WO2002066437A1 - Chinolin-, isochinolin- und phthalazinderivate als antagonisten des gonadotropin freisetzenden hormons - Google Patents
Chinolin-, isochinolin- und phthalazinderivate als antagonisten des gonadotropin freisetzenden hormons Download PDFInfo
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- WO2002066437A1 WO2002066437A1 PCT/EP2002/001882 EP0201882W WO02066437A1 WO 2002066437 A1 WO2002066437 A1 WO 2002066437A1 EP 0201882 W EP0201882 W EP 0201882W WO 02066437 A1 WO02066437 A1 WO 02066437A1
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- 0 **(*C(c1c2c(O)c(*)c(*)c1*)[Np])C2=O Chemical compound **(*C(c1c2c(O)c(*)c(*)c1*)[Np])C2=O 0.000 description 2
- BETDUNCFYKZZDO-UHFFFAOYSA-N CCOC(C(C(c1c2[N+]([O-])=O)=O)=CN(Cc(c(F)ccc3)c3F)c1ccc2F)=O Chemical compound CCOC(C(C(c1c2[N+]([O-])=O)=O)=CN(Cc(c(F)ccc3)c3F)c1ccc2F)=O BETDUNCFYKZZDO-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
Definitions
- the gonadotropin releasing hormone is a hormone that is predominantly, but not exclusively, synthesized in mammals by hypothalamic nerve cells, transported via the portal vein to the pituitary gland and released to the gonadotrophic cells in a regulated manner.
- GnRH gonadotropin releasing hormone
- the gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH) released by GnRH stimulate the production of sex steroids and the germ line maturation in both sexes.
- GnRH also called GnRH1
- GnRH2 there are two other forms of GnRH, namely GnRH2 and 3.
- the GnRH receptor is used as a pharmacological target in a number of diseases that depend on functioning sex hormone production, for example prostate cancer, premenopausal breast cancer, endometriosis and uterine fibroids. GnRH superagonists or antagonists can be successfully used in these diseases. Another possible indication is male fertility control in combination with a substitution dose of androgens.
- GnRH antagonists compared to superagonists are their immediate effectiveness in blocking gonadotropin secretion.
- Superagonists initially over-stimulate the pituitary gland, leading to increased gonadotropin and sex steroid releases. This hormonal response is only due to desensitization and downregulation of GnRH receptor concentrations after one some delay ended.
- GnRH superagonists both alone and in combination with testosterone, may therefore not be able to effectively suppress sperm production in men and are therefore not suitable for male fertility control.
- peptide GnRH antagonists especially in combination with a substitution dose of androgen, are capable of causing significant human oligozoospermia.
- GnRH peptide antagonists have a number of disadvantages. They are considerably less effective than superagonists and must therefore be administered in considerably higher doses. Their oral bioavailability is also low, so they have to be administered by injection. Repeated injections in turn reduce compliance. In addition, the synthesis of peptide GnRH antagonists is complex and expensive compared to non-peptide compounds.
- the object on which the present invention was based was to provide new GnRH antagonists which are superior to known peptide compounds and represent an effective alternative to known non-peptide compounds.
- the new GnRH antagonists are said to have both a high potency and a high oral bioavailability. Furthermore, they should be easy to synthesize and at the lowest possible cost. This object is achieved by compounds of the general formula (1):
- R 1 (a) is an acyl group -CO-R11 or CN, where R11 is a saturated, unsaturated, cyclic and / or (hetero) aromatic organic
- Radical in particular a straight or branched alkyl chain with 1-10 C atoms, or a phenyl, furan or thiophene group which is optionally substituted by alkyl groups or halogen atoms,
- Oxygen atom or the group -SO x - with X 0, 1 or 2, R14 and
- R15 are each independently a hydrogen atom or a straight or branched alkyl chain with 1-10 C atoms and R16 is a straight or branched alkyl chain with 1-10 C atoms, a cycloalkyl group with 3- 10 carbon atoms, a cycloalkylalkyl group with 7-20 carbon atoms, an aralkyl group with 7-20 carbon atoms, where the aryl radical can optionally be substituted by alkyl groups or halogen atoms, a phenyl group optionally substituted by alkyl groups or halogen atoms or a possibly is heterocyclic ring substituted by alkyl groups or halogen atoms, R2 is a group -CH (R21) R22, where R21 is a hydrogen atom, a C 1-4 alkyl group or an optionally substituted phenyl ring and R22 is an optionally substituted phenyl ring or naphthyl ring, or a group -
- R3 can also be a halogen atom
- R5 is a group linked via the radical Z
- R6 is the group CH 2 -N (R61) R62, where R61 each independently represents a hydrogen atom or an alkyl group and R62 is an alkyl group or an optionally substituted aralkyl group or heteroarylalkyl group with 7-20 C -Atoms are and
- R1 straight or branched alkyl chain a methyl, ethyl, n-propyl
- Nonyl, n-decyl group The methyl or ethyl group is preferred.
