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US 6,645,953 B2Granted
Meiosis regulating compounds
AssigneeNovo Nordisk A/S
InventorsFrederik Christian Gronvald, Peter Faarup, Erling Guddal
Life of this patent
Estimating the term…
Abstract
Sterol derivative compounds, structurally related to natural compounds which can be extracted from bull testes and from human follicular fluid, useful for regulating meiosis in oocytes and in male germ cells. Some of these compounds are useful in the treatment of infertility, whereas other compounds are useful as contraceptives.
Claims12
A method of regulating meiosis in a mammalian germ cell comprising administering to a germ cell in need of such regulation, an effective amount of a compound of formula (I)
- wherein R1 and R2, independently, are selected from the group consisting of hydrogen and branched or unbranched C1-C6 alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R1 and R2 together designate methylene or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring;
- R3 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOR26 wherein R26 is hydrogen or C1-C3 alkyl, halogen, and C1-C4 alkyl;
- R4 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOR27 wherein R27 is hydrogen or C1-C3 alkyl, halogen, and C1-C4 alkyl;
- R5 designates, together with R6, an additional bond between the carbon atoms to which R5 and R6 are bound;
- R9 is hydrogen;
- R10 is hydrogen;
- R11 is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, alkanoyloxyalkyl, acyloxy, sulphonyloxy, phosphonyloxy, oxo, ═NOR28 wherein R28 is hydrogen or C1-C3 alkyl, halogen and C1-C4 alkyl;
- R12 is selected from the group consisting of hydrogen, C1-C3 alkyl, vinyl, C1-C3 alkoxy and halogen;
- R13 designates, together with R14, an additional bond between the carbon atoms to which R13 and R14 are bound;
- R15 is selected from the group consisting of hydrogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo, and ═NOR23 wherein R23 is hydrogen or C1-C3 alkyl;
- R16 is selected from the group consisting of hydrogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and ═NOR24 wherein R24 is hydrogen or C1-C3 alkyl;
- R17 is hydrogen or hydroxy;
- R18 and R19 are, independently, hydrogen or fluoro;
- R25 is selected from the group consisting of hydrogen, C1-4 alkyl, methylene, hydroxy and oxo;
- A is a carbon atom;
- R7 is selected from the group consisting of hydrogen, hydroxy and fluoro, and R8 is selected from the group consisting of hydrogen, C1-C4 alkyl, methylene and halogen;
- R20 is selected from the group consisting of C1-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl and R21 is selected from the group consisitning of C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C3-C6 cycloalkyl;
- provided that the compound of formula (I) does not have any cumulated double bonds and further provided that the compound is not one of the following compounds:
- Cholesta-8,14-diene-3β-ol;
- 4-Methylcholesta-8,14-diene-3β-ol;
- 4-Ethylcholesta-8,14-diene-3β-ol;
- 4,4-Dimethylcholesta-8,14-diene-3β-ol;
- 4α-Methyl-4β-ethylcholesta-8,14-diene-3β-ol;
- 4α-Ethyl-4β-methylcholesta-8,14-diene-3β-ol;
- 4,4-Diethylcholesta-8,14-diene-3β-ol;
- 4-Propylcholesta-8,14-diene-3β-ol;
- 4-Butylcholesta-8,14-diene-3β-ol;
- 4-Isobutylcholesta-8,14-diene-3β-ol;
- 4,4-Tetramethylenecholesta-8,14-diene-3β-ol;
- and
- 4,4-Pentamethylenecholesta-8,14-diene-3β-ol;
- or esters or ethers thereof.
