WO2024023360A1 - Composés substitués par ip5 - Google Patents

Composés substitués par ip5 Download PDF

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Publication number
WO2024023360A1
WO2024023360A1 PCT/EP2023/071141 EP2023071141W WO2024023360A1 WO 2024023360 A1 WO2024023360 A1 WO 2024023360A1 EP 2023071141 W EP2023071141 W EP 2023071141W WO 2024023360 A1 WO2024023360 A1 WO 2024023360A1
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Prior art keywords
compound
salt
inositol
aspects
condition
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PCT/EP2023/071141
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English (en)
Inventor
Carolina Salcedo Roca
María Del Mar PÉREZ FERRER
Miquel David FERRER REYNÉS
Mohamad Firas BASSISSI
Carme Serra Comas
Juan Lorenzo Catena Ruiz
Amadeu Llebaria Soldevila
Joan PERELLÓ BESTARD
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Sanifit Therapeutics, S.A.
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Publication of WO2024023360A1 publication Critical patent/WO2024023360A1/fr

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    • 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 System
    • 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
    • C07F9/117—Esters of phosphoric acids with cycloaliphatic alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic
    • C07C35/08—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic containing a six-membered rings
    • C07C35/14—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic containing a six-membered rings with more than one hydroxy group bound to the ring
    • C07C35/16—Inositols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/18—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C43/188—Unsaturated ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/18—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C43/196—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D201/00—Preparation, separation, purification or stabilisation of unsubstituted lactams
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/65031—Five-membered rings having the nitrogen atoms in the positions 1 and 2
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having three nitrogen atoms as the only ring hetero atoms
    • C07F9/6518—Five-membered rings
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to IP5 substituted compounds, their processes of synthesis, and their uses.
  • HAP Hydroxyapatite
  • Caio(P04)6(OH)2 a calcium phosphate of formula Caio(P04)6(OH)2
  • IP5 pentaphosphate myo-inositol
  • WO2021219135, W02017098047, and W02020058321 describe the use of these compounds for the treatment of pathologies associated with calcium.
  • IP5 substituted derivatives that could be effective in inhibiting HAP formation and growth and/or pathological crystallization.
  • the present invention discloses a compound of general formula I: a pharmaceutically acceptable salt thereof, or a combination thereof, wherein
  • R 1 , R 2 , R 3 , R 5 , and R 6 independently represent -OPO 3 H 2 and R 4 is a substituent group of formula II or formula III, or Ri, R2, R 3 , R 4 , and R 5 independently represent OPO 3 H 2 and Re is a substituent group of formula II or formula III, ii III
  • R 1 , R 3 , R 4 , R 5 , and R 6 independently represent -OPO 3 H 2 and R 2 is a substituent group of formula II or formula III,
  • R 1 , R 2 , R 3 , R 4 , and R 6 independently represent -OPO 3 H 2 and R 5 is a substituent group of formula II or formula III,
  • R 2 , R 3 , R 4 , R 5 , and R 6 independently represent -OPO 3 H 2 and Ri is a substituent group of formula II; or R 1 , R 2 , R 4 , R 5 , and R 6 independently represent -OPO 3 H 2 and R 3 is a substituent group of formula II or formula III, wherein, for formula II, n is an integer between 1 and 30, wherein the terminal group X is selected from the group consisting of -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, - NHCOOR, -OCONR, -NHSO 2 R, -NHCONRR', halogen, -CF 3 , alkyl, alkenyl, alkynyl, carbocycle (saturated or unsaturated), and heterocycle (saturated or unsaturated), and wherein R and R' are H or an alkyl group, and wherein, for formula III, y and
  • the compound of formula I is selected from the group consisting of Compounds 1 to Compound 53.
  • the pharmaceutically acceptable salt is a sodium or magnesium salt.
  • the sodium salt is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, decasodium salt or undecasodium salt.
  • the invention also provides a pharmaceutical composition comprising a compound of formula I disclosed above and at least one pharmaceutically acceptable excipient.
  • calcium salts/crystals e.g., calcium phosphates, hydroxyapatite (HAP)
  • the invention provides a method to treat or prevent a disease or condition associated with pathological crystallization in a subject in need thereof comprising administering to the subject an effective amount of a compound of formula I, or a pharmaceutical composition of disclosed herein.
  • Also provided is a method to inhibit the progression of a crystallization process in a subject in need thereof comprising administering to the subject an effective amount of a compound of formula I, or a pharmaceutical composition of disclosed herein.
  • the invention also provides a method to recover or increase blood perfusion in a subject in need thereof comprising administering to the subject an effective amount of a compound of formula I, or a pharmaceutical composition of disclosed herein.
  • the subject is human.
  • the administration is topical, enteral or parenteral.
  • the parenteral administration is intravenous.
  • the intravenous administration is by bolus injection or by infusion.
  • the present invention also provides a kit or article of manufacture comprising at least one compound of formula I or a pharmaceutical composition comprising a compound of formula I and instructions for administration according to any method disclosed herein.
  • the kit or article of manufacture may also comprise at least one compound selected from the group consisting of the compounds listed in Table 1.
  • the present invention provides additionally a method for the manufacture of a compound of formula I (e.g., Compound 1 to Compound 53) which comprises using at least one compound selected from the group consisting of the compounds listed in Table 1.
  • FIG. 1A and Fig. IB present representative structures of Compounds I_A: IP5-4 substituted compounds.
  • FIG. 2A and Fig. 2B present representative structures of Compounds I_B: IP5-2 substituted compounds.
  • FIG. 3 presents representative structures of Compounds I_C: IP5-5 substituted compounds.
  • Fig. 4 presents representative structures of Compounds I_D: IP5-1 substituted compounds.
  • Fig. 5 is a schematic representation of synthesis Scheme 1.
  • Fig. 6 is a schematic representation of synthesis Scheme 2.
  • Fig. 7A and Fig. 7B are schematic representations of syntheses Scheme 3 and Scheme 6, respectively.
  • Fig. 8A and Fig. 8B are schematic representations of syntheses Scheme 4 and Scheme 7, respectively.
  • Fig. 9A and Fig. 9B are schematic representations of syntheses Scheme 5 and Scheme 8, respectively. Detailed description of the invention
  • IP5 substituted compounds are a compound of general formula I: a pharmaceutically acceptable salt thereof, or a combination thereof, wherein
  • R 1 , R 2 , R 3 , R 5 , and R 6 independently represent -OPO 3 H 2 and R 4 is a substituent group of formula II or formula III, or Ri, R2, R 3 , R 4 , and R 5 independently represent - OPO 3 H 2 and R 6 is a substituent group of formula II or formula III, (See Fig. 1A, IB)
  • R 1 , R 3 , R 4 , R 5 , and R 6 independently represent -OPO 3 H 2 and R2 is a substituent group of formula II or formula III, (See Fig. 2A, 2B)
  • R 1 , R 2 , R 3 , R 4 , and R 6 independently represent -OPO 3 H 2 and R 5 is a substituent group of formula II or formula III, (See Fig. 3)
  • R 2 , R 3 , R 4 , R 5 , and R 6 independently represent -OPO 3 H 2 and Ri is a substituent group of formula II; or R 1 , R 2 , R 4 , R 5 , and R 6 independently represent -OPO 3 H 2 and R 3 is a substituent group of formula II or formula III (See Fig.
