KR20080030622A - Non-steroidal progesterone receptor modulators - Google Patents

Abstract

The present invention relates to non-steroidal progesterone receptor modulators of the general formula (I), a process for their preparation, the use of the progesterone receptor modulators for producing medicaments, and pharmaceutical compositions comprising these compounds. The compounds according to the invention are suitable for the therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional (bleeding)and dysmenorrhoea, and for the therapy and prophylaxis of hormone-dependent tumours and for use for female fertility control and for hormone replacement therapy.

Description

Nonsteroidal Progesterone Receptor Modulator {NON-STEROIDAL PROGESTERONE RECEPTOR MODULATORS}

The present invention relates to nonsteroidal progesterone receptor modulators, methods for their preparation, the use of progesterone receptor modulators for the manufacture of a medicament, and pharmaceutical compositions comprising these compounds.

The steroid hormone progesterone plays a crucial role in regulating the reproduction process in the female body. During the reproductive cycle and during pregnancy, progesterone is secreted from the ovary or placenta. The interaction of estrogen with progesterone results in periodic changes in the uterine mucosa (endometrium) in the menstrual cycle. After ovulation, the effects of elevated progesterone levels change the uterine mucosa into a state where embryos (blastocysts) can implant. During pregnancy, progesterone regulates the relaxation of the myometrium and maintains the function of the decidual tissue.

In addition, it is known that progesterone inhibits proliferation of the endometrium by inhibiting estrogen-mediated mitosis in uterine tissue (K. Chwalisz, RM Brenner, U. Fuhrmann, H. Hess-Stumpp, W). Elger, Steroids 65, 2000, 741-751).

It is also known that progesterone and progesterone receptors play an important role in pathophysiological progression. Progesterone receptors are found in tumors of the uterus, breast and CNS as well as in lesions of endometriosis. In addition, it is known that fibroids proliferate in a progesterone-dependent manner.

The effects of progesterone in the tissues of the reproductive organs and other tissues are caused by interactions with progesterone receptors, which manifest themselves as cellular effects.

Progesterone receptor modulators are pure agonists or partially or wholly inhibit the action of progesterone. Thus, such substances are defined as pure agonists, partial agonists (SPRMs) and pure antagonists.

Depending on the ability of progesterone receptor modulators to influence the effects of progesterone receptors, these compounds have significant potential as therapeutics for obstetrics diseases and contraception as well as for gynecological diseases and tumor indications.

Pure progesterone receptor antagonists completely inhibit the effects of progesterone on progesterone receptors. In addition to antiovulation, it has the ability to inhibit the effects of estrogen until the endometrium is completely contracted. Thus, it may intervene during the female reproductive process, for example to prevent implantation after ovulation; It is suitable to increase the responsiveness of the uterus to prostaglandins or oxytocin during pregnancy, to achieve cervical opening and softening (“maturation”), and to induce the uterine muscle to be fully prepared for contraction.

In lesions of endometriosis or tumor tissue with progesterone receptors, a beneficial effect on the progression of the disease following administration of pure progesterone receptor antagonists is expected. If ovulation inhibition can additionally be achieved by progesterone receptor antagonists, there will be particular advantages influencing pathological conditions such as endometriosis or uterine myoma. Ovulation inhibition also obviates the production of some ovarian hormones and the stimulatory effects on pathologically altered tissue derived from this portion.

The first described progesterone receptor antagonist RU 486 (also called mifepristone) followed by a number of analogs with varying degrees of progesterone receptor-antagonistic activity. While RU 486 also exhibits antiglucocorticoid action in addition to progesterone receptor-antagonist action, later synthesized compounds stand out by more selective action than progesterone receptor antagonists.

In addition to steroid compounds, such as onapristone or lilopristone, which are prominent in the relatively better segregation action against RU 486 in progesterone-receptor-antagonist effects and antiglucocorticoid effects, various nonsteroidal properties studied for progesterone receptors have been studied. Constructs are known from the literature (see, eg, SA Leonhardt and DP Edwards, Exp. Biol. Med. 227: 969-980 (2002)) and R. Winneker, A. Fensome, JE Wrobel, Z. Zhang. , P. Zhang, Seminars in Reproductive Medicine, Volume 23: 46-57 (2005)). However, previously known compounds have only moderate antagonistic activity compared to known steroid constructs. It is reported that the most effective nonsteroidal compounds have an in vitro activity of 10% of the activity of RU 486.

Antiglucocorticoid activity is disadvantageous in therapeutic applications where the inhibition of progesterone receptors is the key to treatment. Antiglucocorticoid activity causes undesirable side effects in the case of therapeutically necessary dosages. This may prevent the application of a therapeutically useful dosage or lead to termination of treatment.

Thus, partial or complete reduction in antiglucocorticoid properties is an important prerequisite for treatment with progesterone receptor antagonists, especially indications requiring treatment lasting weeks or months.

In contrast to pure antagonists, progesterone receptor partial agonists (SPRMs) exhibit residual efficacy, which may vary in intensity. This has led to the discovery that these substances have potential potent action on progesterone receptors in certain organ systems (D. DeManno, W. Elger, R. Garg, R. Lee, B. Schneider, H. Hess- Stumpp, G. Schuber, K. Chwalisz, Steroids 68, 2003, 1019-1032). This organ-specific and dissociative action can be therapeutically beneficial for the indications described above.

It is therefore an object of the present invention to provide additional nonsteroidal progesterone receptor modulators. Such compounds will have reduced antiglucocorticoid activity and will therefore be suitable for the treatment and prevention of gynecological diseases such as endometriosis, uterine myoma, dysfunctional uterine bleeding and dysmenorrhea. In addition, the compounds according to the invention will be suitable for the treatment and prevention of hormone-dependent tumors such as breast cancer, endometrial cancer, ovarian cancer and prostate cancer. In addition, the compounds will be suitable for use in female contraception and female hormone replacement therapy.

According to the present invention the object of the present invention is achieved by providing the following non-steroidal compounds of general formula (I) and pharmaceutically acceptable salts thereof.

Where

R ¹ and R ² are each independently a hydrogen atom or a straight or non-linear, branched or unbranched C ₁ -C ₅ -alkyl group, and together with the C atoms of the chain form a total of 3 to 7 membered rings and,

R ³ is a radical C≡CR ^a [where

R ^a is hydrogen or C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -optionally substituted one or more times with K in the same or different ways C ₁₀ -cycloalkyl or heterocycloalkyl, or aryl or heteroaryl optionally substituted one or more times with L in the same or different ways,

K is cyano, halogen, hydroxy, nitro, -C (O) R ^b , CO ₂ R ^b , -OR ^b , -SR ^b , SO ₂ NR ^c R ^d , -C (O) -NR ^c R ^d , -OC (O) -NR ^c R ^d , -C = NOR ^b -NR ^c R ^d Or C ₃ -C ₁₀ -cycloalkyl, or heterocycloalkyl optionally substituted one or more times with M in the same or different ways, or aryl or heteroaryl optionally substituted with one or more times,

L is C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₁ -C ₆ -perfluoroalkyl, C ₁ -C ₆ -perfluoroalkoxy, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - _{alkoxy, (CH 2) p -C 3} -C 10 - cycloalkyl, (CH _{2) p} - _{heterocycloalkyl, (CH 2) p CN,} (CH ₂ ) _p Hal, (CH ₂ ) _p NO ₂ , (CH ₂ ) _p -C ₆ -C ₁₂ -aryl, (CH ₂ ) _p -heteroaryl,-(CH ₂ ) _p PO ₃ (R ^b ) ₂ , -(CH ₂ ) _p NR ^c R ^d ,-(CH ₂ ) _p NR ^e COR ^b ,-(CH ₂ ) _p NR ^e CSR ^b ,-(CH ₂ ) _p NR ^e S (O) R ^b ,-( CH ₂ ) _p NR ^e S (O) ₂ R ^b ,-(CH ₂ ) _p NR ^e CONR ^c R ^d ,-(CH ₂ ) _p NR ^e COOR ^b ,-(CH ₂ ) _p NR ^e C (NH) NR ^c R ^d ,-(CH ₂ ) _p NR ^e CSNR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) NR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) ₂ NR ^c R ^d ,-(CH ₂ ) _p COR ^b ,-(CH ₂ ) _p CSR ^b ,-(CH ₂ ) _p S (O) R ^b ,-(CH ₂ ) _p S (O) (NH) R ^b , -(CH ₂ ) _p S (O) ₂ R ^b ,-(CH ₂ ) _p S (O) ₂ NR ^c R ^d ,-(CH ₂ ) _p SO ₂ OR ^b ,-(CH ₂ ) _p CO ₂ R ^b ,-(CH ₂ ) _p CONR ^c R ^d ,-(CH ₂ ) _p CSNR ^c R ^d ,-(CH ₂ ) _p OR ^b ,-(CH ₂ ) _p SR ^b ,-(CH ₂ ) _p CR ^b (OH) -R ^e ,-(CH ₂ ) _p -C = NOR ^b , -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -O-CH = CH- or-(CH ₂ ) _{n + 2-} , where n is 1 or 2, the terminal oxygen atoms and / or carbon atoms are directly connected to adjacent ring carbon atoms,

