Patent Application
20090099147
The present invention relates to non-steroidal progesterone receptor modulators, to a process for their preparation, to the use of the progesterone receptor modulators for producing medicaments, and to pharmaceutical compositions which comprise these compounds.
The steroid hormone progesterone controls in a decisive manner the reproductive process in the female body. Progesterone is secreted in large quantities during the cycle and pregnancy respectively by the ovary and the placenta. Progesterone in cooperation with oestrogens brings about cyclic changes in the uterine mucosa (endometrium) during the menstrual cycle. Elevated progesterone levels after ovulation influence the uterine mucosa to convert it into a state permitting nidation of an embryo (blastocyst). During pregnancy, progesterone controls the relaxation of the myometrium and maintains the function of the decidual tissue.
It is further known that progesterone inhibits endometrial proliferation by suppressing oestrogen-mediated mitosis in uterine tissue (K. Chwalisz, R. M. Brenner, U. Fuhrmann, H. Hess-Stumpp, W. Elger, Steroids 65, 2000, 741-751).
Progesterone and progesterone receptors are also known to play a significant part in pathophysiological processes. Progesterone receptors have been detected in the foci of endometriosis, but also in tumours of the uterus, of the breast and of the CNS. It is further known that uterine leiomyomas grow progesterone-dependently.
The effects of progesterone in the tissues of the genital organs and in other tissues occur through interactions with progesterone receptors which are responsible for the cellular effects.
Progesterone receptor modulators are either pure agonists or inhibit the effect of progesterone partly or completely. Accordingly, substances are defined as pure agonists, partial agonists (selective progesterone receptor modulators=SPRMs) and pure antagonists.
In accordance with the ability of progesterone receptor modulators to take effect via the progesterone receptor, these compounds have a considerable potential as therapeutic agents for gynaecological and oncological indications and for obstetrics and fertility control.
Pure progesterone receptor antagonists completely inhibit the effect of progesterone on the progesterone receptor. They have anti-ovulatory properties and the ability to inhibit oestrogen effects in the endometrium, as far as complete atrophy. They are therefore particularly suitable for intervening in the female reproductive process, e.g. post-ovulation, in order to prevent nidation of a fertilized egg cell, during pregnancy in order to increase the reactivity of the uterus to prostaglandins or oxytocin, or in order to achieve opening and softening (“ripening”) of the cervix, and to induce a great readiness of myometrium to contract.
A beneficial effect on the pathological event is expected in foci of endometriosis and in tumour tissues which are equipped with progesterone receptors after administration of pure progesterone receptor antagonists. There might be particular advantages for influencing pathological states such as endometriosis or uterine leiomyomas if ovulation inhibition can additionally be achieved by the progesterone receptor antagonists. Ovulation inhibition also dispenses with some of the ovarian hormone production and thus the stimulating effect, deriving from this proportion, on the pathologically altered tissue.
The first progesterone receptor antagonist described, RU 486 (also mifepristone), was followed by the synthesis and characterization of a large number of analogues with progesterone receptor-antagonistic activity of varying strength. Whereas RU 486 shows an antiglucocorticoid effect in addition to the progesterone receptor-antagonistic effect, compounds synthesized later are notable in particular for a more selective effect as progesterone receptor antagonists.
Besides steroidal compounds such as onapristone or lilopristone, which are notable by comparison with RU 486 for a better dissociation of the progesterone receptor-antagonistic effect and the antiglucocorticoid effect, also known from the literature are various non-steroidal structures whose antagonistic effect on the progesterone receptor is being investigated [see, for example, S. A. Leonhardt and D. P. Edwards, Exp. Biol. Med. 227: 969-980 (2002) and R. Winneker, A. Fensome, J. E. Wrobel, Z. Zhang, P. Zhang, Seminars in Reproductive Medicine, Volume 23: 46-57 (2005)]. However, non-steroidal compounds disclosed to date have only moderate antagonistic activity compared with the known steroidal structures. The most effective non-steroidal compounds are reported to have in vitro activities which are 10% of the activity of RU 486.
The antiglucocorticoid activity is disadvantageous for therapeutic use, where the inhibition of progesterone receptors is at the forefront of the therapy. An antiglucocorticoid activity causes unwanted side effects at the dosages necessary for therapy. This may prevent administration of a therapeutically worthwhile dose or lead to discontinuation of the treatment.
Partial or complete reduction of the antiglucocorticoid properties is therefore an important precondition for therapy with progesterone receptor antagonists, especially for those indications requiring treatment lasting weeks or months.
In contrast to the pure antagonists, partial progesterone receptor agonists (SPRMs) show a residual agonistic property which may vary in strength. This leads to these substances showing agonistic effects on the progesterone receptor 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). Such an organ-specific and dissociated effect may be of therapeutic benefit for the described indications.
It is therefore an object of the present invention to provide further non-steroidal progesterone receptor modulators. These compounds are intended to have a reduced antiglucocorticoid effect and therefore be suitable for the therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea. The compounds according to the invention are additionally intended to be suitable for the therapy and prophylaxis of hormone-dependent tumours, for example of breast, endometrial, ovarian and prostate carcinomas. The compounds are intended furthermore to be suitable for use in female fertility control and for female hormone replacement therapy.
The object is achieved according to the present invention by the provision of non-steroidal compounds of the general formula I
in which
The compounds according to the invention of the general formula (I) may, owing to the presence of centres of asymmetry, exist as different stereoisomers. Both the racemates and the separate stereoisomers belong to the subject matter of the present invention.
The present invention further includes the novel compounds as active pharmaceutical ingredients, the preparation thereof, their therapeutic use and pharmaceutical dosage forms which comprise the novel substances.
The compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts can be used to produce a medicament, in particular for the treatment and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea. The compounds according to the invention may further be used for the treatment and prophylaxis of hormone-dependent tumours such as, for example, for breast, prostate and endometrial carcinoma.
The compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts are suitable for use for female fertility control or for female hormone replacement therapy.
The non-steroidal compounds according to the invention of the general formula I have strong antagonistic or strong partial agonistic effects on the progesterone receptor. They show a strong dissociation of effects in relation to their strength of binding to the progesterone receptor and to the glucocorticoid receptor. Whereas known progesterone receptor antagonists such as mifepristone (RU 486) show, besides the desired high binding affinity for the progesterone receptor, likewise a high affinity for the glucocorticoid receptor, the compounds according to the invention are notable for a very low glucocorticoid receptor binding with simultaneously a high progesterone receptor affinity.
The substituents, defined as groups, of the compounds according to the invention of the general formula I may in each case have the following meanings:
C1-C5—, C1-C6- and C1-C8-alkyl group means linear or nonlinear, branched or unbranched alkyl radicals. Examples thereof are a methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl, an n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl, hexyl, heptyl or octyl group.
Preferred in the meaning of Ra in this connection are the methyl, ethyl, n-propyl or n-butyl group and an n-pentyl group.
Preferred in the meaning of Ra and R2 are methyl or ethyl.
A hydrogen is preferred according to the invention for R4a and R4b.
Alkenyl means branched or unbranched alkenyl radicals. Examples of the meaning of a C2-C8-alkenyl group in the context of the invention are the following: vinyl, allyl, 3-buten-1-yl or 2,3-dimethyl-2-propenyl. If the aromatic system A is substituted by a C2-C8-alkenyl radical, it is preferably a vinyl group.
Alkynyl means branched or unbranched alkynyl radicals. A C2-C8-alkynyl radical is intended to be for example an ethynyl, propynyl, butynyl, pentynyl, hexynyl and octynyl group, preferably an ethynyl or propynyl group.
