Patent Application
20090270381
The present invention relates to non-steroidal progesterone receptor modulators, a method for their preparation, the use of the progesterone receptor modulators for the manufacture of medicaments, and 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 display their 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 the 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 also 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 activity of 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, 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 also 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 effects on the progesterone receptor with high potency. 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-C3-, C1-C4-, C1-C5-, C1-C6- and C1-C8-alkyl group means unbranched or optionally branched 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.
In the meaning of R1, R2 and R3, the methyl, ethyl, n-propyl or n-butyl group and an n-pentyl group are preferred.
According to the invention, preference is given to methyl or ethyl for R5, and to hydrogen for R6a and R6b.
Alkenyl means unbranched or optionally branched 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. When the aromatic in R3 is substituted by a C2-C8-alkenyl radical, it is preferably a vinyl group.
Alkynyl means unbranched or optionally branched alkynyl radicals. A C2-C8-alkynyl radical is intended to be for example an ethynyl, propynyl, butynyl, pentynyl, hexynyl and octynyl group, but preferably an ethynyl or propynyl group.
A C1-C3-acyl radical in the context of Rf is a formyl, acetyl and an n- or isopropionyl radical. An acetyl radical is preferred for Rf.
C1-C3-Alkoxy is understood to mean a methoxy, ethoxy and an n- or isopropoxy radical. Methoxy and ethoxy are preferred.
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-C3-, C1-C4- and C1-C6-fluoroalkyl group are in particular the trifluoromethyl or pentafluoroethyl group.
A halogen atom may be a fluorine, chlorine, bromine or iodine atom. Fluorine, chlorine or bromine is preferred here.
Possible examples of a mono- or bicyclic C6-C12-aryl radical in the meaning of R3, or Rc, Rd, Re, and also K and L, are, for example, a phenyl or naphthyl radical, preferably a phenyl radical.
Examples of a 3-12-membered heteroaryl radical in the meaning of R3, K and L, and also Rc and Rd, 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.
5- to 6-membered C3-C10-cycloalkyl in the meaning of A, R3, K and L and 3- to 12-membered heterocycloalkyl groups in the meaning of A, R3, K and L are understood to mean both monocyclic and bicyclic groups.
Heteroatoms for 3-12-membered heteroaryls in the meaning of Rb and 5-12-membered heteroaryls in the meaning of Rc and Rd are nitrogen, sulfur or oxygen.
Examples which may be mentioned of monocyclic C3-C10-cycloalkyl in the meaning of Rc and Re are cyclopropane, cyclobutane, cyclopentane and cyclohexane. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.
Examples of monocyclic 3-12-membered or 5-12-membered heterocyclic radicals in the meaning of A, Z, K, R3 or R4 are morpholine, tetrahydrofuran, piperidine, pyrrolidine, oxirane, oxetane, aziridine, dioxolane, dioxane, thiophene, furan, pyran, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, piperazine, thiazole, oxazole, furazan, pyrroline, thiazoline, triazole, tetrazole, using any of the chemically possible isomers in relation to the positions of the heteroatoms.
Examples which may be mentioned of bicyclic 3-12-membered or 5-12-membered heterocycles are quinoline, quinazoline and naphthyridine.
For R4, according to the invention, the bicyclic ring systems specified under B and C are preferred.
R1 and R2 which, together with the carbon atom of the chain, can form a carbocyclic ring having a total of 3-7 members are understood to mean carbocycles having 3 to 7 carbon atoms, preferably 3 to 6 carbon atoms. Particular preference is given to cyclopropyl, cyclopentyl and cyclohexyl.
Heterocycles in the sense of R1 and R2, which can be formed together with the carbon atom of the chain, may be cyclic ring compounds having at least one heteroatom, preferably oxygen, nitrogen and sulphur. Particular preference is given to tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl.
The number p for the (CH2)p radical may be a number 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1 or 2. “Radical” means according to the invention all functional groups which are mentioned under L in connection with (CH2)p.
In the case where the compounds of the general formula I 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) preferred according to the present invention are those in which A is a hydrogen atom.
Further preferred are compounds in which:
In the case that Y is (CH2)m, m is preferably 1.
Irrespective of m, in the case that Y is (CH2)m, R4 is a phenyl ring substituted by 2 of the radicals specified under L.
