WO2024259428A2 - Composés oestrogènes et formulations pour complications associées à la grossesse - Google Patents

Composés oestrogènes et formulations pour complications associées à la grossesse Download PDF

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WO2024259428A2
WO2024259428A2 PCT/US2024/034368 US2024034368W WO2024259428A2 WO 2024259428 A2 WO2024259428 A2 WO 2024259428A2 US 2024034368 W US2024034368 W US 2024034368W WO 2024259428 A2 WO2024259428 A2 WO 2024259428A2
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acid
phosphonic
sulfonic
sulfonic acid
phosphonic acid
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WO2024259428A3 (fr
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Fatima CHLEILAT
Michael P. Snyder
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Leland Stanford Junior University
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Leland Stanford Junior University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone

Definitions

  • the invention is generally directed toward compounds, formulations, and methods of treatment to prolong gestation and for treatment of gestational complications.
  • Various gestational complications include spontaneous preterm labor, spontaneous abortion, early term birth, recurrent preterm birth, recurrent early term birth, and recurrent pregnancy loss. Each of these disorders is related to premature uterine contractions during pregnancy.
  • Spontaneous preterm labor is the opening of the cervix after week 20 and before week 37 of gestation, and can result in a preterm birth that can dramatically hinder the health and may result in death of the newborn and/or mother.
  • Spontaneous abortion also referred to as miscarriage
  • miscarriage is the spontaneous loss of a pregnancy before week 20 of gestation.
  • Recurrent preterm birth is a condition in which a woman experiences two or more pregnancies that go into labor prior to week 37 of gestation.
  • Recurrent early term birth is a condition in which a woman experiences two or more pregnancies that go into labor prior to week 39 of gestation.
  • Recurrent pregnancy loss is a condition in which a woman experiences two or more spontaneous losses of pregnancy.
  • individuals with a short cervix e.g., cervix less than 30 mm, and especially less than 24 mm
  • Various embodiments are directed towards formulations, compounds and methods to prolong gestation and for treating gestational complications, including recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, short cervix, early term birth, spontaneous preterm birth or spontaneous abortion.
  • the techniques described herein relate to a method of treating a pregnant individual for recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, or a short cervix, including: administering an estrogenic compound to an individual, wherein the individual is pregnant and has a medical history indicating recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, or a short cervix.
  • the techniques described herein relate to a method, wherein the estrogenic compound is administered in a therapeutically effective amount.
  • the techniques described herein relate to a method, wherein the administering step is to begin upon a determination that the individual is pregnant.
  • the techniques described herein relate to a method, wherein the administering step is to end by one of: week 40 of gestation, week 39 of gestation, week 38 of gestation, or week 37 of gestation.
  • the techniques described herein relate to a method of treating a pregnant individual for early term birth, spontaneous preterm birth or spontaneous abortion, including: determining that a pregnant individual is experiencing uterine contractions related to early term birth, spontaneous preterm birth or spontaneous abortion; and administering an estrogenic compound to an individual.
  • the techniques described herein relate to a method, wherein the estrogenic compound is administered in a therapeutically effective amount.
  • the techniques described herein relate to a method, wherein the administering step is to begin upon a determination that the uterine contractions are occurring prior to one of: week 39 of gestation or week 37 of gestation.
  • the techniques described herein relate to a method, wherein the administering step is to end by one of: week 40 of gestation, week 39 of gestation, week 38 of gestation, or week 37 of gestation.
  • the techniques described herein relate to a medicament for use in mitigating uterine contractions in an individual, the medicament including: an estrogenic compound.
  • the techniques described herein relate to a medicament, wherein the estrogenic compound is of formula: wherein R1 is OH, phosphonic acid, sulfonic acid, or OR5; R2 is O, OH, phosphonic acid, sulfonic acid, or OR6; R3 is H, OH, phosphonic acid, sulfonic acid, or OR7; R4 is H, OH, phosphonic acid, sulfonic acid, or OR8; and OR5, OR6, OR7, and OR8 can each individually be galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fum
  • the techniques described herein relate to a medicament, wherein R1 is OH, R2 is OH, R3 is OH and R4 is H, matching the formula for estriol.
  • the techniques described herein relate to a medicament, wherein R1 is OH, R2 is OH, R3 is phosphonic acid or sulfonic acid or OR7, and R4 is H.
  • the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5, R2 is OH, R3 is OH, and R4 is H.
  • the techniques described herein relate to a medicament, wherein R1 is OH, R2 is phosphonic acid or sulfonic acid or OR6, R3 is OH, and R4 is H. [0019] In some aspects, the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5, R2 is OH, R3 is phosphonic acid or sulfonic acid or OR7, and R4 is H.
