NZ527597A - Quinoline, isoquinoline and phthalazine derivatives as antagonists of the gonadotropin-releasing hormone - Google Patents
Quinoline, isoquinoline and phthalazine derivatives as antagonists of the gonadotropin-releasing hormoneInfo
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- NZ527597A NZ527597A NZ527597A NZ52759702A NZ527597A NZ 527597 A NZ527597 A NZ 527597A NZ 527597 A NZ527597 A NZ 527597A NZ 52759702 A NZ52759702 A NZ 52759702A NZ 527597 A NZ527597 A NZ 527597A
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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
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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
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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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
- A61P15/18—Feminine contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
- A61P5/02—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
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- 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
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- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract
Disclosed herein are quinoline, isoquinoline and phthalazine derivatives that are suitable as antagonists of the gonadotropin-releasing hormone.
Description
New Zealand Paient Spedficaiion for Paient Number 527597
527597
Quinoline, isoquinoline and phthalazine derivatives as antagonists of the gonadotropin-releasing hormone
. Description,
Gonadotropin-releasing hormone (GnRH) is a hormone which is synthesized mainly, but not exclusively, in mammals by nerve cells of the hypothalamus, transported to the hypophysis via the portal vein and released in a 10 regulated manner in the gonadotropic cells. By interaction with its receptor, which has 7 transmembrane domains, GnRH stimulates the production and the release of gonadotropic hormones by means of the second messenger inositol-1,4,5-trisphosphate and Ca2+ 15 ions. The gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secreted by GnRH stimulate the production of sexual steroids and germ-cell maturation in both sexes. In addition to GnRH (also designated GnRHl), there are two further forms of 20 GnRH, namely GnRH2 and 3.
The GnRH receptor is used as a pharmacological target in a number of diseases which are dependent on functioning sex hormone production, for example 25 prostate cancer, premenopausal breast cancer, endometriosis and uterine fibroids. In these diseases, GnRH superagonists or superantagonists can be employed successfully. In particular, male fertility control in combination with a substitution dose of androgens forms 30 a possible further indication.
An advantage of GnRH antagonists in comparison with superagonists is their immediate efficacy in blocking gonadotropin secretion. Superagonists initially bring 3 5 about an overstimulation of the hypophysis, which leads to increased secretions of gonadotropin and sexual steroid.
\
This hormonal reaction is ended only after a certain delay on account of desensitization and downregulation of the GnRH receptor concentrations. Possibly, GnRH superagonists, both on their own and in combination 5 with testosterone, can therefore not effectively suppress sperm production in men and are thus not suitable for male fertility control. In contrast to this, peptide GnRH antagonists, in particular in combination with a substitution dose of androgens, are 10 able to produce significant oligozoospermia in man.
Peptide GnRH antagonists, however, have a number of disadvantages. They for instance have a considerably lower activity than superagonists and must consequently 15 be administered in considerably higher doses. Their oral bioavailability is also low, so that they need to be administered by injection. Repeated injections in turn lead to a lowering of compliance. Moreover, the synthesis of peptide GnRH antagonists in comparison .20 with nonpeptide compounds is laborious and expensive.
Quinoline derivatives as nonpeptide GnRH antagonists are disclosed, for example, in W097/14682. Up to now, however, no nonpeptide GnRH antagonists have been 25 brought onto the market.
The object underlying the present invention consisted in making available novel GnRH antagonists which are superior to known peptide compounds and represent an 30 effective alternative to known nonpeptide compounds. The novel GnRH antagonists should possess both a high activity and' also a high oral bioavailability. Furthermore, they should be able to be synthesized simply and with costs which are as low as possible.
The' abovementioned objects should be' read disjuncti with the object to at least provide a useful alternative.
40 This object is achieved by compounds of the general formula (1):
r4
r5
r1
(1)
r3 r2
in which
(a) is an acyl group -C0-R11 or CN, where Rll is a saturated, unsaturated, cyclic or/and (hetero)-aromatic organic radical, in particular a linear or branched alkyl chain having 1-10 C atoms, or a phenyl, furan or thiophene group optionally substituted by alkyl groups or halogen atoms, and
(b) a carboxylic acid ester group -CO-OR12 or carboxamide group -CO-NR12NR13 or a group -S0X-R12 where X = 0, 1 or 2 or -S02-NR12NR13, where R12 is a saturated, unsaturated, cyclic or/and (hetero)-aromatic organic radical, in particular a linear or branched alkyl chain having 1-10 C atoms, an aralkyl group having 7-20 C atoms, where the aryl radical can optionally be substituted by alkyl groups or halogen atoms, or a phenyl radical optionally substituted by alkyl groups or halogen atoms and R13 can be a hydrogen atom or a linear or branched alkyl chain having 1-10 C atoms,
(c) is the group -A-NR14-CO-NR15R16, in which A is an alkylene group having 1-4 C atoms, in particular having 1 C atom, optionally substituted by a C1-C6-alkyl group, a carbonyl group, an oxygen atom or the group -S0X- where X = 0, 1 or 2, R14 and R15 in each case independently are a hydrogen atom or a linear or branched alkyl chain having 1-10 C atoms and R16 is a linear or branched alkyl chain having 1-10 C atoms, a cycloalkyl group having 3-10 C atoms, a cycloalkylalkyl group having 7-2 0 C atoms, an aralkyl group having 7-2 0 C 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 heterocyclic ring optionally substituted by alkyl groups or halogen atoms, - • -
is a group -CH(R21)R22, where R21 is a hydrogen atom, a Ci-Cio-alkyl group or an optionally substituted phenyl ring and R22 is an optionally substituted phenyl ring or naphthyl ring, or a group -CH2CH (R23) R2 4, with R23 and R24 meaning an optionally substituted phenyl ring,
and R4 in each case independently can be a in which G is -C=C-, -C=N-, -N=C-, an oxygen or sulfur atom, Z is a direct bond, an oxygen or a sulfur atom, the group CH-R52 or -CHR52-CH-R53-, where R52 and R53 independently of one another have the meaning of a hydrogen atom or an alkyl group and n is the numbers 1 and 2, a -C=C- triple bond or a group -CR52=CR53- or C=CR52R53 having the E or Z configuration, where R52 and R53 independently of one another have the meaning of a hydrogen atom or an alkyl group, L is a CH2 or an NH group, Q is a carbonyl or -S0X group where X = 0, 1 or 2 and R51 is an amino group optionally substituted by an alkyl group, or a linear or branched alkyl group optionally substituted by halogen atoms, hydroxyl or alkoxy groups, or a cycloalkyl group having 3-7 ring members, optionally substituted by halogen atoms, hydroxyl or alkoxy groups,
hydrogen atom or an alkyl group having 1-10 C atoms and R3 can also be a halogen atom,
is a group linked via the radical Z,
is the group CH2-N (R61) R62, where R61 in each case independently is a hydrogen atom or an alkyl group and R62 is an alkyl group or an optionally substituted aralkyl group or heteroarylalkyl group having 7-2 0 C atoms and - -
can be the groups
—W-X-Y—
~rn—ttt rr in any orientation, and further all stereoisomers of the structures mentioned, and salts thereof with physiologically tolerable acids or bases.
the compounds of the formula (1), by way of example
R1 Linear or branched alkyl chain: means a methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl, n-pentyl, 2,2-dimethylpropyl or 3-methylbutyl group, an n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl group. The methyl or ethyl group is preferred.