  • n is an integer between 1 and 30, wherein the terminal group X is selected from the group consisting of -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, - NHCOOR, -OCONR, -NHSO 2 R, -NHCONRR', halogen, -CF 3 , alkyl, alkenyl, alkynyl, carbocycle (saturated or unsaturated), and heterocycle (saturated or unsaturated), and wherein R and R' are H or an alkyl group, and wherein, for formula III, y and y’ are an integer between 0 and 10, wherein Cy is a cyclic linker, wherein the terminal group Z is selected from the group consisting of alkyl, -COR, -OR, -NRR', -COOR, -CONRR', - NHCOR, -NHCOOR, -OCONR -NHSO
  • the IP5 substituted compound is a sodium or magnesium salt. In some aspects, the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, decasodium salt or undecasodium salt.
  • the invention includes aspects in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the invention includes aspects in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone).
  • the term “and/or” as used in a phrase such as "A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
  • the term “approximately,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain aspects, the term “approximately” refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).
  • Bolus administration As used herein, the terms “bolus administration” and “bolus injection” refer a fast intravenous injection lasting less than 10 seconds, or an intravenous infusion lasting less than 3 minutes.
  • Compound As used herein, the term “compound,” is meant to include any and all free bases, isomers, and isotopes of the structure depicted. As used herein, the term “isomer” means any geometric isomer, tautomer, zwitterion, stereoisomer, enantiomer, or diastereomer of a compound. Compounds can include one or more chiral centers and/or double bonds and can thus exist as stereoisomers, such as double-bond isomers (i.e., geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
  • double-bond isomers i.e., geometric E/Z isomers
  • diastereomers e.g., enantiomers (i.e., (+) or (-) or cis/trans isomers).
  • the present invention encompasses any and all isomers of the compounds described herein, including stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures (e.g., racemates). Enantiomeric and stereomeric mixtures of compounds and means of resolving them into their component enantiomers or stereoisomers are well- known.
  • a compound, salt, or complex of the present invention can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods.
  • the term compound is used to refer to an IP5 substituted compound of the present invention.
  • Effective amount As used herein, the term "effective amount" of a therapeutic agent, in reference to (i) an IP5 substituted compound of the present invention, (ii) any dosage form, pharmaceutical composition, or formulation disclosed herein comprising at least one IP5 substituted compound of the present invention, or (iii) a combination of an IP5 substituted compound of the present invention with one or more additional therapeutic agents), is that amount sufficient to effect beneficial or desired results.
  • the beneficial or desired results are, for example, clinical results, and, as such, an "effective amount” depends upon the context in which it is being applied.
  • the term “effective amount” can be used interchangeably with “effective dose,” “therapeutically effective amount,” or “therapeutically effective dose.”
  • an effective amount relates to the specific use of an IP5 substituted compound.
  • an IP5 substituted compound when used to inhibit the formation or growth of a calcium salt/crystal (e.g., a calcium phosphate, HAP), an effective amount would be an amount of the IP5 substituted compound capable of achieving the desired effect (e.g., the reduction of HAP crystallization/formation in blood serum or plasma).
  • a calcium salt/crystal e.g., a calcium phosphate, HAP
  • Enteral administration refers to any administration of an IP5 substituted compound of the present invention or a pharmaceutical composition comprising said compound via the gastrointestinal tract. Enteral administration includes, but is not limited to, the oral, sublingual, and rectal routes of administration.
  • Prophylaxis refers to a measure taken to maintain health and prevent or delay the onset of a disease or condition or to mitigate its extent and/or severity of the symptoms.
  • a prophylactic use of a therapeutic agent disclosed herein for example, (i) an IP5 substituted compound of the present invention, or (ii) a combination thereof, or (iii) any dosage form comprising at least one IP5 substituted compound of the present invention, or (iv) any formulation comprising at least one IP5 substituted compound of the present invention, or a (v) combination of an IP5 substituted compound of the present invention with one or more additional therapeutic agents, corresponds to that amount sufficient to effect beneficial or desired results.
  • any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
  • IP5 substituted, compounds of the present invention refers to a compound of formula I wherein its substituents are those disclosed in compound Families I_A, I_B, I_C, and I_D described in detail below, and salts thereof (e.g., pharmaceutically acceptable salts thereof).
  • the term IP5 substituted compound of the present invention encompasses Compounds 1 to 53, any salt thereof (e.g., a sodium salt), and any combination thereof.
  • IP5 substituted compound of the present invention encompasses a compound of formula I which is an intermediate in the synthesis of Compounds 1 to 53, e.g., a compound selected from the group consisting of the compounds listed in Table 1, any salt thereof (e.g., a sodium salt), and any combination thereof.
  • IP5 substituted compound of the present invention encompasses a compound of formula I which is Compound 1 to Compound 53 and a compound selected from the group consisting of the compounds listed in Table 1, any salt thereof (e.g., a sodium salt), and any combination thereof.
  • Group consisting of Compound 1 to Compound 53 refers to a group of compounds that comprises Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, and 53.
  • the group consisting of Compound 1 to Compound 53 also comprises combinations thereof.
  • a combination of compounds from the group consisting of Compound 1 to Compound 53 can comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or more compounds from the group consisting of Compound 1 to Compound 53.
  • Group consisting of the compounds listed in Table 1 refers to a group of intermediate compounds used, e.g., for the synthesis of an IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) i.e., Intermediates II_A, II_B, II_B’, II_C, and II_D, Intermediates III_A, III_B, III_C, and III_D, Intermediates IV_A, IV_B, IV_C, and IV_D, Intermediates V_A, V_B, V_C and V_D, Intermediates VI_A, Intermediates VII_A, Intermediates VIII_B and VIII B’, Intermediates IX_D and Intermediates X_D.
  • an IP5 substituted compound of the present invention e.g., a compound selected from the group consisting of Compound 1 to Compound 53
  • Intermediates II_A, II_B, II_B’, II_C, and II_D Intermediates III_A,
  • the group consisting of the compounds listed in Table 1 also comprises combinations thereof.
  • a combination of compounds from the group consisting of the compounds listed in Table 1 can comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or more compounds from the group consisting of the compounds listed in Table 1.
  • Non-bolus administration refers to an intravenous injection lasting 10 or more seconds, or an intravenous infusion lasting 3 or more minutes.
  • parenteral administration refers to the administration of an IP5 substituted compound of the present invention characterized by the physical breaching of a tissue of a subject and the administration of the compound through said breach in the tissue.
  • Parenteral administration includes, but is not limited to, the administration of an IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) or a pharmaceutical composition comprising the compound, by the application of the compound or the composition through, for instance, a surgical incision or through a tissue-penetrating non-surgical wound.
  • parenteral administration includes, but is not limited to, the epidural, intraarterial, intradermal, intrathecal, intramuscular, intraperitoneal, intrastemal injection, intravascular, intravenous, intravenous infusion, spinal, subcutaneous, and subcutaneous depot routes of administration.
  • Subject By “subject” or “individual” or “animal” or “patient” or “mammal,” is meant any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired.
  • Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, zoo animals, sport animals, pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; bears, food animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; rodents such as mice, rats, hamsters and guinea pigs; and so on.
  • the mam include, but
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
  • Therapeutic agent' is used in a broad sense to include a composition comprising an IP5 substituted compound of the present invention that can provide a significant therapeutic benefit to a subject in need thereof.
  • the subject in need thereof is a subject suffering or at risk of developing a disease or condition associated to pathological crystallization (e.g., a calcium phosphate or HAP crystallization).
  • a therapeutic agent according to the present invention can be an IP5 substituted compound of the present invention, alone or in combination with one or more additional therapeutic agents, that is administered in an amount sufficient to effect beneficial or desired results.
  • therapeutic agent also encompasses prophylactic, diagnostic or imaging agents comprising an IP5 substituted compound of the present invention, wherein the therapeutic agent is administered (i.e., topically, enterally or parenterally).