- Chlorine, bromine, iodophenyl group, a 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-, difluoro, dichloro, dibromo, or diiodophenyl group or a naphthyl group, a phenyl group is preferred.
- An optionally substituted furan or thiophene group an unsubstituted 2- or 3-thienyl or 2- or 3-fur l group or a 3-methyl, 3-ethyl, 3-fluoro, 3-chloro, 3-bromo, 3-iodo-2-furyI or -2-thienyl group, a 4-methyl, 4-ethyl -, 4-fluoro, 4-chloro, 4-bromo, 4-iodo-2-furyl or 2-thienyl group, a 5-methyl, 5-ethyl, 5-fluoro, 5-chloro , 5-bromo, 5-iodo-2-furyl or - 2-thienyl group, a 2-methyl, 2-ethyl, 2-fluoro, 2-chloro, 2-
- a 2-thienyl or 2-furyl group is preferred.
- An aralkyl group with 7-20 C atoms a benzyl group, a 1-phenyl-ethyl-propyl, -butyl, -hexyl, -2-methylethyl, -2-ethylethyl, -2,2-dimethylethyl- group, an o-, m- p- methyl, ethyl, propyl, isopropylbenzyl group, a 2 ', 3'-, 2 ⁇ 4'-, 2', 5'-,
- a CrC ⁇ alkyl group a straight or branched alkyl group with 1-6 C atoms such as a methyl, ethyl, n-propyl, iso-propyl, n, iso, tert-butyl, n-pentyl -, 2,2-Dimethylpropyl- or 3-
- a cycloalkyl radical a cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, decahydronaphthalene radical.
- a cycloalkylalkyl radical is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptylmethyl radical, a 1-cyclopropyl, 1-cyclobutyl, 1-cyclopentyl, 1-cyclohexyl, 1- Cycloheptyl-ethyl, a 2-cyclopropyl, 2-cyclobutyl, 2-cyclopentyl, 2-cyclohexyl, 2-cycloheptyl-ethyl radical.
- a heterocyclic ring an unsubstituted 2- or 3-thienyl or 2- or 3-furyl group or a 3-methyl, 3-ethyl, 3-
- Fluorine, 3-chloro, 3-bromo, 3-iodo-2-furyl or -2-thienyl group a 4-methyl, 4-ethyl, 4-fluoro, 4-chloro, 4- Bromine, 4-iodo-2-furyl or -2-thienyl group, a 5-methyl, 5-ethyl, 5-fluoro, 5-chloro, 5-bromo, 5-iodo-2-furyl - or -2-thienyl group, a 2-methyl, 2-ethyl, 2-fluoro, 2-chloro, 2-bromo, 2-iodo-3-furyl or -
- 3-thienyl group a 4-methyl, 4-ethyl, 4-fluoro, 4-chloro, 4-bromo, 4-iodo-3-furyl or -3-thienyl group, a 5-methyl, 5-ethyl, 5-fluorine, 5-chloro, 5-bromo, 5-iodo-3-furyl or -3-thienyl group, an unsubstituted 2-, 3- or 4-pyridyl group or a 3-methyl -, 3-ethyl, 3-fluorine, 3-chloro, 3-bromo, 3-iodine
- 2-pyridyl group a 4-methyl, 4-ethyl, 4-fluoro, 4-chloro, 5-bromo, 4-iodo-2-pyridyl group, a 5-methyl, 5-ethyl, 5 -Fluoro, 5-chloro, 5-bromo, 5-iodo-2-pyridyl group, a 2-methyl, 2-ethyl, 2-fluoro, 2-chloro, 2-bromo, 2- Iodine-3-pyridyl group, a 4-methyl, 4-ethyl, 4-fluoro, 4-chloro, 4-bromo, 4-iodo-3-pyridyl group, a 5-methyl, 5-ethyl , 5-fluoro, 5-chloro, 5-bromo, 5-iodo-3-pyridyl group, a 2-, 4-, 5-, 6- pyrimidinyl group, a 3-, 4-, 5-, 6- Pyridazinyl group or a 2- or 3-pyrazin
- alkyl group a straight or branched alkyl group with 1 -
- An optionally substituted phenyl ring or naphthyl ring a phenyl, an o-, m-, p-methyl, -ethyl, -propyl, -isopropylphenyl group, a 2,3-, 2,4-, 2,5- , 2,6-, 3,4-, 3,5-dimethyl or - diethylphenyl group, an o-, m-, p- fluorine, chlorine, bromine, Iodophenyl group, a 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-difluoro, dichloro, dibromo, or diiodophenyl group, an o-, m- , p-trihalomethylphenyl group, a 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-di-trihalophenyl group, an o-, m-, p-
- Naphthyl A 2,5-difluorophenyl group is preferred.
