EP1121376A1 - Pregnane glucuronides - Google Patents
Pregnane glucuronidesInfo
- Publication number
- EP1121376A1 EP1121376A1 EP99953101A EP99953101A EP1121376A1 EP 1121376 A1 EP1121376 A1 EP 1121376A1 EP 99953101 A EP99953101 A EP 99953101A EP 99953101 A EP99953101 A EP 99953101A EP 1121376 A1 EP1121376 A1 EP 1121376A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- glucuronide
- pregnane
- pharmaceutically acceptable
- acceptable salt
- triol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- -1 Pregnane glucuronides Chemical class 0.000 title claims description 15
- 229930182480 glucuronide Natural products 0.000 title claims description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 239000000583 progesterone congener Substances 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 8
- 208000024827 Alzheimer disease Diseases 0.000 claims description 7
- 206010012289 Dementia Diseases 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 208000015114 central nervous system disease Diseases 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229940011871 estrogen Drugs 0.000 claims description 6
- 239000000262 estrogen Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- WIKQEUJFZPCFNJ-UHFFFAOYSA-N carbonic acid;silver Chemical compound [Ag].[Ag].OC(O)=O WIKQEUJFZPCFNJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 4
- KQTXIZHBFFWWFW-UHFFFAOYSA-L silver(I) carbonate Inorganic materials [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 claims description 4
- 229910019020 PtO2 Inorganic materials 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims description 3
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- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 3
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- 125000005208 trialkylammonium group Chemical group 0.000 claims description 3
- CRRKVZVYZQXICQ-RJJCNJEVSA-N Pregnenolone acetate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H](C(C)=O)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 CRRKVZVYZQXICQ-RJJCNJEVSA-N 0.000 claims description 2
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- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 claims description 2
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- JWMFYGXQPXQEEM-GCOKGBOCSA-N 5α-pregnane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](CC)[C@@]2(C)CC1 JWMFYGXQPXQEEM-GCOKGBOCSA-N 0.000 claims 1
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- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000001457 vasomotor Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J17/005—Glycosides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0007—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa
- C07J5/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa not substituted in position 16
Definitions
- estrogenic compositions of substantial purity and low toxicity such as PREMARIN (conjugated equine estrogens) has become a preferred medical treatment for alleviating the symptoms of menopausal syndrome, osteoporosis/osteopenia in estrogen deficient women and in other hormone related disorders.
- the estrogenic components of the naturally occurring estrogenic compositions have been generally identified as sulfate esters of estrone, equilin, equilenin, 17- ⁇ -estradiol, dihydroequilenin and 17- ⁇ -dihydroequilenin (U.S. Patent 2,834,712).
- the estrogenic compositions are usually buffered or stabilized with alkali metal salts of organic or inorganic acids at a substantially neutral pH of about 6.5 to 7.5.
- Urea has also been used as a stabilizer (U.S. 3,608,077).
- the incorporation of antioxidants to stabilize synthetic conjugated estrogens and the failure of pH control with tris(hydroxymethyl)aminomethane (TRIS) to prevent hydrolysis is discussed in U.S. 4,154,820.
- Pharmaceutically acceptable salts of 5 ⁇ -Pregnane-3 ⁇ ,(20S), 21-triol 20-O- ⁇ - glucuronide and 5 ⁇ -Pregnane-3 ⁇ ,20R-diol 20-O- ⁇ -glucuronide are not limited to the naturally occurring form, but also include the alkali metal salts, alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group as well as any other atom or molecules which have a positive charge.
- this invention also provides 5 ⁇ -Pregnane-3 ⁇ ,(20S), 21-triol 20-O- ⁇ -glucuronide and 5 ⁇ -Pregnane-3 ⁇ ,20R-diol 20-O- ⁇ -glucuronide and their pharmaceutically acceptable salts in greater than 1 percent purity.
- This invention also provides compounds consisting essentially of 5 ⁇ -
- This invention further provides a method of using 5 ⁇ -Pregnane-3 ⁇ ,(20S), 21- triol glucuronide and 5 ⁇ -Pregnane-3 ⁇ ,20R-diol glucuronide or a pharmaceutically acceptable salt of the related glucuronides as progestational agents.
- the starting materials used in this synthesis are either commercially available or can be prepared using standard chemical methodology.
- the compounds of this invention are progestational agents, and are therefore useful as oral contraceptives (male and female), in hormone replacement therapy (particularly when combined with an estrogen), in the treatment of endometriosis, luteal phase defects, benign breast and prostatic diseases and prostatic and endometrial cancers.
- the compounds of this invention are also useful in protecting against epileptic seizures, in cognition enhancement, in treating Alzheimer's disease, dementias, vasomotor symptoms related to menopause, and other central nervous system disorders
- the compounds of this invention are further useful in stimulating erythropoieses.
- the compounds of this invention can be used alone as a sole therapeutic agent or can be used in combination with other agents, such as other estrogens, progestins, or androgens.
- the compounds of this invention can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice.
- the pharmaceutical carrier may be solid or liquid.
- a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents: it can also be an encapsulating material.
- the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient.
- Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
- Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
- the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
- the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g.
- cellulose derivatives preferably sodium carboxymethyl cellulose solution
- alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and oils (e.g. fractionated coconut oil and arachis oil).
- the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
- Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
- the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
- Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
- the compounds of this invention can also be administered orally either in liquid or solid composition form.
- the compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository.
- the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
- the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
- the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
- the creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type.
- Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
- a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
- the dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated.
- the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
- the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
- the unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, pre filled syringes or sachets containing liquids.
- the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
- Example 5 5 ⁇ -Pregnane-3 ⁇ .20S.21-triol 20-O- ⁇ -D- lucuronide sodium salt 8
- Compound 7 (1.57 g, 1.7 mmol) was suspended in MeOH (20 mL) and treated with an aqueous solution of NaOH (6.4 mL, 0.5 N) and stirred for 5 minutes which allowed all of the starting material to go into solution. The solution was then mixed with 0.65 g of product from a previous run and the combination stripped onto silica gel and column chromatographed on silica gel (MeOH:CH 2 Cl 2 , 4:6 then 5:5).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17034298A | 1998-10-13 | 1998-10-13 | |
US170342 | 1998-10-13 | ||
PCT/US1999/023467 WO2000021977A1 (en) | 1998-10-13 | 1999-10-07 | Pregnane glucuronides |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1121376A1 true EP1121376A1 (en) | 2001-08-08 |
Family
ID=22619512
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99953101A Withdrawn EP1121376A1 (en) | 1998-10-13 | 1999-10-07 | Pregnane glucuronides |
Country Status (17)
Country | Link |
---|---|
EP (1) | EP1121376A1 (ko) |
JP (1) | JP2002527448A (ko) |
KR (1) | KR20010080102A (ko) |
CN (1) | CN1330659A (ko) |
AR (1) | AR020778A1 (ko) |
AU (1) | AU751708B2 (ko) |
BR (1) | BR9914521A (ko) |
CA (1) | CA2346693A1 (ko) |
CZ (1) | CZ20011343A3 (ko) |
EA (1) | EA200100437A1 (ko) |
HU (1) | HUP0103992A3 (ko) |
IL (1) | IL142441A0 (ko) |
NO (1) | NO20011825L (ko) |
PL (1) | PL347270A1 (ko) |
TW (1) | TW499435B (ko) |
WO (1) | WO2000021977A1 (ko) |
ZA (1) | ZA200103012B (ko) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE0104423D0 (sv) | 2001-12-27 | 2001-12-27 | Umecrine Ab | Pregnane steroids and their use in the treatment of CNS disorders |
KR100440607B1 (ko) * | 2001-12-28 | 2004-07-15 | 주식회사 엘컴사이언스 | 프레그난 배당체 화합물 및 이를 유효성분으로 함유하는퇴행성 뇌신경계 질환의 예방 및 치료제 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2029011B (en) * | 1978-09-01 | 1983-02-02 | Coulson W | Use of a synthetic bifunctional ligand for the immunimetric determination of the concentration ratio of two solutes |
-
1999
- 1999-10-07 CA CA002346693A patent/CA2346693A1/en not_active Abandoned
- 1999-10-07 CZ CZ20011343A patent/CZ20011343A3/cs unknown
- 1999-10-07 HU HU0103992A patent/HUP0103992A3/hu unknown
- 1999-10-07 IL IL14244199A patent/IL142441A0/xx unknown
- 1999-10-07 AU AU65115/99A patent/AU751708B2/en not_active Ceased
- 1999-10-07 TW TW088117305A patent/TW499435B/zh active
- 1999-10-07 BR BR9914521-9A patent/BR9914521A/pt not_active IP Right Cessation
- 1999-10-07 CN CN99814413A patent/CN1330659A/zh active Pending
- 1999-10-07 EA EA200100437A patent/EA200100437A1/ru unknown
- 1999-10-07 WO PCT/US1999/023467 patent/WO2000021977A1/en not_active Application Discontinuation
- 1999-10-07 PL PL99347270A patent/PL347270A1/xx not_active Application Discontinuation
- 1999-10-07 JP JP2000575882A patent/JP2002527448A/ja active Pending
- 1999-10-07 EP EP99953101A patent/EP1121376A1/en not_active Withdrawn
- 1999-10-07 KR KR1020017004572A patent/KR20010080102A/ko not_active Application Discontinuation
- 1999-10-12 AR ARP990105144A patent/AR020778A1/es unknown
-
2001
- 2001-04-10 NO NO20011825A patent/NO20011825L/no not_active Application Discontinuation
- 2001-04-11 ZA ZA200103012A patent/ZA200103012B/en unknown
Non-Patent Citations (1)
Title |
---|
See references of WO0021977A1 * |
Also Published As
Publication number | Publication date |
---|---|
HUP0103992A2 (hu) | 2002-04-29 |
BR9914521A (pt) | 2001-06-26 |
AU6511599A (en) | 2000-05-01 |
TW499435B (en) | 2002-08-21 |
AU751708B2 (en) | 2002-08-22 |
NO20011825L (no) | 2001-06-05 |
WO2000021977A1 (en) | 2000-04-20 |
JP2002527448A (ja) | 2002-08-27 |
EA200100437A1 (ru) | 2001-10-22 |
CN1330659A (zh) | 2002-01-09 |
CZ20011343A3 (cs) | 2002-04-17 |
NO20011825D0 (no) | 2001-04-10 |
AR020778A1 (es) | 2002-05-29 |
ZA200103012B (en) | 2002-07-11 |
PL347270A1 (en) | 2002-03-25 |
KR20010080102A (ko) | 2001-08-22 |
HUP0103992A3 (en) | 2002-12-28 |
IL142441A0 (en) | 2002-03-10 |
CA2346693A1 (en) | 2000-04-20 |
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