  • the techniques described herein relate to a medicament, wherein R1 is OH, R2 is phosphonic acid or sulfonic acid or OR6, R3 is phosphonic acid or sulfonic acid or OR7, and R4 is H.
  • the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5, R2 is phosphonic acid or sulfonic acid or OR6, R3 is OH, and R4 is H.
  • the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5, R2 is phosphonic acid or sulfonic acid or OR6, R3 is phosphonic acid or sulfonic acid or OR7, and R4 is H.
  • the techniques described herein relate to a medicament, wherein R1 is OH, R2 is OH, R3 is H, and R4 is H.
  • the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5, R2 is OH, R3 is H, and R4 is H.
  • the techniques described herein relate to a medicament, wherein R1 is OH, R2 is phosphonic acid or sulfonic acid or OR6, R3 is H, and R4 is H.
  • the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5, R2 is phosphonic acid or sulfonic acid or OR6, R3 is H, and R4 is H.
  • the techniques described herein relate to a medicament, wherein R1 is OH, R2 is O, R3 is H, and R4 is H. [0028] In some aspects, the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5 or, R2 is 0, R3 is H, and R4 is H. [0029] In some aspects, the techniques described herein relate to a medicament, wherein R1 is OH, R2 is OH, R3 is OH and R4 is OH.
  • the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5, R2 is OH, R3 is OH, and R4 is OH.
  • the techniques described herein relate to a medicament, wherein R1 is OH, R2 is phosphonic acid or sulfonic acid or OR6, R3 is OH, and R4 is OH.
  • the techniques described herein relate to a medicament, wherein R1 is OH, R2 is OH, R3 is phosphonic acid or sulfonic acid or OR7, and R4 is OH.
  • the techniques described herein relate to a medicament, wherein, R1 is OH, R2 is OH, R3 is OH, and R4 is phosphonic acid or sulfonic acid or OR8.
  • the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5, R2 is phosphonic acid or sulfonic acid or OR6, R3 is OH, and R4 is OH.
  • the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5, R2 is OH, R3 is phosphonic acid or sulfonic acid or OR7, and R4 is OH.
  • the techniques described herein relate to a medicament, wherein R1 is OH, R2 is phosphonic acid or sulfonic acid or OR6, R3 is phosphonic acid or sulfonic acid or OR7, and R4 is OH.
  • the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5, R2 is OH, R3 is OH, and R4 is phosphonic acid or sulfonic acid or OR8. [0038] In some aspects, the techniques described herein relate to a medicament, wherein R1 is OH, R2 is phosphonic acid or sulfonic acid or OR6, R3 is OH, and R4 is phosphonic acid or sulfonic acid or OR8.
  • the techniques described herein relate to a medicament, wherein R1 is OH, R2 is OH, R3 is phosphonic acid or sulfonic acid or OR7, and R4 is phosphonic acid or sulfonic acid or OR8.
  • the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5, R2 is phosphonic acid or sulfonic acid or OR6, R3 is phosphonic acid or sulfonic acid or OR7, and R4 is OH.
  • the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5, R2 is phosphonic acid or sulfonic acid or OR6, R3 is OH, and R4 is phosphonic acid or sulfonic acid or OR8.
  • the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5, R2 is OH, R3 is phosphonic acid or sulfonic acid or OR7, and R4 is phosphonic acid or sulfonic acid or OR8.
  • the techniques described herein relate to a medicament, wherein R1 is OH, R2 is phosphonic acid or sulfonic acid or OR6, R3 is phosphonic acid or sulfonic acid or OR7, and R4 is phosphonic acid or sulfonic acid or OR8.
  • the techniques described herein relate to a medicament, wherein R1 is phosphonic acid or sulfonic acid or OR5, R2 is phosphonic acid or sulfonic acid or OR6, R3 is phosphonic acid or sulfonic acid or OR7, and R4 is phosphonic acid or sulfonic acid or OR8.
  • the techniques described herein relate to a medicament, wherein the estrogenic compound is a synthetic estrogen selected from: dienestrol, dienstrol diacetate, dienestrol dipopropionate, dienestrol monobenzoate, hexestrol, hexestrol diacetate, hexestrol dipropionate, hexestrol monobenzoate, methallenestril, methallenestril acetate, methallenestril benzoate, methallenestril propionate, mestranol, 3-(2'.3'-epoxypropoxy)-1 .3.5.(10)-estratrien-16.alpha, estriol-3-glycidyl ether, estriol-6- carboxymethyl oxime, or ethinylestradiol.