  • therapeutic agents of the present invention include agents that inhibit the formation or growth of calcium salts/crystals (e.g., calcium phosphates, HAP) and/or can ameliorate and/or prevent any symptom associated with pathological crystallization.
  • Topical administration refers to any administration of an IP5 substituted compound of the present invention or a pharmaceutical composition comprising said compound by applying the compound or composition to a particular place on or in the body, such as the skin or a mucous membrane.
  • Topical administration includes, but is not limited to, the aural, cutaneous, nasal, transdermal, urethral, vaginal, and urethral routes of administration.
  • Treating, treatment, therapy refers to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, reducing incidence of one or more symptoms or features of disease, or any combination thereof.
  • a treatment comprising an IP5 substituted compound of the present invention can be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition, and/or to a subject who exhibits only early signs of a disease, disorder, and/or condition for the purpose of, e.g., (i) decreasing the risk of developing a pathology associated with the disease, disorder, and/or condition, (ii) delaying the onset of the disease, disorder, and/or condition, or a pathology associated with said disease, disorder, and/or condition, or (iii) mitigating the symptoms and/or sequels of the disease, disorder, and/or condition or a pathology associated with said disease, disorder, and/or condition.
  • treatment refers to countering the effects caused as a result of the disease or pathological condition of interest in a subject including (i) inhibiting the disease or pathological condition, in other words, slowing or stopping the development or progression thereof; (ii) relieving the disease or pathological condition, in other words, causing said disease or pathological condition, or the symptoms thereof, to regress; (iii) stabilizing the disease or pathological condition, and (iv) any combination thereof.
  • ug, uM, uL As used herein, the terms “ug,” “uM,” and “uL” are used interchangeably with “pg,” “pM,” and “pL” respectively.
  • IP5 substituted compounds are a compound of general formula I: a pharmaceutically acceptable salt thereof, or a combination thereof, wherein
  • R 1 , R 2 , R 3 , R 5 , and R 6 independently represent -OPO 3 H 2 and R 4 is a substituent group of formula II or formula III, or Ri, R2, R 3 , R 4 , and R 5 independently represent - OPO 3 H 2 and Re is a substituent group of formula II or formula III,
  • R 1 , R 3 , R 4 , R 5 , and R 6 independently represent -OPO 3 H 2 and R2 is a substituent group of formula II or formula III,
  • R 1 , R 2 , R 3 , R 4 , and R 6 independently represent -OPO 3 H 2 and R 5 is a substituent group of formula II or formula III,
  • R 2 , R 3 , R 4 , R 5 , and R 6 independently represent -OPO 3 H 2 and Ri is a substituent group of formula II; or R 1 , R 2 , R 4 , R 5 , and R 6 independently represent -OPO 3 H 2 and R 3 is a substituent group of formula II or formula III,
  • n is an integer between 1 and 30, wherein the terminal group X is selected from the group consisting of -H, -OR, -NRR', -COOR, -CONRR', - NHCOR, -NHCOOR, -OCONR, -NHSO 2 R, -NHCONRR', halogen, -CF 3 , alkyl, alkenyl, alkynyl, carbocycle (saturated or unsaturated), and heterocycle (saturated or unsaturated), and wherein R and R' are H or an alkyl group, and wherein, for formula III, y and y’ are an integer between 0 and 10, wherein Cy is a cyclic linker, wherein the terminal group Z is selected from the group consisting of alkyl, -COR, -OR, -NRR', -COOR, -CONRR', - NHCOR, -NHCOOR, -OCONR -NHSO
  • an IP5 substituted compound of the present invention can be, for example, a tetraionic salt (e.g., tetrasodium salt), a pentaionic salt (e.g., pentasodium salt), a hexaionic salt (e.g., hexasodium salt), a heptaionic salt (e.g., heptasodium salt), an octaionic salt (e.g., octasodium salt), a nonaionic salt (e.g., nonasodium salt), a decaionic salt (e.g., decasodium salt) or a undecaionic salt (e.g., undecasodium salt).
  • a tetraionic salt e.g., tetrasodium salt
  • a pentaionic salt e.g., pentasodium salt
  • a hexaionic salt
  • the presence of additional negatively charges group in a IP5 substituted compounds can lead to the formation of complexes with additional ions.
  • the IP5 substituted compound of the present invention is a sodium salt.
  • the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, decasodium or undecasodium salt.
  • the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt.
  • the IP5 substituted compound is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • Formula I and the rest of formulas presented in the invention are meant to encompass any isomers of the compounds covered thereby.
  • alkenyl or “alkenyl chain” in the context of the present invention refers to a linear or branched alkyl chain (e.g., containing between 2 and 10 carbon atoms) containing one or more double bonds, either substituted or non-substituted. Examples include, among others, ethenyl, 1 -propenyl, 2-propenyl, isopropenyl. 1-butenyl, 2- butenyl, 3-butenyl, and 1,3-butadienyl.
  • alkyl or "alkyl chain” in the context of the present invention refers to a hydrocarbon moiety, which can be saturated, partially unsaturated, linear, branched, cyclic or cyclic with linear or branched side chains containing from 1 to 30 carbon atoms. Examples include but are not limited are to C1-C4 alkyls such as methyl, ethyl, propyl, isopropyl, n- or isobutyl, and cycloalkyl such as cyclohexyl.
  • alkyl can extend to alkyl groups linked or bridged by hetero atoms. Hetero atoms in the context of the present invention are nitrogen (N), sulfur (S), oxygen (O), and halogen.
  • alkynyl or “alkynyl chain” in the context of the present invention refers to a linear or branched alkyl chain (e.g., containing between 2 and 10 carbon atoms) containing one or more triple bonds, either substituted or non-substituted. Examples include, among others, ethynyl, propynyl, 1-butynyl, and 3-butynyl.
  • An "amine function” or “amine group” is a function NRR’, with R and R’ selected independently, e.g., from hydrogen (-H) and an alkyl group such as an Ci-C n alkyl, wherein n is and integer between 0 and 30.
  • a "hydroxy function" or "hydroxy group” is OH.
  • a “carboxylic acid function” or “carboxylic acid group” is COOH or its anion, COO .
  • a “carboxylic amide” is CONRR’ or NCOR, with R and R’ selected independently, e.g., from hydrogen (-H) and an alkyl group such as an Ci-C n alkyl, wherein n is and integer between 0 and 20.
  • a “carbocycle” refers to a three- to 10-membered carbocyclic ring that can be saturated, partially unsaturated or aromatic (e.g., phenyl, cyclopentyl, cyclopropyl) and which is bound to the rest of the molecule via any available C atom.
  • a "heterocycle” refers to a three- to 10-membered cyclic ring containing at least one heteroatom selected from among N, O, and S, that can be saturated, partially unsaturated or aromatic (e.g., triazole, piperazine, pyrazole) and which is bound to the rest of the molecule via any available C atom or N atom.
  • the term includes heterocycle rings substituted with one or more halogen atoms.
  • a "Cy” refers to a cyclic linker comprising a carbocycle or a heterocycle.
  • Examples of carbocycles and heterocycles include, among others, 1,3-phenyl, 1,4-phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, piperazyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzothiazolyl, cyclopropyl, cyclobutyl, cyclopen
  • a "halogen” group refers to fluorine, chlorine, bromine or iodine.
  • -OPO3 2 in the context of the present invention refers also indistinctly to -OPO 3 H + and -OPO 3 H 2 .
  • IP5 substituted compounds of the present invention or intermediate compounds disclosed herein can be detected and/or quantified using the methods disclosed in US9612250. See also, US8377909, US8778912 and US20070066574.