3-10-Membered cycloalkyl or heterocycloalkyl means both monocyclic and bicyclic radicals.
Examples which may be mentioned of monocyclic C3-C10-cycloalkyl in the meaning of R3, K, L, Rb, Rc, Rd, R4, R6a and R6b are cyclopropane, cyclobutane, cyclopentane and cyclohexane. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.
Heterocycloalkyl in the meaning of Ra, K and L means 3-8-membered monocyclic heterocycloalkyl radicals. Examples of heterocycloalkyl are morpholine, tetrahydrofurane, pyrane, piperazine, piperidine, pyrrolidine, oxirane, oxetane, aziridine, dioxolane and dioxane, it being possible to use any chemically reasonable isomer in relation to the positions of the heteroatoms.
Possible examples of C1-C6-alkoxyl-C1-C6-alkoxy group are methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy.
A radical ORb in the context of the invention is a hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-, iso-, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy or 3-methylbutoxy group. Hydroxy, methoxy and ethoxy are preferred.
Suitable for a partly or completely fluorinated C1-C5-alkyl group are the perfluorinated alkyl groups above. Of these, preference is given in particular to the trifluoromethyl or pentafluoroethyl group and, partly fluorinated alkyl groups, for example the 5,5,4,4-pentafluoropentyl or 5,5,5,4,4,3,3-heptafluoropentyl group.
Suitable C1-C3- and C1-C6-perfluoroalkyl groups are likewise in particular trifluoromethyl or the pentafluoroethyl group.
Preferred C1-C3- and C1-C6-perfluoroalkoxy groups are the trifluoromethoxy or pentafluoroethoxy radical.
A halogen atom may be a fluorine, chlorine, bromine or iodine atom. Fluorine, chlorine or bromine is preferred here.
If R1 and R2 form together with the C atom of the chain a 3-7 membered ring, this is for example a cyclopropyl, -butyl, -pentyl or -hexyl ring. The cyclopropyl and the cyclopentyl ring are preferred.
The mono- or bicyclic carbocyclic aromatic ring A, which may be substituted more than once, is a carbocyclic or heterocyclic aryl radical.
In the former case it is for example a phenyl or naphthyl radical, preferably a phenyl radical.
It is possible to use as heterocyclic radical for example a monocyclic heterocyclic radical, for example the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radical, in particular all the possible isomers in relation to the positions of the heteroatoms.
R3 means in the case of a C6-C12-aryl radical an optionally substituted phenyl, 1- or 2-naphthyl radical, with preference for the phenyl radical. Examples of a heteroaryl radical are the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2- or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radical.
The number p for a (CH2)p radical may be an integer from 0 to 6, preferably 0, 1 or 2. “Radical” means according to the invention all functional groups mentioned under L and A in connection with (CH2)p.
In the case where the compounds of the general formula I (B═—CH2—) are in the form of salts, this is possible for example in the form of the hydrochloride, sulphate, nitrate, tartrate, citrate, fumarate, succinate or benzoate.
If the compounds according to the invention are in the form of racemic mixtures, they can be fractionated by methods of racemate resolution familiar to the skilled person into the pure optically active forms. For example, the racemic mixtures can be separated into the pure isomers by chromatography on a support material which is itself optically active (CHIRALPAK AD®). It is also possible to esterify the free hydroxy group in a racemic compound of the general formula I with an optically active acid, and to separate the resulting diastereoisomeric esters by fractional crystallization or chromatography and to hydrolyse the separated esters in each case to the optically pure isomers. It is possible to use as optically active acid for example mandelic acid, camphorsulphonic acid or tartaric acid.
Compounds of the general formula (I) which are preferred according to the present invention are those in which:
R1 and R2 are each independently of one another a hydrogen atom, a methyl or an ethyl radical, or form together with the C atom of the chain a ring having a total of 3-7 members. Particularly preferred compounds are those in which R1 and R2 are simultaneously a hydrogen atom, a methyl or cyclopropyl radical, particularly preferably a methyl or cyclopropyl radical.
Further preferred compounds are those in which R3 is an alkynyl radical of the formula C≡C—Ra, where Ra is a C1-C4-alkyl, C3-C10-cycloalkyl, 3-8-membered heterocycloalkyl radical which is optionally substituted by K, or optionally a C6-C12-aryl or 3-8-membered heteroaryl radical which is substituted by L, and
K is a cyano, halogen, hydroxy, —O—Rb, SO2NRcRd, —C(O)—NRcRd, NRcRd or a 3-8-membered heterocycloalkyl radical which is optionally substituted one or more times, identically or differently, by M, or an aryl or heteroaryl radical which is optionally substituted more than once by L, and
L is a C1-C4-alkyl, C1-C4-perfluoroalkyl, (CH2)p—C3-C10-cycloalkyl, (CH2)p-heterocycloalkyl radical, (CH2)pCN, (CH2)pHal, (CH2)pNO2, (CH2)p—C6-C12-aryl, (CH2)p-heteroaryl, —(CH2)pNRcRd, or —(CH2)pNReS(O)2Rb, —(CH2)pS(O)2NRcRd, —(CH2)pCONRcRd, —(CH2)pORb, —(CH2)pOCORb, —(CH2)pCRb(OH)—Re, —(CH2)pCO2Rb, and
M is a C1-C4-alkyl radical or a group —CO2Rb, —O—Rb or —NRcRd, where Rb is a hydrogen or a C1-C6-alkyl, C3-C10-cycloalkyl, C6-C12-aryl or C1-C3-perfluoroalkyl and
Rc and Rd are independently of one another a hydrogen atom, a C1-C6-alkyl, C3-C10-cycloalkyl, C6-C12-aryl, C(O)Rb or a hydroxy group, where if Rc is a hydroxy group, then Rd can only be a hydrogen, a C1-C6-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-C10-cycloalkyl or C6-C12-aryl, and vice versa,
and Re is a hydrogen, C1-C6-alkyl or C6-C12-aryl, and
p may be a number, 1, 2 or 3.
Particularly preferred compounds are those in which
Ra is a C1-C4-alkyl radical which is optionally substituted by K, or a phenyl or hetaryl radical which is optionally substituted by L, where L is preferably a methyl, trifluoromethyl, methoxy, acetoxy, hydroxy, carboxyl or carboxyalkyl radical.
Additionally preferred compounds are those in which
R4 is a phenyl ring, particularly preferably a phenyl ring substituted by 1-3 radicals. Preferred substituents on the phenyl ring are nitro, trifluoromethyl, pentafluoroethyl, cyano, chlorine, fluorine, methyl.
Likewise preferred compounds are those in which R4 is one of the following groups:
B: 6-membered/5-membered ring systems:
with the meanings already mentioned for R5 and R6a and R6b.
A is preferably substituted by the following radicals: C1-C8-alkyl, C1-C6-perfluoroalkyl, C1-C6-perfluoroalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy, (CH2)p—C3-C10-cycloalkyl, (CH2)p-heterocycloalkyl, (CH2)pCN, (CH2)pHal, (CH2)pNO2, (CH2)p—C6-C12-aryl, (CH2)p-heteroaryl, —(CH2)pNRcRd, —(CH2)pNReCORb, —(CH2)pNReS(O)2Rb, (CH2)pNReCONRcRd, —(CH2)pNReS(O)2NRcRd, —(CH2)pCORb, —(CH2)pCSRb, —(CH2)pS(O)(NH)Rb, —(CH2)pS(O)2Rb, —(CH2)pS(O)2NRcRd, —(CH2)pCO2Rb, —(CH2)pCONRcRd, —(CH2)pORb, —(CH2)pSRb, —(CH2)pCRb(OH)—Rd, —(CH2)p—C═NORb, —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH— or —(CH2)n+2—, where n is 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring carbon atoms.