- R3 an alkyl group: a straight or branched alkyl group and R4 with 1-6 C atoms such as a methyl, ethyl, n-propyl, iso-propyl, n-, iso-, tert-butyl, n -Pentyl-, 2,2-dimethylpropyl- or 3-
- Methylbutyl A hydrogen atom is preferred.
- R5 an alkyl group: a straight or branched alkyl group with 1 -
- Methylbutyl A hydrogen atom is preferred.
- R6 an alkyl group: a straight or branched alkyl group with 1-
- An aralkyl group with 7-20 C atoms a benzyl group, a 1-phenyl-ethyl, -propyl-, -butyl-, -hexyl-, -2-methlethyl-, -2-ethylethyl-, -2,2- dimethylethyl group, an o-, m- p- methyl, ethyl, propyl, isopropylbenzyl group, a 2 ⁇ 3'-, 2 ', 4'-, 2', 5'-,
- a heteroaralkyl group with 7-20 C atoms a 2-, 3- or 4-pyridyl-methyl, -ethyl, or -propyl group, a 2- or 3-furyl- methyl, ethyl or propyl group, a 2- or 3-thienylmethyl, ethyl or propyl group, 2-, 3-, 4-, 5-, 6- or 7-indolyl -methyl, -ethyl or -propyl group.
- the benzyl group is preferred.
- R11 has, for example, the preferred meaning methyl, ethyl, i-propyl, phenyl, 2-thienyl and 2-furyl. If R1 has the meaning -CO-OR12, then R12 can, for example, preferably be methyl, ethyl or i-propyl.
- R2 is an aromatic group substituted on the aromatic ring by one or more halogen atoms, in particular fluorine atoms, e.g. B. is a benzyl group, for example a 2 ', 6'-difluorobenzyl group.
- R 3 and R 4 are hydrogen atoms.
- L is preferably an NH group, while Q is preferably a carbonyl group and R51 is a Ci-Cö-alkyl group.
- Particularly preferred meanings for R61 are hydrogen atoms or C 3 -C 3 -alkyl groups, in particular methyl groups, and for R62 an aralkyl radical, for example a benzyl group.
- the compounds (1) are preferably prepared by (a) reaction of a compound of the general formula (2)
- R7 is a leaving group, e.g. represents a halogen atom or an alkyl, perfluoroalkyl or arylsulfonyl group and all other radicals have the meaning given for compound (1), with a compound of the general formula (3)
- R8 is a hydrogen atom or a metal atom, such as. B. represents a lithium, sodium, potassium, cesium, calcium or barium atom and R61 and R62 have the meanings given for compound (1),
- R9 is the group -OSO 2 CnF 2 n + ⁇ , a halogen atom, especially a bromine or iodine atom or another leaving group and all other radicals have the meaning given for compound (1), with a compound of the general formula (5)
- R10 is a group containing a metal, such as a trialkyltin group, a halogen magnesium group or a group containing a non-metal, such as boron, silicon etc., a dialkoxyboron or a dihydroxyboron group, optionally in a metal salt such as e.g. B. a lithium, sodium, potassium, cesium, calcium, barium, silver or copper salt, transferred hydroxyl or mercapto group, the group -C ⁇ C-R31 or an E- or Z-configured
- a metal salt such as e.g. B. a lithium, sodium, potassium, cesium, calcium, barium, silver or copper salt, transferred hydroxyl or mercapto group, the group -C ⁇ C-R31 or an E- or Z-configured
- Compound (1) have the meaning given, with or without the participation of a catalyst, such as. B. copper, nickel, palladium, platinum or organic derivatives of the metals mentioned; (c) when Y in compound (1) is a nitrogen atom, by
- R32 is a hydrogen atom or a metal atom, such as. B. is a lithium, sodium, potassium, cesium, calcium, barium, silver or copper atom, and all other radicals have the meaning given for compound (1), with a compound of general formula (7) R33-R2 (7)
- R33 represents a leaving group, e.g. a halogen atom or an alkyl, perfluoroalkyl or arylsulfonyl group, and R2 has the meaning given for compound (1), or
- R32 is a hydrogen atom or a metal atom, such as. B. a lithium, potassium, cesium, calcium, barium, silver or copper atom, and all other radicals are those in connection
- R33 is a leaving group, e.g. represents a halogen atom or an alkyl, perfluoroalkyl or arylsulfonyl group, and R1 has the meaning given for compound (1).