For L, particular preference is given to a cyano radical, a chlorine and/or a trifluoromethyl radical.
In the case that Y is (CH2)m, R4, alternatively to the substituted phenyl ring, may also be defined as follows:
For these, the following substituents are preferred:
Preference is additionally given to compounds of the general formula (I) in which
Preference is additionally given to compounds of the general formula (I) in which
Particular preference is given in this context in turn to a tetrahydropyranyl ring, a piperidinyl ring or a tetrahydrothiopyranyl ring.
The compounds mentioned 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:
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 ethylenediamine tetraacetate, 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 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 table which follows shows, by way of example, results from the transactivation test on antagonistic activity on (PR-B).
Table 2 shows results from the transactivation test on antagonistic activity at PR-A. Both the efficacy and the IC50 are shown. All substances exhibit significant antagonism. The IC50 values of the inventive compounds shown by way of example in table 2 are in the range of 1-60 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 the treatment of endometriosis, leiomyomas of the uterus and dysfunctional bleeding, and for use in fertility control and for hormone replacement therapy. For oncological indications, daily dosages in the range from 1 μg to 2000 mg of the compound according to the invention are to be administered.
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, colourants, 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 the 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 the manufacture of 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 the manufacture of 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 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 antioestrogenic activity (oestrogen receptor antagonists or aromatase inhibitors) or selective oestrogen 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 antioestrogen (oestrogen 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 antioestrogens (oestrogen receptor antagonists or aromatase inhibitors) or SERMs: tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulphinyl]pentyloxy}phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7alpha-[9-(4,4,5,5-pentafluoropentylsulphinyl)nonyl]estra-1,3,5(10)-triene-3,17beta-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(110)-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 antioestrogenic activity, and aromatase inhibitors such as, for example, fadrozole, formestane, letrozole, anastrozole or atamestane.
Finally, the present invention also relates to the use of the compounds of the general formula I, where appropriate together with an antioestrogen or SERM, for the manufacture of 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 manufactured 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 form suitable for oral administration. Examples of such dosage forms are tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, solutions or suspensions, where appropriate as depot form.
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 may be synthesized, for example, as shown in scheme 1. An α-hydroxylation of the ester of the general formula II and subsequent oxidation of the alcohol III formed to the ketone gives rise to compounds of the general formula IV.
For the preparation of compounds of the general formula III by α-hydroxylation of esters, various processes known from the literature are useful (for example Davis et al. in J. Org. Chem., 1984, 49, 3241 using 2-sulphonyloxaziridine). The oxidation to compounds of the general formula IV can then be effected by known standard methods. The amides of the general formula VI are prepared, for example, via the formation of the acid chlorides and subsequent reaction with the corresponding amines. Alternatively, for this purpose, it is also possible to utilize other methods of amide formation according to the amine to be introduced. The compounds of the general formula I are then prepared from the amides of the general formula VI by addition of organometallic compounds such as magnesium, lithium or organozinc compounds. Steps 1-5 can, though, also be performed in an altered sequence.
Some intermediate compounds of the general formulae III-V are commercially available. The substituents A, X, Y, R1, R2, R3 and R4 may optionally be modified further after they have been introduced. Possible reactions for this purpose include, for example, oxidation, reduction, alkylations, acylations, nucleophilic additions or else transition metal-catalysed coupling reactions.
Functional groups in compounds of the general formulae II-VI are optionally provided intermediately with protective groups which are then detached again at a suitable stage.
The examples which follow serve to illustrate the subject-matter of the invention in detail without any intention to restrict it to them.
The preparation of 6-amino-4-methyl-2,3-benzoxazin-1-one is described in WO 199854159.
To a solution of 2-cyclohexylacetic acid ethyl ester (1.2 g) in tetrahydrofuran (25 ml) was added, at −70° C., a solution of potassium hexamethyldisilizide (20 ml, 0.5 M in toluene). The mixture was left to stir at −70° C. for a further 30 minutes and then a solution of 3-phenyl-2-phenylsulphonyloxaziridine (2.6 g) in tetrahydrofuran (25 ml) was added. The mixture was left to stir at −70° C. for one hour. The reaction mixture was then poured onto saturated aqueous ammonium chloride solution. The mixture was stirred for a further 30 minutes and the phases were separated. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The resulting crude product was chromatographed on silica gel. 1.3 g of product were obtained.
