silicas, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, DL-Leucine, PEG, sodium oleate, sodium lauryl sulfate, and in particular stearate magnesium.
- the composition may comprise a lubricant content ranging from 0.1 to 10% by weight, and especially from 0.2 to 5% by weight relative to the total weight of the composition.
- composition may also comprise other excipients, such as dyes, flavoring agents and sweeteners, in particular known in the pharmacy.
- the subject of the invention is also the use of at least one co-crystal calix [n] arene, one of its derivatives, and a biologically active molecule for the preparation of a medicament, in particular for the treatment of infectious diseases, in particular bacterial and / or viral diseases, parasitic diseases, fungal diseases, prion diseases, allergic diseases, cardiovascular diseases, dermatological diseases, rare diseases (called orphan diseases ), genetic diseases, especially classified by organ, apparatus or function or by region of the globe, chromosomal diseases, in particular due to an anomaly in number or to a deletion, intoxication diseases, diseases due to cellular degeneration, in particular cancers, leukemias, Alzheimer's and Parkinson's diseases, environmental diseases, including obesity alcoholism hypertension, mala dies caused by deficiencies, autoimmune and inflammatory diseases, diseases with uncertain cause or multiple causes, diseases of the eye, tissue and cell trauma.
- infectious diseases in particular bacterial and / or viral diseases, parasitic diseases, fungal diseases, prion diseases, allergic diseases, cardiovascular diseases, dermatological diseases
- said at least one calix [n] arene corresponds to formula (I) in which the variables R1, R2, R3, R4, R6, R6, X, n, x and are as previously defined in this document.
- Said medicaments according to the invention can be administered by different routes.
- administration routes that can be used for the medicaments according to the invention, mention may be made of the oral, rectal, cutaneous, pulmonary, nasal, sublingual, parenteral, in particular intradermal, subcutaneous, intramuscular, and intravenous routes. intra-arterial, intra- rachidian, intra-articular, intra-pleural, intraperitoneal.
- the medicaments according to the invention can be administered in one or more times or in continuous release, in particular by continuous infusion.
- the medicaments according to the invention may be in various forms, in particular in a form selected from the group consisting of tablets, capsules, lozenges, syrups, suspensions, solutions, powders, granules, emulsions , microspheres and injectable solutions, preferably tablets, injectable solutions, sublingual sprays and skin patches.
- Formulations suitable for parenteral administration the pharmaceutically acceptable vehicles suitable for this route of administration and the corresponding formulation and administration techniques may be carried out according to methods well known to those skilled in the art, in particular those described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa., 20th Edition, 2000).
- the co-crystal according to the invention may be present in the medicament in an amount ranging from 50 mg to 5 g per unit dose, in particular from 100 mg to 2 g.
- the medicament according to the invention may be administered in one or more doses per day, preferably in 1 to 4 doses per day.
- the subject of the invention is a process for preparing co-crystals of at least one calix [n] arene, or at least one of its derivatives, with at least one biologically active molecule comprising at least the steps of:
- said at least one calix [n] arene corresponds to formula (I) in which the variables R1, R2, R3, R4, R6, R6, X, n, x and y are as previously defined in this document.
- the preparation of the co-crystals according to the invention is carried out according to a multi-solvent crystallization process, in particular belonging to the same chemical class.
- solvents that may be used include ethanol and water. Ethanol can make it possible to prepare a solution of a calix [n] arene or a derivative thereof, and the water to prepare a solution of a biologically active molecule.
- the process for preparing the co-crystals according to the invention may comprise at least the steps of: slowly adding an alcoholic solution of calix [n] arene, or a derivative thereof, to an aqueous solution of a biologically active molecule of so that a crystallization can take place, in particular at the interface of these two phases, and recover the co-crystals obtained.
- the process for preparing the co-crystals may comprise the following steps:
- the formation time of the crystals is generally of the order of a few days.
- the subject of the invention is the use of calix [n] arene or one of its derivatives for prepare a co-crystal calix [n] arene-molecule biologically active.
- said calix [n] arene corresponds to formula (I) in which the variables R1, R2, R3, R4, R6, R6, X, n, x and y are as previously defined in this document.
- the invention also relates to the use of calix [n] arene, or a derivative thereof, as an agent for the formation of a co-crystal with a biologically molecule. active.
- said calix [n] arene corresponds to formula (I) in which the variables R1, R2, R3, R4, R6, R6, X, n, x and y are as previously defined in this document.
- the procedure for preparing the co-crystals is carried out by pouring carefully, so as to obtain an ethanol-water interface, in a tube and in the following order:
- All diffraction instruments have the following components: a radiation source (KCCD difractometer), a sample positioning fixture, a detector and a computerized control and data collection system.
- a radiation source KCCD difractometer
- sample positioning fixture a sample positioning fixture
- detector a detector
- computerized control and data collection system a computerized control and data collection system.
- a monocrystal is selected and mounted on the sample support by aligning the center of mass; setting collection parameters (temperature in the sample chamber, detector distance to sample, interval and degree of crystal rotation).
- the crystals have a periodic molecular arrangement through a stack of identical planes in a crystal. These structural properties allow the analysis of crystals by X-ray diffraction. The distances between each crystalline plane correspond to the lattice distance.
- dhki represents the lattice distance, the indices designating the direction considered in the crystal,
- L represents the wavelength of monochromatic radiation
- - 2 ⁇ kI represents the angle between the incident ray and the diffracted ray.