- the compounds (1) according to the invention can be used as antagonists of the gonadotropin-releasing hormone, for example for male fertility control, for hormone therapy, for the treatment of female sub- and infertility, for female contraception and for combating tumors.
- the compounds of the invention reduce spermatogenesis.
- Combined administration with androgens, for example testosterone or testosterone derivatives, such as testosterone esters, is preferably carried out.
- Testosterone derivatives can be obtained e.g. by injection, e.g. by intramuscular depot injection.
- hormone therapy for example for the treatment of endometriosis, uterine leiomyomas and uterine fibroids
- Estrogens and / or progestins can be used. Combinations of the GnRH antagonists according to the invention and tissue-selective partial estrogen agonists such as Raloxifene® are particularly preferred.
- the compounds (1) according to the invention can be used to increase female fertility, for example by inducing ovulation, and
- Treatment of sterility can be used.
- the compounds (1) are also suitable for contraception in women.
- the GnRH antagonist can on days 1 to 15 of the cycle together with estrogen, preferably with very low estrogen dosages administered> be.
- Progestagen of the estrogen-GnRH-antagonist combination is added on days 16 to 21 of the intake cycle.
- the GnRH antagonist can be administered continuously throughout the cycle. In this way, a reduction in hormone doses and thus a reduction in the side effects of unphysiological hormone levels can be achieved.
- advantageous effects can be achieved in women who suffer from polycystic ovary syndrome and androgen-dependent diseases such as acne, seborrhea and hirsutism. Improved cycle control over previous administration methods is also to be expected.
- Other indications are benign prostatic hyperplasia, gonadal protection during chemotherapy, controlled ovarian stimulation / artificial Reproductive techniques, early childhood developmental disorders, such as puberty praecox and polycystic ovaries.
- the GnRH agonists according to the invention can also be used for the treatment of hormone-dependent tumor diseases, such as premenopausal breast cancer, prostate cancer, ovarian cancer and endometrial cancer, by suppressing the endogenous sex steroid hormones.
- the compounds (1) according to the invention are GnRH antagonists for administration to humans, but also for veterinary purposes, e.g. suitable for domestic and farm animals, but also for wild animals.
- the administration can be carried out in a known manner, for example orally, topically, rectally, intravaginally, nasally or by injections. Oral administration is preferred.
- the compounds (1) are brought into an administrable form and, if appropriate, are mixed with pharmaceutically acceptable carriers or diluents.
- Oral administration can take place, for example, in solid form as a tablet, capsule, dragee or powder, but also in the form of a drinkable solution.
- the non-oral administration can take place, for example, by intravenous, subcutaneous or intramuscular injection or by ointments, creams or suppositories. If necessary, it can also be administered as a slow-release form.
- the dosage can vary depending on the type of indication, the severity of the disease, the age, gender, body weight and the sensitivity of the subject to be treated. Dosages of from 0.01 to 30 mg, particularly preferably from 0.1 to 3 mg and most preferably from 0.1 to 1 mg per kg of body weight and day are preferably administered. Administration can be in a single dose or multiple separate doses.