  • the estrogenic compound is a synthetic estrogen selected from: dienestrol, dienstrol diacetate, dienestrol dipopropionate, dienestrol monobenzoate, hexestrol, hexestrol diacetate
  • the techniques described herein relate to a medicament, wherein the estrogenic compound is an estriol ester or estriol amino ester selected from: 3,17.beta.-Diisobutyryloxy-1 ,3,5(10)-estratrien-16.alpha.-ol, 3,17.beta.-Divaleryloxy- 1 ,3,5(10)- estratrien-16.alpha.-ol, 3, 17.beta.-Dihexanoyloxy-1 ,3,5(10)-estratrien- 16.alpha.-ol, 3, 17.beta.-Dipivaloyloxy-1 ,3,5(10)-estratrien-16.alpha.-ol, 3, 17.beta.- Didecanoyloxy-1 ,3,5(10)-estratrien-16.
  • alpha. -ol 3, 17.beta.-Dibenzoyloxy-1 ,3,5(10)- estratrien-16. alpha. -ol, 3, 17.beta.-Dibutyryloxy-1 ,3,5(10)-estratrien-16. alpha. -ol, 6- alpha.-aminoestriol-16,17-diaceteate, 6.alpha.(N-diglycolylamido) estriol, 6.alpha.- aminoestriol, 6.alpha.-(N-diglycoylamido)estriol NHS-ester, estriol-N-hydroxysuccinimide (NHS) ester, estriol-aminooxy, or estriol-carboxylic acid hydrazide.
  • NHS-ester estriol-N-hydroxysuccinimide (NHS) ester, estriol-aminooxy, or estriol-carboxylic acid hydrazide.
  • the techniques described herein relate to a medicament, wherein the estrogenic compound is a metabolite of estriol, estradiol, estrone, or estetrol selected from: 16a-hydroxyestrone, 2-m ethoxyestrone, 2-hydroxyestrone, 4- hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestradiol, or 16-ketoestradiol.
  • the techniques described herein relate to a medicament, wherein the medicament is for recurrent preterm birth, recurrent early term birth, recurrent pregnancy loss, or a short cervix.
  • the techniques described herein relate to a medicament, wherein the medicament is for early term birth, spontaneous preterm birth or spontaneous abortion.
  • Figure 1 provides examples of chemical structures in accordance with various embodiments.
  • Figure 2A provides a schematic of an experiment performed on a mouse model of preterm birth.
  • Figures 2B and 2C provide data results of an experiment performed on a mouse model of preterm birth.
  • Figures 3A and 3B provide data results of an experiment performed on mice to mitigate uterine contraction.
  • Figure 4 provides a data chart of the concentration of circulating estrone-3- sulfate in pregnant women over the period of gestation.
  • an individual is administered a compound that modulates uterine contraction.
  • an individual having a gestational complication such as (for example) spontaneous preterm labor, spontaneous abortion, recurrent preterm birth, early term birth, or recurrent pregnancy loss is administered a compound described herein to treat the gestational complication.
  • the compound to treat the gestational complication is an estrogen steroid or a derivative thereof. Four naturally occurring estrogen steroids are estrone, estradiol, estriol, and estetrol.
  • Preterm birth or birth before 37 weeks of gestation, is the leading cause of infant mortality and morbidity, associated with 70% of neonatal deaths.
  • the incidence of preterm birth is rising in many countries, including the United States, where the frequency increased from 10.7% of all births in 1992 to 12.3% of all births 11 years later. Between 70-80% of these preterm births resulted from preterm labor.
  • Current methods for the intervention of preterm labor include the acute treatment with tocolytic agents such as magnesium sulfate, nifedipine, beta-adrenoceptor agonists, and prostaglandin synthase inhibitors in order to delay delivery by 48-72 hours.
  • a formulation comprises an estrogenic compound for the treatment of spontaneous preterm labor, spontaneous abortion, early term birth, recurrent preterm birth, recurrent early term birth, and recurrent pregnancy loss.
  • an individual experiencing spontaneous preterm labor, spontaneous abortion, early term birth, recurrent preterm birth, recurrent early term birth, or recurrent pregnancy loss is administered an estrogenic compound.
  • a formulation comprises estriol or an estrogenic compound for prolonging gestation.
  • an individual is administered an estrogenic compound to prolong their pregnancy.
  • Estrogenic compounds include estrone and estrone-related compounds, estradiol and estradiol-related compounds, estriol and estriol-related compounds, and estetrol and estetrol related compounds.
  • Several embodiments are directed towards formulations and compounds and their use as therapeutics and/or supplements to treat an individual experiencing a gestational complication or to prolong gestation of the individual.
  • a number of compounds have been identified that that reduce uterine cell contractions and thus can be utilized to mitigate complications that arise from premature and/or abnormal uterine contractions.
  • the compounds is an estrogenic compound.
  • a compound is estrone or estrone-related.
  • An estrone-related compound that has a structural derivative of estrone or a metabolite of estrone.
  • a compound is estriol.
  • a compound is estriol-related.