- the analysis of the collected data begins with the identification of intensity peaks, followed by the indexing of the diffraction spots. From this diffraction map, the information on the arrangement of the molecules in the crystal is determined and subsequently the basic structure of complex - elementary mesh. The parameters of the mesh are tested for the highest degree of symmetry. A list of possible space groups is given, then the one that gives the lowest error is chosen. This is how one learns the composition of the elementary mesh, the nature and the number of the molecules composing it.
- the next step is to determine the interactions between the component molecules of the elementary cell from ".cif" file. For this, the evaluation of any intra- and intermolecular bonds, such as hydrogen bonds, dipolar interactions or aromatic interactions, is necessary.
- the software and the program used are the DS ViewerPro software and the Mercury program.
- Example 1 co-crystal chlorhexidine / para-sulphonic acid calix [4] arene
- para-sulphonic acid calix [4] arene (5,11,17,23-tetrakis (p-sulphonic acid) -25,26,27,28-tetrahydroxycalix [4] arene) has the formula below:
- the co-crystal chlorohexidine / para-sulphonic acid calix [4] arene is prepared according to the general procedure described above.
- dihydrophosphonic acid calix [4] arene 25,27-bis (dihydroxyphosphoriloxy) -26,28-dihydroxycalix [4] arene
- formula below is represented by the formula below:
- the co-crystal chlorhexidine / dihydrophosphonic acid calix [4] arene is prepared according to the general procedure described above.
- the crystallographic data are:
- Dimethoxycarboxy calix [4] arene (25,27-bis (methoxycarboxy) -26,28-dihydroxycalix [4] arene is represented by the formula below:
- the co-crystal chlorhexidine / dimethoxycarboxy calix [4] arene is prepared according to the general procedure described above.
- the co-crystal tetracaine / para-sulphonic acid calix [4] arene is prepared according to the general procedure described above.
- the co-crystal Tamoxifen / para-sulphonic acid calix [4] arene is prepared according to the general procedure described above.
- the co-crystal Pilocarpine / dihydrophosphonic acid calix [4] arene is prepared according to the general procedure described above.
- the co-crystal Piribedil / para-sulphonic acid calix [4] arene is prepared according to the general procedure described above.
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Abstract
Description
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FR0603405A FR2899814B1 (en) | 2006-04-18 | 2006-04-18 | CO-CRYSTALS OF CALIXARENES AND BIOLOGICALLY ACTIVE MOLECULES |
PCT/FR2007/051129 WO2007119029A2 (en) | 2006-04-18 | 2007-04-18 | Co-crystals of calixarenes and biologically active molecules |
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FR2939666B1 (en) * | 2008-12-17 | 2012-11-30 | Irsn | COSMETIC AND PHARMACEUTICAL FORMULATIONS OF CALIX MOLECULES [6] ARENES |
FR2944105B1 (en) * | 2009-04-06 | 2011-06-17 | Centre Nat Rech Scient | ADDIFIF FOR CRYSTALLIZING PROTEINS, USE AND METHOD |
ES2360027B1 (en) * | 2009-11-19 | 2012-02-24 | Universidad De Santiago De Compostela | LIOFILIZABLE VESICLES WITHOUT CRIOPROTECTOR |
GB201604639D0 (en) | 2016-03-18 | 2016-05-04 | Univ London Queen Mary | Chlorhexidine crystal forms and uses thereof in medicine |
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EP0958268B1 (en) * | 1997-10-01 | 2005-05-04 | Leonard R. Macgillivray | Spherical molecular assembly |
US6519335B1 (en) * | 1999-04-08 | 2003-02-11 | Lucent Technologies Inc. | Apparatus, method and system for personal telecommunication incoming call screening and alerting for call waiting applications |
WO2001012177A1 (en) * | 1999-08-12 | 2001-02-22 | Atwood Jerry L | Formation of nanometer-scale structures |
US6832203B1 (en) * | 1999-11-05 | 2004-12-14 | Cim, Ltd. | Skills based contact routing |
ATE391551T1 (en) * | 2001-09-17 | 2008-04-15 | Central P Bv | NEW DISPERSIBLE COLLOIDAL CALIXARENE SYSTEMS IN THE FORM OF NANOPARTICLES |
EP1596869B1 (en) * | 2003-01-21 | 2014-06-04 | New Form Pharmaceuticals Inc. | Novel cocrystallization |
US7050566B2 (en) * | 2003-06-13 | 2006-05-23 | Assurant, Inc. | Call processing system |
US8000989B1 (en) * | 2004-03-31 | 2011-08-16 | Avaya Inc. | Using true value in routing work items to resources |
US8234141B1 (en) * | 2004-09-27 | 2012-07-31 | Avaya Inc. | Dynamic work assignment strategies based on multiple aspects of agent proficiency |
US7995717B2 (en) * | 2005-05-18 | 2011-08-09 | Mattersight Corporation | Method and system for analyzing separated voice data of a telephonic communication between a customer and a contact center by applying a psychological behavioral model thereto |
US20090043671A1 (en) * | 2006-09-14 | 2009-02-12 | Henrik Johansson | System and method for network-based purchasing |
US8259924B2 (en) * | 2009-09-21 | 2012-09-04 | Genesys Telecommunications Laboratories, Inc. | System for creation and dynamic management of incoming interactions |
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2006
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2007
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- 2007-04-18 WO PCT/FR2007/051129 patent/WO2007119029A2/en active Application Filing
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FR2899814A1 (en) | 2007-10-19 |
WO2007119029A3 (en) | 2007-12-21 |
CA2650534A1 (en) | 2007-10-25 |
WO2007119029A2 (en) | 2007-10-25 |
FR2899814B1 (en) | 2008-09-12 |
US20090233941A1 (en) | 2009-09-17 |
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