  • IP5 substituted compounds of the present invention can be present in any form commonly used in pharmaceutical technology. Particular aspects include, but are not limited to, the sodium salt, magnesium salt, potassium salt, ammonium salt, free acid, or a mixture of the preceding forms. Other pharmaceutically acceptable salts are known to the skilled artisan and can be obtained by methods previously described (Haynes M, el al., J. Pharmaceutical Sci. 2005; 94:2111-2120.
  • an IP5 substituted compound of the present invention comprises or consists of an IP5 substituted compound selected from the group consisting of Compounds 1 to 53 and combinations thereof.
  • an IP5 substituted compound of the present invention comprises or consists of Compound 1.
  • an IP5 substituted compound of the present invention comprises or consists of Compound 2.
  • an IP5 substituted compound of the present invention comprises or consists of Compound 3.
  • an IP5 substituted compound of the present invention comprises or consists of Compound 4.
  • an IP5 substituted compound of the present invention comprises or consists of Compound 5.
  • an IP5 substituted compound of the present invention comprises or consists of Compound 6.
  • an IP5 substituted compound of the present invention comprises or consists of Compound 7. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 8. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 9. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 10. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 11. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 12. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 13. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 14.
  • an IP5 substituted compound of the present invention comprises or consists of Compound 15. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 16. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 17. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 18. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 19. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 20. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 21. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 22.
  • an IP5 substituted compound of the present invention comprises or consists of Compound 23. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 24. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 25. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 26. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 27. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 28. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 29. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 30.
  • an IP5 substituted compound of the present invention comprises or consists of Compound 31. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 32. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 33. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 34. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 35. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 36. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 37. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 38.
  • an IP5 substituted compound of the present invention comprises or consists of Compound 39. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 40. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 41. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 42. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 43. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 44. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 45. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 46.
  • an IP5 substituted compound of the present invention comprises or consists of Compound 47. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 48. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 49. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 50. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 51. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 52. In some aspects, an IP5 substituted compound of the present invention comprises or consists of Compound 53.
  • IP5 substituted compounds of the present invention are disclosed in myo form.
  • the present invention also provides chemical intermediate compounds useful in the preparations of IP5 substituted compound of the present invention (e.g., Compound 1 to Compound 53).
  • such intermediates are the compounds listed in Table 1.
  • An intermediate compound disclosed herein can be converted to an IP5 substituted compound of the present invention by utilizing the procedures described herein.
  • the present invention provides methods to produce an IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53) comprising utilizing an intermediate compound selected from the group consisting of the compounds listed in Table 1.
  • the present invention also provides methods of producing the intermediate compounds disclosed herein. Accordingly, the present invention provides methods of producing intermediates compounds selected from the group consisting of the compounds listed in Table 1 for producing IP5 substituted compounds of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53).
  • an IP5 substituted compound of the present invention comprises or consists of a compound of the following formula:
  • n is an integer between 1 and 30, alkyl is CH 2 and X is -H, -OH, -OMe, pyrazole, triazole, -COOH, CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO 2 R, -NHCONRR', -CF 3 , alkyl, cyclopropane, cyclopentane or pyrazole. See Fig. 1A.
  • n is an integer between 1 and 20.
  • n is an integer between 1 and 10.
  • n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the IP5 substituted compound is a sodium salt. In some aspects, the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP5 substituted compound is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP5 substituted compound is an octasodium salt.
  • n is 5, alkyl is CH 2 and X is -H (Compound 1).
  • n is 3, alkyl is CH 2 and X is -H (Compound 24).
  • n is 1, alkyl is CH 2 and X is -H (Compound 22).
  • n is 5, alkyl is CH 2 and X is -OH (Compound 2).
  • n is 10, alkyl is CH 2 and X is -OH (Compound 21).
  • n is 5, alkyl is CH 2 and X is -OMe (Compound 3).
  • n 7 alkyl is CH 2 and X is -OMe (Compound 23). In some aspects, n is 5, alkyl is CH 2 and X is -COOH (Compound 4). In some aspects, n is 10, alkyl is CH 2 and X is - COOH (Compound 20). In some aspects, n is 3, alkyl is CH 2 and X is - CH(CH 3 ) 2 (Compound 12). In some aspects, n is 5, alkyl is CH 2 and X is -CF 3 (Compound 13). In some aspects, n is 5, alkyl is CH 2 and X is -NHCOMe (Compound 19).
  • n is 2, alkyl is CH 2 and X is cyclopentane (Compound 16). In some aspects, n is 2, alkyl is CH 2 and X is cyclopropane (Compound 17). In some aspects, n is 5, alkyl is CH 2 and X is pyrazole (Compound 18). In some aspects, n is 5, alkyl is CH 2 and X is - CONH 2 (Compound 33).
  • n is an integer between 3 and 30, alkyl is CH 2 and X is an amine group. See Fig. 1A; Wang, 2014, supra. In some aspects, n is an integer between 3 and 20. In some aspects, n is an integer between 3 and 10. In some aspects, n is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the IP5 substituted compound is a sodium salt. In some aspects, the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP5 substituted compound is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP5 substituted compound is an octasodium salt. In some aspects, n is 3, alkyl is CH 2 and X is -NH2 (Compound 27). In some aspects, n is 6, alkyl is CH 2 and X is -NH 2 (Compound 28).
  • an IP5 substituted compound of the present invention comprises or consists of a compound of the following formula: v
  • n is an integer between 1 and 30, alkyl is CH 2 and X is -H, -OH, -OMe, amine group, pyrazole, triazole, -COOH, CONRR', -NHCOR, -NHCOOR, -OCONR, - NHSO 2 R, -NHCONRR', -CF 3 , cyclopropane, cyclopentane, pyrazole or alkynyl group. See Fig. 2A.
  • n is an integer between 1 and 20. In some aspects, n is an integer between 1 and 10.
  • n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.
  • the IP5 substituted compound is a sodium salt.
  • the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt.
  • the IP5 substituted compound is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP5 substituted compound is an octasodium salt.
  • n is 5, alkyl is CH 2 and X is -H (Compound 6). In some aspects, n is 3, alkyl is CH 2 and X is -H (Compound 34). In some aspects, n is 5, alkyl is CH 2 and X is -OH (Compound 40). In some aspects, n is 5, alkyl is CH 2 and X is -OMe (Compound 7).
  • n 9, alkyl is CH 2 and X is -OMe (Compound 8). In some aspects, n is 19, alkyl is CH 2 and X is -OMe (Compound 9). In some aspects, n is 29, alkyl is CH 2 and X is -OMe (Compound 10). In some aspects, n is 5, alkyl is CH 2 and X is -NHCOMe (Compound 35). In some aspects, n is 5, alkyl is CH 2 and X is -CF 3 (Compound 36). In some aspects, n is 5, alkyl is CH 2 and X is - CONH 2 (Compound 37).
  • an IP5 substituted compound of the present invention comprises or consists of a compound of the following formula:
  • n is an integer between 1 and 30, alkyl is CH 2 and X is -H, -OH, -OMe, amine group, pyrazole, triazole, -COOH, CONRR', -NHCOR, -NHCOOR, -OCONR, - NHSO 2 R, -NHCONRR', -CF 3 , cyclopropane, cyclopentane or pyrazole. See Fig. 3A.
  • n is an integer between 1 and 20.
  • n is an integer between 1 and 10.
  • n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the IP5 substituted compound is a sodium salt. In some aspects, the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP5 substituted compound is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP5 substituted compound is an octasodium salt.
  • n is 3, alkyl is CH 2 and X is -H (Compound 29).
  • n is 9, alkyl is CH 2 and X is -OMe (Compound 31).