A phenyl group optionally substituted by alkyl groups or halogen atoms: means 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-fluoro-, chloro-, bromo-, 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: means an unsubstituted 2- or 3-thienyl group or 2- or 3-fury 1 group or a 3-methyl-, 3-ethyl-, 3-fluoro-, 3-chloro-, 3-bromo-,
3-iodo-2-furyl or -2-thienyl group, a
4-methyl-, 4-ethyl-, 4-fluoro-, 4-chloro-,
4-bromo-, 4-iodo-2-furyl or -2-thienyl group, a
-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
-methyl-, 5-ethyl-, 5-fluoro-, 5-chloro-, 5-bromo-, 5-iodo-3-furyl or -3-thienyl group. A
2-thienyl or 2-furyl group is preferred.
An aralkyl group having 7-20 C atoms: means a benzyl group, a 1-phenylethyl, -propyl, -butyl, -hexyl, -2-methlethyl, -2-ethylethyl, -2,2-di-15 methylethyl group, an o-, m-, p-methyl-,
ethyl-, propyl-, isopropylbenzyl group, a 2',3'-, 2',4'-, 2',5'-, 2',6'-, 3',4'-, 3',5'-dimethyl- or -diethylbenzyl group, a 2'-, 3'-, 4'-fluoro-, chloro-, bromo-, iodobenzyl group, 20 a 2',3'-, 2',4'-, 2',5'-, 2',6'-, 3',4'-,
3',5'-, difluoro-, dichloro-, dibromo-, or diiodobenzyl group or a 2- or 3-naphthylmethyl group, a 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl group.
A Ci~C6~alkyl group: means a linear or branched alkyl group having 1-6 C atoms such as a methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl, n-pentyl, 2,2-dimethylpropyl or 30 3-methylbutyl group.
A cycloalkyl radical: means a cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclo-heptane, decahydronaphthalene radical.
A cycloalkylalkyl radical: means a cyclo-propyl-, cyclobutyl-, cyclopentyl-, cyclo-hexyl-, cycloheptylmethyl radical, a 1-cyclo-propyl-, 1-cyclobutyl-, 1-cyclopentyl-,
1-cyclohexyl-, 1-cycloheptylethyl radical, a
2-cyclopropyl-, 2-cyclobutyl-, 2-cyclopentyl-, 2-cyclohexyl-, 2-cycloheptylethyl radical.
A heterocyclic ring: -means an unsubstituted
2- or 3-thienyl or 2- or 3-furyl group or a
3-methyl-, 3-ethyl-, 3-fluoro-, 3-chloro-,
3-bromo-, 3-iodo-2-furyl or -2-thienyl group, a
4-methyl-, 4-ethyl-, 4-fluoro-, 4-chloro-, 10 4-bromo-, 4-iodo-2-furyl or -2-thienyl group, a
-methyl-, 5-ethyl-, 3-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 15 4-methyl-, 4-ethyl-, 4-fluoro-, 4-chloro-,
4-bromo-, 4-iodo-3-furyl or -3-thienyl group, a
-methyl-, 5-ethyl-, 5-fluoro-, 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-fluoro-, 3-chloro-,
3-bromo-, 3-iodo-2-pyridyl group, a 4-methyl-,
4-ethyl-, 4-fluoro-, 4-chloro-, 4-bromo-,
4-iodo-2-pyridyl group, a 5-methyl-, 5-ethyl-,
-fluoro-, 5-chloro-, 5-bromo-, 5-iodo-2 5 2-pyridyl group, a 2-methyl-, 2-ethyl-,
2-fluoro-, 2-chloro-, 2-bromo-, 2-iodo-3-pyridyl group, a 4-methyl-, 4-ethyl-, 4-fluoro-, 4-chloro-, 4-bromo-, 4-iodo-
3-pyridyl group, a 5-methyl-, 5-ethyl-, 30 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-pyrazinyl group.
In R2 An alkyl group: means a linear or branched alkyl group having 1-6 C atoms such as a methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl, n-pentyl, 2,2-dimethylpropyl or 3-
methylbutyl group. A hydrogen atom is preferred.
An optionally substituted phenyl ring or 5 naphthyl■ ring: - means 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-fluoro-, chloro-, bromo-, iodophenyl group, a 10 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-ditrihalophenyl group, an o-, m-, p-methoxy-, -ethoxy-, 15 -propoxy-, -isopropoxyphenyl group or a naphthyl group. A 2,5-difluorophenyl group is preferred.
In R3 An alkyl group: means a linear or 2 0 and R4 branched alkyl group having 1-6 C atoms such as a methyl, ethyl, ..n-propyl, isopropyl, n-, iso-, tert-butyl, n-pentyl, 2,2-dimethylpropyl or 3-methylbutyl group. A hydrogen atom is preferred.
R5 An alkyl group: means a linear or branched alkyl group having 1-6 C atoms such as a methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl, n-pentyl, 2,2-dimethylpropyl or 3-methylbutyl group. A hydrogen atom is preferred.
R6 An alkyl group: means a linear or branched alkyl group having 1-6 C atoms such as a methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl, n-pentyl, 2,2-dimethylpropyl or 3-methylbutyl group. A methyl group is preferred.
In
In
An aralkyl group having 7-20 C atoms: means a benzyl group, a 1-phenylethyl, -propyl, -butyl, -hexyl, -2-methlethyl, -2-ethyl-ethyl, -2,2-dimethylethyl group, an o-, m-, p-methyl-, 5 ethyl-,- propyl-, isopropylbenzyl group, a
2',3'-, 2',4'-, 2',5'-, 2',6'-, 3',4'-, 3',5'-dimethyl- or -diethylbenzyl group, a 2'-, 3'-, 4'-fluoro-, chloro-, bromo-, iodobenzyl group, a 2',3'-, 2',4'-, 2',5'-, 2',6'-, 3',4'-, 10 3',5'-, difluoro-, dichloro-, dibromo-, or diiodobenzyl group or a 2- or 3-naphthylmethyl group, a 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl group.
A heteroaralkyl group having 7-20 C atoms:
means a 2-, 3-, or 4-pyridylmethyl, -ethyl, or -propyl group, a 2- or 3-furylmethyl, -ethyl, or -propyl group, a 2- or 3-thienylmethyl, -ethyl, or -propyl group, a 2-, 3-, 4-, 5-, 6-, 20 or 7-indolylmethyl, -ethyl or -propyl group.
The benzyl group is preferred.
Preferred compounds of the formula (1) are those in which
voi-vny n — c— c c —n — n is the group | i or i i
H I
If Rl is the group -CO-Rll, then Rll has, for example, the preferred meaning methyl, ethyl, i-propyl, phenyl, 30 2-thienyl and 2-furyl. If Rl has the meaning -C0-0R12, then R12 can be, for example, preferably methyl, ethyl or i-propyl.