M is C ₁ -C ₆ -alkyl or -COR ^b , CO ₂ R ^b , -OR ^b , or -NR ^c R ^d ,

R ^b is hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl, C ₆ -C ₁₂ -aryl or C ₁ -C ₃ -perfluoroalkyl,

R ^c and R ^d are each independently hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl, C _6- C ₁₂ -aryl, C (O) R ^b or a hydroxy group wherein if R ^c is a hydroxy group, R ^d is only hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl or C ₆ -C ₁₂ -aryl, and vice versa,

R ^e is hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl or C ₆ -C ₁₂ -aryl,

p may be a number from 0 to 6], or

R ³ is a radical C = CR ^g R ^h wherein

R ^g and R ^h are each independently hydrogen or C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₈ -optionally substituted one or more times with X in the same or different ways; Alkynyl,

X is cyano, halogen, hydroxy, nitro, -C (O) R ^b , CO ₂ R ^b , -OR ^b , -C (O) -NR ^c R ^d , -NR ^c R ^d , where R ^b , R ^c and R ^d are as defined above;

R ⁴ is a hydrogen atom, a methyl or ethyl group, or a partially or fully fluorinated C ₁ -C ₃ -alkyl group,

A is a monocyclic or bicyclic carbocyclic or heterocyclic aromatic ring (which is C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₁ -C ₆ -perfluoroalkyl, C ₁ -C ₆ -perfluoroalkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy, (CH ₂ ) _p -C ₃ -C ₁₀ -cycloalkyl, (CH ₂ ) _p -heterocycloalkyl, (CH ₂ ) _p CN, (CH ₂ ) _p Hal, (CH ₂ ) _p NO ₂ , (CH ₂ ) _p -C ₆ -C ₁₂ -aryl, (CH ₂ ) _p -heteroaryl,-(CH ₂ ) _p PO ₃ (R ^b ) ₂ ,-(CH ₂ ) _p NR ^c R ^d ,-(CH ₂ ) _p NR ^e COR ^b ,-(CH ₂ ) _p NR ^e CSR ^b ,-(CH ₂ ) _p NR ^e S (O) R ^b ,-(CH ₂ ) _p NR ^e S (O) ₂ R ^b ,-( CH ₂ ) _p NR ^e CONR ^c R ^d ,-(CH ₂ ) _p NR ^e COOR ^b ,-(CH ₂ ) _p NR ^e C (NH) NR ^c R ^d ,-(CH ₂ ) _p NR ^e CSNR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) NR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) ₂ NR ^c R ^d ,-(CH ₂ ) _p COR ^b ,-(CH ₂ ) _p CSR ^b ,-(CH ₂ ) _p S (O) R ^b ,-(CH ₂ ) _p S (O) (NH) R ^b ,-(CH ₂ ) _p S (O) ₂ R ^b ,-( CH ₂ ) _p S (O) ₂ NR ^c R ^d ,-(CH ₂ ) _p SO ₂ OR ^b ,-(CH ₂ ) _p CO ₂ R ^b ,-(CH ₂ ) _p CONR ^c R ^d ,-(CH ₂ ) _p CSNR ^c R ^d ,-(CH ₂ ) _p OR ^b ,-(CH ₂ ) _p SR ^b ,-(CH ₂ ) _p CR ^b (OH) -R ^d ,-(CH ₂ ) _p -C = NOR ^b , May be optionally substituted one or more times with -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -O-CH = CH- or-(CH ₂ ) _{n + 2-} Wherein n is 1 or 2 and the terminal oxygen atom and / or carbon atom is directly connected to an adjacent ring carbon atom), or

A is a radical —CO ₂ R ^b , C (O) NR ^c R ^d , COR ^b, or

A is an alkenyl group -CR ⁵ = CR ⁶ R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are the same or different and independently of one another are a hydrogen atom, a halogen atom, an aryl radical, or an unsubstituted or partially or fully Fluorinated C ₁ -C ₅ -alkyl group), or

A is an alkynyl group —C≡CR ⁵ , wherein R ⁵ has the meanings mentioned above,

B is a carbonyl group or a CH ₂ group.

The compounds of the general formula (I) according to the invention may exist in other stereoisomers because they have an asymmetric center. Both racemates and individual stereoisomers belong to the subject of the invention.

In addition, the present invention includes novel compounds as pharmaceutically active ingredients, their preparation, their therapeutic uses, and pharmaceutical dosage forms comprising such novel substances.

The compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts can in particular be used for the manufacture of a medicament for the treatment and prevention of gynecological diseases such as endometriosis, uterine fibroids, dysfunctional uterine bleeding and dysmenorrhea have. In addition, the compounds according to the invention can be used for the treatment and prevention of hormone-dependent tumors such as breast cancer, prostate cancer and endometrial cancer.

The compounds of general formula (I) or pharmaceutically acceptable salts thereof according to the invention are suitable for use for female contraception or female hormone replacement therapy.

The invention additionally relates to a process for the preparation of compounds of formula (I). The substituent R ³ is introduced into the keto group by the selective addition reaction of organometallic compounds such as lithium alkynyl or magnesium haloalkynyl. This gives a compound of the general formula (I) according to the invention either directly or after further modifications.

The compounds according to the invention are prepared by selective addition reactions of organometallic compounds to ketoamides, which are disclosed, for example, in the published applications US 2002/0077356, US 6,323, 199B1, WO 200375915 and WO 9854159. The organometallic compound may be, for example, a lithium alkynyl compound or a magnesium haloalkynyl compound. It can be prepared, for example, by reacting a suitable alkyne with a butyllithium or Grignard compound. Similarly, corresponding organometallic alkenyl compounds can also be prepared. Compared to the amide carbonyl or benzoxazinone, the reactivity of the keto group in this case is quite high, and with the appropriate choice of reaction conditions, selective addition reactions are achieved. Alternatively, the alkynyl or alkenyl radicals introduced as R ³ can also be further modified afterwards. Suitable reactions for such modifications known to those skilled in the art include, for example, oxidation, reduction, substitution, alkylation, or palladium-catalyzed reactions. Optionally present protecting groups are removed when appropriate.

Nonsteroidal compounds of the general formula (I) according to the invention have a strong antagonistic effect or a strong partial efficacy effect on the progesterone receptor. They exhibit a strong dissociation action with respect to their binding strength to progesterone receptors and glucocorticoid receptors. Although known progesterone receptor antagonists such as mifepristone (RU 486) exhibit similarly high affinity for glucocorticoid receptors, in addition to exhibiting the desired high binding affinity for progesterone receptors, the compounds according to the invention have high progesterone receptor affinity. And at the same time very low glucocorticoid receptor binding capacity.

Substituents of the compounds of the general formula (I) according to the invention, defined as groups, may in each case have the following meanings.

C ₁ -C _5- , C ₁ -C ₆ -or C ₁ -C ₈ -alkyl groups are defined as straight or non-chain, branched or unbranched alkyl radicals. Examples thereof include methyl, ethyl, n-propyl, iso-propyl, n-, iso-, tert-butyl, n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl, hexyl, heptyl or octyl groups.

In the meaning of R ^a , methyl, ethyl, n-propyl or n-butyl groups and n-pentyl groups are preferred in this case.

In the meaning of R ¹ and R ² , methyl or ethyl is preferred.

Alkenyl means straight or non-chain, branched or unbranched alkenyl radicals. Within the context of the present invention, examples of meaning C ₂ -C ₈ -alkenyl are as follows. Vinyl, allyl, 3-buten-1-yl- or 2,3-dimethyl-2-propenyl. When aromatic compound A is substituted with a C ₂ -C ₈ -alkenyl radical, it is preferably a vinyl group.

Alkynyl means straight-chain or non-chain, branched or unbranched alkynyl radicals. The C ₂ -C ₈ -alkynyl radical is for example an ethynyl, propynyl, butynyl, pentynyl, hexynyl or octinyl group, preferably an ethynyl or propynyl group.

Examples that may be referred to as C ₃ -C ₁₀ -cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preference is given to cyclopropyl, cyclopentyl and cyclohexyl.

In the meaning of R ^a , K or L, heterocycloalkyl means a 3- to 8-membered heterocycloalkyl radical. Examples of heterocycloalkyl are morpholinyl, tetrahydrofuranyl, pyranyl, piperazinyl, piperadinyl, pyrrolidinyl, oxiranyl, oxetanyl, aziridinyl, dioxolanyl and dioxanyl . In this case the position of the heteroatom relative to the position of the linkage can be any chemically possible position.

The C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy group can be methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy.

Within the context of the present invention, the radical OR ^b is hydroxy, methoxy, ethoxy, n-propoxy, iso-propoxy, n-, iso-, or tert-butoxy group, or n-pentoxy, 2 , 2-dimethylpropoxy or 3-methylbutoxy group. Preference is given to hydroxy, methoxy and ethoxy.

Suitable as partially or fully fluorinated C ₁ -C ₅ -alkyl groups are those perfluorinated alkyl groups. Among them, trifluoromethyl group or pentafluoroethyl group is particularly preferable, and as the partially fluorinated alkyl group, for example, 5,5,5,4,4-pentafluoropentyl group or 5,5, Preference is given to 5,4,4,3,3-heptafluoropentyl groups.