  • n is 5, alkyl is CH 2 and X is -OMe (Compound 44).
  • n is 5, alkyl is CH 2 and X is -CF 3 (Compound 45).
  • n is 2, alkyl is CH 2 and X is cyclopropane (Compound 30).
  • an IP5 substituted compound of the present invention comprises or consists of a compound of the following formula:
  • n is an integer between 1 and 30, alkyl is CH 2 and X is -H, -OH, -OMe, amine group, pyrazole, triazole, -COOH, CONRR', -NHCOR, -NHCOOR, -OCONR, - NHSO 2 R, -NHCONRR', -CF 3 , cyclopropane, cyclopentane or pyrazole. See Fig. 4.
  • n is an integer between 1 and 20.
  • n is an integer between 1 and 10.
  • n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the IP5 substituted compound is a sodium salt. In some aspects, the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP5 substituted compound is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP5 substituted compound is an octasodium salt.
  • n 3, alkyl is CH 2 and X is -H (Compound 32).
  • n 9, alkyl is CH 2 and X is -OMe (Compound 47).
  • n 5, alkyl is CH 2 and X is -NHCOMe (Compound 49).
  • n 5, alkyl is CH 2 and X is -CF 3 (Compound 50).
  • n is 2, alkyl is CH 2 and X is cyclopropane (Compound 48).
  • n is 2, alkyl is CH 2 and X is cyclopentane (Compound 51).
  • an IP5 substituted compound of the present invention comprises or consists of a compound of the following formula:
  • y and y' is an integer between 0 and 10
  • alkyl is CH 2
  • Cy is selected from the group consisting of 1,3-substituted phenyl, 1,4-substituted phenyl, piperazine, triazole- 1, and triazole-2
  • Z is selected from the group consisting of -CH3, -OMe, - CF 3 , COCH 3 , and -COOH 3 .
  • the IP5 substituted compound is a sodium salt.
  • the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP5 substituted compound is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP5 substituted compound an octasodium salt or nonasodium salt.
  • y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • y is 3, y' is 0, alkyl is CH 2 , Cy is 1,4-substituted phenyl, and Z is -CH3 (Compound 11).
  • y is 3, y' is 0, alkyl is CH 2 , Cy is 1,4-substituted phenyl, and Z is - OMe (Compound 14).
  • y is 3, y' is 0, alkyl is CH 2 , Cy is 1,3-substituted phenyl, and Z is -CF 3 (Compound 15).
  • y is 2, y' is 0, alkyl is CH 2 , Cy is piperazine, and Z is -COCH 3 (Compound 5).
  • y is 3, y' is 2, alkyl is CH 2 , Cy is triazole-1, and Z is -COOH (Compound 25).
  • y is 6, y' is 0, alkyl is CH 2 , Cy is triazole-1, and Z is -COOH (Compound 26).
  • an IP5 substituted compound of the present invention comprises or consists of a compound of the following formula:
  • y and y' is an integer between 0 and 10
  • alkyl is CH 2
  • Cy is selected from the group consisting of 1,3-substituted phenyl, 1,4-substituted phenyl, piperazine, triazole- 1, and triazole-2
  • Z is selected from the group consisting of -CH3, -OMe, - CF 3 , COCH 3 , and -COOH 3 .
  • the IP5 substituted compound is a sodium salt.
  • the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP5 substituted compound is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP5 substituted compound an octasodium salt or nonasodium salt.
  • y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • y is 5, y' is 1, alkyl is CH 2 , Cy is triazole-1, and Z is -OMe (Compound 41).
  • y is 1, y' is 2, alkyl is CH 2 , Cy is triazole-2, and Z is -COOH (Compound 46).
  • an IP5 substituted compound of the present invention comprises or consists of a compound of the following formula: [95] wherein y and y' is an integer between 0 and 10, alkyl is CH 2 , Cy is selected from the group consisting of 1,3-substituted phenyl, 1,4-substituted phenyl, piperazine, triazole- 1, and triazole-2, and Z is selected from the group consisting of -CH3, -OMe, - CF 3 , COCH 3 , and -COOH 3 . See Fig. 3.
  • the IP5 substituted compound is a sodium salt.
  • the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP5 substituted compound is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP5 substituted compound an octasodium salt or nonasodium salt.
  • y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • y is 5, y' is 1, alkyl is CH 2 , Cy is triazole-1, and Z is -OMe (Compound 42).
  • an IP5 substituted compound of the present invention comprises or consists of a compound of the following formula:
  • y and y' is an integer between 0 and 10
  • alkyl is CH 2
  • Cy is selected from the group consisting of 1,3-substituted phenyl, 1,4-substituted phenyl, piperazine, triazole-1, and triazole-2
  • Z is selected from the group consisting of -CH3, -OMe, - CF 3 , COCH 3 , and -COOH 3 .
  • the IP5 substituted compound is a sodium salt.
  • the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some aspects, the IP5 substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some aspects, the IP5 substituted compound is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt.
  • the IP5 substituted compound an octasodium salt or nonasodium salt.
  • y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • y is 5, y' is 1, alkyl is CH 2 , Cy is triazole-1, and Z is -OMe (Compound 52).
  • y is 1, y' is 2, alkyl is CH 2 , Cy is triazole-2, and Z is -COOH (Compound 53).
  • IP5 substituted compounds of the present invention and intermediates for their synthesis can be synthesized by using the methods described herein, as well as other processes known in the field of the organic chemistry.
  • the methods include, but are not limited to, the general procedures shown in the synthesis Schemes 1, 2, 3, 4, 5, 6, 7 and 8 described herein.
  • the present invention provides a method to manufacture an IP5 substituted compound of the present invention comprising applying synthetic Scheme 1 disclosed below.
  • the present invention provides a method to manufacture an IP5 substituted compound of the present invention comprising applying synthetic Scheme 2 disclosed below.
  • the present invention provides a method to manufacture an IP5 substituted compound of the present invention comprising applying synthetic Scheme 3 disclosed below.
  • the present invention provides a method to manufacture an IP5 substituted compound of the present invention comprising applying synthetic Scheme 4 disclosed below. In some aspects, the present invention provides a method to manufacture an IP5 substituted compound of the present invention comprising applying synthetic Scheme 5 disclosed below. In some aspects, the present invention provides a method to manufacture an IP5 substituted compound of the present invention comprising applying synthetic Scheme 6 disclosed below. In some aspects, the present invention provides a method to manufacture an IP5 substituted compound of the present invention comprising applying synthetic Scheme 7 disclosed below. In some aspects, the present invention provides a method to manufacture an IP5 substituted compound of the present invention comprising applying synthetic Scheme 8 disclosed below.
  • the present invention provides a method to manufacture an intermediate for the synthesis of an IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) comprising applying any of synthetic Scheme 1, Scheme 2, Scheme 3, Scheme 4, Scheme, 5, Scheme 6, Scheme 7 or Scheme 8 disclosed below as applicable.
  • the IP5 substituted compounds of the present invention can be obtained by deprotecting the intermediates of formula IV_A (Scheme 1).
  • the "protective group” or GP can be, without limitation, benzyl, levulinylbenzyl, tert-butyl, o,o ’-xylenyl (by union of 2 PG in the same phosphate), 9- fluorenylmethyl, cyanoethyl and other suitable protective groups in each case.
  • Intermediates of formula IV_A may be achieved by phosphorylation of an intermediate of formula III_A according to procedures described in the literature such as reaction with a phosphoroamidite derivative and subsequent oxidation.
  • intermediates of formula III_A can be obtained by hydrolysis in acid media of intermediates of formula II_A.
  • intermediates of formula II_A may be obtained by alkylation of intermediate (2) with an alkylating agent.