  • estriol- related compound that has a structural derivative of estriol or a metabolite of estriol.
  • a compound is estradiol or estradiol-related.
  • An estradiol-related compound that has a structural derivative of estradiol or a metabolite of estradiol.
  • a compound is estetrol or estetrol-related.
  • An estetrol-related compound that has a structural derivative of estetrol or a metabolite of estetrol.
  • a formula to prolong gestation or for the treatment of spontaneous preterm labor, spontaneous abortion, early term birth, recurrent preterm birth, recurrent early term birth, or recurrent pregnancy loss comprises a compound having the structure: wherein R 1 is OH, phosphonic acid, sulfonic acid, or OR 5 ;
  • R 2 is O, OH, phosphonic acid, sulfonic acid, or OR 6 ;
  • R 3 is H, OH, phosphonic acid, sulfonic acid, or OR 7 ;
  • R 4 is H, OH, phosphonic acid, sulfonic acid, or OR 8
  • OR 5 , OR 6 , OR 7 , and OR 8 can each individually be galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid, sulfuric acid, phosphoric acid, methanolate, ethanolate
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • the formula can be 16a, 16(3, 16a and 17(3, 16(3 and 17a, 16a and 17a , 16(3 and 17(3, 16a 17(3 and 18(3, 16a 17(3 and 18 a, 16a 17a and 18(3, 16a 17a and 18a, 16(3 17(3 and 18(3, 16(3 17(3 and 18 a, 16(3 17a and 18(3, or 16(3 17a and 18a.
  • the formulae can further be provided as a therapeutically acceptable salt or a hydrate (e.g., hemihydrate).
  • R 1 is OH
  • R 2 is OH
  • R 3 is OH
  • R 4 is H, matching the formula for estriol.
  • R 1 is OH
  • R 2 is OH
  • R 3 is phosphonic acid or sulfonic acid or OR 7
  • R 4 is H.
  • OR 7 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid,
  • R 1 is phosphonic acid or sulfonic acid or OR 5
  • R 2 is OH
  • R 3 is OH
  • R 4 is H.
  • OR 5 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid,
  • R 1 is OH
  • R 2 is phosphonic acid or sulfonic acid or OR 6
  • R 3 is OH
  • R 4 is H.
  • OR 6 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid,
  • R 1 is phosphonic acid or sulfonic acid or OR 5
  • R 2 is OH
  • R 3 is phosphonic acid or sulfonic acid or OR 7
  • R 4 is H.
  • OR 5 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, buty
  • Any acid can be an anionic formulation of that acid (e g., oxalic acid can be oxalate).
  • OR 7 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • R 1 is OH
  • R 2 is phosphonic acid or sulfonic acid or OR 6
  • R 3 is phosphonic acid or sulfonic acid or OR 7
  • R 4 is H.
  • OR 6 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, buty
  • Any acid can be an anionic formulation of that acid (e g., oxalic acid can be oxalate).
  • OR 7 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • R 1 is phosphonic acid or sulfonic acid or OR 5
  • R 2 is phosphonic acid or sulfonic acid or OR 6
  • R 3 is OH
  • R 4 is H.
  • OR 5 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, buty
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • R 1 is phosphonic acid or sulfonic acid or OR 5
  • R 2 is phosphonic acid or sulfonic acid or OR 6
  • R 3 is phosphonic acid or sulfonic acid or OR 7
  • R 4 is H.
  • OR 5 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid, sulfuric acid, phosphoric acid, methanolate, ethanolate, propanolate, or butanolate.
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 6 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid,
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 7 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • OR 5 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid, sulfuric acid, phosphoric acid, methanolate, ethanolate, propanolate, or butanolate. Any acid can be
  • R 1 is OH
  • R 2 is phosphonic acid or sulfonic acid or OR 6
  • R 3 is H
  • R 4 is H.
  • OR 6 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, be
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 6 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • R 1 is OH
  • R 2 is 0,
  • R 3 is H
  • R 4 is H, matching the formula for estrone.
  • R 1 is OH
  • R 2 is OH
  • R 3 is OH
  • R 4 is OH, matching the formula for estetrol.
  • R 1 is OH
  • R 2 is OH
  • R 3 is phosphonic acid or sulfonic acid or OR 7
  • R 4 is OH.
  • OR 7 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid
  • R 1 is OH
  • R 2 is OH
  • R 3 is OH
  • R 4 is phosphonic acid or sulfonic acid or OR 8 .
  • OR 8 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid
  • R 1 is phosphonic acid or sulfonic acid or OR 5
  • R 2 is phosphonic acid or sulfonic acid or OR 6
  • R 3 is OH
  • R 4 is OH
  • OR 5 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, but
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 6 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • R 1 is phosphonic acid or sulfonic acid or OR 5
  • R 2 is OH
  • R 3 is phosphonic acid or sulfonic acid or OR 7
  • R 4 is OH.