1H NMR (ppm, CDCl3, 400 MHz): 1.11-1.27 (6H), 1.31 (3H), 1.44 (1H), 1.61-1.79 (4H), 2.73 (1H), 4.01 (1H), 4.25 (2H).
To a solution of the compounds described under a) in 20 ml of dichloromethane were added 20 ml of a 0.35 molar solution of 1,1-dihydro-1,1,1-triacetoxy-1,2-benzodioxol-3(1H)-one (Dess-Martin periodane) in dichloromethane. The mixture was left to stir at 23° C. for 14 hours. Subsequently, the mixture was diluted with 500 ml of methyl tert-butyl ether and then poured onto 1 l of an aqueous solution of 34 g of sodium hydrogencarbonate and 100 g of sodium thiosulphate. The mixture was left to stir for 30 minutes, then the phases were separated and the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over sodium sulphate. The crude product was chromatographed on silica gel. 0.8 g of product was obtained.
1H NMR (ppm, CDCl3, 400 MHz): 1.15-1.29 (5H), 1.36 (3H), 1.67-1.91 (5H), 3.03 (1H), 4.32 (2H).
To a solution of the compound described under b) in 13 ml of ethanol was added a solution of 0.5 g of sodium hydroxide in 8 ml of water. The mixture was left to stir at 23° C. for a further 14 hours, then diluted with water and extracted with ethyl acetate. Subsequently, the aqueous phase was acidified with 2 normal hydrochloric acid (pH 4). The mixture was then extracted with ethyl acetate and the organic phase was washed with saturated aqueous sodium chloride solution. It was then dried over sodium sulphate and concentrated under reduced pressure. The resulting crude product (0.7 g) was used in the next stage without purification.
The carboxylic acid described under c) was dissolved in 20 ml of N,N-dimethylacetamide. 0.38 ml of thionyl chloride was added at −10° C. and the mixture was left to stir at −10° C. for one hour. Subsequently, 0.92 g of 3-chloro-4-cyanoaniline was added in portions. The mixture was then stirred for a further 3 hours (−10° C. to 0° C.). Subsequently, the reaction mixture was poured on ice-water. It was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with a mixture of hexane/ethyl acetate. 1.2 g of product were obtained.
1H NMR (ppm, CDCl3, 400 MHz): 1.22-1.46 (5H), 1.72-1.96 (5H), 3.42-3.50 (1H), 7.59 (1H), 7.67 (1H), 8.02 (1H), 8.96 (1H).
A 1 molar solution of phenylmagnesium bromide in tetrahydrofuran (0.9 ml) was diluted with 10 ml of absolute tetrahydrofuran. The mixture was cooled to −70° C. and then a solution of 100 mg of N-(3-chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide in 6 ml of tetrahydrofuran was added. Subsequently, the mixture was left to stir at −70° C. for a further 2.5 hours. The reaction mixture was then poured onto 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. 130 mg of product were obtained.
1H NMR (ppm, CDCl3, 400 MHz): 0.84 (1H), 1.10-1.43 (5H), 1.71-1.84 (4H), 2.60 (2H), 7.29-7.42 (3H), 7.48 (1H), 7.57 (1H), 7.65 (2H), 7.96 (1H), 8.95 (1H).
To a solution of 94 μl of phenylacetylene in tetrahydrofuran (5 ml) was added, at −78° C., n-butyllithium (540 μl, 1.6 M in hexane). The mixture was left to stir at this temperature for a further 30 minutes and then a solution of N-(3-chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (100 mg) in 5 ml of tetrahydrofuran was added dropwise. Subsequently, the mixture was allowed to come to 23° C. over approx. 3 h and then stirred for a further 10 h. The reaction mixture was then poured onto ice-cold saturated ammonium chloride solution. The mixture 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. 110 mg of product were obtained.
1H NMR (ppm, DMSO-d6, 400 MHz): 0.84 (1H), 1.14-1.28 (5H), 1.60-1.98 (6H), 6.86 (1H), 7.36-7.46 (5H), 7.94 (2H), 8.27 (1H), 10.41 (1H).