  • Preparation of (2) was previously described in the literature (Martin S, et al., J Org Chem 1994; 59(17): 4805-4820, Kardivel M, Org Biomol Chem 2008; 6(11): 1966-1972).
  • the "leaving Group” or LG may be, without limitation, chloride, bromide, iodide, toluenesulfonyl (Ts) or methylsulfonyl (Ms). See Fig. 5.
  • Scheme 2 As an alternative to Scheme 1, when R 4 or Re contain a substituted 1,2,3-triazole, compounds of formula I_A can be obtained by following the alternative route described in Scheme 2. In this way, intermediates of formula III_A can be obtained via a click reaction by using as starting materials an intermediate of formula VI_A and an alkynyl “click agent”. Intermediates VI_A can be achieved by alkylation and hydrolysis of intermediate 2 with an appropriate reagent. As another alternative, when R 4 or Re contain a terminal amine group, compounds of formula I_A can be obtained by phosphorylation of compound VI_A in order to obtain compounds VII- A, and by the subsequent deprotection/reduction of such compounds. See Fig. 6.
  • Scheme 3 Compounds I_B may be obtained using a similar synthetic route used for compounds I_A.
  • compounds I_B may be obtained by deprotecting intermediates of formula IV_B (Scheme 3).
  • Intermediates of formula IV_B may be attained by phosphorylating an intermediate of formula III_B.
  • intermediates of formula III_B can be obtained by the hydrolysis in acid media of intermediates of formula II_B or VIII_B.
  • Intermediates of formula VIII_B may be achieved by the debenzylation of intermediates II_B’.
  • intermediates of formula II_B or B’ may be obtained by the alkylation of intermediates (3) or (4), respectively, with an alkylating agent.
  • Scheme 4 Compounds I_C can be obtained by the deprotection of intermediates of formula IV_C (Scheme 4). Intermediates of formula IV_C may be achieved phosphorylating intermediates of formula IV_C. Intermediates of formula III_C can be obtained by the debenzylation of intermediates II_C. Finally, intermediates of formula II_C may be obtained by the alkylation of intermediate (33) with an appropriate alkylating agent. Preparation of (33) has been previously described in the art (Phenix C. et al., ChemBioChem 2008; 9(10): 1591-1602). See Fig. 8A.
  • Scheme 6 As an alternative to Scheme 3, when R2 contain a substituted 1,2,3- triazole or an acylamine, compounds of formula I_B can be obtained by following the alternative route described in Scheme 6. In this way, intermediates of formula III_B can be also obtained via a click reaction by using as starting materials an azide intermediate of formula V_B and an alkynyl “click agent”. Intermediate V_B can be achieved by alkylation of intermediate 3 with an appropriate reagent. As another alternative, when R2 contains a terminal acylamine group, compounds of formula III_B can be obtained by amidation of the corresponding amino compound III_B. See Fig. 7B.
  • Scheme 7 As an alternative to Scheme 4, when R 5 contain a substituted 1,2,3- triazole, compounds of formula I_C can be obtained by following the alternative route described in Scheme 7. In this way, intermediates of formula II_C can be also obtained via a click reaction by using as starting materials an azide intermediate of formula V_C and an alkynyl “click agent”. Intermediate V_C can be achieved by alkylation of intermediate 33 with an appropriate reagent. See Fig. 8B.
  • IP5 substituted compounds of the present invention e.g., a compound selected from the group consisting of Compound 1 to Compound 53
  • any exemplary IPS substituted compound of the present invention in the myo conformation is not limited to the representative conformation displayed.
  • Compounds 1 to S3 and the intermediates presented herein are in the myo conformation.
  • the natural myo isomer has a structure in which five of the six hydroxyls (the first, third, fourth, fifth, and sixth) are equatorial, whereas the second hydroxyl group is axial.
  • the present invention also provides methods to manufacture a medicament for the treatment of pathological crystallization comprising using an intermediate compound selected from the group consisting of the compounds listed in Table 1. Also provided is a compound of formula I (e.g., selected from the group consisting of Compound 1 to Compound 53) for use as a medicament. Also provided is the use of a compound of formula I (e.g., selected from the group consisting of Compound 1 to Compound 53) for the manufacture of a medicament for the prevention or treatment of a disease related to pathological crystallization.
  • a compound of formula I e.g., selected from the group consisting of Compound 1 to Compound 53
  • the present invention also provides pharmaceutical compositions for use in the methods for the prevention and/or treatment of diseases and conditions disclosed herein (e.g., pathological crystallizations), wherein the pharmaceutical composition comprises at least one IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53).
  • the pharmaceutical composition comprises an IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) alone or together with one or more pharmaceutically acceptable excipients or carriers.
  • excipient refers to a substance which helps absorption of the elements of the pharmaceutical composition, stabilizes said elements, activates or helps preparation of the composition.
  • excipients used in parenteral formulations include, but are not limited to, antimicrobial agents (e.g., benzalkonium chloride, metacresol, thimerosal), co-solvents (e.g., ethanol), buffers, tonicity agents (e.g., NaCl) and pH adjusting factors (e.g., carbonate, citrate, phosphate solutions).
  • the "pharmaceutically acceptable vehicle” is a substance used in the composition to dilute any of the components contained therein to a determined volume or weight (e.g., a 0.9% (w/v) NaCl aqueous solution).
  • the pharmaceutically acceptable vehicle is an inert substance or a substance with an analogous action to any of the elements comprising the pharmaceutical composition of the present invention.
  • the role of said vehicle is to allow the incorporation of other elements, allow better dosing and administration or to provide consistency and shape to the composition.
  • compositions can comprise from approximately 1% to approximately 95% active ingredient.
  • the pharmaceutical compositions of the present invention can comprise from approximately 20% to approximately 90% active ingredient (i.e., an IP5 substituted compound of the present invention or a combination thereof, alone or in combination, e.g., with one or more additional therapeutic agents).
  • Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient, e.g., an IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53), combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline (e.g., a 0.9% (w/v) NaCl aqueous solution).
  • a pharmaceutically acceptable carrier such as sterile water or sterile isotonic saline (e.g., a 0.9% (w/v) NaCl aqueous solution).
  • Such formulations can be prepared, packaged, or sold in a form suitable for bolus administration or for non-bolus administration.
  • Injectable formulations can be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative.
  • Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations can further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents.
  • the active ingredient e.g., an IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53), is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the pharmaceutical compositions can be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution.
  • This suspension or solution can be formulated according to the known art, and may comprise, in addition to the active ingredient (e.g., an inositol phosphate of the present invention), additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein.
  • Such sterile injectable formulations can be prepared using a non-toxic parenterally acceptable diluent or solvent, such as water or 1,3 -butanediol, for example.
  • Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides.
  • compositions for sustained release or implantation can comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.
  • compositions and methods of making formulations for administering the IP5 substituted compounds of the present invention, including controlled- or sustained-release formulations containing the said active agents, are described in the art.
  • Medicaments according to the invention are manufactured by methods known in the art, especially by conventional mixing, coating, granulating, dissolving or lyophilizing.
  • the present invention also provides a compound or a combination of compounds or pharmaceutical formulation according to any of the above aspects of the invention, in the broadest definition given, or as specified in any of the aspects presented above, for use as a medicament.
  • the present invention also provides a compound or combination of compounds or pharmaceutical formulation according to any of the above aspects of the invention, in the broadest definition given, or as specified in any of the aspects presented above, for use in the treatment and/or prevention of a disease or condition disclosed herein.