Particularly preferred compounds are those in which A is substituted by C1-C4-alkyl, C1-C2-perfluoroalkyl, C1-C2-perfluoroalkoxy, (CH2)pCN, (CH2)pHal, —(CH2)pNRcRd, —(CH2)pS(O)(NH)Rb, —(CH2)pS(O)2Rb, —(CH2)pS(O)2NRcRd, —(CH2)pORb or —(CH2)pSRb and p and Rb, Rc and Rd have the meanings already mentioned.
Very particularly preferred compounds are those in which A is either an unsubstituted phenyl ring or a phenyl ring which is substituted once or twice, identically or differently, by fluorine, chlorine, bromine, methyl, trifluoromethyl or methoxy.
Further preferred compounds are those in which B is a carbonyl group or a —CH2 group.
Preferred compounds are likewise those in which p is 0 or 1.
The compounds specified below, and the use thereof, are preferred according to the invention:
Progesterone receptor modulators can be identified with the aid of simple methods, test programmes known to the skilled person. It is possible for this purpose for example to incubate a compound to be tested together with a progestogen in a test system for progesterone receptor ligands and to check whether the effect mediated by progesterone is altered in the presence of the modulator in this test system.
The substances according to the invention of the general formula I were tested in the following models:
Measurement of the receptor binding affinity:
The receptor binding affinity was determined by competitive binding of a specifically binding 3H-labelled hormone (tracer) and of the compound to be tested on receptors in the cytosol from animal target organs. The aim in this case was receptor saturation and reaction equilibrium.
The tracer and increasing concentrations of the compound to be tested (competitor) were coincubated at 0-4° C. for 18 h with the receptor-containing cytosol fraction. After removal of unbound tracer with carbon-dextran suspension, the receptor-bound tracer content was measured for each concentration, and the IC50 was determined from the concentration series. The relative molar binding affinity (RBA) was calculated as ratio of the IC50 values for reference substance and compound to be tested (×100%) (RBA of the reference substance=100%).
The following incubation conditions were chosen for the receptor types:
Uterus cytosol of the estradiol-primed rabbit, homogenized in TED buffer (20 mMTris/HCl, pH 7.4; 1 mM ethylenediaminetetraacetate, 2 mM dithiothreitol) with 250 mM sucrose; stored at −30° C. Tracer: 3H-ORG 2058, 5 nM; reference substance: progesterone.
Thymus cytosol from the adrenalectomized rat, thymi stored at −30° C.; buffer: TED. Tracer: 3H-dexamethasone, 20 nM; reference substance: dexamethasone.
The competition factors (CF values) for the compounds according to the invention of the general formula (I) on the progesterone receptor are between 0.2 and 35 relative to progesterone. The CF values on the glucocorticoid receptor are in the range from 3 to 35 relative to dexamethasone.
The compounds according to the invention accordingly have a high affinity for the progesterone receptor, but only a low affinity for the glucocorticoid receptor.
The transactivation assay is carried out as described in WO 02/054064.
The IC50 values are in the range of from 0.1 to 150 nM.
The transactivation assay is carried out as described in Fuhrmann et al. (Fuhrmann U., Hess-Stump H., Cleve A., Neef G., Schwede W., Hoffmann J., Fritzemeier K.-H., Chwalisz K., Journal of Medicinal Chemistry, 43, 26, 2000, 5010-5016). The EC50 values are in the range from 0.01 to 150 nM.
The progesterone receptor modulators can be administered orally, enterally, parenterally or transdermally for the use according to the invention.
Satisfactory results are generally to be expected in the treatment of the indications mentioned hereinbefore when the daily doses cover a range from 1 μg to 1000 mg of the compound according to the invention for gynaecological indications such as treatment of endometriosis, leiomyomas of the uterus and dysfunctional bleeding, and for use in fertility control and for hormone replacement therapy. Daily dosages to be administered for oncological indications are in the range from 1 μg to 2000 mg of the compound according to the invention.
Suitable dosages of the compounds according to the invention in humans for the treatment of endometriosis, of leiomyomas of the uterus and dysfunctional bleeding and for use in fertility control and for hormone replacement therapy are from 50 μg to 500 mg per day, depending on the age and constitution of the patient, it being possible to administer the necessary daily dose by single or multiple administration.
The dosage range for the compounds according to the invention for the treatment of breast carcinomas is 10 mg to 2000 mg per day.
The pharmaceutical products based on the novel compounds are formulated in a manner known per se by processing the active ingredient with the carrier substances, fillers, substances influencing disintegration, binders, humectants, lubricants, absorbents, diluents, masking flavours, colorants, etc. which are used in pharmaceutical technology, and converting into the desired administration form. Reference should be made in this connection to Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980).
Suitable for oral administration are in particular tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions.
Preparations for injection and infusion are possible for parenteral administration.
Appropriately prepared crystal suspensions can be used for intraarticular injection.
Aqueous and oily solutions for injection or suspensions and corresponding depot preparations can be used for intramuscular injection.
For rectal administration, the novel compounds can be used in the form of suppositories, capsules, solutions (e.g. in the form of enemas) and ointments, both for systemic and for local therapy.
Furthermore, compositions for vaginal use may also be mentioned as preparation.
For pulmonary administration of the novel compounds, they can be used in the form of aerosols and inhalants.
Patches are possible for transdermal administration, and formulations in gels, ointments, fatty ointments, creams, pastes, dusting powders, milk and tinctures are possible for topical application. The dosage of the compounds of the general formula I in these preparations should be 0.01%-20% in order to achieve an adequate pharmacological effect.
Corresponding tablets can be obtained for example by mixing active ingredient with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as maize starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or means to achieve a depot effect such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also consist of a plurality of layers.
Correspondingly, coated tablets can be produced by coating cores produced in analogy to the tablets with compositions normally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. The tablet covering may in this case also consist of a plurality of layers, it being possible to use the excipients mentioned above for tablets.
Solutions or suspensions of the compounds according to the invention of the general formula I may additionally comprise taste-improving agents such as saccharin, cyclamate or sugar, and, for example, flavourings such as vanillin or orange extract. They may additionally comprise suspending excipients such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.
Capsules comprising the compounds of the general formula I can be produced for example by mixing the compound(s) of the general formula I with an inert carrier such as lactose or sorbitol and encapsulating it in gelatin capsules.
Suitable suppositories can be produced for example by mixing with carriers intended for this purpose, such as neutral fats or polyethylene glycol or derivatives thereof.
The compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts can be used, because of their antagonistic or partial agonistic activity, for producing a medicament, in particular for the treatment and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea. They can furthermore be employed to counteract hormonal irregularities, for inducing menstruation and alone or in combination with prostaglandins and/or oxytocin to induce labour.
The compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts are furthermore suitable for producing products for female contraception (see also WO 93/23020, WO 93/21927).
The compounds according to the invention or their pharmaceutically acceptable salts can additionally be employed alone or in combination with estrogens, estrogen derivatives, substances having estrogenic activity or with a selective oestrogen receptor modulator (SERM) for female hormone replacement therapy.
In addition, the said compounds have an antiproliferative effect in hormone-dependent tumours. They are therefore suitable for the therapy of hormone-dependent carcinomas such as, for example, for breast, prostate and endometrial carcinomas.