- Particularly preferred compounds (1) are listed below: Particularly preferred compounds
- styryl compound 450 mg are dissolved in 25 ml of tetrahydrofuran and 7 ml of water, and 0.11 ml of a 2.5% solution of osmium tetroxide in tert-butanol is added. After stirring for 15 minutes at room temperature, 482 mg, 100 mg after 20 and 22 hours and a further 100 mg of sodium periodate after 24 hours are added. After 26 hours, the mixture is diluted with water and extracted with ethyl acetate. After drying the organic phase with sodium sulfate, the mixture is evaporated. 352 mg of the title compound are obtained as a foam.
- This compound is formed from 6- (4-acetamidophenoxy) -5- (N-benzyl-N-methylaminomethyl) -1- (2 ' , 6 ' -difluorobenzyl) -1, 4-dihydro-4-oxo-quinoline-3- carboxylic acid ethyl ester by heating with titanium tetraisopropylate in isopropanol.
- Example 1 / c 4- isobutyramidophenol used instead of 4-acetamidophenol and analogous to Example 1 / d. to example 1 / i. continues to implement.
- the title compound is obtained by reacting 6- (4-acetamidophenyl) -1-benzyl-5- (N-benzyl-N-methylaminomethyl) phthalazin-4-one in the presence of a base such as sodium carbonate or sodium hydroxide with acetyl chloride or acetic anhydride.
- a base such as sodium carbonate or sodium hydroxide
- 6- (4-Acetamidophenyl) -1-benzyl-5- (N-benzyl-N-methylaminomethyl) - phthalazin-4-one can be obtained in the following way: a. 6- (4-acetamidophenyl) -1-benzyl-5-iodophthalazin-4-one
- the starting material 6- (4-acetamidophenoxy) -5- (chloromethyl) -1, 4-dihydro-4-oxo-1 - (2'-trifluoromethylbenzyl) quinoline-3-carboxylic acid ethyl ester is analogous to that in Examples 1a to 1i described route prepared using 2'-trifluoromethyl-benzyl bromide instead of 2,6-difluoromethyl benzyl bromide.
- the starting material 6- (4-methylaminocarbonyI-phenoxy) -5- (chloromethyl) - 1- (2 ⁇ 6 -d ⁇ fluorobenzyl) -1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester is analogous to that in the Examples 1a to 1i route described using 4-hydroxy-N-methylbenzoic acid amide instead of 4-acetamidophenol.
- the starting material 6- (4-acetamidophenoxy) -5- (chloromethyl) -1- (1-naphthyl-methyl) -1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester is analogous to that in Examples 1a to 1 i described route using 1-chloromethylnaphthalene instead of 2,6-difluoromethylbenzyl bromide.
- Buserelin was purchased from Welding (Frankfurt Main, Germany). The compound was labeled with 125 l using the chloramine T method and Na 125 l (4000 Ci / mmol; Amersham-Buchler, Braunschweig, Germany). The labeled substance was purified by reverse phase HPLC on a Spherisorb ODS II column (250 ⁇ 4 mm, particle size 3 ⁇ m) by elution with 50% acetonitrile / 0.15% trifluoroacetic acid at a flow rate of 0.5 ml / min. The specific activity was 2000 Ci / mmol.
- the supernatant was centrifuged at 18,000 rpm in a Sorvall SS34 rotor for 30 minutes.
- the pellet (cell membranes) was suspended by potting in 5 ml assay buffer (0.25 mol / l sucrose, 0.01 mol / l triethanolamine, pH 7.5, 1 mg / ml ovalbumin) and in 200 ⁇ l aliquots at -20 ° C kept.
- the protein was determined by the Bradford method (Anal. Biochem. 72 (1976), 248-254).
- a test sample contained 60 ⁇ l cell membrane suspension (10 ⁇ g protein for ⁇ T3-1 cells or 40 ⁇ g protein for CHO3 cells), 20 ⁇ l 125 l labeled buserelin (100,000 Ipm per sample for competition curves and between 1,500 and 200,000 Ipm for saturation experiments) and 20 ⁇ l test buffer or test connection solution.
- the test compounds were dissolved in distilled water or 50% ethanol. Serial dilutions (5 x 10 "6 mol / l to 5 x 10 " 12 mol / l) were made in test buffer. The non-specific binding was determined in the presence of an excess of unlabelled buserelin (10 "6 mol / l).