  • OR 5 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, but
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 7 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • R 1 is OH
  • R 2 is phosphonic acid or sulfonic acid or OR 6
  • R 3 is phosphonic acid or sulfonic acid or OR 7
  • R 4 is OH.
  • OR 6 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, but
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 7 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 8 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • R 1 is OH
  • R 2 is phosphonic acid or sulfonic acid or OR 6
  • R 3 is OH
  • R 4 is phosphonic acid or sulfonic acid or OR 8 .
  • OR 6 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, but
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 8 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • R 1 is OH
  • R 2 is OH
  • R 3 is phosphonic acid or sulfonic acid or OR 7
  • R 4 is phosphonic acid or sulfonic acid or OR 8 .
  • OR 7 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, but
  • R 1 is phosphonic acid or sulfonic acid or OR 5
  • R 2 is phosphonic acid or sulfonic acid or OR 6
  • R 3 is phosphonic acid or sulfonic acid or OR 7
  • R 4 is OH.
  • OR 5 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid, sulfuric acid, phosphoric acid, methanolate, ethanolate, propanolate, or butanolate.
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 6 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid,
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 7 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • R 1 is phosphonic acid or sulfonic acid or OR 5
  • R 2 is phosphonic acid or sulfonic acid or OR 6
  • R 3 is OH
  • R 4 is phosphonic acid or sulfonic acid or OR 8 .
  • OR 5 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid, sulfuric acid, phosphoric acid, methanolate, ethanolate, propanolate, or butanolate.
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 6 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid,
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 8 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • R 1 is phosphonic acid or sulfonic acid or OR 5
  • R 2 is OH
  • R 3 is phosphonic acid or sulfonic acid or OR 7
  • R 4 is phosphonic acid or sulfonic acid or OR 8 .
  • OR 5 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid, sulfuric acid, phosphoric acid, methanolate, ethanolate, propanolate, or butanolate.
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 7 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid,
  • Any acid can be an anionic formulation of that acid (e g., oxalic acid can be oxalate).
  • OR 8 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • R 1 is OH
  • R 2 is phosphonic acid or sulfonic acid or OR 6
  • R 3 is phosphonic acid or sulfonic acid or OR 7
  • R 4 is phosphonic acid or sulfonic acid or OR 8 .
  • OR 6 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid, sulfuric acid, phosphoric acid, methanolate, ethanolate, propanolate, or butanolate.
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 7 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid,
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 8 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • R 1 is phosphonic acid or sulfonic acid or OR 5
  • R 2 is phosphonic acid or sulfonic acid or OR 6
  • R 3 is phosphonic acid or sulfonic acid or OR 7
  • R 4 is phosphonic acid or sulfonic acid or OR 8 .
  • OR 5 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid, sulfuric acid, phosphoric acid, methanolate, ethanolate, propanolate, or butanolate.
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 6 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 7 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid,
  • Any acid can be an anionic formulation of that acid (e.g., oxalic acid can be oxalate).
  • OR 8 is galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4- cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid
  • Fig. 1 Provided in Fig. 1 are examples of chemical structures of compounds that can be utilized in accordance with the various embodiments of the disclosure.
  • the structures are derivatives of estriol.
  • any of the ester functional groups (-O-R) extending from the C17 within the structures of Fig. 1 can be utilized at any alcohol group (OH) in: estrone, estradiol, estriol, or estetrol.
  • a formula to prolong gestation or for the treatment of spontaneous preterm labor, spontaneous abortion, early term birth, recurrent preterm birth, recurrent early term birth, or recurrent pregnancy loss comprises a synthetic form of estrogen.
  • synthetic estrogens include (but are not limited to) dienestrol,dienstrol diacetate, dienestrol dipopropionate, dienestrol monobenzoate, hexestrol, hexestrol diacetate, hexestrol dipropionate, hexestrol monobenzoate, methallenestril, methallenestril acetate, methallenestril benzoate, methallenestril propionate, mestranol, 3-(2'.3'-epoxypropoxy)-1 ,3.5.(10)-estratrien-16.alpha, estriol-3-glycidyl ether, estriol-6- carboxymethyl oxime, and ethinylestradiol.
  • a formula to prolong gestation or for the treatment of spontaneous preterm labor, spontaneous abortion, early term birth, recurrent preterm birth, recurrent early term birth, or recurrent pregnancy loss comprises hydroxyestriol.
  • Hydroxyestriol include (but are not limited to) 2-hydroxyestriol, 4-hydroxyestriol, and estetrol.