The halogen atom may be a fluorine, chlorine, bromine or iodine atom. Preference is given here to fluorine, chlorine or bromine.

When R ¹ and R ² together with the C atoms of the chain form a 3- to 7-membered ring it is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. Preference is given to cyclopropyl rings and cyclopentyl rings.

Monocyclic or bicyclic carbocyclic aromatic rings A, which may be substituted more than once, are carbocyclic or heterocyclic aryl radicals.

In the former case it is, for example, a phenyl or naphthyl radical, preferably a phenyl radical.

As heterocyclic radicals, for example, monocyclic heterocyclic radicals such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyri Daginyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, or tetrazolyl radicals, and especially all possible isomers related to the position of the heteroatoms, are to be used. Can be.

R ³ in the case of an aryl radical means an optionally substituted phenyl, 1- or 2-naphthyl radical, preferably a phenyl radical. Examples of heteroaryl radicals include 2-, 3- or 4-pyridinyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imida Zolyl, pyrazinyl, 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radicals.

The number p for the (CH ₂ ) _p radical may be a number from 0 to 6, preferably 0 to 2. "Radial" means all functional groups mentioned in connection with (CH ₂ ) _p according to the invention.

If the compound of the general formula (I) (B = -CH _2- ) is present in the form of a salt, it may be for example in the form of hydrochloride, sulfate, nitrate, tartrate, citrate, fumarate, succinate or benzoate Can be.

If the compounds according to the invention are present as racemic mixtures, they can be separated in optically active pure form according to racemic separation methods familiar to those skilled in the art. For example, racemic mixtures can be separated into pure isomers by chromatography on an optically active support material (chiralpak AD®). The free hydroxy groups in the racemic compound of general formula (I) are esterified with an optically active acid, the diastereomeric esters obtained by fractional crystallization or chromatography are separated and the separated esters in each case are hydrolyzed optically. It is also possible to form pure isomers. As optically active acids, for example, mandelic acid, camphorsulfonic acid or tartaric acid can be used.

The compounds listed below and their uses are preferred according to the invention.

Biological Properties of the Compounds According to the Invention

Identification of progesterone receptor modulators can be performed using simple methods, test programs known to those skilled in the art. For this purpose, for example, the compounds to be tested can be incubated with progestogens in a test system for progesterone receptors, and tested in this test system whether the progesterone-mediated effect changes in the presence of a modulator.

The materials of general formula (I) according to the invention were tested in the following models.

Progesterone Receptor Binding Assay

Receptor binding affinity measurement:

Receptor binding affinity was determined by competitive binding of ³ H-labeled hormones (tracers) that specifically bind on receptors in the cytoplasm from animal target organs and the compounds to be tested. The purpose of this case was receptor saturation and reaction equilibrium.

The tracer and increasing concentrations of compound to be tested (competitors) were co-incubated with the receptor-containing cytoplasmic fraction at 0-4 ° C. over 18 hours. After removal of the unbound tracer with a carbon-dextran suspension, the receptor-bound tracer portion was measured at each concentration and the IC ₅₀ was determined from the concentration sequence. The relative molecular binding affinity (RBA) was calculated as the ratio of the IC ₅₀ value of the reference material and the test compound (x 100%) (RBA = 100% of the reference material).

Depending on the receptor type, the following incubation conditions were selected.

Progesterone Receptor:

Uterine cytoplasm of estradiol-infused rabbit homogenized in TED buffer (tris / HCl 20 mM, pH 7.4; ethylenediaminetetraacetate 1 mM, dithiothritol 2 mM) with sucrose 250 mM; Store at -30 ° C. Tracer: ³ H-ORG 2058, 5 nM; Reference substance: progesterone.

Glucocorticoid Receptor:

Thymic cytoplasm of adrenal isolated rats, thymus stored at −30 ° C .; Buffer: TED. Tracer: ³ H-dexamethasone, 20 nM; Reference substance: Dexamethasone.

The relative receptor binding affinity (RBA value) of the compounds of general formula (I) according to the invention for progesterone receptors is 3 to 100% for progesterone. The RBA value for the glucocorticoid receptor is 3-30% for dexamethasone.

Thus, the compounds according to the invention have a high affinity for the progesterone receptor but a low affinity for the glucocorticoid receptor.

PR Antagonism at the -B Progesterone Receptor

Transactivation assays are performed as described in WO 02/054064.

PR Efficacy at the -B Progesterone Receptor

Fuhrmann, U .; described by Fuhrmann et al .; Hess-Stump, H .; Cleve, A .; Neef, G .; Schwede, W .; Hoffmann, J .; Fritzemeier, K.-H., Chwalisz, K .; Transition activity analysis is performed according to the Journal of Medicinal Chem., 43, 26, 2000, 5010-5016.

number Antagonist activity Efficacy Activity IC ₅₀ [nM] validity[%] EC ₅₀ [nM] validity[%] 5 0.2 86 0.2 10 14 6 53 7 35 16 0.7 82 0.5 13 17b 0.03 88 n.b. 7 18 0.2 89 n.b. 8 24 2 100 0 35 2 100 0

Dosage

For use according to the invention, progesterone receptor modulators can be administered orally, enterally, parenterally or transdermally.

In general, satisfactory results can be expected in the treatment of the indications if the daily dose comprises 1 μg to 500 mg of the compound according to the invention.

The dosage of a compound according to the invention suitable for the treatment of endometriosis, uterine fibroids and dysfunctional uterine bleeding in humans, and for contraceptive use and hormone replacement therapy is between 50 μg and 500 mg per day, Depending on the constitution, the daily dose required may be administered once or multiple times.

The dosage range of the compound according to the invention for the treatment of breast cancer is 10 mg to 1000 mg per day.

Pharmaceutical products based on the novel compounds are formulated in a manner known in the art to contain the active ingredient in carrier materials, fillers, agents affecting disintegration, binders, wetting agents, lubricants, absorbents, diluents, taste masking agents, It is formulated by processing with colorants and the like and converting it to the desired dosage form. In this case, Remington's Pharmaceutical Science, 15 ^th Ed. Mack Publishing Company, East Pennsylvania (1980).

For oral administration in particular tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions are suitable.

For parenteral administration, injection and infusion preparations are possible.

For intraarticular injection, suitably prepared crystal suspensions can be used.

For intramuscular injection, aqueous and oily injection solutions or suspensions and the corresponding depot preparations can be used.

For rectal administration, the new compounds can be used for systemic and topical treatment in the form of suppositories, capsules, solutions (eg in the form of enema) and ointments.

In addition, agents for vaginal application may also be referred to as preparations.

For pulmonary administration of the novel compounds, they can be used in the form of aerosols and inhalants.

For transdermal administration, patches are possible, or for topical administration gels, ointments, fatty ointments, creams, pastes, dusting powders, tonsils and tinctures are possible. In order to achieve adequate pharmacological action, the dosage of the compound of general formula (I) in these preparations should be 0.01% to 20%.

Corresponding tablets may be prepared by, for example, the active ingredient with known excipients, for example inert diluents such as dextrose, sugars, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch Or gelatin, lubricants such as magnesium stearate or talc and / or means for obtaining the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also consist of several layers.

Thus, coated tablets may be prepared using coating cores prepared similarly to tablets and compositions commonly used in tablet coating, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugars. Can be. In such cases, the tablet shell may consist of a plurality of layers, and the above-mentioned excipients may be used in the tablet.

Solutions or suspensions of the compounds of general formula (I) according to the invention may further comprise taste-enhancing agents such as saccharin, cyclates or sugars and eg flavoring substances such as vanilla or orange extracts. In addition, they may include suspending excipients such as sodium carboxy methyl cellulose or preservatives such as p-hydroxybenzoate.

Capsules comprising a compound of general formula (I) can be prepared, for example, by mixing the compound (s) of general formula (I) with an inert carrier such as lactose or sorbitol and encapsulating in gelatin capsules.

Suitable suppositories can be prepared, for example, in admixture with a carrier provided for this purpose, such as triglycerides or polyethylene glycols or derivatives.

The compounds of the general formula (I) according to the invention or pharmaceutically acceptable salts thereof, due to their antagonism or partial efficacy action, in particular treat gynecological diseases such as endometriosis, uterine myoma, dysfunctional uterine bleeding and dysmenorrhea And for the manufacture of a medicament for prophylaxis. In addition, they can be used to correct hormonal irregularities to induce menstruation and to induce labor alone or in combination with prostaglandins and / or oxytocin.

In addition, the compounds of the general formula (I) or pharmaceutically acceptable salts thereof according to the invention are suitable for the preparation of contraceptive preparations for women (see also WO 93/23020, WO 93/21927).

In addition, the compounds according to the invention or pharmaceutically acceptable salts thereof can be used in female hormone replacement therapy alone or in combination with a selective estrogen receptor modulator (SERM).

In addition, the aforementioned compounds have antiproliferative effects in hormone-dependent tumors. Thus, the compounds are suitable for the treatment of hormone-dependent cancers such as breast cancer, prostate cancer or endometrial cancer.

The compounds according to the invention or their pharmaceutically acceptable salts can be used for the treatment of hormone-dependent cancers in primary and secondary therapies, in particular after tamoxifen therapy failure.