The racemic mixture obtained in Example 2 was separated by preparative chiral HPLC (column: Chiralpak AD 250×10 mm) into enantiomers 2a and 2b.
2a: [α]D20: +2.30 (CHCl3, 11.3 mg/l ml; λ=589 nM)
2b: [α]D20: −2.00 (CHCl3, 11.0 mg/1 ml; λ=589 nM)
A 2 molar solution of benzylmagnesium chloride in tetrahydrofuran (430 μl) was diluted with 4 ml of absolute tetrahydrofuran. The mixture was cooled to −70° C. and then a solution of 100 mg of N-(3-chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide in 6 ml of tetrahydrofuran was added. Subsequently, the mixture was left to stir at −70° C. for a further 2 hours. The reaction mixture was then poured onto ice-cold saturated ammonium chloride solution. The mixture 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. 78 mg of product were obtained.
1H NMR (ppm, DMSO-d6, 400 MHz): 1.01-1.76 (10H), 1.93 (1H), 2.87 (1H), 3.02 (1H), 5.46 (1H), 7.05-7.28 (5H), 7.69-7.78 (2H), 8.01 (1H), 9.69 (1H).
N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (100 mg) was reacted with 4-methylphenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 45 mg of product were obtained.
1H NMR (ppm, CDCl3, 400 MHz): 1.16-1.35 (5H), 1.66-1.88 (4H), 2.05-2.14 (2H), 2.35 (3H), 3.02 (1H), 7.13 (2H), 7.35 (2H), 7.56 (1H), 7.62 (1H), 7.98 (1H), 8.80 (1H).
N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (150 mg) was reacted with 4-trifluoromethylphenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 140 mg of product were obtained.
1H NMR (ppm, CDCl3, 400 MHz): 1.12-1.39 (5H), 1.64-1.90 (4H), 2.08-2.16 (2H), 3.08 (1H), 7.54-7.65 (6H), 7.99 (1H), 8.80 (1H).
N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (150 mg) was reacted with 4-fluorophenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 140 mg of product were obtained.
1H NMR (ppm, CDCl3, 400 MHz): 1.21-1.37 (5H), 1.64-1.91 (4H), 2.05-2.16 (2H), 2.95 (1H), 7.02 (2H), 7.45 (2H), 7.56 (1H), 7.64 (1H), 7.98 (1H), 8.79 (1H).
N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (150 mg) was reacted with 4-(1-3-dioxolanyl)phenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 180 mg of product were obtained.
1H NMR (ppm, DMSO-d6, 400 MHz): 1.07-1.25 (5H), 1.56-1.95 (6H), 3.88-4.03 (4H), 5.70 (1H), 6.86 (1H), 7.42 (4H), 7.91 (2H), 8.24 (1H), 10.38 (1H).
To a solution of the compound described under 7a (50 mg) in methanol (2 ml) was added HCl (1 M in water, 0.4 ml) at 23° C. The mixture was left to stir at 23° C. for a further 24 hours. The reaction mixture was then poured onto saturated sodium hydrogen carbonate 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. 20 mg of product 7b and 23 mg of the following product 7c were obtained.
1H NMR (ppm, DMSO-d6, 400 MHz): 1.10-1.30 (5H), 1.64-1.79 (4H), 1.94-1.99 (2H), 7.66 (2H), 7.89-7.97 (4H), 8.26 (1H), 10.02 (1H).
Compound 7c was obtained as a by-product in the purification of 7b.
1H NMR (ppm, DMSO-d6, 400 MHz): 1.11-1.29 (5H), 1.62-1.78 (4H), 1.92-1.99 (2H), 3.24 (6H), 5.40 (1H), 7.39 (2H), 7.46 (2H), 7.80 (1H), 7.96 (1H), 8.26 (1H).
N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (150 mg) was reacted with 3-methylphenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 140 mg of product were obtained.
1H NMR (ppm, CDCl3, 400 MHz): 1.22-1.42 (5H), 1.73-1.94 (4H), 2.09-2.19 (2H), 2.37 (3H), 3.07 (1H), 7.20-7.33 (4H), 7.60 (1H), 7.67 (1H), 8.02 (1H), 8.84 (1H).
N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (150 mg) was reacted with 2-methylphenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 160 mg of product were obtained.