  • Any alcohol group (OH) of the hydroxy estriol can be esterified with galacturonic acid, glucoside, glucuronide, mannuronic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, 1 ,4-cyclohexanedicarboxylic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, glutaconic acid, muconic acid, citraconic acid, mesaconic acid, itaconic acid, malic acid, tartaric acid, mucic acid, saccharic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, benzoic acid, cypionic acid, sulfuric acid, phosphoric acid, methanolate, ethanolate,
  • a formula to prolong gestation or for the treatment of spontaneous preterm labor, spontaneous abortion, early term birth, recurrent preterm birth, recurrent early term birth, or recurrent pregnancy loss comprises an estriol ester.
  • a formula to prolong gestation or for the treatment of spontaneous preterm labor, spontaneous abortion, early term birth, recurrent preterm birth, recurrent early term birth, or recurrent pregnancy loss comprises an estriol amino ester.
  • a formula to prolong gestation or for the treatment of spontaneous preterm labor, spontaneous abortion, early term birth, recurrent preterm birth, recurrent early term birth, or recurrent pregnancy loss comprises an estriol ester or estriol amino ester selected from: 3,17.beta.-Diisobutyryloxy-1 ,3,5(10)-estratrien-16. alpha.
  • a formula to prolong gestation or for the treatment of spontaneous preterm labor, spontaneous abortion, early term birth, recurrent preterm birth, recurrent early term birth, or recurrent pregnancy loss comprises a metabolite of estriol, estradiol, estrone, or estetrol.
  • Metabolites of estriol include (but are not limited to) 16a-hydroxyestrone, 2-methoxyestrone, 2-hydroxyestrone, 4-hydroxyestrone, 2- hydroxyestradiol, 2-hydroxyestradiol, and 16-ketoestradiol.
  • Immunogens include (but are not limited to) bovine serum albumin, pneumococcal polysaccharide serotype-14 (PPS-14), keyhole limpet hemocyanin, and ovalbumin.
  • compositions and/or supplements for use in a treatment and/or prophylaxis of menstrual complications, gestational complications, and/or to prolong gestation, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other active ingredients.
  • Proper formulation is dependent upon the route of administration chosen.
  • pharmaceutical formulae are utilized within a therapeutic and thus utilized to treat a condition.
  • pharmaceutical formulae are utilized within a supplement (e.g., prenatal supplement) as a prophylaxis. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art.
  • compositions may be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared utilizing the various method embodiments as described herein.
  • active ingredient refers to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients or carriers, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder.
  • active ingredients include any one of the compounds listed herein.
  • an active ingredient is estriol or an estriol-related compound.
  • an active ingredient is estradiol or an estradiol-related compound.
  • an active ingredient is estrone or an estrone-related compound.
  • an active ingredient is estetrol or an estetrol-related compound.
  • the compounds disclosed herein can exist as therapeutically acceptable salts.
  • the term "therapeutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are therapeutically acceptable as defined herein.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound with a suitable acid or base.
  • Therapeutically acceptable salts include acid and basic addition salts.
  • Stah and Wermuth, Ed. (Wiley-VCH and VHCA, Zurich, 2002) or S. M. Berge, L. D. Bighley and D. C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19.
  • the coating agent is one which acts as a coating agent in conventional delayed release oral formulations, including polymers for enteric coating.
  • examples include hypromellose phthalate (hydroxy propyl methyl cellulose phthalate; HPMCP); hydroxypropylcellulose (HPC; such as KLLICEL®); ethylcellulose (such as ETHOCEL®); and methacrylic acid and methyl methacrylate (MAA/MMA; such as EUDRAGIT®).
  • a disintegrating agent is a super disintegrant agent.
  • disintegrants are combined with a resin.
  • Additional disintegrating agents include, but are not limited to, agar, calcium carbonate, maize starch, potato starch, tapioca starch, alginic acid, alginates, certain silicates, and sodium carbonate.
  • Suitable super disintegrating agents include, but are not limited to crospovidone, croscarmellose sodium, AMBERLITE (Rohm and Haas, Philadelphia, Pa.), and sodium starch glycolate.
  • a formulation further utilize other components and excipients.
  • sweeteners include, but are not limited to, fructose, sucrose, glucose, maltose, mannose, galactose, lactose, sucralose, saccharin, aspartame, acesulfame K, and neotame.
  • flavoring agents and flavor enhancers that may be included in the formulation of the present invention include, but are not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
  • a formulation also include a surfactant.
  • surfactants are selected from the group consisting of Tween 80, sodium lauryl sulfate, and docusate sodium.
  • a formulation also include a lubricant.
  • lubricants are selected from the group consisting of, but are not limited to, magnesium stearate, stearic acid, sodium stearyl fumarate, calcium stearate, hydrogenated vegetable oil, mineral oil, fish oil, castor oil, sesame oil, polyethylene glycol, polyethylene glycol 4000-6000, talc, and glyceryl behenate.