Compounds of the general formula (I) or pharmaceutically acceptable salts thereof according to the invention having antagonistic or partial agonistic action are also compounds having estrogen action (estrogen receptor antagonism) for the manufacture of pharmaceutical products for the treatment of hormone-dependent tumors. Agents or aromatase inhibitors) or selective estrogen receptor modulators (SERMs). For the treatment of endometriosis or fibroids, the compounds according to the invention can also be used in combination with SERMs or antiestrogens (estrogen receptor antagonists or aromatase inhibitors). In the treatment of hormone-dependent tumors, progesterone receptor modulators and antiestrogens (estrogen receptor antagonists or aromatase inhibitors) or SERMs may be provided for simultaneous or sequential administration. In sequential administration, an anti-estrogen (estrogen receptor antagonist or aromatase inhibitor) or SERM is preferably administered first, followed by a progesterone receptor modulator.

In combination with the nonsteroidal progesterone receptor modulator according to the invention, for example, the following antiestrogens (estrogen receptor antagonists or aromatase inhibitors) or SERMs are contemplated.

Tamoxifen, 5- (4- {5-[(RS)-(4,4,5,5,5-pentafluoropentyl) sulfinyl] -pentyloxy} phenyl) -6-phenyl-8,9-di Hydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7alpha- [9- (4,4,5,5-pentafluoropentylsulfinyl) nonyl] estra-1, 3,5 (10) -triene-3,17-beta-diol), 11beta-fluoro-7alpha- [5- (methyl {3-[(4,4,5,5,5-pentafluoro) Lofentyl) sulfanyl] propyl} amino) pentyl] estra-1,3,5 (10) -triene-3,17beta-diol (WO98 / 07740), 11beta-fluoro-7alpha- {5- [Methyl (7,7,8,8,9,9,10,10,10-nonafluorodecyl) amino] pentyl} estra-1,3,5 (10) -triene-3,17beta-diol (WO 99/33855), 11beta-fluoro-17alpha-methyl-7alpha- {5- [methyl (8,8,9,9,9-pentafluorononyl) amino] pentyl} estra-1, 3,5 (10) -triene-3,17beta-diol (WO 03/045972), clomiphene, raloxifene and additional compounds having antiestrogenic activity, and aromatase inhibitors such as padrazole, formemstan, retro Sol Nastrozol or atamestan.

Finally, the present invention also relates to the use of the compounds of general formula (I), optionally in combination with antiestrogens or SERMs, for the manufacture of a medicament.

The invention also relates to a pharmaceutical composition comprising at least one compound according to the invention, optionally in the form of a pharmaceutically / pharmacologically compatible salt, in the presence or absence of a pharmaceutically compatible excipient and / or carrier.

The pharmaceutical compositions and medicaments may be provided for oral, rectal, vaginal, subcutaneous, transdermal, intravenous or intramuscular administration. The compositions and medicaments comprise, in addition to the carriers and / or diluents which are commonly used, one or more compounds according to the invention.

The medicament of the present invention may be prepared in a known manner using conventionally used solid or liquid carriers or diluents and commonly used pharmaceutical-technical excipients which correspond to administration of the desired manner at a suitable dosage. Preferred formulations are in dosage forms suitable for oral administration. Such dosage forms include, for example, tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, solutions or suspensions, or depot forms.

Pharmaceutical compositions comprising at least one compound according to the invention are preferably administered orally.

Parenteral preparations such as injection solutions are also suitable. In addition, suppositories and vaginal application agents may also be mentioned as preparations, for example.

The following examples are used to illustrate the subject matter of the present invention in more detail, but are not intended to be limited to these examples.

Starting compound 6- [4- (2-chloro-5-fluorophenyl) -4-methyl-2-oxovaleroylamino] -4-methyl-2,3-benzoxazin-1-one, 6- [4- (2-Chloro-4-fluorophenyl) -4-methyl-2-oxovaleroylamino] -4-methyl-2,3-benzoxazin-1-one and 6- {3- [ Preparation of 1- (2-chlorophenyl) cyclopentyl] -2-oxopropionylamino} -4-methyl-2,3-benzoxazine-1-one is described in US Pat. No. 2002/0077356, Compound 6- [4- (2,3-dihydro-7-benzofuranyl) -4-methyl-2-oxopentanoylamino] -4-methyl-2,3-benzoxazinone is disclosed in US Pat. No. 6,323,199B1 No. (herein included Example 87), the compound 6- (4-methyl-4-phenyl-2-oxovaleroylamino) -4-methyl-2,3-benzoxazin-1-one is disclosed in Patent WO 199854159 to compound 6- [3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionyl-amino] -4-methyl-2,3-benzoxazine- 1-on is described in patent WO 200375915.

Common way

One-( Benzo [1,3] dioxol -4-yl) -1- Methylethanol

57.2 ml of methyl magnesium chloride solution (3M in THF) was added to 25.5 g of 4-acetylbenzo [1,3] dioxol in 375 ml of THF under argon at room temperature. The mixture was stirred at rt for 16 h and added to ice / 2N hydrochloric acid. Then it was extracted with ethyl acetate and the organic phase was washed with water and brine and dried (Na ₂ SO ₄ ). 27.89 g of 1- [benzo (1,3) dioxol-4-yl] -1-methylethanol were obtained as a brown oil.

4-( Benzo [1,3] dioxol -4-yl) -4- methyl -2- Oxopentanoic Acid

47 ml of tin (IV) chloride was added to 9.5 g of 1- (benzo [1,3] dioxol-4-yl) -1-methylethanol and 200 mg of ethyl 2-trimethylsilyloxyacrylate in 200 ml of dichloromethane at −70 ° C. to g. After 15 minutes, the solution was added to potassium carbonate solution. After extraction with diethyl ether, the organic phase is washed with water, dried and evaporated.

14.4 g of ethyl 4- (benzo [1,3] dioxol-4-yl) -4-methyl-2-oxopentanoate obtained in this manner was dissolved in 150 ml of 1 M sodium hydroxide and 300 ml of methanol at room temperature. Stir for hours. Then methanol was removed under vacuum and the remaining solution was extracted with diethyl ether. The aqueous phase was acidified with 1 M hydrochloric acid and extracted with diethyl ether. Drying and evaporation gave 11.1 g of 4- (benzo [1,3] dioxol-4-yl) -4-methyl-2-oxopentanoic acid as a yellow oil. MS (ei) m / e: M ⁺ = 251

6- [4- ( Benzo [1,3] dioxol -4-yl) -4- methyl -2- Oxovaleroylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on

10 g of 4- (benzo [1,3] dioxol-4-yl) -4-methyl-2-oxopentanoic acid are dissolved in 125 ml of dimethylacetamide and 3.5 ml of thionyl chloride under argon at −0 ° C. Added. After 20 min stirring at -3 to + 3 ° C, 7.6 g of 6-amino-4-methyl-2,3-benzoxazin-1-one (WO 00/32584) was added. The mixture is stirred at rt for 96 h, water is added, then extracted with ethyl acetate, the organic phase is washed with water, dried (Na ₂ SO ₄ ), the solvent is evaporated and the crude product is hexanes / silica gel on silica gel. 6- [4- (benzo [1,3] dioxol-4-yl) -4-methyl-2-oxovaleroylamino] -4 by chromatography with ethyl acetate (100: 0-> 60:40) 6.56 g of -methyl-2,3-benzoxazin-1-one were obtained as a beige solid. mp = 165-166 ° C., MS (ei) m / e: M ⁺ = 409

Synthesis Example

(-)-6- {2- [2- (2,3- ( Methylenedioxy ) Phenyl )-2- Methylpropyl ]-2- Hydroxy oct -3- this Noil} -4- methyl -2,3- Mercedes-Benz Photo -1-on One  And (+)-6- {2- [2- (2,3- ( Methylenedioxy ) Phenyl ) -2-methylpropyl] -2- Hydroxy oct -3- Innoyl }-4- methyl -2,3- Mercedes-Benz Photo -1-on 2

nBuLi (0.7 ml, 1.6 M in hexane) was added to a solution of 1-hexine (0.5 ml) in THF (4 ml) at −78 ° C. The mixture is stirred at -78 ° C for 20 minutes and 6- [4- (benzo [1,3] dioxol-4-yl) -4-methyl-2-oxovaleroylamino] -4-methyl-2 , 3-Benzoxazine-1-one (192 mg) was added and the mixture was stirred at -78 ° C for 4 h. Then water was added and the mixture brought to room temperature. Extract with ethyl acetate, wash with saturated sodium chloride solution, dry over sodium sulphate and purify by column chromatography on silica gel to give 82 mg of white foam, followed by preparative chiral HPLC (chiralpak AD 250 x 10 mm, eluate) : Acetonitrile / water 55/45 v / v, flow rate 4.7 ml / min, temperature 40 ° C., retention time: 12.2 min (+)-enantiomer, 15.7 min (-)-enantiomer), using compound (- ) -6- {2- [2- (2,3- (methylenedioxy) phenyl) -2-methylpropyl] -2-hydroxyoct-3-inoyl} -4-methyl-2,3-benz Oxazine-1-one (Synthesis Example 1) and (+)-6- {2- [2- (2,3- (methylenedioxy) phenyl) -2-methylpropyl] -2-hydroxyoct-3 -Inoyl} -4-methyl-2,3-benzoxazine-1-one (Synthesis Example 2).

rac -6- {2- [2- (2- Chloro -5- Fluorophenyl )-2- Methylpropyl ] -2,7- Dihydroxyhept -3- furnace Il} -4-methyl-2,3- Mercedes-Benz Photo -1-on 3

Step A: 5- (tert-Butyldimethylsilyloxy) pent-1-yne (531 mg), nBuLi (0.7 ml, 1.6 M in hexane) and 6- [4- (2-chloro-5-fluorophenyl) -4-methyl-2-oxovaleroylamino] -4-methyl-2,3-benzoxazin-1-one (207 mg) was reacted at −78 ° C. as described in Synthesis Example 1 , and silica Column chromatography on gels gave a colorless oil (86 mg).