The compounds according to the invention or their pharmaceutically acceptable salts can be employed for the treatment of hormone-dependent carcinomas both in first-line therapy and in second-line therapy, especially after tamoxifen failure.
The compounds according to the invention, having antagonistic or partially agonistic activity, of the general formula (I) or their pharmaceutically acceptable salts can also be used in combination with compounds having antiestrogenic activity (estrogen receptor antagonists or aromatase inhibitors) or selective estrogen receptor modulators (SERM) for producing pharmaceutical products for the treatment of hormone-dependent tumours. The compounds according to the invention can likewise be used in combination with SERMs or an antiestrogen (estrogen receptor antagonist or aromatase inhibitor) for the treatment of endometriosis or of leiomyomas of the uterus.
Suitable for combination with the non-steroidal progesterone receptor modulators according to the invention in this connection are for example the following antiestrogens (estrogen receptor antagonists or aromatase inhibitors) or SERMs: tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulphynyl]pentyloxy}-phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7alpha-[9-(4,4,5,5-pentafluoropentylsulphynyl)nonyl]estra-1,3,5(10)-triene-3,17-beta-diol), 11beta-fluoro-7alpha-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulphanyl]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-3,17-beta-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), clomifene, raloxifene, and further compounds having antiestrogenic activity, and aromatase inhibitors such as, for example, fadrozole, formestane, letrozole, anastrozole or atamestane.
Suitable for combination of the progesterone receptor modulators according to the invention with suitable estrogens, estrogen derivatives or substances having estrogenic activity are the following: 17β-estradiol, 17β-ethinylestradiol, estriol, 17β-estradiol 3-alkylsulphonates, 17β-ethinylestradiol 3-alkylsulphonates, estradiol 3- or 17-esters such as estradiol 3-benzoate or estradiol 17-valerate, 17β-ethinylestradiol 3-ethers such as 17β-ethinylestradiol 3-methyl ether (mestranol) or conjugated equine estrogens (CEE).
In the case of the estrogen 3-alkylsulphonates such as 17β-estradiol 3-alkylsulphonate and 17β-ethinylestradiol 3-alkylsulphonate, suitable for the alkylsulphonate are in particular saturated, branched or unbranched C1-C5-alkyl groups, with the meanings mentioned in the definitions on page 9 applying to C1-C5-alkyl. Mention may be made here by way of example, without restriction thereto, of 17β-estradiol 3-isopropylsulphonate and of 17β-ethinylestradiol 3-propylsulphonate (turisterone).
Finally, the present invention also relates to the use of the compounds of the general formula I, where appropriate together with an antiestrogen, an estrogen or estrogen derivative and a substance having estrogenic activity, or a SERM, for producing a medicament.
The present invention further relates to pharmaceutical compositions which comprise at least one compound according to the invention, where appropriate in the form of a pharmaceutically/pharmacologically acceptable salt.
These pharmaceutical compositions and medicaments may be intended for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration. Besides conventional carriers and/or diluents, they comprise at least one compound according to the invention.
The medicaments of the invention are produced with the conventional solid or liquid carriers or diluents and the excipients normally used in pharmaceutical technology appropriate for the desired mode of administration with a suitable dosage in a known manner. The preferred preparations consist of a dosage suitable for oral administration. Examples of such dosage forms are tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, solutions or suspensions or else depot forms.
The pharmaceutical compositions comprising at least one of the compounds according to the invention are preferably administered orally.
Also suitable are parenteral preparations such as solutions for injection. Further preparations which may also be mentioned are for example suppositories and compositions for vaginal use.
The compounds of the general formula I can be synthesized as shown in scheme 1. Carboxylic acids of the general formula II have been described for example in previously described WO 199854159, WO 200375915 and WO 9854159. The amides of the general formula III are prepared for example by forming the acid chlorides and subsequently reacting with the appropriate amines. However, as an alternative thereto, it is also possible to use other methods for amide formation, depending on the amine to be introduced. The compounds of the general formula I are then prepared from the amides of the general formula III by addition of Grignard or organolithium compounds. Steps 1 and 2 can, however, also be carried out in the reverse sequence.
The substituents A, R1, R2, R3 and R4 may also where appropriate be further modified after introduction has taken place. Suitable for this purpose are for example oxidation, reduction, alkylations, acylations, nucleophilic additions or especially also transition metal-catalyzed coupling reactions.
Functional groups in compounds of the general formulae II, III and IV are provided where appropriate with temporary protective groups which are then eliminated again at a suitable stage.
The following examples serve to explain the subject-matter of the invention in more detail, without intending to restrict it thereto.
Preparation of 3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid is described in WO 200375915.
3-[1-(2-Fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid (500 mg) was dissolved in 10 ml of N,N-dimethylacetamide. At −10° C., 155 μl of thionyl chloride were added, and the mixture was stirred at −10° C. for one hour. Subsequently, 368 mg of 4-amino-2-chlorobenzonitrile were added in portions. This was followed by stirring for 2 hours (−10° C. to 23° C.). The reaction mixture was then poured into ice-water. It was stirred for 2 hours and filtered with suction. The resulting solid was purified by column chromatography on silica gel with a hexane/ethyl acetate mixture. 495 mg of product were obtained.
1H-NMR (ppm, CDCl3, 300 MHz): 1.00 (4H), 3.30 (2H), 7.08 (1H), 7.45-7.57 (2H), 7.60-7.75 (2H), 7.92 (1H), 8.80 (1H).
At −78° C., n-butyllithium (314 μl, 1.6 M in hexane) was added to a solution of 62 μl of phenylacetylene in tetrahydrofuran (5 ml). The mixture was stirred at this temperature for 30 minutes and then a solution of the compound (100 mg) described in 1a) in 4 ml of tetrahydrofuran was added dropwise. The mixture was then allowed to reach 23° C. over about 3 h and was subsequently stirred for 10 h. The reaction mixture was then poured into ice-cold saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. The crude product was chromatographed on silica gel. 93 mg of product were obtained.
1H-NMR (ppm, CDCl3, 400 MHz): 0.88 (1H), 0.95-1.11 (3H), 2.41 (1H), 2.66 (1H), 2.99 (1H, 7.02 (1H), 7.22-7.38 (6H), 7.40 (1H), 7.60 (2H), 7.80 (1H), 8.70 (1H).
The racemic mixture obtained in Example 1b was separated into the enantiomers 1c and 1d by preparative chiral HPLC (Chiralpak AD 250×10 mm column).
1c: [α]D20=+7.1° (CHCl3, 8.9 mg/1 ml; λ=589 nM)
1d: [α]D20=−8.7° (CHCl3, 9.2 mg/l ml; λ=589 nM)
The compound described in Example 2 was prepared from the compound described in 1a), 4-methylphenylacetylene and n-butyllithium in analogy to the process described in Example 1b).
1H-NMR (ppm, CDCl3, 300 MHz): 0.86 (1H), 0.92-1.10 (3H), 2.33 (3H), 2.40 (1H), 2.67 (1H), 2.97 (1H), 7.00 (1H), 7.09 (2H), 7.20 (2H), 7.33 (1H), 7.40 (1H), 7.55-7.65 (2H), 7.79 (1H), 8.70 (1H).
The compound described in Example 3a) was prepared from 3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid and 4-amino-2-trifluoromethyl-benzonitrile in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 1.02 (4H), 3.30 (2H), 7.08 (1H), 7.49 (1H), 7.70 (1H), 7.82 (1H), 7.93 (1H), 8.08 (1H), 8.94 (1H).