  • Modes of administration include, but are not limited to, oral, intravenous, subcutaneous, intramuscular, intrauterine (e.g., an implantable depot such as a hormone releasing intrauterine device), intraperitoneal, transdermal (e.g., patch), transmucosal (e.g., sublingual, nasal, vaginal or rectal) or a combination thereof.
  • the actual amount of drug needed will depend on factors such as the size, age and severity of disease in the afflicted individual. The actual amount of drug needed will also depend on the effective concentration ranges of the various active ingredients.
  • Vehicles of administration include ointments, solutions, gels, creams, suppositories, implants, tablets, or capsules, as appropriate.
  • active ingredients are administered in a therapeutically effective amount as part of a course of treatment.
  • to "treat” means to ameliorate at least one symptom of a disorder to be treated or to provide a beneficial physiological effect.
  • one such amelioration of a symptom could be reduction of risk of spontaneous preterm labor, spontaneous abortion, recurrent preterm birth, early term birth, or recurrent pregnancy loss.
  • a therapeutically effective amount can be an amount sufficient to prevent reduce, ameliorate or eliminate the symptoms of gestational complications susceptible to such treatment.
  • Data obtained from cell culture assays or animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration or within the local environment to be treated in a range that includes the ED50 as determined in cell culture or animal models. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by mass spectrometry.
  • an "effective amount” is an amount sufficient to effect beneficial or desired results.
  • a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms.
  • An effective amount can be administered in one or more administrations, applications or dosages.
  • a therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week; including once every other day, as determined to be beneficial. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
  • treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments. For example, several divided doses may be administered daily, one dose, or cyclic administration of the compounds to achieve the desired therapeutic result.
  • Preservatives and other additives can also be present.
  • One common preservative is benzyl alcohol. (See generally, Remington: The Science and Practice of Pharmacy, 21 st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005.) Methods of Treatment
  • estriol, estradiol, estrone, estetrol, and related compounds thereof are administered to an individual having a deficiency of the metabolic compound in relation to gestational progress. In some embodiments, estriol, estradiol, estrone, estetrol, and related compounds thereof are administered to an individual to prolong their gestation. In some embodiments, estriol, estradiol, estrone, estetrol, and related compounds thereof are administered to an individual as prophylaxis. In some embodiments, a prophylaxis is administered without knowing the individual’s risk of gestational complications, and/or administered to a generally healthy pregnant individual. In some embodiments, compounds or derivatives thereof are utilized as a supplement, including (for example) a prenatal supplement for any individual.
  • the individual when an individual is determined to be experiencing spontaneous preterm labor or early term labor or spontaneous loss of pregnancy, the individual is administered a compound described herein, including estriol, estradiol, estrone, estetrol, or a related compound thereof.
  • administering can be combined with standards of care for the complication.
  • an individual is additionally administered betamethasone, progesterone, 17-a-hydroxyprogesterone, antibiotics, magnesium sulfate, or a combination thereof.
  • an individual is administered is additionally administered at least one other tocolytic drug.
  • Tocolytic drugs include (but are not limited to) indomethacin, orciprenaline, ritodrine, terbutaline, salbutamol, nifedipine, fenoterol, nylidrin, or isoxsuprine.
  • administering can be combined with standards of care for the complication.
  • an individual is additionally administered betamethasone, progesterone, 17-a-hydroxyprogesterone, antibiotics, magnesium sulfate, or a combination thereof.
  • an individual is administered is additionally administered at least one other tocolytic drug.
  • Tocolytic drugs include (but are not limited to) indomethacin, orciprenaline, ritodrine, terbutaline, salbutamol, nifedipine, fenoterol, nylidrin, or isoxsuprine.
  • an individual is additionally administered a compound in combination with progesterone, 17-a-hydroxyprogesterone, human menopausal gonadotropin, a derivative thereof, or a combination thereof.
  • an individual is administered a compound described herein, including estriol, estradiol, estrone, estetrol, or a related compound thereof, for a period of 1 to 24 hours, 24 to 48 hours, 48 to 96 hours, 96 to 168 hours, 1 to 2 weeks, 2 to 4 weeks, for a period of 4 to 6 weeks, for a period of 6 to 8 weeks, for a period of 8 to 10 weeks, for a period of 10 to 12 weeks, for a period of 12 to 14 weeks, for a period of 14 to 19 weeks, 20 to 25 weeks, 25 to 30 weeks, 30 to 35 weeks, or 35 to 39 weeks.
  • an individual is administered a compound described herein, including estriol, estradiol, estrone, estetrol, or a related compound thereof, up until the week 37 of gestation, up until week 38 of gestation, up until week 39 of gestation, or up to week 40 of gestation.