Compounds are furthermore preferred in which R2 is an 35 aromatic group substituted on the aromatic ring by one or more halogen atoms, in particular fluorine atoms, e.g. a benzyl group, for example a 2',6'-difluorobenzyl
group. Compounds are likewise preferred in which at least one of R3 and R4, in particular both, are hydrogen atoms.
A preferred meaning of Z is a direct bond or an oxygen atom, while G is preferably a -C=C- group. L is preferably an NH group, while Q is preferably a carbonyl group and R51 is a Ci-C6-alkyl group. Particularly preferred meanings for R61 are hydrogen 10 atoms or Ci-C3-alkyl groups, in particular methyl groups, and for R62 an aralkyl radical, e.g. a benzyl group.
The compounds (1) are preferably prepared by
(a) reaction of a compound of the general formula (2)
r7.
r5.
r4'
r3 r2
where R7 is a leaving group, e.g. a halogen atom or an alkyl-, perfluoroalkyl- or arylsulfonyl group and all other radicals have the meaning indicated in compound (1), with a compound of the general formula (3)
R8-N(R61)R62 (3)
where R8 is a hydrogen atom or a metal atom, such as, for example, a lithium, sodium, potassium, cesium, calcium or barium atom and R61 and R62 have the meanings indicated in compound (1) ,
reaction of a compound of the general formula (4)
(4)
in which R9 is the group -0S02CnF2n+i, a halogen atom, particularly a bromine or iodine atom or another leaving group, and all other radicals have the meaning indicated in compound (1), with a compound of the general formula (5)
™^>U'Q-R51
where RIO is a group containing a metal, such as a trialkyltin group, a halomagnesium group or a group containing a nonmetal, such as boron, silicon etc., group containing, a dialkoxyboron or a dihydroxyboron group, a hydroxyl or mercapto group optionally converted into a metal salt, such as, for example, a lithium, sodium, potassium, cesium, calcium, barium, silver or copper salt, the group -C=C-R31 or a group -CR52=CR53R31 or -CR31=CR52R53 having the E or Z configuration, in which R31 is a group containing a metal or a nonmetal, such as boron, silicon etc., such as a trialkyltin group, a halomagnesium group, a dialkoxyboron group or a dihydroxyboron group, and all other radicals have the meaning indicated in compound (1), with or without participation of a catalyst, such as, for
example, copper, nickel, palladium, platinum or organic derivatives of the metals mentioned; (c) if Y in compound (1) is a nitrogen atom, by-
reaction of a compound of the general formula
(6) -
(6)
where R32 is a hydrogen atom or a metal atom, 10 such as, for example, a lithium, sodium,
potassium, cesium, calcium, barium, silver or copper atom, and all other radicals have the meaning indicated in compound (1), with a compound of the general formula (7)
R33R2 (7)
where R33 is a leaving group, e.g. a halogen atom or an alkyl-, perf luoroalkyl- or aryl-20 sulfonyl group, and R2 has the meaning indicated in compound (1), or
(d) if W in compound (1) is a nitrogen atom, by reaction of a compound of the general formula (8)
r32
(8)
where R32 is a hydrogen atom or a metal atom, such as, for example, a lithium, potassium, cesium, calcium, barium, silver or copper atom, and all other radicals have the meaning 5 indicated in compound <lr), with a compound of the general formula (9)
R33-R1 (9)
where R33 is a leaving group, e.g. a halogen atom or an alkyl-, perfluoroalkyl- or arylsulfonyl group, and Rl has the meaning indicated in compound (1).
The compounds (1) according to the invention can be employed as antagonists of 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 tumor 2 0 control.
In male fertility control, the compounds according to the invention bring about a lowering of spermatogenesis. Preferably, combined administration 25 with androgens takes place, e.g. testosterone or testosterone derivatives, such as, for example, testosterone esters. The administration of the testosterone derivatives can be carried out, for example, by injection, e.g. by intramuscular depot 30 injection.
In hormone therapy too, for example for the treatment of endometriosis, uterine leiomyomas and uterine fibroids, the compounds (1) can optionally be employed 35 in combination with other hormones, e.g. estrogens or/ and progestins. Combinations of the GnRH antagonists according to the invention and tissue-selective partial estrogen agonists such as Raloxifene® are particularly preferred. Moreover, the compounds (1) according to the
invention can be employed for increasing female fertility, for example by inducing ovulation, and the treatment of sterility.
On the other hand, the-compounds- (1) are also suitable for contraception in women. Thus the GnRH antagonist can be administered on days 1 to 15 of the cycle together with estrogen, preferably with very low estrogen doses. On days 16 to 21 of the taking cycle, 10 progestagen is added to the estrogen-GnRH antagonist combination. The GnRH antagonist can be administered continuously over the entire cycle period. In this way, a lowering of the hormone doses and thus a lowering of the side effects of nonphysiological hormone levels can 15 be achieved. Furthermore, advantageous effects can be achieved in women who suffer from polycystic ovarian syndrome and androgen-dependent diseases such as acne, seborrhea and hirsutism. An improved cycle control compared with previous administration methods is also 20 to be expected. Further indications are benign prostate hyperplasia, gonadal protection during chemotherapy, controlled ovarian stimulation/artificial reproduction techniques, early infantile developmental disorders, e.g. precocious puberty and polycystic ovaries.
Finally, the GnRH agonists according to the invention can also be employed for the treatment of hormone-dependent oncoses, such as premenopausal breast cancer, prostate cancer, ovarian cancer and endometrial cancer 30 in that they suppress the endogenous sexual steroid hormones.
The compounds (1) according to the invention are suitable as GnRH antagonists for administration to man, 35 but also for veterinary medical purposes, e.g. in domestic and productive animals, but also in wild animals.
Administration can be carried out in a known manner, for example orally, topically, rectally, intra-vaginally, nasally or by injections. Oral administration is preferred. The compounds (1) are 5 brought into ar form -- capable - ©f administration and optionally mixed with pharmaceutically acceptable vehicles and/or diluents. Oral administration can be carried out, for example, in solid form as tablets, capsules, coated tablets or powders, but also in the 10 form of a drinkable solution. Nonoral administration can be carried out, for example, by means of intravenous, subcutaneous or intramuscular injection or by means of ointments, creams or suppositories. Optionally, it is also possible to carry out 15 administration as a delayed-release form. The dose can vary depending on the type of indication, the severity of the disease, the age, sex, body weight and the sensitivity of the subject to be treated. Preferably, doses of 0.01 to 3 0 mg, particularly preferably of 0.1 20 to 3 mg and most preferably of 0.1 to 1 mg per kilogram of body weight per day are administered. Administration can be carried out in a single dose or a number of a separate doses.