1H NMR (ppm, CDCl3, 400 MHz): 1.22-1.37 (5H), 1.70-1.90 (4H), 2.05-2.16 (2H), 2.45 (3H), 3.07 (1H), 7.15 (1H), 7.20-7.29 (3H), 7.43 (1H), 7.56 (1H), 7.64 (1H), 7.98 (1H), 8.81 (1H).
N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (750 mg) was reacted with 4-methoxyphenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 1 g of product was obtained.
1H NMR (ppm, CDCl3, 400 MHz): 1.13-1.37 (5H), 1.66-1.89 (4H), 2.05-2.16 (2H), 3.08 (1H), 3.82 (3H), 6.85 (2H), 7.40 (2H), 7.56 (1H), 7.63 (1H), 7.98 (1H), 8.83 (1H).
To a solution of the compound described in 10a (200 mg) in dichloromethane (6 ml) was added boron tribromide (1 M in dichloromethane, 2.8 ml) at −15° C. The reaction mixture was left to warm at 23° C. over 3 hours and left to stir over a further 24 hours. The reaction mixture was then poured onto ice-cold saturated sodium hydrogencarbonate 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. 81 mg of product were obtained.
1H NMR (ppm, CDCl3, 400 MHz): 1.16-1.43 (5H), 1.65-1.98 (5H), 2.44 (1H), 3.20 (1H), 5.22 (1H), 6.55 (1H), 6.78 (2H), 7.19 (2H), 7.44 (1H), 7.70 (1H), 8.14 (1H).
N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (150 mg) was reacted with tetrahydro-2-(2-propynyloxy)-2H-pyran and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 190 mg of product were obtained.
1H NMR (ppm, DMSO-d6, 400 MHz): 1.06-1.20 (5H), 1.43-1.87 (12H), 3.39-3.44 (1H), 3.66-3.73 (1H), 4.25 (2H), 4.74 (1H), 7.89 (2H), 8.19 (1H).
To a solution of the compound described in 11a (50 mg) in acetone (2 ml) was added HCl (1 M in water, 0.4 ml) at 23° C. The mixture was left to stir at 23° C. for a further 24 hours. Thereafter, the reaction mixture was poured onto saturated sodium hydrogencarbonate 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. 40 mg of product were obtained.
1H NMR (ppm, DMSO-d6, 400 MHz): 1.05-1.23 (5H), 1.49-1.93 (6H), 4.13 (2H), 5.22 (1H), 6.66 (1H), 7.89-7.97 (2H), 8.24 (1H), 10.30 (1H).
N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (140 mg) was reacted with 4-ethynylbenzoic acid methyl ester and lithium diisopropylamide in tetrahydrofuran in analogy to Example 2. After column chromatography, 130 mg of product were obtained.
1H NMR (ppm, DMSO-d6, 400 MHz): 1.07-1.26 (5H), 1.58-1.72 (4H), 1.87-1.95 (2H), 3.82 (3H), 6.93 (1H), 7.55 (2H), 7.86-7.95 (4H), 8.23 (1H), 10.41 (1H).
To a solution of the compound described in 12a (50 mg) in methanol (1.5 ml) was added a solution of potassium carbonate (100 mg) in water (50 μl) at 23° C. The mixture was left to stir at 23° C. for a further 4 days. The reaction mixture was then warmed to 40° C. and left to stir for a further 4 hours. The reaction mixture was then poured onto 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. 28 mg of product were obtained.
1H NMR (ppm, DMSO-d6, 400 MHz): 1.02-1.31 (5H), 1.58-1.76 (4H), 1.87-1.95 (2H), 6.93 (1H), 7.53 (2H), 7.86-7.95 (4H), 8.23 (1H), 10.41 (1H), 13.11 (1H).
N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (150 mg) were reacted with 2,5-dimethylphenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 190 mg of product were obtained.
1H NMR (ppm, CDCl3, 400 MHz): 1.14-1.38 (5H), 1.70-1.90 (4H), 2.05-2.16 (2H), 2.29 (3H), 2.40 (3H), 3.07 (1H), 7.09 (2H), 7.25 (1H), 7.56 (1H), 7.63 (1H), 7.98 (1H), 8.82 (1H).
N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (750 mg) was reacted with 3-methoxyphenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 1.0 g of product was obtained.