  • the present invention also provides a compound or combination of compounds or pharmaceutical formulation according to any of the above aspects of the invention, in the broadest definition given, or as specified in any of the aspects presented above, for the manufacture of a medicament for the prevention and/or treatment of a disease or condition disclosed herein.
  • the present invention also provides articles of manufacture and kits.
  • Such articles of manufacture and kits can comprise a container (e.g., a box) comprising one or more vials containing a formulation comprising one or more of the IP5 substituted compounds of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) and/or solvents for their medical administration or other uses according to the methods disclosed herein.
  • kit or article of manufacture can also comprise brochures or instructions describing the process of medical administration and dosages disclosed herein, or the use of the IP5 substituted compounds of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) according to the methods disclosed herein.
  • kit or article of manufacture can comprise multiple vials, each one of them containing a single dose.
  • kit or article of manufacture can comprise one or more vials, each one of them comprising more than one dose.
  • the article of manufacture is a bag containing a solution of an IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53).
  • the article of manufacture is a bottle (e.g., a glass bottle or a plastic bottle) containing a solution of an IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53).
  • the article of manufacture is a bag containing an IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) in powder form for reconstitution in an appropriate solvent.
  • the article of manufacture is a bottle (e.g., a glass bottle or a plastic bottle) containing an IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) in powder form for reconstitution in an appropriate solvent.
  • an IP5 substituted compound of the present invention e.g., a compound selected from the group consisting of Compound 1 to Compound 53
  • kits and articles of manufacture can include instructions for carrying out one or more administrations of the IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) according to the methods and dosages disclosed herein.
  • the IP5 substituted compound of the present invention e.g., a compound selected from the group consisting of Compound 1 to Compound 53
  • kits and articles of manufacture can be affixed to packaging material or can be included as a package insert. While the instructions are typically written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated. Such media include, but are not limited to, electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. As used herein, the term "instructions" can include the address of an internet site that provides the instructions.
  • the present invention provides methods for using the IP5 substituted compounds of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) to treat diseases and conditions.
  • the medical uses disclosed herein relate to the ability of the IP5 substituted compounds of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) to inhibit the formation or growth of calcium salts/crystals (e.g., calcium phosphates, HAP) in a subject in need thereof comprising administering to the subject an effective amount of a compound of formula I, or a pharmaceutical composition of disclosed herein.
  • the IP5 substituted compounds of the present invention e.g., a compound selected from the group consisting of Compound 1 to Compound 53
  • the present invention provides methods to treat and/or prevent pathological crystallizations and/or the consequences thereof in a subject in need thereof comprising administering an IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53), wherein the administration of the IP5 substituted compound effectively treats and/or prevents pathological crystallization and/or the consequences thereof in the subject.
  • an IP5 substituted compound of the present invention e.g., a compound selected from the group consisting of Compound 1 to Compound 53
  • the present invention also provides methods to manufacture a medicament for the treatment of pathological crystallization comprising using an intermediate compound selected from the group consisting of the compounds listed in Table 1. Also provided is a compound selected from the group consisting of Compound 1 to Compound 53 for the treatment of pathological crystallizations and/or the consequences thereof in a subject in need thereof.
  • the IP5 substituted compound of the present invention e.g., a compound selected from the group consisting of Compound 1 to Compound 53
  • Step 1 9-Methoxynonan-1-ol (6): A mixture of 9-bromononan-l-ol (0.5 g, 2.24 mmol) and sodium methoxide 4 N (25 mL, 100 mmol)) was stirred for 18 h at 40°C. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by flash chromatography (silica gel, hexane (Hex):ethyl acetate (EtOAc) 4:1) to afford 324 mg of (6) (83% yield).
  • Step 2 9-Methoxynonyl 4-methylbenzenesulfonate (7): To a solution of (6) (1.5 g, 8.61 mmol) in (28.7 mL), TEA (1.80 mL, 12.91 mmol) and Ts-Cl (2.13 g, 11.19 mmol) were added. The reaction mixture was stirred for 24 h at rt then quenched with water and washed with brine. The organic layer was dried over with Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 4:1) to afford 2.15 g of (7) (76%).
  • Step 1 2-((9-Bromononyl)oxy)tetrahvdro-2H-pyran (8): To a mixture of 9- bromononan-l-ol (2.18 g, 9.77 mmol) and p-TsOH (37 mg, 0.19 mmol), 3,4-dihydro-2H- pyran (1.3 mL, 14.65 mmol) was added. The reaction mixture was stirred for 3.5 days at 60°C. The mixture was diluted with water, extracted with ethyl ether (2x), dried over with Na 2 SO 4 , filtered, and the solvents removed in vacuo.
  • Step 3 IQ-Methoxydec-1-yne (10): To a (9) (8.17 g, 35.2 mmol), a solution 5 M of sodium methoxide in MeOH (35.2 mL, 176 mmol) was added. The reaction mixture was stirred for 18 h days at 45°C. The mixture was diluted with water, extracted with ethyl ether (2x), dried over with Na 2 SO 4 , filtered, and the solvents removed in vacuo. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 20:1) rending 4 g of (10) (67% yield).
  • Step 4 2-((19-Methoxynonadec-10-vn-1-yl)oxy)tetrahvdro-2H-pyran (11): In an tetrahydrofurane (THF) and hexamethylphosphoramide (HMPA) mixed solution (1.2:1) of (10) (1.41 g, 8.42 mmol) cooled to -40° C., an Hex. solution 1.6M of n-BuLi (7.45 mL, 11.93 mmol) was slowly added, followed by stirring at the same temperature for 30 minutes and further stirring at 0°C for 30 minutes. After cooling to -20°C., a HMPA solution of (8) (2.16 g, 7.02 mmol) was slowly added.
  • THF tetrahydrofurane
  • HMPA hexamethylphosphoramide
  • Step 5 19-Methoxynonadec-lO-vn-1-ol (12): To a solution of (11) (3.28 g, 8.31 mmol) in MeOH (0.6M), p-TsOH (95 mg, 0.5 mmol) was added. The reaction mixture was stirred for 3.5 days at 60°C. The mixture was diluted with water, extracted with ethyl ether (2x), dried over with Na2SO4, filtered, and the solvents removed in vacuo. The filtrate was concentrated yielding 2.6 g of (12) (>99% yield).
  • Step 2 29-Methoxynonacosa-9,20-divn-1-ol
  • an n-hcxanc solution 1.6M of n-BuLi (1.9 mL, 3.09 mmol) was slowly added, followed by stirring at the same temperature for 30 minutes and further stirring at 0°C. for 30 minutes.
  • a HMPA solution of (14) (462 mg, 1.24 mmol) was slowly added. After stirring at the same temperature for 10 minutes, the temperature was increased to room temperature.
  • Step 3 29-Methoxynonacosa-9,20-divn-1-yl 4-methylbenzenesulfonate (16): To a solution of (15) (69.7 mg, 0.156 mmol) in DCM (0.1M) at 0°C, TEA (43uL, 0.325 mmol), DMAP (3.3 mg, 0.027 mmol) and Ts-Cl (62 mg, 0.325 mmol) were added. Then, the reaction mixture was diluted with water and tBuMeO. The organic layer was washed with sat aq NaHCO 3 and brine, dried over Na2SO 4 , filtered and the solvent was removed under reduced pressure to afford a yellow oil.
  • Step 1 6-Azidohexan-1-ol (21): A solution of 6-bromohexan-l-ol (428 pL, 3.27 mmol) and sodium azide (850 mg, 13.08 mmol) in DMF (0.8 M) was stirred for 18 h at 80°C. Then, the reaction mixture was quenched with water/EtOAc, and washed with brine (3x). The organic layer was dried over with Na 2 SO 4 , filtered, and concentrated in vacuum to afford 470 mg of (21) (>99%).