- test samples were incubated for 30 min at room temperature. Bound and free ligand were removed by filtration (Whatman GF / C filter 2.5 cm in diameter ) separated using an Amicon 10x collecting device and twice with 5 ml of 0.02 mol / l Tris / HCl, pH 7.4 washed. The filters were moistened with 0.3% polyethyleneimine (Serva; Heidelberg, Germany) for 30 min in order to reduce the non-specific binding. The radioactivity retained by the filters was determined in a 5-channel gamma counter (Wallac-LKB 1470 Wizard).
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
UA2003087846A UA73409C2 (en) | 2001-02-21 | 2002-02-21 | Quinoline, isoquinoline and phthalazine derivatives as antagonists of the gonadotropin-releasing hormone. |
HU0303219A HUP0303219A2 (hu) | 2001-02-21 | 2002-02-21 | Kinolin-, izokinolin- és ftalazinszármazékok mint gonadotropinfelszabadító hormon antagonisták és eljárás az előállításukra |
MXPA03007348A MXPA03007348A (es) | 2001-02-21 | 2002-02-21 | Derivados de quinolina, isoquinolina y ftalazina como antagonistas de la hormona de liberacion de gonadotropina. |
KR1020037010965A KR100701806B1 (ko) | 2001-02-21 | 2002-02-21 | 고나도트로핀 방출 호르몬 길항제로서의 퀴놀린 유도체 및 이의 제조방법 |
NZ527597A NZ527597A (en) | 2001-02-21 | 2002-02-21 | Quinoline, isoquinoline and phthalazine derivatives as antagonists of the gonadotropin-releasing hormone |
AU2002247737A AU2002247737B2 (en) | 2001-02-21 | 2002-02-21 | Quinoline, isoquinoline and phthalazine derivatives as antagonists of the gonadotropin-releasing hormone |
CA002438709A CA2438709A1 (en) | 2001-02-21 | 2002-02-21 | Quinoline, isoquinoline and phthalazine derivatives as antagonists of the gonadotropin-releasing hormone |
IL15730302A IL157303A0 (en) | 2001-02-21 | 2002-02-21 | Quinoline, isoquinoline and phthalazine derivatives as antagonists of the gonadotropin-releasing hormone |
BR0207451-6A BR0207451A (pt) | 2001-02-21 | 2002-02-21 | Derivados de quinolina, isoquinolina e ftalazina como antagonistas do hormÈnio liberador de gonadotropina |
JP2002565954A JP2004528298A (ja) | 2001-02-21 | 2002-02-21 | ゴナドトロピン放出ホルモンのアンタゴニストとしてのキノリン、イソキノリン及びフタラジン誘導体 |
EP02716803A EP1362034A1 (de) | 2001-02-21 | 2002-02-21 | Chinolin-, isochinolin- und phthalazinderivate als antagonisten des gonadotropin freisetzenden hormons |
SK1162-2003A SK11622003A3 (sk) | 2001-02-21 | 2002-02-21 | Chinolínové, izochinolínové a ftalazínové deriváty ako antagonisty gonádoliberínu |
NO20033698A NO325675B1 (no) | 2001-02-21 | 2003-08-20 | Quinolin, isoquinolin og ftalazinderivater, fremgangsmate for fremstilling derav samt anvendelse av forbindelsene |
BG108165A BG108165A (en) | 2001-02-21 | 2003-09-09 | Quinoline, isoquinoline and phthalazine derivatives as antagonists of the gonadotropin-releasing hormone |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2001108271 DE10108271A1 (de) | 2001-02-21 | 2001-02-21 | Chinolin-, Isochinolin- und Phthalazinderivate als Antagonisten des Gonadotropin freisetzenden Hormons |
DE10108271.1 | 2001-02-21 | ||
US60/274,914 | 2001-03-12 | ||
US27491401P | 2001-03-13 | 2001-03-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002066437A1 true WO2002066437A1 (de) | 2002-08-29 |
Family
ID=26008581
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2002/001882 WO2002066437A1 (de) | 2001-02-21 | 2002-02-21 | Chinolin-, isochinolin- und phthalazinderivate als antagonisten des gonadotropin freisetzenden hormons |
Country Status (17)
Country | Link |
---|---|
EP (1) | EP1362034A1 (de) |