A number of particularly preferred compounds (1) are listed below:
Particularly preferred compounds
H^_/
vnrn ? ? &
2-Propyl 6-(4-
acetamidophenyl)-5-(N-benzyl-N-methylaminomethyl)-1-(2',6'-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate o
v&ux
0 ^yj0^
Ethyl 6-(4-acetamidophenyl)-5-(N-benzyl-N-
methylaminomethyl)-1-(2',6'-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
F
£
6-(4-Acetamidophenyl)-3-iso-butyryl-5-(N-benzyl-N-methyl-aminomethy1)-1-(2',6'-difluorobenzyl)-1,4-dihydro-4-oxoquinoline o ,
vM-1 v v y »oxy^ » ■
Isopropyl 6-(2-acetamido-5-pyridyl)-5-(N-benzyl-N-methylaminomethyl)-1-(2',6'-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
-q_/
jyrs o o
° viccv^
2-Propyl 6-(3-acetamido-6-pyridyl)-5-(N-benzyl-N-methylaminomethyl)-1-(2',6'-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
hQ /
VN~frN1 9 9
0 s IJJ
2-Propyl 6-(5-acetamido-2-thienyl)-5-(N-benzyl-N-methylaminomethyl)-1-(2', 6' -difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate q_,
1 1 ° 0
o fTTYy"0"7
njl
Ethyl 6-[1-(4-
acetamidophenyl)vinyl]-5 - (N-benzyl-N-methylaminomethyl)-1-(2',6'-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
11 00
Ethyl R- and S- and R,S-6-[1-(4-
acetamidophenyl)ethyl]-5-(N-benzyl-N-methylaminomethyl)-1-(2',6'-difluorobenzyl)-1,4-di-hydro-4-oxoquino1ine-3-carboxylate
"J o 0
Ethyl 5-(N-benzyl-N-methylaminomethyl)-1-(2',6'-difluorobenzyl)-1,4-dihydro-6-(4-methanesulfonyl-amidophenoxy)-4-oxoquinoline-3-carboxylate
Q_,
V_M
O 0
o°ox-r X1
Ethyl 6-(3-acetamidophenoxy)-5-(N-benzyl-N-
methylaminomethyl)-1-(2',6'-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
"^0 0
o' jct0rYV^
An N F
x>
Ethyl 6-(2-acetamido-5-pyridyloxy)-5-(N-benzyl-N-methylaminomethyl)-1-(2',6'-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
Ethyl 6- (2-
methylaminocarbonyl- 5-pyridyloxy)-5-(N-benzyl-N-methylaminomethyl)-1-(2',6'-difluo-r ©benzyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate vcalswi^
1-[6-(4-Acetamidophenoxy)-5-(N-benzyl-N-
methylaminomethyl)-1-(2', 6' -difluorobenzyl)-1,4-dihydro-4-oxoquinolin-3-yl)methyl]-3-pyridin-2-ylurea
^ - o ^
^ jq°xhc>°hati *' £> ;1-[6-(4-Acetamidophenoxy)-5-(N-benzyl-N- ;methylaminomethyl)-1-(2',6'-difluorobenzyl)-1,4-dihydro-4-oxoquinolin-3-yl)oxy]-3-pyridin-2-ylurea q_ / ;l ° ° ;Ethyl 6-(4-hydroxyacetamido-phenoxy)-5-(N-benzyl-N-methylaminomethyl ) -1 - (2 ' , 6 ' -difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate ;O 0 ;^ a$T ;Ethyl 6-(acetamidophenoxy)-5-(N-benzyl-N- ;methylaminomethyl)-1-[bis(2-fluorophenyl)methyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate ;^ 00 ;Ethyl 6-(acetamidophenoxy)-5-(N-benzyl-N-methylaminomethyl)-1-diphenylmethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate ;- 19 - ;The invention will be furthermore illustrated by the following examples. ;Working examples ;5 ;Example 1 ;Ethyl 6-(4-acetamidophenoxy)-5-(N-benzyl-N-methyl aminomethyl) -1- (2',6'-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate ;78 mg of etyl 6-(4-acetamidophenoxy)-5-(chloromethyl)-1-(2', 6'-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-15 carboxylate, dissolved in 3 ml of dimethylformamide, were treated at 0°C with 84 \il of N-methylbenzylamine and 84 \xl of N,N-diisopropylethylamine and the mixture was stirred at room temperature for 20 hours. After addition of 2 0 ml of aqueous sodium bicarbonate 20 solution, the precipitate was filtered off with suction, washed with water and then with n-hexane and dried at room temperature in vacuo. 7 0 mg of the title compound are obtained. ;25 NMR: <5 = 1.3 (t; 3H; CH3) ; 1.9 (s; 3H; NCH3) ; 2.05 (s; ;3H; CH3) ; 3.55 (s; 2H; NCH2) ; 4.27 (q; 2H; OCH2) ; 4.91 (s; 2H; NCH2); 5.68 (s; 2H; NCH2) ; 6.85 (d; 2H; ArCH) ; 7.1-7.22 (m; 7H; ArCH); 7.26 (d; 1H; ArCH); 7.42-7.6 (m; 4H; ArCH); 30 8.72 (s; 1H; NCH); 9.9 (s; 1H; NH) ;MS: FAB: M^+ 1 = 52 6 [M = 525] ;- 20 - ;The starting material, etyl 6-(4-acetamidophenoxy)-5-(chloromethyl)-1-(2',6'-difluorobenzyl)-1,4-dihydro-4-oxoguinoline-3-carboxylate, was obtained in the 5 following way: - - - • — ;a. Ethyl l,4-dihydro-6-fluoro-5-nitro-4-oxoquinoline-3-carboxylate ;10 ;NO, O O ;f °"\ ;50 g of 4-f luoro-3-nitroaniline and 69 g of diethyl ethoxymethylenemalonate were heated at 12 0°C for 15 3 hours. The mixture was added to n-hexane, stirred for 2 hours and the crystalline material was filtered off with suction and dried in vacuo at room temperature. 93 g of diethyl N-(4-fluoro-3-nitrophenyl)amino-methylenemalonate are obtained. In 3 portions of 31 g, 20 this is added to in each case 150 ml of a mixture of 26.5% diphenyl and 73.5% diphenyl ether (DOWTHERM A®), which has been preheated to 2 60°C, and the mixture is stirred at this temperature for 30 minutes. After cooling, it is diluted with 500 ml of 25 n-hexane and the precipitate is filtered off with suction. A total of 64 g of a mixture of ethyl 1,4-dihydro-6-fluoro-5-nitro-4-oxoquinoline-3-carboxylate and of ethyl 1,4-dihydro-6-fluoro-7-nitro-4-oxo-quinoline-3-carboxylate is obtained. ;30 ;NMR: <5 = 1.31 (t; 3H; CH3); 4.25 (q; 2H; 0CH2) ; 7.88 (s; 1H; ArCH; isomer A); 7.92 (s; 1H; ArCH; isomer A); 8.1 (d; 1H; ArCH; isomer B) ; 8.45 (d; 1H; ArCH; isomer B); 8.59 + 8.69 (2s; 35 each 1H; NCH; A + B) ;- 21 - ;MS: EI: M = 280 [M = 280] ;b. Ethyl 1-(26'-difluorobenzyl)-1,4-dihydro-6- ;fluoro-5-nitro-4-oxoquinoline-3-carboxylate ;5 ;22 g of the mixture described above are stirred at room temperature for 5 hours with 16 g of potassium 10 carbonate and 23.7 g of 2,6-difluorobenzyl bromide in 500 ml of dimethylformamide. The reaction mixture is added to 1 1 of aqueous ammonium chloride solution and extracted three times with ethyl acetate. After drying with sodium sulfate and evaporating in vacuo, 500 ml of 15 n-hexane are added and the mixture is stirred for 15 minutes. After decanting the hexane phase, the residue is recrystallized from ethyl acetate. 