The compound described in Example 3b) was prepared from 3a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.87 (1H), 0.95-1.1 (3H), 2.40 (1H), 2.72 (1H), 3.02 (1H), 7.00 (1H), 7.25-7.42 (6H), 7.59 (1H), 7.72-7.83 (2H), 7.91 (1H), 8.87 (1H).
The racemic mixture obtained in Example 3b was separated into the enantiomers 3c and 3d by preparative chiral HPLC (Chiralpak AD 250×10 mm column).
3c: [α]D20=+5.3° (CHCl3, 9.6 mg/l ml; λ=589 nM)
3d: [α]D20=−5.7° (CHCl3, 9.4 mg/l ml; λ=589 nM)
The compound described in Example 4 was prepared from 3a) in analogy to Example 2.
1H-NMR (ppm, CDCl3, 300 MHz): 0.83 (1H), 0.92-1.13 (3H), 2.33 (3H), 2.39 (1H), 2.73 (1H); 3.00 (1H), 7.00 (1H), 7.09 (2H), 7.20 (2H), 7.30 (1H), 7.57 (1H), 7.72-7.85 (2H), 7.90 (1H), 8.85 (1H).
The racemic mixture obtained in Example 4 was separated into the enantiomers 4a and 4b by preparative chiral HPLC (Chiralpak AD 250×10 mm column).
4a: [α]D20=+2.8° (CHCl3, 10.0 mg/1 ml; λ=589 nM)
4b: [α]D20=−3.7° (CHCl3, 10.5 mg/l ml; λ=589 nM)
The compound described in Example 5a) was prepared from 3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid and 4-nitro-3-trifluoromethyl-phenylamine in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 400 MHz): 1.02 (4H), 3.31 (2H), 7.09 (1H), 7.04 (1H), 7.48 (1H), 7.70 (1H), 7.99 (2H), 8.05 1H), 8.97 (1H).
The compound described in Example 5b) was prepared from 5a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.87 (1H), 0.95-1.12 (3H), 2.40 (1H), 2.73 (1H), 3.01 (1H), 7.00 (1H), 7.23-7.40 (6H), 7.60 (1H), 7.82-7.99 (3H), 8.90 (1H).
The racemic mixture obtained in Example 5b was separated into the enantiomers 5c and 5d by preparative chiral HPLC (Chiralpak AD 250×10 mm column).
5c: [α]D20=+5.9° (CHCl3, 8.7 mg/l ml; λ=589 nM)
5d: [α]D20=−6.9° (CHCl3, 9.0 mg/l ml; λ=589 nM)
The compound described in Example 6 was prepared from 5a) in analogy to Example 2.
1H-NMR (ppm, CDCl3, 400 MHz): 0.85 (1H), 0.95-1.12 (3H), 2.32 (3H), 2.39 (1H), 2.72 (1H), 2.97 (1H), 7.01 (1H), 7.10 (2H), 7.21 (2H), 7.32 (1H), 7.60 (1H), 7.84-8.00 (3H), 8.90 (1H).
2.15 ml of hydrogen peroxide solution (30% strength in water) were added to 4.2 ml of trifluoroacetic acid at 23° C. After stirring at 23° C. for 30 minutes, a solution of 2 g of 5-nitrobenzo[b]thiophene in 15 ml of trifluoroacetic acid was slowly added. After stirring at 23° C. for one hour, the reaction mixture was poured into ice-water. It was then stirred for 3 hours. The precipitate was then filtered off with suction and washed with water. The resulting crude product was chromatographed on silica gel. 1.08 mg of product were obtained.
1H-NMR (ppm, CDCl3, 300 MHz): 7.32 (2H), 8.11 (1H), 8.36 (2H).
1.45 g of the compound obtained in 7a were suspended in 50 ml of ethanol. 8.38 g of tin(II) chloride dihydrate were added, and the mixture was stirred at 70° C. for 10 minutes. The reaction mixture was then poured into ice-cold saturated ammonium chloride solution. Stirring for 2 hours was followed by dilution with ethyl acetate and removal of the precipitated salts by filtration through Celite. The phases were then separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The resulting crude product was chromatographed on silica gel. 505 mg of product were obtained.
1H-NMR (ppm, DMSO-D6, 300 MHz): 5.06 (2H), 6.71 (1H), 6.97 (1H), 7.15 (1H), 7.50-7.63 (2H).
The compound described in Example 7c) was prepared from 3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid and the compound described in 7b) in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 1.01 (4H), 3.35 (2H), 7.09 (1H), 7.30 (1H), 7.40 (1H), 7.48 (2H), 7.73 (1H), 7.82 (1H), 8.24 (1H), 8.74 (1H).
The compound described in Example 7d) was prepared from 7c) in analogy to Example 2.
1H-NMR (ppm, CDCl3, 300 MHz): 0.80-1.12 (4H), 2.33 (3H), 2.46 (1H), 2.59 (1H), 3.15 (1H), 6.96 (1H), 7.09 (2H), 7.21 (2H), 7.24-7.48 (3H), 7.48 (1H), 7.66 (1H), 7.80 (1H), 8.11 (1H), 8.50 (1H).
The compound described in Example 8a) was prepared from 3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid and 1,1-dioxo-2,3-dihydro-1H-1λ6-benzo[b]thiophen-5-ylamine in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 400 MHz): 1.02 (4H), 3.30 (2H), 3.37 (2H), 3.50 (2H), 7.09 (1H), 7.48 (2H), 7.71 (2H), 7.87 (1H), 8.83 (1H).
The compound described in Example 8b) was prepared from 8a) in analogy to Example 2.
1H-NMR (ppm, CDCl3, 300 MHz): 0.87 (1H), 0.92-1.12 (3H), 2.32 (3H), 2.43 (1H), 2.60 (1H), 3.04 (1H), 3.34 (2H), 3.50 (2H), 6.98 (1H), 7.09 (2H), 7.20 (2H), 7.34 (2H), 7.60 (1H), 7.67 (1H), 7.80 (1H), 8.70 (1H).
The racemic mixture obtained in Example 8 was separated into the enantiomers 9a and 9b by preparative chiral HPLC (Chiralpak AD 250×10 mm column).
9a: [α]D20: +20.6° (CHCl3, 10.0 mg/1 ml; λ=589 nM)
9b: [α]D20: −20.7° (CHCl3, 9.6 mg/1 ml; λ=589 nM)
The compound described in Example 10a) was prepared from 3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxopropionic acid and 1,1-dioxo-1H-1λ6-benzo[b]thiophen-5-ylamine in analogy to the process described in Example 1a).
1H-NMR (ppm, DMSO-D6, 300 MHz): 0.92 (4H), 3.24 (2H), 7.28-7.38 (2H), 7.48 (2H), 7.74 (2H), 7.86 (1H), 8.01 (1H), 10.78 (1H).
The compound described in Example 10) was prepared from 10a) in analogy to Example 2.
1H-NMR (ppm, CDCl3, 400 MHz): 0.86 (1H), 0.95-1.10 (3H), 2.32 (3H), 2.43 (1H), 2.62 (1H), 3.05 (1H), 6.72 (1H), 7.00 (1H), 7.07-7.25 (5H), 7.30 (1H), 7.48 (1H), 7.56-7.68 (2H), 7.80 (1H), 8.73 (1H).
The compound described in Example 11a) was prepared from 3-[1-(2-chloro-6-fluorophenyl)dimethyl]-2-oxopropionic acid and 4-amino-2-trifluoromethylbenzonitrile in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 1.69 (3H), 1.71 (3H), 3.82 (2H), 6.94 (1H), 7.09-7.16
The compound described in Example 11b) was prepared from 11a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 1.77 (3H), 1.86 (3H), 2.93-3.04 (3H), 6.86 (1H), 6.97 (1H), 7.06 (1H), 7.31-7.36 (5H), 7.79-7.88 (2H), 8.02 (1H), 8.89 (1H).