  • the therapeutically effective amount of a compound described herein, including estriol, estradiol, estrone, estetrol, or a related compound thereof 1 -10mcg/day, 10-20mcg/day, 20-30mcg/day, 30-40mcg/day, 40-50mcg/day, - 60mcg/day, 60-70mcg/day, 70-80mcg/day, 80-90mcg/day, 90-100mcg/day, 100- 200mcg/day, 200-300mcg/day, 300-400mcg/day, 400-500mcg/day, 500-600mcg/day, 600-700mcg/day, 700-800mcg/day, 800-900mcg/day, 900-1 OOOmcg/day, 1 -10mg/day, 10-20mg/day, 20-30mg/day, 30-40mg/day, 40-50mg/day, 50-60mg/day,
  • Biological data support the formulations, compounds, and methods to prolong gestation and treating gestational complications.
  • examples of formulations, compounds, and methods to prolong gestation and treating gestational complications i.e., gestational age and/or time to delivery
  • the compounds described herein can be utilized to prolong gestation and/or treat an individual having a gestational complication.
  • Example 1 Compound Treatment in Mouse Models of Preterm birth
  • FIG. 2A Provided in Fig. 2A is an experimental schematic of compound treatment in mouse models of moderate preterm birth.
  • Pregnant CD1 mice were intraperitoneally administered 2mg/kg LPS (Escherichia coli 0127:B8, chromatographically pure, Sigma- Aldrich) or PBS (as control) on E16.
  • LPS Eryichia coli 0127:B8, chromatographically pure, Sigma- Aldrich
  • PBS as control
  • mice were then treated with either intraperitoneal injections of vehicle (100 pl, 30% DMSO in pharmaceutical sesame oil), estriol-16- glucuronide (100 pl vehicle, 0.8mg/mouse first and second dose; 0.5 mg/mouse third and fourth dose), estriol (100 pl vehicle, 0.8mg/mouse first and second dose; 0.5 mg/mouse third and fourth dose), or estriol-3-sulfate (100 pl vehicle, 0.8mg/mouse first and second dose; 0.5 mg/mouse third and fourth dose).
  • Compounds were administered via intraperitoneal injections after LPS: first dose at 6 hours, second dose at 12 hours, third dose at 24 hours, and fourth dose at 36 hours. Date and time of delivery was monitored 24 hours a day using infrared night-vision cameras. Results are provided in Figs. 2B and 2C.
  • Estriol and estriol-3-sulfate prolonged gestation and mitigated preterm delivery (Fig. 2B). Data are presented as mean ⁇ standard deviation (SD). Statistical analysis was conducted using one-way AN OVA followed by pairwise t-tests comparing each group with the Preterm group. Significant differences are indicated by asterisks (*) above the bars (p ⁇ 0.05).
  • Estriol and estriol-3-sulfate also increased survival rate of mouse pups (Fig. 2C).
  • the survival rate is calculated as the percentage of 'Y' (Yes) responses for Birth Confirmation out of the total responses (Y + N).
  • the data demonstrate the proportion of successful births for each group.
  • mice were treated with estriol or estriol-3-sulfate at three concentrations (1 pM, 1 mM, 10 mM).
  • the contractility is measured and plotted as a relative force ratio compared to baseline for each treatment group.
  • the relative contractile force is normalized to baseline values to show the effect of increasing concentrations of the compounds.
  • the results indicates a dose-dependent response in uterine contractility upon treatment with estriol (Fig. 3A) or with estriol-3-sulfate (Fig. 3B). Error bars indicate the standard error of the mean (SEM).
  • the level of estrone-3-sulfate was tracked through gestation in 86 healthy, pregnant women (Fig. 4). Data points represent the mean levels of Estrone 3-sulfate across different gestational ages, rounded to the nearest whole number.
  • the red vertical dashed line marks the mean birth age, providing a clear reference point for parturition.
  • the x-axis denotes gestational age in weeks, while the y-axis represents the concentration of Estrone 3-sulfate.

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Abstract

L'invention concerne des formulations, des composés et des procédés pour prolonger la grossesse et pour le traitement de complications associées à la grossesse. Les traitements comprennent l'administration d'un composé oestrogène pour atténuer les contractions utérines.
PCT/US2024/034368 2023-06-16 2024-06-17 Composés oestrogènes et formulations pour complications associées à la grossesse Ceased WO2024259428A2 (fr)

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EP2149371A1 (fr) * 2008-07-28 2010-02-03 PregLem S.A. Utilisation d'inhibiteurs de sulfatase de stéroïde pour le traitement des accouchements prématurés
CN114728013A (zh) * 2019-09-23 2022-07-08 斯坦福大学托管董事会 延长妊娠以及月经或妊娠的并发症的治疗方法

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