10.4 g of the title compound are obtained. ;20 NMR: <5 = 1.3 (t; 3H; CH3) ; 4.25 (q; 2H; OCH2) ; 5.84 (s; ;2H; NCH2) ; 7.15 - 7.25 (m; 2H; ArCH); 7.45 -7.55 (m; 1H; ArCH); 7.92 (dd; 1H; ArCH); 8.04 - 8.14 (m; 1H; ArCH); 8.96 (s; 1H; NCH); ;£TN ;MS: EI: M = 406 [M = 406] ;25 ;c. Ethyl 6-(4-acetamidophenoxy)-1-(2',6'-difluorobenzyl) -1,4-dihydro-5-nitro-4-oxoquinoline-3-carboxylate ;- 22 - ;no2 o o t..oxo> ;n f ;3.74 g of 4-acetamidophenol in 40 ml of dimethyl-formamide are treated with 733 mg of sodium hydride 5 (80% in mineral oil) and the mixture is stirred at room temperature for 15 minutes. This solution is then added to 5 g of the compound described above, dissolved in 40 ml of dime thy 1 f ormami de. After 5 hours at room temperature, the mixture is added to ice water and the 10 precipitate is filtered off with suction. After chromatography on silica gel (eluent dichloromethane/ 2-propanol 95:5), 5.17 g of the title compound are obtained. ;15 NMR: 6 = 1.3 (t; 3H; CH3) ; 2.03 (s; 3H; CH3) ; 4.27 (q; ;2H; OCH2) ; 5.79 (s; 2H; NCH2) ; 7.01 (d; 2H; ArCH); 7.13 - 7.23 (m; 2H; ArCH); 7.43 - 7.56 ;(m; 2H; ArCH); 7.61 (d; 2H; ArCH); 7.8 (d; ;1H; ArCH); 8.93 (s; 1H; NCH) ; 9.97 (1H; S; 2 0 NCH) ;MS: EI: M = 537 [M = 537] ;d. Ethyl 6-(4-ace.tamidophenoxy)-5-amino-l-(2', 6' - ;difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-2 5 carboxylate ;- 23 - ;5.1 g of the aforementioned compound are hydrogenated using 510 mg of palladium/carbon (10%) in 650 ml of methanol. After filtering off the catalyst with suction and evaporating, 4.55 g of the title compound are 5 obtained. - * —
NMR: 5 = 1.29 (t; 3H; CH3); 2.02 (s; 3H; CH3) ; 3.25 (s
2H; NH2) ; 4.25 (q; 2H; OCH2) ; 5.55 (s; 2H
NCH2) ; 6.55 (d; 1H; ArCH); 6.86 (d; 2H
ArCH); 7.07 (d; 1H; ArCH); 7.1-7.22 (m; 2H
ArCH); 7.4 - 7.55 (m; 3H; ArCH); 8.71 (s; 1H NCH); 9.8 (s; 1H; NH);
MS: EI: M = 507 [M = 507]
e. Ethyl 6-(4-acetamidophenoxy)-1-(2',6'-difluoro benzyl) -lf4-dihydro-5-iodo-4-oxoquinoline-3-carboxylate
! o o h ' '
2 g of the aforementioned compound are dissolved in a mixture of 24 ml of concentrated sulfuric acid and 12 ml of water and the mixture is treated with 32 5 mg of sodium nitrite in 4 ml of water at 0°C. After 25 15 minutes, the mixture is adjusted to a pH of 3 using sodium bicarbonate solution and 100 mg of urea are added. 723 mg of potassium iodide in 0.5 ml of water are then added and the mixture is stirred at room temperature for one hour. After extraction with 30 dichloromethane/methanol (95:5, v/v), the organic phase is washed with aqueous sodium thiosulfate solution, dried and evaporated. After chromatography on silica gel (eluent dichloromethane containing 0-15%
isopropanol) , 697 mg of the title compound are obtained.
NMR: <5 = 1.3 (t; 3H; CH3); 2.02 (s; 3H; CH3) ; 4.25 (q
2H; OCH2) ; 5.71 (s; 2H^ NCH2) ; 6.83 (d; 2H
ArCH); 7.1 - 7.2 (2H; m; ArCH); 7.3 (d; 1H
ArCH); 7.41 - 7.63 (m; 4H; ArCH); 8.83 (s 1H; N-CH); 9.95 (s; 1H; NH)
MS: es: M + 1 = 493 [M = 492]
f. Ethyl 6-(4-acetamidophenoxy)-1-(2',6'-difluorobenzyl) -1,4-dihydro-4-oxo-5-styrylquinoline-3-carboxylate
550 mg of the abovementioned iodo compound, 198 mg of styrylboronic acid, 55 mg of 10 tetrakistriphenyl-ohosphinepalladium(O), 1.1 ml of 2 molar sodium 20 carbonate solution, 2.2 ml of ethanol and 22 ml of toluene are stirred at 80°C for 6 hours. Water is then added, the mixture is extracted with dichloromethane and the organic phase is washed with sodium chloride solution, dried and evaporated. The residue is purified 25 by chromatography on silica gel (eluent dichloromethane containing 0-10% isopropanol) . 902 mg of the title compound are obtained.
NMR: <5 =
1.28 (t; 3H; CH3) ; 2.0 (s; 3H; CH3); 4.24 (q 2H; OCH2) ; 5.7 (s; 2H; N-CH2) ; 6.75 - 6.85 (m 3H; ArCH; CH=CH) ; 7.08 - 7.28 (m; 3H; ArCH)
7.3 - 7.68 (m; 9H; ArCH); 7.86 (d; 1H; CH=CH); 8.75 (s; 1H; NCH); 9.72 (1H; S; NH)
MS: es:
M® + 1 = 595 [M = 594]
g. Ethyl 6-(4-acetamidophenoxy)-1-(2',6'-difluorobenzyl )-1,4-dihydro-5-fonny1-4-oxoquinoline-3-carboxylate
0
° jTy0
h o-f
450 mg of the abovementioned styryl compound are dissolved in 25 ml of tetrahydrofuran and 7 ml of water and treated with 0.11 ml of a 2.5 percent solution of osmium tetroxide in tert-butanol. After stirring at 15 room temperature for 15 minutes, 482 mg, after 2 0 and 22 hours 100 mg and after 24 hours a further 100 mg of sodium periodate, are added. After 2 6 hours, the mixture is diluted with water and extracted with ethyl acetate. After drying the organic phase using sodium 20 sulfate, it is evaporated. 352 mg of the title compound are obtained as a foam.