Step B: The resulting oil was stirred in THF (3 ml) at room temperature under argon (3 hours). Water was added, extracted with ethyl acetate, washed with saturated brine and dried over sodium sulfate. Purification by column chromatography on silica gel gave the title compound as a white foam (43 mg).

rac -6- {2- [2- (2- Chloro -5- Fluorophenyl )-2- Methylpropyl ]-2- Hydroxy oct -3- Innoyl }-4- methyl -2,3- Mercedes-Benz Photo -1-on 4

1-hexine (0.6 ml), nBuLi (0.7 ml, 1.6 M in hexane) and 6- [4- (2-chloro-5-fluorophenyl) -4-methyl-2-oxovaleroylamino] -4 -Methyl-2,3-benzoxazin-1-one (207 mg) was reacted at -78 ° C as described in Synthesis Example 1, column chromatography on silica gel, preparative thin layer chromatography and viscous oil (12 mg) was obtained.

rac -6- {2-[(2- Chlorophenyl ) Cyclopentyl ] methyl -2-hydroxy-4- Phenyl Boot -3- Innoyl Amino} -4- methyl -2,3- Mercedes-Benz Photo -1-on 5

Lithiumphenylacetylide (0.65 ml, 1 M in THF) was added to 6- {3- [1- (2-chlorophenyl) -cyclopentyl] -2-oxopropionylamino} -4-methyl-2 at -78 ° C. , 3-benzoxazine-1-one (110 mg) was added and allowed to reach room temperature overnight under argon. Post-treatment as described in Synthesis Example 1, column chromatography on silica gel and oil-pump drying gave the title compound as a foam (54 mg).

6- {2- [2- (2,3- Dehydro -7- Benzofuranyl )-2- Methylpropyl ] -2-hydroxy-3- Octinoyl Amino} -4- methyl -2,3- Mercedes-Benz Photo -1-on 6

1-hexine (0.4 ml), nBuLi (0.7 ml, 1.6 M in hexane) and 6- [4- (2,3-dihydro-7-benzofuranyl) -4-methyl-2-oxopentanoylamino] 4-Methyl-2,3-benzoxazin-1-one (99.5 mg) was reacted at -78 ° C in THF (3 ml) as described in Synthesis Example 1, and column chromatography on silica gel And dried under vacuum to afford a solidified colorless oil (42 mg).

rac -6- {4- (2- Chloro -4- Fluorophenyl ) -2-hydroxy-2-[(4- Hydroxyphenyl ) Eti NEIL] -4- Methylpentanoylamino }-4- methyl -2,3- Mercedes-Benz Photo -1-on 7

Step A: Compound of Synthesis Example 10 (57.8 mg), triphenylphosphine (6.8 mg), copper iodide (5 mg), 4-iodophenyl acetate in THF (1 ml) and triethylamine (3 ml) ( 51 mg), a suspension of palladium acetate (5 mg) was reacted in an ultrasonic bath for 1 hour under argon. Saturated aqueous ammonium chloride solution was added, then extracted with ethyl acetate and washed with water and brine. Dried over sodium sulfate, then concentrated and purified by column chromatography on silica gel. A white solid (46.7 mg) was obtained.

Step B: A suspension of compound (46.7 mg) and sodium bicarbonate (128 mg) from Step A in methanol was stirred at room temperature for 6 hours under argon. A small amount of sodium hydrogen carbonate was then added and the mixture was stirred overnight. It was diluted with ethyl acetate, water was added, the phases were separated and then extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, concentrated and column chromatography on silica gel to give the title compound as a viscous oil (29 mg).

rac -6- {2- [2- (2- Chloro -4- Fluorophenyl )-2- Methylpropyl ]-2- Hydroxydes -3- Innoyl -Amino} -4- methyl -2,3- Mercedes-Benz Photo -1-on 8

1-octin (0.4 ml), nBuLi (0.6 ml, 1.6 M in hexane) and 6- [4- (2-chloro-4-fluorophenyl) -4-methyl-2-oxovaleroylamino] -4 -Methyl-2,3-benzoxazin-1-one (110 mg) was reacted in THF (3 ml) at -78 ° C as described in Synthesis Example 1, and column chromatography on silica gel gave white solid. (25 mg) was obtained.

rac -6- {2- [2- (2- Chloro -4- Fluorophenyl )-2- Methylpropyl ] -2-hydroxy-5- Phenylphene Tri-3- Inoylamino }-4- methyl -2,3- Mercedes-Benz Photo -1-on 9

3-phenyl-1-propine (0.17 ml), nBuLi (0.51 ml, 1.6 M in hexane) and 6- [4- (2-chloro-4-fluorophenyl) -4-methyl-2-oxovalero Monoamino] -4-methyl-2,3-benzoxazin-1-one (140 mg) is reacted in THF (3 ml) at −78 ° C. as described in Synthesis Example 1 and column on silica gel Chromatography and then dried under vacuum yielded a white foam (116 mg).

rac -6- {4- (2- Chloro -4- Fluorophenyl )-2- Ethynyl -2-hydroxy-4- Methylpentanoyl Mino} -4-methyl-2,3- Mercedes-Benz Photo -1-on 10

Ethinylmagnesium bromide (2.2 ml, 0.5 M in THF) was added to 6- [4- (2-chloro-4-fluorophenyl) -4-methyl-2-oxovaleroylamino]-in THF (4 ml). To an ice cold solution of 4-methyl-2,3-benzoxazin-1-one (208 mg). Under argon, the reaction solution was allowed to reach room temperature over 3 hours. Post-treatment as described in Synthesis Example 1, column chromatography on silica gel and oil-pump drying gave the title compound as a foam (84 mg).

rac -6- {4- (2- Chloro -4- Fluorophenyl ) -2-hydroxy-4- methyl 2-vinyl- Pentanoyl Mino} -4- methyl -2,3- Mercedes-Benz Photo -1-on 11

Vinylmagnesium bromide solution (0.5 ml, 1 M in THF) was added to 6- [4- (2-chloro-4-fluorophenyl) -4-methyl-2-oxovalero at -78 ° C. Ylamino] -4-methyl-2,3-benzoxazine-1-one (103 mg) and the mixture was allowed to reach room temperature overnight under argon. Aqueous ammonium chloride solution was added, then extracted with ethyl acetate and washed with saturated sodium chloride solution. Dry over sodium sulfate, then concentrate on a rotary evaporator and purify by column chromatography on silica gel to give the title compound as a solidified oil (18 mg).

rac -6- {4- (2- Chloro -4- Fluorophenyl ) -2-hydroxy-2-[(4- Methoxyphenyl ) Ethynyl ] -4-M Tilpentanoyl Army No} -4- methyl -2,3- Mercedes-Benz Photo -1-on 12

4-methoxyphenylacetylene (0.4 ml), nBuLi (0.6 ml, 1.6 M in hexane) and 6- [4- (2-chloro-4-fluorophenyl) -4-methyl-2-oxovaleroylamino ] -4-methyl-2,3-benzoxazin-1-one (110 mg) was reacted at -78 ° C as described in Synthesis Example 1 and column chromatography on silica gel gave the title compound white. Obtained as a solid (44 mg).

rac -6- {4- (2- Chloro -4- Fluorophenyl ) -2-hydroxy-4- methyl -2-( Phenylethynyl )- pen Tanoylamino) -4- methyl -2,3- Mercedes-Benz Photo -1-on 13

Lithium phenylacetylide (0.65 ml, 1 M in THF) was added to 6- [4- (2-chloro-4-fluorophenyl) -4-methyl-2-oxovaleroylamino] -4- at −78 ° C. To methyl-2,3-benzoxazin-1-one (136 mg) was added and the mixture was stirred at -78 ° C for 2.5 h under argon. Post-treatment as described in Synthesis Example 1, column chromatography on silica gel and oil-pump drying gave the title compound as a white foam (102 mg).