29 more elements
A method of producing mature male germ cells by administration of a compound to testicular tissue, wherein the compound is a compound of formula (I)
- wherein R1 and R2, independently, are selected from the group consisting of hydrogen and branched or unbranched C1-C6 alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R1 and R2 together designate methylene or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring;
- R3 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOR26 wherein R26 is hydrogen or C1-C3 alkyl, halogen, and C1-C4 alkyl;
- R4 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOR27 wherein R27 is hydrogen or C1-C3 alkyl, halogen, and C1-C4 alkyl;
- R5 designates, together with R6, an additional bond between the carbon atoms to which R5 and R6 are bound;
- R9 is hydrogen;
- R10 is hydrogen;
- R11 is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, alkanoyloxyalkyl, acyloxy, sulphonyloxy, phosphonyloxy, oxo, ═NOR28 wherein R28 is hydrogen or C1-C3 alkyl, halogen and C1-C4 alkyl;
- R12 is selected from the group consisting of hydrogen, C1-C3 alkyl, vinyl, C1-C3 alkoxy and halogen;
- R13 designates, together with R14, an additional bond between the carbon atoms to which R13 and R14 are bound;
- R15 is selected from the group consisting of hydrogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo, and ═NOR23 wherein R23 is hydrogen or C1-C3 alkyl;
- R16 is selected from the group consisting of hydrogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and ═NOR24 wherein R24 is hydrogen or C1-C3 alkyl;
- R17 is hydrogen or hydroxyl;
- R18 and R19 are, independently, hydrogen or fluoro;
- R25 is selected from the group consisting of hydrogen, C1-C4 alkyl, methylene, hydroxy and oxo;
- A is a carbon atom, R7 is selected from the group consisting of hydrogen, hydroxy and fluoro, and R8 is selected from the group consisting of hydrogen, C1-C4 alkyl, methylene and halogen;
- R20 is selected from the group consisting of C1-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl and R21 is selected from the group consisitning of C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C3-C6 cycloalkyl;
- provided that the compound of formula (I) does not have any cumulated double bonds and further provided that the compound is not one of the following compounds:
- Cholesta-8,14-diene-3β-ol;
- 4-Methylcholesta-8,14-diene-3β-ol;
- 4-Ethylcholesta-8,14-diene-3β-ol;
- 4,4-Dimethylcholesta-8,14-diene-3β-ol;
- 4β-Methyl-4β-ethylcholesta-8,14-diene-3β-ol;
- 4α-Ethyl-4β-methylcholesta-8,14-diene-3β-ol;
- 4,4-Diethylcholesta-8,14-diene-3β-ol;
- 4-Propylcholesta-8,14-diene-3β-ol;
- 4-Butylcholesta-8,14-diene-3β-ol;
- 4-Isobutylcholesta-8,14-diene-3β-ol;
- 4,4-Tetramethylenecholesta-8,14-diene-3β-ol;
- and 4,4-Pentamethylenecholesta-8,14-diene-3β-ol;
- or esters or ethers thereof.
27 more elements
A method of promoting meiotic maturation in an oocyte, comprising culturing the oocyte in the presence of a compound of formula (I)
- wherein R1 and R2, independently, are selected from the group consisting of hydrogen and branched or unbranched C1-C6 alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R1 and R2 together designate methylene or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring;
- R3 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOR26 wherein is hydrogen or C1-C3 alkyl, halogen, and C1-C4 alkyl;
- R4 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOR27 wherein R27 is hydrogen or C1-C3 alkyl, halogen, and C1-C4 alkyl;
- R5 designates, together with R6, an additional bond between the carbon atoms to which R5 and R6 are bound;
- R9 is hydrogen;
- R10 is hydrogen;
- R11 is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, alkanoyloxyalkyl, acyloxy, sulphonyloxy, phosphonyloxy, oxo, ═NOR28 wherein R28 is hydrogen or C1-C3 alkyl, halogen and C1-C4 alkyl;
- R12 is selected from the group consisting of hydrogen, C1-C3 alkyl, vinyl, C1-C3 alkoxy and halogen;
- R13 designates, together with R14, an additional bond between the carbon atoms to which R13 and R14 are bound;
- R15 is selected from the group consisting of hydrogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo, and ═NOR23 wherein R23 is hydrogen or C1-C3 alkyl;
- R16 is selected from the group consisting of hydrogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and ═NOR24 wherein R24 is hydrogen or C1-C3 alkyl;
- R17 is hydrogen or hydroxy;
- R18 and R19 are, independently, hydrogen or fluoro;
- R25 is selected from the group consisting of hydrogen, C1-C6 alkyl, methylene, hydroxy and oxo;
- A is a carbon atom, R7 is selected from the group consisting of hydrogen, hydroxy and fluoro, and R8 is selected from the group consisting of hydrogen, C1-C4 alkyl, methylene and halogen;
- R20 is selected from the group consisting of C1-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl and R21 is selected from the group consisitning of C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C3-C6 cycloalkyl;
- provided that the compound of formula (I) does not have any cumulated double bonds and further provided that the compound is not one of the following compounds:
- Cholesta-8,14-diene-3β-ol;
- 4-Methylcholesta-8,14-diene-3β-ol;
- 4-Ethylcholesta-8,14-diene-3β-ol;
- 4,4-Dimethylcholesta-8,14-diene-3β-ol;
- 4α-Methyl-4β-ethylcholesta-8,14-diene-3β-ol;
- 4α-Ethyl-4β-methylcholesta-8,14-diene-3β-ol;
- 4,4-Diethylcholesta-8,14-diene-3β-ol;
- 4-Propylcholesta-8,14-diene-3β-ol;
- 4-Butylcholesta-8,14-diene-3β-ol;
- 4-Isobutylcholesta-8,14-diene-3β-ol;
- 4,4-Tetramethylenecholesta-8,14-diene-3β-ol;
- and 4,4-Pentamethylenecholesta-8,14-diene-3β-ol;
- or esters or ethers thereof.
27 more elements
Dependencies are inferred from the claim text.