NMR: 5 = 1.29 (t; 3H; CH3); 2.01 (s; 3H; CH3) ; 4.27 (q 2H; OCH2) ; 5.71 (s; NCH2) ; 7.12 - 7.22 (m; 2H
ArCH); 7.4 (d; 1H; ArCH); 7.43 - 7.64 (m; 3H ArCH); 7.72 (d; 1H; ArCH); 9.0 (d; 1H; NCH) 9.97 (s; 1H; NH); 10.44 (s; 1H; CHO)
MS: FAB: M + 1 = 521 [M = 52 0]
3 0 h. Ethyl 6-(4-acetamidophenoxy)-1-(26'-difluorobenzyl ) -1,4-dihydro-5-hydroxymethyl-4-oxoquinoline- 3-carboxylate
ho o-7
300 mg of the abovementioned aldehyde are dissolved in 13.8 ml of acetic acid and treated with 3 portions of 5 10 mg each of sodium borohydride at intervals of 10 minutes. After diluting with water, the mixture is extracted with ethyl acetate and the organic phase is washed neutral using sodium bicarbonate solution. After drying with sodium sulfate, it is evaporated. By 10 chromatography on silica gel (eluent dichloromethane containing 0-10% isopropanol), 129 mg of the title compound are obtained as a foam.
NMR: <5 = 1.31 (t; 3H; CH3); 2.02 (s; 3H; CH3) ; 4.27 (q
2H; OCH2) ; 4.86 (d; 2H; 0CH2) ; 5.12 (t; 1H OH); 5.8 (s; 2H; NCH2); 6.85 (d; 2H; ArCH) 7.12 - 7.22 (m; 2H; ArCH); 7.38 (d; 1H ArCH); 7.42 - 7.59 (m; 3H; ArCH); 7.63 (d 1H; ArCH); 8.94 (s; 1H; NCH); 9.5 (s; 1H; NH)
MS: FAB: M + 1 = 523 [M = 522]
i. Ethyl 6-(4-acetamidophenoxy)-5-chloromethyl-l-
(2',6'-difluorobenzyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylate
ci.
80 mg of the abovementioned alcohol are dissolved in 2 ml of dichloromethane and treated with 0.1 ml of thionyl chloride. After 2 0 minutes at room temperature, water is added, the mixture is extracted with 5 dichloromethane-and the organic-phase is washed with sodium chloride solution. After drying with sodium sulfate, it is evaporated. 80 mg of the title compound are obtained as a foam.
NMR: <5 = 1.33 (t; 3H; CH3); 2.07 (s; 3H; CH3); 4.3 (q
2H; 0CH2) ; 5.66 (s; 2H; CH2Cl) ; 5.75 (s; 2H
NCH2) ; 6.98 (d; 2H; ArCH); 7.13 - 7.25 (m
2H; ArCH); 7.3 (d; 1H; ArCH); 7.53 (t; 1H
ArCH); 7.61 (d; 2H; ArCH); 7.68 (d; 1H 15 ArCH); 8.82 (s; 1H; NCH); 9.98 (s; 1H; NH)
MS: es: M + 1 = 541/543 [M = 540/542]
Example 2
2-Propyl 6-(4-acetamidophenoxy)-5-(N-benzyl-N-methy1-20 aminomethyl)-l-(2',6'-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
This compound is formed from ethyl 6-(4-acetamido-phenoxy)-5-(N-benzyl-N-methylaminomethyl)-1-(2',6'-di-fluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate by heating with titanium tetraisopropoxide in isopropanol.
Example 3
Ethyl 5- (N-benzyl-N-methylaminomethyl) -1- (2', 6' -di-
fluorobenzyl)-1,4-dihydro-6-(4-isobutyramidophenoxy)-4-oxoquinoline-3-carboxylate
This compound is formed analogously to example 1 from etyl 5-(chloromethyl)-1-(2',6'-difluorobenzyl)-1,4-
dihydro-6-(4-isobutyramidophenoxy)-4-oxoquinoline-3-carboxylate and N-methylbenzylamine as a foam.
a. Etyl 5-(chloromethyl)-1-(2',6'-difluorobenzyl)-1,4-dihydro-6-(4-isobutyramidophenoxy)-4-oxo-15 quinoline-3-carboxylate i xyx\
This compound is obtained if 4-isobutyramidophenol is 20 used instead of 4-acetamidophenol in example 1/c. and reacted further analogously to example 1/d. to example 1/i. .
Example 4
3-Acetyl-6-(4-acetamidophenyl)-l-benzyl-5-(N-benzyl-N-methylaminomethyl)phthalazin-4-one
The title compound is obtained by reacting 6-(4-acetamidophenyl)-l-benzyl-5-(N-benzyl-N-methylamino-methyl)phthalazin-4-one with acetyl chloride or acetic anhydride in the presence of a base such as sodium carbonate or sodium hydroxide.
6-(4-Acetamidophenyl)-l-benzyl-5-(N-benzyl-N-methyl-aminomethyl)phthalazin-4-one is obtained in the following way:
a. 6-(4-Acetamidophenyl)-l-benzyl-5-iodophthalazin-4-one l-Benzyl-5,6-diiodophthalazin-4-one (Indian J. Chem. 16B, 1978, 301-304) are reacted with 1 equivalent of 4-acetamidophenylboronic acid analogously to example 1/f.. The title compound is obtained pure by chromatography on silica gel.
b. 6-(4-Acetamidophenyl)-l-benzyl-5-chloromethyl-phthalazin-4-one
6-(4-Acetamidophenyl)-l-benzyl-5-iodophthalazin-4-one is reacted further to give the title compound 5 analogously to example l/f.-i..
Example 5
Ethyl 6- (4-acetamidophenoxy) -5- (N-benzyl-N-methyl-
aminomethyl)-1,4-dihydro-4-oxo-l-(2'-trifluoro-10 methylbenzyl)quinoline-3-carboxylate
130 mg (0.22 6 mrnol) of ethyl 6-(4-acetamidophenoxy)-5-15 (chloromethyl)-1,4-dihydro-4-oxo-l-(2'-trifluoromethyl-benzyl)quinoline-3-carboxylate, dissolved in 5 ml of DMF, are treated with 125 \il of N, N-diisopropylethylamine and 12 6 ]il (0.97 mmol) of N-benzylmethyl-amine at -5°C. After warming to room temperature, the 20 reaction mixture is stirred for 20 hours and then added to 50 ml of saturated sodium bicarbonate solution. The solid is filtered off with suction, washed with water and dried in vacuo. Further purification is carried out
by chromatography on silica gel using an eluent consisting of
90 parts of dichloromethane, 10 parts of ethanol and 1 part of conc. ammonia 5 (Rf : 0.38) .2
45 mg of the title compound are obtained as a foam. MS/molar peak, M+ = 658
The starting material ethyl 6-(4-acetamidophenoxy)-5-10 (chloromethyl)-1,4-dihydro-4-oxo-l-(2'-trifluoromethyl-benzyl)quinoline-3-carboxylate is prepared analogously to the route described in examples la to li using 2'-trifluoromethylbenzyl bromide instead of 2,6-di-fluoromethylbenzyl bromide.