The compound described in Example 12a) was prepared from 3-[1-(2-chloro-6-fluorophenyl)dimethyl]-2-oxopropionic acid and 4-amino-2-chlorobenzonitrile in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 1.69 (3H), 1.71 (3H), 3.80 (2H), 6.94 (1H), 7.07-7.17 (2H), 7.52 (1H), 7.64 (1H), 7.95 (1H), 8.85 (1H).
The compound described in Example 12b) was prepared from 12a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 1.72 (3H), 1.80 (3H), 2.92 (2H), 3.04 (1H), 6.81 (1H), 6.94 (1H), 7.03 (1H), 7.26-7.43 (6H), 7.58 (1H), 7.82 (1H), 8.72 (1H).
The racemic mixture obtained in Example 12b was separated into the enantiomers 12c and 12d by preparative chiral HPLC (Chiralpak AD 250×10 mm column).
12c: [α]D20=+13.9° (CHCl3, 10.6 mg/l ml; λ=589 nM)
12d: [α]D20=−14.0° (CHCl3, 10.8 mg/l ml; λ=589 nM)
The compound described in Example 12a) was prepared from 3-[1-(2-chloro-6-fluorophenyl)dimethyl]-2-oxopropionic acid and 4-nitro-3-trifluoromethylaniline in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 1.70 (3H), 1.71 (3H), 3.82 (2H), 6.92 (1H), 7.08-7.17 (2H), 8.00 (2H), 8.09 (1H), 9.01 (1H).
The compound described in Example 13b) was prepared from 13a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 1.72 (3H), 1.81 (3H), 2.95 (2H), 3.01 (1H), 6.78-7.03 (3H), 7.27-7.39 (5H), 7.86-7.96 (3H), 8.90 (1H).
The compound described in Example 14a) was prepared from 3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid and 4-aminobenzonitrile in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 1.01 (4H), 3.31 (2H), 7.09 (1H), 7.48 (1H), 7.63-7.73 (5H), 8.79 (1H).
The compound described in Example 14b) was prepared from 14a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.86-0.90 (1H), 0.97-1.08 (3H), 2.45 (1H), 2.64 (1H), 3.05 (1H), 7.00 (1H), 7.29-7.35 (6H), 7.60-7.63 (5H), 8.68 (1H).
The compound described in Example 15a) was prepared from 3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid and aniline in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 1.00 (4H), 3.33 (2H), 7.09 (1H), 7.16 (1H), 7.35 (2H), 7.48 (1H), 7.58 (2H), 7.73 (1H), 8.61 (1H).
The compound described in Example 15b) was prepared from 15a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.85-1.09 (4H), 2.47 (1H), 2.57 (1H), 3.17 (1H), 6.98 (1H), 7.14 (1H), 7.28-7.35 (8H), 7.50 (2H), 7.64 (1H), 8.40 (1H).
The compound described in Example 16a) was prepared from {3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid}(4-cyano-3-trifluoromethylphenyl)amide (see Example 3a) and 3-tert-butylsilyloxypropyne in analogy to the process described in Example 1b).
1H-NMR (ppm, CDCl3, 300 MHz): 0.07 (6H), 0.76-0.84 (1H), 0.88 (9H), 1.07-0.92 (3H), 2.24 (1H), 2.69 (1H), 3.11 (1H), 4.23 (2H), 7.02 (1H), 7.31-7.36 (1H), 7.54 (1H), 7.76 (2H), 7.85 (1H), 8.82 (1H).
Tetrabutylammonium fluoride (280 μL, 1M in THF) was added to a solution of the compound (170 mg) described in 16a) in 5 ml of THF. The mixture was stirred at 23° C. for 4 h. The reaction mixture was then poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated.
The crude product was chromatographed on silica gel. 137 mg of product are obtained.
1H-NMR (ppm, CDCl3, 400 MHz): 0.81-0.86 (1H), 0.90-1.02 (3H), 1.25 (1H), 2.30 (1H), 2.64 (1H), 4.17 (2H), 7.04 (1H), 7.36 (1H), 7.54 (1H), 7.77 (2H), 7.89 (1H), 8.87 (1H).
The racemic mixture obtained in Example 16b was separated into the enantiomers 16c and 16d by preparative chiral HPLC (Chiralpak AD 250×10 mm column).
16c: [α]D20=+36.9° (CHCl3, 10.1 mg/l ml; λ=589 nM)
16d: [α]D20=−37.9° (CHCl3, 10.2 mg/l ml; λ=589 nM)
The compound described in Example 17 was prepared from {3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid}(4-cyano-3-trifluoromethylphenyl)amide and 1-pentyne in analogy to the process described in Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.83-0.90 (1H), 0.96-1.07 (6H), 1.52 (2H), 2.15 (2H), 2.29 (1H), 2.68 (1H), 2.83 (1H), 7.09 (1H), 7.41 (1H), 7.59 (1H), 7.81 (2H), 7.93 (1H), 8.85 (1H).
The racemic mixture obtained in Example 17 was separated into the enantiomers 3a and 3b by preparative chiral HPLC (Chiralpak AD 250×10 mm column).
3a: [α]D20=+27.4° (CHCl3, 21.5 mg/1 ml; λ=589 nM)
3b: [α]D20=−27.1° (CHCl3, 21.9 mg/l ml; λ=589 nM)
The compound described in Example 18a) was prepared from 3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid and 3-trifluoromethylaniline in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 1.01 (4H), 3.32 (2H), 7.10 (1H), 7.33 (1H), 7.41-7.53 (3H), 7.73 (1H), 7.92 (1H), 8.73 (1H).
The compound described in Example 18b) was prepared from Example 18a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.87-0.94 (1H), 1.01-1.13 (3H), 2.49 (1H), 2.70 (1H), 3.14 (1H), 7.04 (1H), 7.32-7.51 (8H), 7.68 (2H), 7.82 (1H), 8.61 (1H).
The compound described in Example 19a) was prepared from {3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxopropionic acid}(4-cyano-3-trifluoromethylphenyl)amide and trimethylsilylacetylene in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.22 (9H), 0.76-0.86 (1H), 0.98-1.14 (3H), 2.28 (1H), 2.74 (1H), 2.87 (1H), 7.08 (1H), 7.42 (1H), 7.61 (1H), 7.80 (2H), 7.92 (1H), 8.85 (1H).
The compound described in Example 19b) was prepared from 19a) in analogy to Example 16b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.81-0.88 (1H), 0.92-1.06 (3H), 2.30 (1H), 2.58 (1H), 2.69 (1H), 3.15 (1H), 7.03 (1H), 7.36 (1H), 7.54 (1H), 7.78 (2H), 7.88 (1H), 8.78 (1H).
Palladium(II) acetate (3.7 mg), triphenylphosphine (8.7 mg) and copper(I) iodide (6.9 mg) were added to a solution of triethylamine (3.9 ml) in THF (7 ml). The mixture was stirred for 2 minutes. Then 4-acetoxyiodobenzene (64 mg) was added. The mixture was stirred for 5 minutes. Then the compound (80 mg) described in 19b) was added, and reaction was allowed to take place in an ultrasonic bath for 2 hours. The reaction mixture was then poured into ice-cold saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product was chromatographed on silica gel and then chromatographed with HPLC. 23 mg of product were obtained.