Compound 14 and Compound 15 were synthesized similarly to Synthesis Example 10, with 6- (4-methyl-4-phenyl-2-oxovaleroylamino) -4-methyl-2,3-benzoxazin-1-one and alkoxy Prepared from Neil-Magnesium Halide.

rac -6- [2- Ethynyl -2-hydroxy-4- methyl -4- Phenylpentanoylamino ]-4- methyl -2,3- Mercedes Benz Oxazine-1-one 14

rac -6- [2-hydroxy-4- methyl -4- Phenyl -2- Propynylpentanoylamino ]-4- methyl -2,3- Ben Zok photo-1-one 15

Compounds 15-28, similar to Synthesis Example 1, were prepared using 6- (4-methyl-4-phenyl-2-oxovaleroylamino) -4-methyl-2,3-benzoxazin-1-one and Prepared from lithium arylacetylides.

rac -6- [2-hydroxy-4- methyl -4- Phenyl -2-( Phenylethynyl ) Pentanoylamino ]-4- methyl 2,3-ben Zok Photo-1-on 16

(+)-6- [2-hydroxy-4- methyl -2-[(4- Methylphenyl ) Ethynyl ]-4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 17a  And

(-)-6- [2-hydroxy-4- methyl -2-[(4- Methylphenyl ) Ethynyl ]-4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 17b

rac -6- [2-hydroxy-2-[(4- Methoxyphenyl ) Ethynyl ]-4- methyl -4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 18

(+)-6- [2-hydroxy-2-[(4- Methoxyphenyl ) Ethynyl ]-4- methyl -4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 18a  And

(-)-6- [2-hydroxy-2-[(4- Methoxyphenyl ) Ethynyl ]-4- methyl -4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 18b

The racemic mixture described in Synthesis Example 18 was separated into enantiomers 18a and 18b using preparative chiral HPLC (Column Chiralpak AD 250x10 mm).

rac -6- [2-hydroxy-2-[(4- (N, N-dimethylamino) Phenyl ) Ethynyl ]-4- methyl -4- Phenylphene Tanoylamino] -4- methyl -2,3- Mercedes-Benz Photo -1-on l9

rac -6- [2-hydroxy-4- methyl -4- Phenyl -2-[(4- Trifluoromethylphenyl ) Ethynyl ]- Penta  Noylamino] -4- methyl -2,3- Mercedes-Benz Photo -1-on 20

(+)-6- [2-hydroxy-4- methyl -4- Phenyl -2-[(4- Trifluoromethylphenyl ) Ethynyl ]- Penta Noylamino] -4- methyl -2,3- Mercedes-Benz Photo -1-on 20a  And

(-)-6- [2-hydroxy-4- methyl -4- Phenyl -2-[(4- Trifluoromethylphenyl ) Ethynyl ]- Penta Noylamino] -4- methyl -2,3- Mercedes-Benz Photo -1-on 20b

The racemic mixture as described in Synthesis Example 20 was separated into enantiomers 20a and 20b using preparative chiral HPLC (column chiralpak AD 250x10 mm).

rac -6- [2-[(4- Cyanophenyl ) Ethynyl ] -2-hydroxy-4- methyl -4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 21

(+)-6- [2-[(4- Cyanophenyl ) Ethynyl ] -2-hydroxy-4- methyl -4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 21a  And

(-)-6- [2-[(4- Cyanophenyl ) Ethynyl ] -2-hydroxy-4- methyl -4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 21b

The racemic mixture described in Synthesis 21 was separated into enantiomers 21a and 21b using preparative chiral HPLC (column chiralpak AD 250x10 mm).

rac -6- [2-hydroxy-4- methyl -4- Phenyl -2-[(4- Phenylphenyl ) Ethynyl ] Pentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 22

(+)-6- [2-hydroxy-4- methyl -4- Phenyl -2-[(4- Phenylphenyl ) Ethynyl ] Pentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 22a  And

(-)-6- [2-hydroxy-4- methyl -4- Phenyl -2-[(4- Phenylphenyl ) Ethynyl ] Pentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 22b

The racemic mixture described in Synthesis Example 22 was separated into enantiomers 22a and 22b using preparative chiral HPLC (Column Chiralpak AD 250x10 mm).

rac -6- [2-hydroxy-4- methyl -4- Phenyl -2-[(3- Trifluoromethylphenyl ) Ethynyl ]- Penta Noylamino] -4- methyl -2,3- Mercedes-Benz Photo -1-on 23

rac -6- [2-hydroxy-4- methyl -4- Phenyl -2-[(2- Trifluoromethylphenyl ) Ethynyl ]- Penta Noylamino] -4- methyl -2,3- Mercedes-Benz Photo -1-on 24

(+)-6- [2-hydroxy-4- methyl -4- Phenyl -2-[(2- Trifluoromethylphenyl ) Ethynyl ]- Pentanoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 24a  And

(-)-6- [2-hydroxy-4- methyl -4- Phenyl -2-[(2- Trifluoromethylphenyl ) Ethynyl ]- Penta Noylamino] -4- methyl -2,3- Mercedes-Benz Photo -1-on 24b

The racemic mixture described in Synthesis Example 24 was separated into enantiomers 24a and 24b using preparative chiral HPLC (Column Chiralpak AD 250x10 mm).

rac -6- [2-hydroxy-4- methyl -2-[(4- Nitrophenyl ) Ethynyl ]-4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 25

rac -6- [2-[[4- (1,1-dimethylethyl) Phenyl ] Ethynyl ] -2-hydroxy-4-methyl-4- Phenylpenta  Noylamino] -4- methyl -2,3- Mercedes-Benz Photo -1-on 26

rac -6- [2-hydroxy-4- methyl -2-[(3- Methylphenyl ) Ethynyl ]-4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 27

rac -6- [2-hydroxy-4- methyl -2-[(2- Methylphenyl ) Ethynyl ]-4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 28

rac -6- [2- (3,3- Dimethylbutynyl ) -2-hydroxy-4- methyl -4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 29

The following compound was prepared from the compound described in Synthesis Example 13 and 4′-iodoacetophenone, similarly to Synthesis Example 7.

rac -6- [2-[(4- Acetylphenyl ) Ethynyl ] -2-hydroxy-4- methyl -4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 30

(+)-6- [2-[(4- Acetylphenyl ) Ethynyl ] -2-hydroxy-4- methyl -4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 30a  And

(-)-6- [2-[(4- Acetylphenyl ) Ethynyl ] -2-hydroxy-4- methyl -4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 30b

The racemic mixture described in Synthesis Example 30 was separated into enantiomers 30a and 30b using preparative chiral HPLC (Column Chiralpak AD 250x10 mm).

Similarly to Synthesis Example 1, Compound 30 and Compound 31 were prepared using 6- [3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionylamino] -4-methyl- Prepared from 2,3-benzoxazine-1-one.

rac -6- [2-[(2- Fluoro -5- Trifluoromethylphenyl ) Cyclopropylmethyl ] -2-hydroxy-4- (4- Trifluoromethylphenyl ) Boot -3- Inoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 31

(+)-6- [2-[(2-fluoro-5- Trifluoromethylphenyl ) Cyclopropylmethyl ] -2-hydroxy-4- (4- Trifluoromethylphenyl ) Boot -3- Inoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 31a  And

(-)-6- [2-[(2-fluoro-5- Trifluoromethylphenyl ) Cyclopropylmethyl ] -2-hydroxy-4- (4- Trifluoromethylphenyl ) Boot -3- Inoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 31b

The racemic mixture described in Synthesis Example 31 was separated into enantiomers 31a and 31b using preparative chiral HPLC (Column Chiralpak AD 250x10 mm).

rac -6- [2-[(2- Fluoro -5- Trifluoromethylphenyl ) Cyclopropylmethyl ] -2-hydroxy-4- (4- Methylphenyl ) Boot -3- Inoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 32

(+)-6- [2-[(2-fluoro-5- Trifluoromethylphenyl ) Cyclopropylmethyl ] -2-hydroxy-4- (4- Methylphenyl ) Boot -3- Inoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 32a  And

(-)-6- [2-[(2-fluoro-5- Trifluoromethylphenyl ) Cyclopropylmethyl ] -2-hydroxy-4- (4- Methylphenyl ) Boot -3- Inoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 32b

The racemic mixture described in Synthesis Example 32 was separated into enantiomers 32a and 32b using preparative chiral HPLC (Column Chiralpak AD 250x10 mm).

The following compound was prepared from the compound described in Synthesis Example 14 and 3′-iodoacetophenone, similar to Synthesis Example 7.

rac -6- [2-[(3- Acetylphenyl ) Ethynyl ] -2-hydroxy-4- methyl -4- Phenylpentanoylamino ] -4-methyl-2,3- Mercedes-Benz Photo -1-on 33

Similar to Synthesis Example 1, compound 34 and compound 35 were prepared using 6- (4-methyl-4-phenyl-2-oxovaleroylamino) -4-methyl-2,3-benzoxazin-1-one and the corresponding Was prepared from lithium arylacetylides.

rac -6- [2-[(2,5- Dimethylphenyl ) Ethynyl ] -2-hydroxy-4- methyl -4-phenyl Pentanoyl Army No] -4- methyl -2,3- Mercedes-Benz Photo -1-on 34

rac -6- [2-[(2,4,5- Trimethylphenyl ) Ethynyl ] -2-hydroxy-4- methyl -4- Phenylpentanoyl Amino] -4- methyl -2,3- Mercedes-Benz Photo -1-on 35

(+)-6- [2-[(2,4,5- Trimethylphenyl ) Ethynyl ] -2-hydroxy-4- methyl -4- Phenylpentanoyl Amino] -4- methyl -2,3- Mercedes-Benz Photo -1-on 35a  And

(-)-6- [2-[(2,4,5- Trimethylphenyl ) Ethynyl ] -2-hydroxy-4- methyl -4- Phenylpentanoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 35b

The racemic mixture described in Synthesis Example 35 was separated into enantiomers 35a and 35b using preparative chiral HPLC (Column Chiralpak AD 250x10 mm).