Example 6
Ethyl 6-(4-methylaminocarbonylphenoxy)-5-(N-benzyl-N-methylaminomethyl)-l-(2',6#-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
mg (0.061 mmol) of ethyl 6-(4-methylaminocarbonylphenoxy) -5-(chloromethyl)-1-(2',6'-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate, dissolved in 1.3 pi of DMF, are treated with 35 pi of N,N-di-25 isopropylethylamine and 35 pi (0.25 mmol) of N-methylbenzylamine at 0°C. After warming to room temperature, the reaction mixture is stirred for 20 hours and then added to 10 ml of saturated sodium bicarbonate solution. The solid formed is filtered off with 30 suction, washed with water and hexane and dried over phosphorus pentoxide in vacuo.
27 mg of the title compound are obtained as a foam.
MS (esi): M++l = 626 [M = 625]
The starting material ethyl 6-(4-methylaminocarbonylphenoxy) -5-(chloromethyl)-1-(2',6'-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate is prepared analogously to the route described in examples la to li
using 4-hydroxy-N-methylbenzamide instead of 4-acet-amidophenol.
Example 7
Ethyl 6-(4-acetamidophenoxy)-5-(N-benzyl-N-methylamino-methyl)-1-(1-naphthylmethyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylate
45 mg (0.081 mmol) of ethyl 6-(4-acetamidophenoxy)-5-10 (chloromethyl)-1-(1-naphthylmethyl)-1,4-dihydro-4-oxo-
quinoline-3-carboxylate, dissolved in 1.7 ml of DMF, are treated with 46 pi of N,N-diisopropylethylamine and
46 pi (0.33 mmol) of N-methylbenzylamine at 0°C. After warming to room temperature, the reaction mixture is
stirred for 20 hours and then added to 15 ml of saturated sodium bicarbonate solution. The solid formed is filtered off with suction, washed with water and hexane and dried over phosphorus pentoxide in vacuo. 32 mg of the title compound are obtained as a foam.
MS (esi) : M++l = 639 [M =?. 638]
The starting material ethyl 6-(4-acetamidophenoxy)-5-(chloromethyl)-1-(naphthylmethyl)-1,4-dihydro-4-oxo-
2 5 quinoline-3-carboxylate is prepared analogously to the route described in examples la to li using 1-chloro-methylnaphthalene instead of 2,6-difluoromethylbenzyl bromide.
3 0 Example 8
Demonstration of the antagonistic action a) Materials
Buserelin was obtained from Welding (Frankfurt/Main, 3 5 Germany). The compound was labelled with 125I by use of the chloramine T method and Na125I (4000 Ci/mmol; Amersham-Buchler, Braunschweig, Germany). The labelled substance was purified by reverse phase HPLC on a Spherisorb ODS II column (250 x 4 mm, particle size
3 pm) by elution with 50% acetonitrile/0.15% trifluoroacetic acid at a flow rate of a 0.5 ml/min. The specific activity was 2000 Ci/mmol.
All other chemicals - were obtained from a commercial source in the highest available degree of purity.
b) Cell culture
Alpha T3-1 cells (Bilezikjian et al. , Mol. Endocinol 5 10 (1991), 347-355) were cultured on plastic tissue culture plates (Nunc, 245 x 245 x 20 mm) in DMEM medium (Gibco-BRL, Eggenstein-Leopoldshafen, Germany),
containing penicillin (100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine (0.01 mol/1) and 10% fetal 15 calf serum (FCS; PAA Laboratories, Coelbe, Germany). CHO-3 cells (Schmid et al. , J. Biol. Chem. 275 (2000), 9193-9200) were cultured under identical conditions, apart from the fact that Ham's F12 medium (Gibco-BRL) was used.
confluent cell culture plates were rinsed twice with 50 ml of phosphate-buffered saline solution (PBS). The cells were harvested in 5 ml of PBS by scraping off with a rubber scraper and sedimented by centrifugation 25 at 800 rpm for 10 min in a laboratory centrifuge (Heraeus) . The cell pellet was resuspended in 5 ml of 0.25 mol/1 sucrose/0.01 mol/1 triethanolamine, pH 7.4. The cells were lyzed by three cycles of freezing in dry ice/ethanol bath and thawing at room temperature. The 30 lyzate was centrifuged at 900 rpm for 10 min and the sediment was discarded. The supernatant was centrifuged at 18,000 rpm in a Sorvall SS34 rotor for 30 min. The pellet (cell membranes) was suspended by pottering in 5 ml of assay buffer (0.25 mol/1 sucrose, 0.01 mol/1 35 triethanolamine, pH 7.5, 1 mg/ml ovalbumin) and stored at -20°C in 200 jj.1 aliquots. The protein determination was carried out according to the method of Bradford (Anal. Biochem. 72 (1976), 248-254).
Claims (26)
1 n 1 n 1 M~r in any orientation, and* further all 10 stereoisomers of the structures mentioned, or salts thereof with physiologically tolerable acids or bases.
2. A compound as claimed in claim 1, wherein Rll is a 15 phenyl, furan or thiophene group.
3. A compound as claimed in claim 1 or claim 2, wherein R12 is an aralkyl group having 7-20 C atoms, where the aryl radical can optionally be 20 substituted by alkyl groups or halogen atoms, or a phenyl radical optionally substituted by alkyl groups or halogen atoms.
4. A compound as claimed in any one of claims 1 to 3, 25 wherein A is a methylene group.
5. A compound as claimed any one of claims 1 to 4, wherein 30 ^ is the group N C 0 or C N—N h
6. A compound as claimed in any one of claims 1 to 5, wherein Rl is the group -C0-R11. 31 AUG 2004 received - 38 -
7. A compound as claimed in claim 6, wherein Rll is selected from methyl, ethyl, i-propyl, phenyl, 2-thienyl and 2-furyl. 5
8. A compound as claimed in any one of claims 1 to 5, wherein Rl is the group -C0-0R12.
9. A compound as claimed in claim 8, wherein R12 is selected from methyl, ethyl or i-propyl. 10
10. A compound as claimed in any one of claims 1 to 9, wherein R2 is a 2' , 5' -difluorobenzyl group.
11. A compound as claimed in any one of claims 1 to 15 10, wherein R3 and R4 are hydrogen atoms.
12. A compound as claimed in any one of claims 1 to 11, wherein Z is a direc-t bond or an oxygen atom. 20
13. A compound as claimed in any one of claims 1 to 12, wherein G is -C=C-.
14. A compound as claimed in any one of claims 1 to 13, wherein L is an NH group.. 25
15. A compound as claimed in any one of claims 1 to 14, wherein Q is a carbonyl group and R51 is a Ci-C-6-alkyl group. 30
16. A compound as claimed in any one of claims 1 to 15, wherein R61 is a hydrogen atom or a methyl group or/and R62 is a benzyl group.
17. The use of a compound as claimed in any one of 35 claims 1 to 16 in the manufacture of a medicament for acting as an antagonist of gonadotropin-releasing hormone (GnRH). intellectual proper office of n.z » 31 AUG 2004 received - 39 -
18. The use as claimed in claim 17 for the manufacture of a medicament for male fertility control, for hormone therapy, for the treatment of female sub-and infertility, for female contraception or for 5 tumor control.