  • Step 1 N -(5-hydroxypentyl (acetamide (28): To a solution of 5-aminopentan-l- ol (50 g, 485 mmol) and 2,5-dioxopyrrolidin-l-yl acetate (75 g, 485 mmol) in dimethylformamide (DMF, 0.5 M), TEA (101 mL, 727 mmol) was added and the solution was stirred for 18 h at 60°C.
  • DMF dimethylformamide
  • Step 2 5-Acetamidopentyl 4-methylbenzenesulfonate (29): To a solution of (28) (70.4 g, 485 mmol) in DCM (0.5 M), TEA (101 mL, 727 mmol) and Ts-Cl (92 g, 485 mmol) were added. The reaction mixture was stirred for 18 h at rt, then, quenched with water/DCM and washed with NaHCO3sat and brine. The organic layer was dried over with Na 2 SO 4 , filtered and concentrated in vacuum to afford 92.45 g of (29) (63%).
  • Step 1 5-Azidopentan-1-ol (36): A solution of 5 -bromopentan- l-ol (0.10 mL, 0.89 mmol) and sodium azide (63 mg, 0.98 mmol) in dimethylformamide (DMF, 0.2 M) was stirred for 18 h at 80°C. Then, the reaction mixture was quenched with water/EtOAc and was washed with brine (3x). The organic layer was dried over with Na 2 SO 4 , filtered, and concentrated in vacuum to afford 57 mg of (36) (50%).
  • DMF dimethylformamide
  • Procedure K Alkyl-inositol derivative (II_B’, II_C, VIII_B’ or IX_D) was dissolved in a mixture of THF/MeOH (7:3, 0.05M) followed by addition of excess palladium hydroxide on carbon. The mixture was placed under hydrogen atmosphere and stirred 2 days at room temperature. The mixture was then purged with nitrogen, filtered and concentrated to afford the desired compounds.
  • reaction mixture was cooled at 0°C and a solution of tert-butyl hydroperoxide in hexane (5.5M) (19.2 eq) was added.
  • the solution was brought to room temperature and stirred for Ih.
  • the mixture was washed with dilute sodium sulfite and extracted with DCM.
  • the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuum.
  • the residue was purified by flash chromatography (silica gel) to afford pure compounds.
  • reaction mixture was cooled at 0°C and a solution of tert-butyl hydroperoxide in hexane (5.5M) (24 eq) was added.
  • the solution was brought to room temperature and stirred for Ih.
  • the mixture was washed with dilute sodium sulfite and extracted with DCM.
  • the organic layer was dried over Na2SO4, filtered and concentrated in vacuum.
  • the residue was purified by flash chromatography (silica gel) to afford pure compounds.
  • reaction mixture was cooled at 0°C and a solution of tert-butyl hydroperoxide in hexane (5.5M) (24 eq) was added.
  • the solution was brought to room temperature and stirred for Ih.
  • the mixture was washed with dilute sodium sulfite and extracted with EtOAc (x2).
  • the organic layer was dried over Na2SO4, filtered and concentrated in vacuum.
  • the residue was purified by flash chromatography (silica gel) to afford pure compounds.
  • Procedure I Phosphorylated compound (IV_A, VII-A, IV_B, IV_C or IV_D) was dissolved in a mixture of THF/MeOH/Water (3:1: 1, 0.01M) followed by addition of excess palladium hydroxide on carbon or palladium on carbon. The mixture was placed under hydrogen atmosphere and stirred 2 days at room temperature. The mixture was then purged with nitrogen, filtered and concentrated. The compound was brought at pH 7 by addition of dilute aqueous NaOH (IN) and the residue was purified on a sephadex column (PD-10, G-25-M) by eluting with water. All fractions were lyophilized and analyzed by 1 H-RMN. The fractions containing product were purified further on a reverse phase cartridge (Sep-Pack, Waters, 1g, C18) by eluting with water. All fractions were lyophilized and analyzed by 1 H-RMN.
  • Procedure J Phosphorylated compound (IV_A, VII-A, IV_B, IV_C or IV_D) was dissolved in a mixture of THF/MeOH/Water (3:1: 1, 0.01M) followed by addition of excess palladium hydroxide on carbon or palladium on carbon. The mixture was placed under hydrogen atmosphere and stirred 2 days at room temperature. The mixture was then purged with nitrogen, filtered and concentrated. The compound was brought at pH 10 by addition of dilute aqueous NaOH (IN) and the solution was stirred for 24-48h. Finally, the solution was purified on a sephadex column (PD-10, G-25-M) by eluting with water. All fractions were lyophilized and analyzed by 1 H-RMN. The fractions containing product were purified further on a reverse phase cartridge (Sep-Pack, Waters, 1g, Cl 8) by eluting with water. All fractions were lyophilized and analyzed by 1 H-RMN.
  • a sephadex column
  • Procedure T Phosphorylated compound (IV_A, VII-A, IV_B, IV_C or IV_D) was treated with thiophenol (40 eq), m-cresol (40 eq) in TFA (0.045 M). Then TBMSBr (40 eq) was added slowly and the mixture was stirred at rt for 4h, quenched with water, and extracted with DCM (3x). The aqueous layer was concentrated in vacuum. The residue was brought at pH 9-10 by addition of water and dilute aqueous NaOH (IN), and the compound was purified on a sephadex column (PD-10, G-25-M) by eluting with water.
  • V_C-1 5-0-(5-Azidopentyl)-l,2,3,4,6-penta-0-benzyl-myo- inositol
  • V_D-1) According to general alkylation Procedure B, from 285 mg of (34) and 254 mg (1.5 eq) of (37), 351mg mg of (V_D-1) were obtained (>99% yield).
  • HPLC-MS (Condition A): rt 5.55 min; m/z: 610 [M+23] + .
  • Condition A High-performance Liquid Chromatography (HPLC) 2795 Alliance Waters Aquity coupled to Detector DAD Agilent 1100 and Detector MS Waters ESI triple cuadrupolo Quattro micro, 10 pL of sample in MeOH was injected.
  • Mass spectroscopy (MS) analyzed by FIA (flux injected analysis) coupled to LCT Premier Orthogonal Accelerated Time of Flight Mass Spectrometer, acquiring data by electrospray ionization (ESI) in positive mode. Spectra have been scanned between 50 and 1500 Da with values every 0.2 seconds and peaks are given m/z (% of basis peak).
  • Stationary phase ZORBAX Extend-C18 3.5 pm 2.1 x 50 mm (T a 35°C).
  • IP5 substituted compounds e.g., Compounds 1 to 32
  • the in vitro efficacy of the IP5 substituted compounds (e.g., Compounds 1 to 32) of the invention on the inhibition of calcium phosphate crystallization in human plasma samples was evaluated according to a spectrophotometric assay previously described in the art (Ferrer M, et al., Sci Rep 2017; 7:6858, doi:10.1038/s41598-017-07203-x).

Abstract

La présente invention concerne des composés substitués par IP5 de formule générale I, leurs procédés de synthèse et leurs utilisations. Les composés substitués par IP5 de l'invention sont caractérisés pour avoir des chaînes -O(alkyl)nX, et-O(alkyl)yCy(alkyl)y'-Z dans les positions R1, R2, R4 et R5. L'invention concerne également des procédés, des compositions pharmaceutiques et des formulations, des procédés d'utilisation, des articles manufacturés et des kits pour le traitement de maladies et d'états tels que des maladies et des états pathologiques liés à la cristallisation pathologique.
PCT/EP2023/071141 2022-07-29 2023-07-31 Composés substitués par ip5 WO2024023360A1 (fr)

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