The following compounds were synthesized similarly to Synthesis Example 9, with 3-phenyl-1-propine, nBuLi and 6- (4-methyl-4-phenyl-2-oxovaleroylamino) -4-methyl-2,3-benz Prepared from oxazine-1-one.

rac -6- {2- (2- Phenyl )-2- Methylpropyl ] -2-hydroxy-5- Phenylpent -3- Inoylamino } -4-methyl-2,3- Mercedes-Benz Photo -1-on 36

Similar to Synthesis Example 1, compound 37 and compound 38 were prepared using 6- (4-methyl-4- (2-chloro-6-fluorophenyl) -2-oxovaleroylamino) -4-methyl-2,3- Prepared from benzoxazine-1-one and the corresponding lithium arylacetylides.

rac -6- [2-hydroxy-4- methyl -4- (2- Chlor -6- Fluorophenyl ) -2- (4- Methylphenylethynyl ) Pentanoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 37

(+)-6- [2-hydroxy-4- methyl -4- (2- Chlor -6- Fluorophenyl ) -2- (4- Methylphenylethynyl ) Pentanoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 37a  And

(-)-6- [2-hydroxy-4- methyl -4- (2- Chlor -6- Fluorophenyl ) -2- (4- Methylphenylethynyl ) Pentanoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 37b

The racemic mixture described in Synthesis Example 37 was separated into enantiomers 37a and 37b using preparative chiral HPLC (Column Chiralpak AD 250x10 mm).

rac -6- [2-hydroxy-4- methyl -4- (2- Chlor -6- Fluorophenyl ) -2- (4- ( Trifluoromethyl ) Phenylethynyl ) Pentanoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 38

(+)-6- [2-hydroxy-4- methyl -4- (2- Chlor -6- Fluorophenyl ) -2- (4- ( Trifluoromethyl ) Phenylethynyl ) Pentanoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 38a  And

(-)-6- [2-hydroxy-4- methyl -4- (2- Chlor -6- Fluorophenyl ) -2- (4- ( Trifluoromethyl ) Phenylethynyl ) Pentanoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 38b

The racemic mixture described in Synthesis Example 38 was separated into enantiomers 38a and 38b using preparative chiral HPLC (Column Chiralpak AD 250x10 mm).

Similar to Synthesis Example 1, compound 39 and compound 40 were prepared using 6- (4-methyl-4- (2-chlorophenyl) -2-oxovaleroylamino) -4-methyl-2,3-benzoxazine- Prepared from 1-one and the corresponding lithium arylacetylides.

rac -6- [2- (2- Chlorphenyl ) Cyclopropylmethyl ] -2-hydroxy-4- (4- Methylphenyl ) Boot -3- Noil Army No] -4- methyl -2,3- Mercedes-Benz Photo -1-on 39

(+)-6- [2- (2- Chlorphenyl ) Cyclopropylmethyl ] -2-hydroxy-4- (4- Methylphenyl ) Boot -3- Noil Army No] -4- methyl -2,3- Mercedes-Benz Photo -1-on 39a  And

(-)-6- [2- (2- Chlorphenyl ) Cyclopropylmethyl ] -2-hydroxy-4- (4- Methylphenyl ) Boot -3- Noil Army No] -4- methyl -2,3- Mercedes-Benz Photo -1-on 39b

The racemic mixture described in Synthesis Example 39 was separated into enantiomers 39a and 39b using preparative chiral HPLC (Column Chiralpak AD 250x10 mm).

rac -6- [2- (2- Chlorphenyl ) Cyclopropylmethyl ] -2-hydroxy-4- (4- Trifluoromethylphenyl ) Boot -3- Inoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 40

(+)-6- [2- (2- Chlorphenyl ) Cyclopropylmethyl ] -2-hydroxy-4- (4- Trifluorome  Tilphenyl) Boot -3- Inoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 40a  And

(-)-6- [2- (2- Chlorphenyl ) Cyclopropylmethyl ] -2-hydroxy-4- (4- Trifluorome Tilphenyl) Boot -3- Inoylamino ]-4- methyl -2,3- Mercedes-Benz Photo -1-on 40b

The racemic mixture described in Synthesis Example 40 was separated into enantiomers 40a and 40b using preparative chiral HPLC (Column Chiralpak AD 250x10 mm).

rac -6- [2-[[3- (1-hydroxy-1- Methylethyl ) Phenyl ] Ethynyl ] -2-hydroxy-4- methyl -4- Fe Nylpentanoylamino] -4- methyl -2,3- Mercedes-Benz Photo -1-on 41

 59 μl of methylmagnesium chloride 3 M solution was diluted with 1 ml of pure tetrahydrofuran. The solution was cooled to −70 ° C. and a solution of 30 mg of the compound described in Synthesis Example 33 in 0.5 ml of tetrahydrofuran was added. After stirring at −70 ° C. for 2.5 hours, the mixture was poured into saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After column chromatography, 16 mg of product was obtained.

The following compound was prepared from the compound described in Synthesis Example 14 and 4-iodobenzyl alcohol similar to Synthesis Example 7.

rac -6- [2-[[4- ( Hydroxymethyl ) Phenyl ] Ethynyl ] -2-hydroxy-4- methyl -4- Phenylpentano Monoamino] -4- methyl -2,3- Mercedes-Benz Photo -1-on 42

The following compound was prepared from the compound described in Synthesis Example 14 and 4-iodobenzyl alcohol similar to Synthesis Example 7.

rac -6- [2-[[3- ( Hydroxymethyl ) Phenyl ] Ethynyl ] -2-hydroxy-4- methyl -4- Phenylpentano Monoamino] -4- methyl -2,3- Mercedes-Benz Photo -1-on 43

The following compound was prepared from a solution of methyl magnesium chloride and the compound described in Synthesis Example 30, similar to Synthesis Example 41.

rac-6- [2-[[4- (1-hydroxy-1-methylethyl) phenyl] ethynyl] -2-hydroxy-4-methyl-4-phenylpentanoylamino] -4-methyl-2 , 3-benzoxazine-1-one 44

Claims (26)

The following general formula (I) and pharmaceutically acceptable salts thereof. <Formula I>