;19. A process for the preparation of a compound of the general formula (1) by (a) reaction of a compound of the general formula 10 (2) (2} r3 r2 where R7 is a leaving group and all other 15 radicals have the meaning indicated in compound (1), with a compound of the general formula (3) R8-N(R61)R62 (3) 20 25 (b) where R8 is a hydrogen atom or a metal atom and R61 and R62 have the meanings indicated in compound (1), reaction of a compound of the general formula (4) (4) intellectual property OFFICE of N.Z 3 1 AUG 2004 4 received - 40 - in which R9 is the group -0S02CnF2n+:u a halogen atom or another leaving group and all other radicals have the meaning indicated in compound (1), with a compound of the general 5 formula (5). where RIO is a group containing a metal or a 10 nonmetal, a hydroxyl or mercapto group optionally converted into a metal salt, the - group -CsC-R31 or a group -CR52=CR53R31 or -CR31=CR52R53 having the E or Z configuration, in which R31 is a group 15 containing a metal or a nonmetal and all other radicals have the meaning indicated in compound (1), with or without, participation of a catalyst; 20 (c) if Y in compound (1) is a nitrogen atom, by reaction of a compound of the general formula (6) 25 30 (6) r3 r32 where R32 is a hydrogen atom or a metal atom and all other radicals have the meaning indicated in compound (1), with a compound of the general formula (7) R33R2 (7) intellectual property OFRCP OF N2 3 J AUG 2004 Received - 41 - where R33 is a leaving group and R2 has the meaning indicated in compound (1), or 10 15 20 25' (d) if W in compound (1) is a nitrogen atom, by reaction of a compound of the general formula (8) r32 (8) where R32 is a hydrogen atom or a metal atom and all other radicals have the meaning indicated in compound (1), with a compound of -the general formula (9) R33-R1 (9) where R33 is a leaving group and Rl has the meaning indicated in compound (1).
20. A process as claimed in claim 19, wherein the halogen atom is bromine or iodine.
21. A compound according to any one of claims 1 to 16, substantially as herein described.
22. A compound according to any one of claims 1 to 16, substantially as herein described with reference any one of Examples 1 to 7.
23. Use according to claim 17 or claim 18, substantially as herein described. • 3 1 AUG 200h JSiceiveo - 42 -
24. Use according to claim 17 or claim 18, substantially as herein described with reference to any one of Examples 1 to 8. 5
25. A process according to claim 19 or claim 20, substantially as herein described.
26. A process according to claim 19 or claim 20, substantially as herein described with reference 10 to any one of Examples 1 to 7. ZENTARIS GMBH END of claims B^jlts A Attorneys BALDWINS 3 I AUG 2004 -RECEH/Fn
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2001108271 DE10108271A1 (en) | 2001-02-21 | 2001-02-21 | New oxo substituted quinoline, isoquinoline and phthalazine derivatives useful as GnRH antagonists in male fertility control, female infertility and contraception and tumor control |
| US27491401P | 2001-03-13 | 2001-03-13 | |
| PCT/EP2002/001882 WO2002066437A1 (en) | 2001-02-21 | 2002-02-21 | Quinoline, isoquinoline and phthalazine derivatives as antagonists of the gonadotropin-releasing hormone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ527597A true NZ527597A (en) | 2004-10-29 |
Family
ID=26008581
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ527597A NZ527597A (en) | 2001-02-21 | 2002-02-21 | Quinoline, isoquinoline and phthalazine derivatives as antagonists of the gonadotropin-releasing hormone |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP1362034A1 (en) |
| JP (1) | JP2004528298A (en) |
| CN (1) | CN1496354A (en) |
| AU (1) | AU2002247737B2 (en) |
| BG (1) | BG108165A (en) |
| BR (1) | BR0207451A (en) |
| CA (1) | CA2438709A1 (en) |
| CZ (1) | CZ20032514A3 (en) |
| HU (1) | HUP0303219A2 (en) |
| IL (1) | IL157303A0 (en) |
| MX (1) | MXPA03007348A (en) |
| NO (1) | NO325675B1 (en) |
| NZ (1) | NZ527597A (en) |
| PL (1) | PL367285A1 (en) |
| RU (1) | RU2280031C2 (en) |
| SK (1) | SK11622003A3 (en) |
| WO (1) | WO2002066437A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR112015023328A2 (en) * | 2013-03-13 | 2017-07-18 | Flatley Discovery Lab | pyridazinone compounds and methods for treating cystic fibrosis |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0876349B1 (en) * | 1995-10-19 | 2002-09-11 | Takeda Chemical Industries, Ltd. | Quinoline derivatives as gnrh antagonists |
| CA2254974A1 (en) * | 1996-05-20 | 1997-11-27 | Mark Goulet | Antagonists of gonadotropin releasing hormone |
-
2002
- 2002-02-21 RU RU2003128647/04A patent/RU2280031C2/en not_active IP Right Cessation
- 2002-02-21 AU AU2002247737A patent/AU2002247737B2/en not_active Ceased
- 2002-02-21 BR BR0207451-6A patent/BR0207451A/en not_active IP Right Cessation
- 2002-02-21 CZ CZ20032514A patent/CZ20032514A3/en unknown
- 2002-02-21 PL PL02367285A patent/PL367285A1/en not_active Application Discontinuation
- 2002-02-21 HU HU0303219A patent/HUP0303219A2/en unknown
- 2002-02-21 SK SK1162-2003A patent/SK11622003A3/en unknown
- 2002-02-21 EP EP02716803A patent/EP1362034A1/en not_active Withdrawn
- 2002-02-21 WO PCT/EP2002/001882 patent/WO2002066437A1/en active IP Right Grant
- 2002-02-21 MX MXPA03007348A patent/MXPA03007348A/en active IP Right Grant
- 2002-02-21 NZ NZ527597A patent/NZ527597A/en unknown
- 2002-02-21 CN CNA028063597A patent/CN1496354A/en active Pending
- 2002-02-21 CA CA002438709A patent/CA2438709A1/en not_active Abandoned
- 2002-02-21 JP JP2002565954A patent/JP2004528298A/en active Pending
- 2002-02-21 IL IL15730302A patent/IL157303A0/en unknown
-
2003
- 2003-08-20 NO NO20033698A patent/NO325675B1/en not_active IP Right Cessation
- 2003-09-09 BG BG108165A patent/BG108165A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO20033698D0 (en) | 2003-08-20 |
| SK11622003A3 (en) | 2004-01-08 |
| PL367285A1 (en) | 2005-02-21 |
| RU2280031C2 (en) | 2006-07-20 |
| AU2002247737B2 (en) | 2006-05-18 |
| CA2438709A1 (en) | 2002-08-29 |
| CZ20032514A3 (en) | 2004-05-12 |
| IL157303A0 (en) | 2004-02-19 |
| BR0207451A (en) | 2004-06-01 |
| JP2004528298A (en) | 2004-09-16 |
| MXPA03007348A (en) | 2003-12-04 |
| WO2002066437A1 (en) | 2002-08-29 |
| CN1496354A (en) | 2004-05-12 |
| NO20033698L (en) | 2003-10-20 |
| NO325675B1 (en) | 2008-07-07 |
| EP1362034A1 (en) | 2003-11-19 |
| HUP0303219A2 (en) | 2003-12-29 |
| BG108165A (en) | 2004-08-31 |
| RU2003128647A (en) | 2005-03-27 |
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