1H-NMR (ppm, CDCl3, 400 MHz): 0.88-0.94 (1H), 1.02-1.13 (3H), 2.34 (3H), 2.44 (1H), 2.77 (1H), 3.10 (1H), 7.03-7.10 (3H), 7.34-7.40 (3H), 7.63 (1H), 7.84 (2H), 7.96 (1H), 8.90 (1H).
A solution of the compound (18 mg) described in 19c) and sodium bicarbonate (41 mg) in MeOH (1 ml) was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product was chromatographed by preparative TLC. 11 mg of product were obtained.
1H-NMR (ppm, CDCl3, 400 MHz): 0.83-0.88 (1H), 0.96-1.09 (3H), 2.38 (1H), 2.71 (1H), 2.98 (1H), 5.17 (1H), 6.75 (2H), 7.01 (1H), 7.21 (2H), 7.32 (1H), 7.58 (1H), 7.79 (2H), 7.91 (1H), 8.87 (1H).
The compound described in Example 20a) was prepared from 3-[1-(2-chlorophenyl)cyclopropyl]-2-oxopropionic acid and 4-amino-2-trifluoromethylbenzonitrile in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 1.02 (4H), 3.36 (2H), 7.15-7.19 (2H), 7.32 (1H), 7.47 (1H), 7.82 (1H), 7.92 (1H), 8.04 (1H), 8.94 (1H).
The compound described in Example 20b) was prepared from 20a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.80-0.88 (1H), 0.96-1.03 (1H), 1.09-1.28 (2H), 2.94 (2H), 7.04-7.14 (2H), 7.27-7.48 (8H), 7.79 (2H), 7.93 (1H), 8.80 (1H).
The racemic mixture obtained in Example 20b was separated into the enantiomers 20c and 20d by preparative chiral HPLC (Chiralpak AD 250×10 mm column).
20c: [α]D20=+17.9° (CHCl3, 10.4 mg/l ml; λ=589 nM)
20d: [α]D20=−17.5° (CHCl3, 10.3 mg/l ml; λ=589 nM)
The compound described in Example 21a) was prepared from 3-[1-(2-chlorophenyl)cyclopropyl]-2-oxopropionic acid and 4-amino-2-chlorobenzonitrile in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 1.01 (4H), 3.35 (2H), 7.15-7.18 (2H), 7.32 (1H), 7.45-7.53 (2H), 7.64 (1H), 7.91 (1H), 8.81 (1H).
The compound described in Example 21b) was prepared from 21a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.83 (1H), 1.00 (1H), 1.08-1.20 (2H), 2.89 (1H), 7.07-7.15 (2H), 7.29-7.49 (8H), 7.59 (1H), 7.81 (1H), 8.86 (1H).
The racemic mixture obtained in Example 21b was separated into the enantiomers 21c and 21d by preparative chiral HPLC (Chiralpak AD 250×10 mm column).
21c: [α]D20=+26.9° (CHCl3, 10.3 mg/l ml; λ=589 nM)
21d: [α]D20=−26.5° (CHCl3, 10.4 mg/l ml; λ=589 nM)
The compound described in Example 22a) was prepared from 3-[1-(2-chlorophenyl)cyclopropyl]-2-oxopropionic acid and 4-nitro-3-trifluoromethylaniline in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 1.07 (4H), 3.41 (2H), 7.20-7.24 (2H), 7.37 (1H), 7.52 (1H), 8.03 (2H), 8.09 (1H), 9.01 (1H).
The compound described in Example 22b) was prepared from 22a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.85 (1H), 1.01 (1H), 1.12-1.20 (2H), 2.93 (2H), 7.06-7.14 (2H), 7.28-7.48 (7H), 7.87-7.97 (3H), 8.84 (1H).
The compound described in Example 23 was prepared from {3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid}(4-cyano-3-trifluoromethylphenyl)amide and 3-(N,N-dimethylamino)propyne in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.80-0.87 (1H), 0.93-1.07 (3H), 2.26-2.31 (7H), 2.74 (1H), 3.19 (2H), 7.06 (1H), 7.37 (1H), 7.56 (1H), 7.82 (2H), 7.94 (1H), 9.03 (1H).
The compound described in Example 24 was prepared from {3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid}(4-cyano-3-trifluoromethylphenyl)amid and 1-methyl-1-imidazol-5-ylethyne in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.77-0.84 (1H), 0.91-1.05 (3H), 2.28 (1H), 2.81 (1H), 3.57 (3H), 7.01 (1H), 7.09 (1H), 7.28 (1H), 7.38 (1H), 7.52 (1H), 7.73-7.81 (2H), 7.92 (1H), 9.24 (1H).
The racemic mixture obtained in Example 24 was separated into the enantiomers 24a and 24b by preparative chiral HPLC (Chiralpak AD 250×10 mm column).
24a: [α]D20=+41.7° (CHCl3, 10.3 mg/l ml; λ=589 nM)
24b: [α]D20=−42.9° (CHCl3, 10.5 mg/l ml; λ=589 nM)
The compound described in Example 25 was prepared from {3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid}(4-cyano-3-trifluoromethylphenyl)amide and 2-pyridinylethyne in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.78-0.83 (1H), 0.92-1.03 (3H), 2.45 (1H), 2.75 (1H), 5.39 (1H), 6.95 (1H), 7.24 (1H), 7.27-7.34 (2H), 7.54 (1H), 7.67 (1H), 7.74 (1H), 7.82 (1H), 7.94 (1H), 8.42 (1H), 9.34 (1H).
The compound described in Example 26a) was prepared from 19b) and methyl 4-iodobenzoate in analogy to Example 19c).
1H-NMR (ppm, CDCl3, 400 MHz): 0.85-0.92 (1H), 0.96-1.06 (3H), 2.44 (1H), 2.62 (1H), 3.18 (1H), 3.92 (3H), 7.01 (1H), 7.21-7.38 (3H), 7.58 (1H), 7.75-7.83 (2H), 7.92 (1H), 7.94 (2H), 8.84 (1H).
A solution of the compound (40 mg) described in 26a) and sodium hydroxide (2M aq, 90 μl) in THF (2 ml) and EtOH (1 ml) was stirred at 23° C. for 16 hours. The reaction mixture was mixed with HCl (2N aq, 350 μl) and extracted with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product was chromatographed by preparative TLC. 15 mg of product are obtained.
1H-NMR (ppm, DMSO-d6, 400 MHz): 0.60-0.66 (1H), 0.94-1.00 (2H), 1.10-1.16 (1H), 2.05 (1H), 2.94 (1H), 7.22 (1H), 7.33 (1H), 7.37 (2H), 7.53-7.67 (2H), 7.88 (2H), 8.04 (2H), 8.20 (1H), 10.67 (1H).
The racemic mixture obtained in Example 26b was separated into the enantiomers 26c and 26d by preparative chiral HPLC (Chiralpak AD 250×10 mm column).
26c: [α]D20=+3.8° (CHCl3, 5.2 mg/l ml; λ=589 nM)
26d: [α]D20=−2.4° (CHCl3, 5.2 mg/l ml; λ=589 nM)
The compound described in Example 27a) was prepared from 3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid and 3,4-dichloroaniline in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 1.00 (4H), 3.30 (2H), 7.09 (1H), 7.40 (2H), 7.48 (1H), 7.71 (1H), 7.84 (1H), 8.62 (1H).
The compound described in Example 27b) was prepared from 27a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.90-0.94 (1H), 1.02-1.13 (3H), 2.49 (1H), 2.65 (1H), 3.06 (1H), 7.05 (1H), 7.32-7.43 (8H), 7.67 (1H), 7.77 (1H), 8.52 (1H).