Where R ¹ and R ² are each independently a hydrogen atom or a straight or non-linear, branched or unbranched C ₁ -C ₅ -alkyl group, and together with the C atoms of the chain form a total of 3 to 7 membered rings and, R ³ is a radical C≡CR ^a [where R ^a is hydrogen or C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -optionally substituted one or more times with K in the same or different ways C ₁₀ -cycloalkyl or heterocycloalkyl, or aryl or heteroaryl optionally substituted one or more times with L in the same or different ways, K is cyano, halogen, hydroxy, nitro, -C (O) R ^b , CO ₂ R ^b , -OR ^b , -SR ^b , SO ₂ NR ^c R ^d , -C (O) -NR ^c R ^d , -OC (O) -NR ^c R ^d , -C = NOR ^b -NR ^c R ^d Or C ₃ -C ₁₀ -cycloalkyl, or heterocycloalkyl optionally substituted one or more times with M in the same or different ways, or aryl or heteroaryl optionally substituted with one or more times, L is C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₁ -C ₆ -perfluoroalkyl, C ₁ -C ₆ -perfluoroalkoxy, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - _{alkoxy, (CH 2) p -C 3} -C 10 - cycloalkyl, (CH _{2) p} - _{heterocycloalkyl, (CH 2) p CN,} (CH ₂ ) _p Hal, (CH ₂ ) _p NO ₂ , (CH ₂ ) _p -C ₆ -C ₁₂ -aryl, (CH ₂ ) _p -heteroaryl,-(CH ₂ ) _p PO ₃ (R ^b ) ₂ , -(CH ₂ ) _p NR ^c R ^d ,-(CH ₂ ) _p NR ^e COR ^b ,-(CH ₂ ) _p NR ^e CSR ^b ,-(CH ₂ ) _p NR ^e S (O) R ^b ,-( CH ₂ ) _p NR ^e S (O) ₂ R ^b ,-(CH ₂ ) _p NR ^e CONR ^c R ^d ,-(CH ₂ ) _p NR ^e COOR ^b ,-(CH ₂ ) _p NR ^e C (NH) NR ^c R ^d ,-(CH ₂ ) _p NR ^e CSNR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) NR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) ₂ NR ^c R ^d ,-(CH ₂ ) _p COR ^b ,-(CH ₂ ) _p CSR ^b ,-(CH ₂ ) _p S (O) R ^b ,-(CH ₂ ) _p S (O) (NH) R ^b , -(CH ₂ ) _p S (O) ₂ R ^b ,-(CH ₂ ) _p S (O) ₂ NR ^c R ^d ,-(CH ₂ ) _p SO ₂ OR ^b ,-(CH ₂ ) _p CO ₂ R ^b ,-(CH ₂ ) _p CONR ^c R ^d ,-(CH ₂ ) _p CSNR ^c R ^d ,-(CH ₂ ) _p OR ^b ,-(CH ₂ ) _p SR ^b ,-(CH ₂ ) _p CR ^b (OH) -R ^e ,-(CH ₂ ) _p -C = NOR ^b , -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -O-CH = CH- or-(CH ₂ ) _{n + 2-} , where n is 1 or 2, the terminal oxygen atoms and / or carbon atoms are directly connected to adjacent ring carbon atoms, M is C ₁ -C ₆ -alkyl or -COR ^b , CO ₂ R ^b , -OR ^b , or -NR ^c R ^d , R ^b is hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl, C ₆ -C ₁₂ -aryl or C ₁ -C ₃ -perfluoroalkyl, R ^c and R ^d are each independently hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl, C _6- C ₁₂ -aryl, C (O) R ^b or a hydroxy group wherein if R ^c is a hydroxy group, R ^d is only hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl or C ₆ -C ₁₂ -aryl, and vice versa, R ^e is hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl or C ₆ -C ₁₂ -aryl, p may be a number from 0 to 6], or R ³ is a radical C = CR ^g R ^h wherein R ^g and R ^h are each independently hydrogen or C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₈ -optionally substituted one or more times with X in the same or different ways; Alkynyl, X is cyano, halogen, hydroxy, nitro, -C (O) R ^b , CO ₂ R ^b , -OR ^b , -C (O) -NR ^c R ^d , -NR ^c R ^d , where R ^b , R ^c and R ^d are as defined above; R ⁴ is a hydrogen atom, a methyl or ethyl group, or a partially or fully fluorinated C ₁ -C ₃ -alkyl group, A is a monocyclic or bicyclic carbocyclic or heterocyclic aromatic ring (which is C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₁ -C ₆ -perfluoroalkyl, C ₁ -C ₆ -perfluoroalkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy, (CH ₂ ) _p -C ₃ -C ₁₀ -cycloalkyl, (CH ₂ ) _p -heterocycloalkyl, (CH ₂ ) _p CN, (CH ₂ ) _p Hal, (CH ₂ ) _p NO ₂ , (CH ₂ ) _p -C ₆ -C ₁₂ -aryl, (CH ₂ ) _p -heteroaryl,-(CH ₂ ) _p PO ₃ (R ^b ) ₂ ,-(CH ₂ ) _p NR ^c R ^d ,-(CH ₂ ) _p NR ^e COR ^b ,-(CH ₂ ) _p NR ^e CSR ^b ,-(CH ₂ ) _p NR ^e S (O) R ^b ,-(CH ₂ ) _p NR ^e S (O) ₂ R ^b ,-( CH ₂ ) _p NR ^e CONR ^c R ^d ,-(CH ₂ ) _p NR ^e COOR ^b ,-(CH ₂ ) _p NR ^e C (NH) NR ^c R ^d ,-(CH ₂ ) _p NR ^e CSNR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) NR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) ₂ NR ^c R ^d ,-(CH ₂ ) _p COR ^b ,-(CH ₂ ) _p CSR ^b ,-(CH ₂ ) _p S (O) R ^b ,-(CH ₂ ) _p S (O) (NH) R ^b ,-(CH ₂ ) _p S (O) ₂ R ^b ,-( CH ₂ ) _p S (O) ₂ NR ^c R ^d ,-(CH ₂ ) _p SO ₂ OR ^b ,-(CH ₂ ) _p CO ₂ R ^b ,-(CH ₂ ) _p CONR ^c R ^d ,-(CH ₂ ) _p CSNR ^c R ^d ,-(CH ₂ ) _p OR ^b ,-(CH ₂ ) _p SR ^b ,-(CH ₂ ) _p CR ^b (OH) -R ^d ,-(CH ₂ ) _p -C = NOR ^b , May be optionally substituted one or more times with -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -O-CH = CH- or-(CH ₂ ) _{n + 2-} Wherein n is 1 or 2 and the terminal oxygen atom and / or carbon atom is directly connected to an adjacent ring carbon atom), or A is a radical —CO ₂ R ^b , C (O) NR ^c R ^d , COR ^b, or A is an alkenyl group -CR ⁵ = CR ⁶ R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are the same or different and independently of one another are a hydrogen atom, a halogen atom, an aryl radical, or an unsubstituted or partially or fully Fluorinated C ₁ -C ₅ -alkyl group), or A is an alkynyl group —C≡CR ⁵ , wherein R ⁵ has the meanings mentioned above, B is a carbonyl group or a CH ₂ group. A compound according to claim 1, wherein R ¹ and R ² are preferably hydrogen atoms, methyl groups or ethyl groups. The compound of claim 1, wherein R ¹ and R ² preferably form together with the C atoms of the chain a total of 3 to 7 membered rings. The compound according to any one of claims 1 to ³ , wherein R ³ is preferably alkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, cycloalkylalkynyl or heterocycloalkylalkynyl. The compound according to any one of claims 1 to 4, wherein R ³ is preferably vinyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, hydroxypropynyl, hydroxy. Butynyl, 3-hydroxy-3-methylbutynyl, hydroxypentynyl, carboxypropynyl, t-butylcarboxypropynyl, phenylethynyl, (hydroxyphenyl) ethynyl, (methoxyphenyl) ethynyl, (Dimethylaminophenyl) ethynyl, (methylphenyl) ethynyl, (cyanophenyl) ethynyl, (trifluoromethyl) ethynyl, (diphenyl) ethynyl, (nitrophenyl) ethynyl, (tert-butylphenyl ) Ethynyl, (acetylphenyl) ethynyl, (acetoxyphenyl) ethynyl, (carboxyphenyl) ethynyl or benzylethynyl group. The compound according to any one of claims 1 to 5, wherein A is preferably an aromatic ring. The compound according to any one of claims 1 to 6, wherein A is preferably a phenyl or naphthyl radical. 8. Compounds according to claim 7, wherein A is preferably an unsubstituted phenyl radical, or optionally a mono- or polysubstituted phenyl radical. The compound of claim 8, wherein the phenyl radical is preferably substituted with one or two halogen atoms or one trifluoromethyl group. 10. Compounds according to claim 9, wherein the halogen atoms are preferably chlorine and / or fluorine. The compound according to claim 1, wherein A is preferably a phenyl ring substituted with —O— (CH ₂ ) _n —O— or —O— (CH ₂ ) _n —CH ₂ —, Wherein each directly adjacent ring carbon atom is linked. The compound of any one of claims 1-11, wherein R ⁴ is a hydrogen atom, or a methyl or trifluoromethyl radical. The compound according to any one of claims 1 to 5, wherein:

A pharmaceutical composition comprising at least one compound of the general formula (I) according to any one of claims 1 to 13 and, where appropriate, at least one further active ingredient together with a pharmaceutically suitable excipient and / or carrier. The pharmaceutical composition of claim 14, wherein the additional active ingredient is SERM (selective estrogen receptor modulator), aromatase inhibitor, antiestrogens or prostaglandins. 15. The process of claim 14 wherein the active ingredient is tamoxifen, 5- (4- {5-[(RS)-(4,4,5,5,5-pentafluoropentyl) sulfinyl] pentyloxy} phenyl) -6 -Phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol, ICI 182 780 (7alpha- [9- (4,4,5,5-pentafluoropentylsulfinyl) nonyl] estra- 1,3,5 (10) -triene-3,17beta-diol), 11beta-fluoro-7alpha- [5- (methyl {3-[(4,4,5,5,5-penta) Fluoropentyl) sulfanyl] propyl} amino) pentyl] estra-1,3,5 (10) -triene-3,17beta-diol, 11beta-fluoro-7alpha- {5- [methyl (7 , 7,8,8,9,9,10,10,10-nonafluorodecyl) amino] pentyl} estra-1,3,5 (10) -triene-3,17beta-diol, 11beta- Fluoro-17alpha-methyl-7alpha- {5- [methyl (8,8,9,9,9-pentafluorononyl) amino] pentyl} estra-1,3,5 (10) -triene- Pharmaceutical composition, which may be 3,17 beta-diol, clomiphene, raloxifene, padrosol, formestan, letrozole, anastrozole or atamestane. Use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament. The use of a compound according to claim 17 for the manufacture of a medicament for the treatment and prophylaxis of gynecological diseases such as endometriosis, uterine fibroids, dysfunctional uterine bleeding and dysmenorrhea. 18. Use of a compound according to claim 17 for the manufacture of a medicament for the treatment and prophylaxis of hormone-dependent tumors. 18. Use of a compound according to claim 17 for the manufacture of a medicament for the treatment and prevention of breast cancer. 18. Use of a compound according to claim 17 for the manufacture of a medicament for the treatment and prevention of endometrial cancer. 18. Use of a compound according to claim 17 for the manufacture of a medicament for the treatment and prophylaxis of ovarian cancer. 18. Use of a compound according to claim 17 for the manufacture of a medicament for the treatment and prophylaxis of prostate cancer. 18. Use of a compound according to claim 17 for the manufacture of a medicament for female hormone replacement therapy. 18. Use of a compound according to claim 17 for female contraception. A method of selectively adding lithium alkynyl and magnesium haloalkynyl compounds to ketoamides.