JP (1) | JP2004528298A (de) |
CN (1) | CN1496354A (de) |
AU (1) | AU2002247737B2 (de) |
BG (1) | BG108165A (de) |
BR (1) | BR0207451A (de) |
CA (1) | CA2438709A1 (de) |
CZ (1) | CZ20032514A3 (de) |
HU (1) | HUP0303219A2 (de) |
IL (1) | IL157303A0 (de) |
MX (1) | MXPA03007348A (de) |
NO (1) | NO325675B1 (de) |
NZ (1) | NZ527597A (de) |
PL (1) | PL367285A1 (de) |
RU (1) | RU2280031C2 (de) |
SK (1) | SK11622003A3 (de) |
WO (1) | WO2002066437A1 (de) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10280160B2 (en) | 2013-03-13 | 2019-05-07 | Flatley Discovery Lab, Llc | Phthalazinone compounds and methods for the treatment of cystic fibrosis |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997014682A1 (en) * | 1995-10-19 | 1997-04-24 | Takeda Chemical Industries, Ltd. | Quinoline derivatives as gnrh antagonists |
WO1997044041A1 (en) * | 1996-05-20 | 1997-11-27 | Merck & Co., Inc. | Antagonists of gonadotropin releasing hormone |
-
2002
- 2002-02-21 RU RU2003128647/04A patent/RU2280031C2/ru not_active IP Right Cessation
- 2002-02-21 AU AU2002247737A patent/AU2002247737B2/en not_active Ceased
- 2002-02-21 BR BR0207451-6A patent/BR0207451A/pt not_active IP Right Cessation
- 2002-02-21 CZ CZ20032514A patent/CZ20032514A3/cs unknown
- 2002-02-21 PL PL02367285A patent/PL367285A1/xx not_active Application Discontinuation
- 2002-02-21 HU HU0303219A patent/HUP0303219A2/hu unknown
- 2002-02-21 SK SK1162-2003A patent/SK11622003A3/sk unknown
- 2002-02-21 EP EP02716803A patent/EP1362034A1/de not_active Withdrawn
- 2002-02-21 WO PCT/EP2002/001882 patent/WO2002066437A1/de active IP Right Grant
- 2002-02-21 MX MXPA03007348A patent/MXPA03007348A/es active IP Right Grant
- 2002-02-21 NZ NZ527597A patent/NZ527597A/en unknown
- 2002-02-21 CN CNA028063597A patent/CN1496354A/zh active Pending
- 2002-02-21 CA CA002438709A patent/CA2438709A1/en not_active Abandoned
- 2002-02-21 JP JP2002565954A patent/JP2004528298A/ja active Pending
- 2002-02-21 IL IL15730302A patent/IL157303A0/xx unknown
-
2003
- 2003-08-20 NO NO20033698A patent/NO325675B1/no not_active IP Right Cessation
- 2003-09-09 BG BG108165A patent/BG108165A/xx unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997014682A1 (en) * | 1995-10-19 | 1997-04-24 | Takeda Chemical Industries, Ltd. | Quinoline derivatives as gnrh antagonists |
WO1997044041A1 (en) * | 1996-05-20 | 1997-11-27 | Merck & Co., Inc. | Antagonists of gonadotropin releasing hormone |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10280160B2 (en) | 2013-03-13 | 2019-05-07 | Flatley Discovery Lab, Llc | Phthalazinone compounds and methods for the treatment of cystic fibrosis |
US10889576B2 (en) | 2013-03-13 | 2021-01-12 | Flatley Discovery Lab, Llc | Phthalazinone compounds and methods for the treatment of cystic fibrosis |
Also Published As
Publication number | Publication date |
---|---|
NO20033698D0 (no) | 2003-08-20 |
SK11622003A3 (sk) | 2004-01-08 |
PL367285A1 (en) | 2005-02-21 |
RU2280031C2 (ru) | 2006-07-20 |
AU2002247737B2 (en) | 2006-05-18 |
CA2438709A1 (en) | 2002-08-29 |
CZ20032514A3 (cs) | 2004-05-12 |
IL157303A0 (en) | 2004-02-19 |
BR0207451A (pt) | 2004-06-01 |
NZ527597A (en) | 2004-10-29 |
JP2004528298A (ja) | 2004-09-16 |
MXPA03007348A (es) | 2003-12-04 |
CN1496354A (zh) | 2004-05-12 |
NO20033698L (no) | 2003-10-20 |
NO325675B1 (no) | 2008-07-07 |
EP1362034A1 (de) | 2003-11-19 |
HUP0303219A2 (hu) | 2003-12-29 |
BG108165A (en) | 2004-08-31 |
RU2003128647A (ru) | 2005-03-27 |
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