The racemic mixture obtained in Example 27b was separated into the enantiomers 27c and 27d by preparative chiral HPLC (Chiralpak AD 250×10 mm column).
27c: [α]D20=+15.4° (CHCl3, 9.1 mg/1 ml; λ=589 nM)
27d: [α]D20=−15.9° (CHCl3, 10.1 mg/l ml; λ=589 nM)
At −30° C., n-butyllithium (170 μl, 1.6 M in hexane) was added to a solution of 320 μl of diisopropylamine in tetrahydrofuran (5 ml). The mixture was stirred at this temperature for 30 minutes and cooled to −78° C. A solution of 3-bromopropyne (170 μl) in 4 ml of tetrahydrofuran was then added dropwise. The mixture was stirred at this temperature for 1 hour and then a solution of {3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid}(4-cyano-3-trifluoromethylphenyl)amide (530 mg) in 4 ml of tetrahydrofuran was added dropwise. The mixture was then stirred at this temperature for about 3 h. The reaction mixture was subsequently poured into ice-cold saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product was chromatographed on silica gel. 184 mg of product were obtained.
1H-NMR (ppm, CDCl3, 400 MHz): 0.83-0.88 (1H), 0.93-1.06 (3H), 2.28 (1H), 2.64 (1H), 2.99 (1H), 3.80 (2H), 7.07 (1H), 7.39 (1H), 7.59 (1H), 7.78 (2H), 7.90 (1H), 8.75 (1H).
Piperidine (17 μl) was added to a suspension of the compound (50 mg) described in 28a) and potassium carbonate (24 mg) in dimethylformamide (2 ml). The mixture was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product was chromatographed by preparative TLC. 37 mg of product were obtained.
1H-NMR (ppm, CDCl3, 400 MHz): 0.76-0.81 (1H), 0.89-1.02 (3H), 1.41 (2H), 1.57 (4H), 2.24 (1H), 2.42 (4H), 2.68 (1H), 3.15 (2H), 7.02 (1H), 7.34 (1H), 7.52 (1H), 7.77 (2H), 7.87 (1H), 8.95 (1H).
The compound described in Example 29 was prepared from rac-{2-hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-(3-bromopropynyl)]propionic acid}(4-cyano-3-trifluoromethylphenyl)amide (see Example 28a) and 1-methylpiperazine in analogy to Example 28b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.75-0.83 (1H), 0.90-1.03 (3H), 1.86 (4H), 2.24 (1H), 2.28 (3H), 2.55 (4H), 2.72 (1H), 3.26 (2H), 7.01 (1H), 7.32 (1H), 7.51 (1H), 7.78 (2H), 7.88 (1H), 8.95 (1H).
The compound described in Example 30a was prepared from rac-{2-hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-(3-bromopropynyl)]propionic acid}-(4-cyano-3-trifluoromethylphenyl)amide and methyl piperidine-4-carboxylate in analogy to Example 28b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.77-0.82 (1H), 0.91-1.02 (3H), 1.72-1.80 (2H), 1.91 (2H), 2.15 (2H), 2.23 (1H), 2.30-2.25 (1H), 2.70 (1H), 2.82 (2H), 3.19 (2H), 3.67 (3H), 7.02 (1H), 7.33 (1H), 7.52 (1H), 7.77 (2H), 7.88 (1H), 8.93 (1H).
The compound described in Example 30b) was prepared from 30a) in analogy to Example 26b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.76 (1H), 0.86 (1H), 0.94 (1H), 1.03 (1H), 1.72 (2H), 1.98 (2H), 2.15-2.26 (4H), 2.58 (1H), 3.15-3.29 (4H), 6.92 (1H), 7.25-7.28 (1H), 7.50 (1H), 7.73 (1H), 7.95 (2H), 9.71 (1H).
The compound described in Example 31a) was prepared from 3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid and 5-aminoindane in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 0.99 (4H), 2.07 (2H), 2.88 (4H), 3.32 (2H), 7.09 (1H), 7.18 (1H), 7.25-7.28 (1H), 7.45-7.51 (2H), 7.73 (1H), 8.57 (1H).
The compound described in Example 31b) was prepared from 31a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.84-1.08 (4H), 2.08 (2H), 2.45 (1H), 2.54 (1H), 2.89 (4H), 3.19 (1H), 6.99 (1H), 7.17 (2H), 7.28-7.34 (6H), 7.43 (1H), 7.64 (1H), 8.32 (1H).
The compound described in Example 32a) was prepared from 3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid and 3,4-dimethylaniline in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 0.99 (4H), 2.23 (3H), 2.25 (3H), 3.32 (2H), 7.06-7.11 (2H), 7.31 (1H), 7.36 (1H), 7.48 (1H), 7.73 (1H), 8.53 (1H).
32b) rac-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-phenylethynyl)]propionic acid}(3,4-dimethylphenyl)amide
The compound described in Example 32b) was prepared from 32a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.86 (1H), 0.94 (1H), 0.98-1.05 (2H), 2.23 (3H), 2.25 (3H), 2.45 (1H), 2.53 (1H), 3.18 (1H), 6.99 (1H), 7.08 (1H), 7.23-7.33 (8H), 7.64 (1H), 8.28 (1H).
The compound described in Example 33a) was prepared from 3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionic acid and 6-aminoquinoline in analogy to the process described in Example 1a).
1H-NMR (ppm, CDCl3, 300 MHz): 1.02 (4H), 3.37 (2H), 7.10 (1H), 7.41 (1H), 7.49 (1H), 7.66 (1H), 7.75 (1H), 8.11 (2H), 8.37 (1H), 8.85-8.87 (2H).
The compound described in Example 33b) was prepared from 33a) in analogy to Example 1b).
1H-NMR (ppm, CDCl3, 400 MHz): 0.86-1.09 (4H), 2.52 (1H), 2.66 (1H), 3.74 (1H), 6.97 (1H), 7.28-7.41 (7H), 7.56 (1H), 7.66 (1H), 8.05 (1H), 8.12 (1H), 8.29 (1H), 8.74 (1H), 8.83 (1H).
Sodium azide (28 mg) was added to a solution of the compound (130 mg) described in 28a) in dimethylformamide (2 ml). The mixture was stirred for 4 hours. The reaction mixture was diluted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product was chromatographed with silica gel. 86 mg of product were obtained.
1H-NMR (ppm, CDCl3, 400 MHz): 0.82-1.03 (4H), 2.32 (1H), 2.68 (1H), 3.12 (1H), 3.85 (2H), 7.06 (1H), 7.38 (1H), 7.56 (1H), 7.77 (2H), 7.88 (1H), 8.76 (1H).
Triphenylphosphine (42 mg) was added to a solution of the compound (73 mg) described in 34a) in tetrahydrofuran (2 ml) and water (20 μl). The mixture was stirred for 7.5 hours. The reaction mixture was diluted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product was chromatographed with silica gel. 12 mg of product were obtained.
1H-NMR (ppm, CDCl3, 400 MHz): 0.83 (1H), 0.92-1.00 (3H), 2.28 (1H), 2.60 (1H), 3.36 (2H), 7.04 (1H), 7.35 (1H), 7.53 (1H), 7.78 (2H), 7.91 (1H), 8.97 (1H).
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.
The entire disclosures of all applications, patents and publications, cited herein and of corresponding U.S. Provisional Application Ser. No. 60/948,763, filed Jul. 10, 2007, are incorporated by reference herein.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 60/948,763 filed Jul. 10, 2007.
| Number | Date | Country | |
|---|---|---|---|
| 60948763 | Jul 2007 | US |