1H NMR (ppm, CDCl3, 400 MHz): 1.14-1.38 (5H), 1.66-1.90 (4H), 2.10-2.18 (2H), 3.15 (1H), 3.80 (3H), 6.92 (1H), 6.98 (1H), 7.06 (1H), 7.22 (1H), 7.56 (1H), 7.63 (1H), 7.98 (1H), 8.83 (1H).
The preparation was effected analogously to Example 3 with 3-methylbenzylmagnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.0-2.2 (m, 11H), 2.20 (s, 1H), 2.29 (s, 3H), 2.90 (d, 1H), 3.45 (d, 1H), 6.97-7.33 (m, 4H), 7.41 (dd, 1H), 7.60 (d, 1H), 7.85 (d, 1H), 8.56 (s, 1H).
The preparation was effected analogously to Example 3 with 4-methoxybenzyl-magnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.09-1.40 (m, 5H), 1.63-2.04 (m, 6H), 2.11 (s, 1H), 2.83 (d, 1H), 3.38 (d, 1H), 3.75 (s, 3H), 6.80 (d, 2H), 7.07 (d, 2H), 7.37 (dd, 1H), 7.55 (d, 1H), 7.84 (d, 1H), 8.54 (s, 1H).
The preparation was effected analogously to Example 3 with 3-methoxybenzyl-magnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.05-1.40 (m, 5H), 1.60-2.05 (m, 6H), 2.88 (d, 1H), 3.30 (d, 1H), 3.70 (s, 3H), 6.75 (m, 3H), 7.16 (dd, 1H), 7.40 (dd, 1H), 7.55 (d, 1H), 7.82 (d, 1H), 8.75 (s, 1H).
35 ml of 3-iodobenzylzinc bromide solution (0.5M in THF) were initially charged in 15 ml of THF and cooled to −75° C. 1.0 g of N-(3-chloro-4-cyanophenyl)-2-cyclohexyl-2-oxoacetamide, dissolved in 15 ml of THF, was added dropwise. The mixture was stirred at −75° C. for 4 h and at room temperature for a further hour, then added to sat. ammonium chloride solution and extracted with ethyl acetate. The organic phases were washed with sat. NaCl solution and dried over sodium sulphate. The crude product was purified by chromatography and then recrystallized from hexane/diisopropyl ether. 338 mg of the desired product were obtained as a colourless solid. 1H NMR (ppm, CDCl3, 400 MHz): 1.0-1.4 (m, 5H), 1.6-2.0 (m, 6H), 2.03 (s, 1H), 2.85 (d, 1H), 3.27 (d, 1H), 6.97 (dd, 1H), 7.12 (d, 1H), 7.36 (dd, 1H), 7.55 (m, 3H), 7.79 (s, 1H), 8.46 (s, 1H).
rac-N-(3-Chloro-4-cyanophenyl)-2-cyclohexyl-2-hydroxy-3-(2-iodophenyl)propionamide was prepared analogously to Example 18.
390 mg of the iodine compound and 197 mg of 4-acetylphenylboronic acid were initially charged in 6 ml of 1:1 toluene/ethanol, and 1.5 ml of 1M sodium carbonate solution and 90 mg of tetrakis(triphenylphosphine)palladium were added. The mixture was heated at 120° C. in a microwave for 25 min, then filtered through Celite and rinsed with ethyl acetate. The solution was washed with sat. NaCl solution, dried over sodium sulphate and concentrated. The crude product was purified by chromatography. 137 mg of the desired product were obtained as a colourless foam. 1H NMR (ppm, DMSO-D6, 400 MHz): 0.95-1.35 (m, 5H), 1.50-1.80 (m, 6H), 2.63 (s, 3H), 3.03 (d, 1H), 3.16 (d, 1H), 7.09 (m, 1H), 7.23 (m, 2H), 7.46 (d, 2H), 7.59 (m, 1H), 7.76 (dd, 1H), 7.84 (d, 1H), 7.97 (d, 2H), 8.05 (d, 1H), 9.91 (s, 1H).
The racemic mixture obtained was separated into the enantiomers 19a and 19b by preparation chiral HPLC (column Chiralpak 1A 5μ 250×200 mm eluent hexane/ethanol 85:15).
Rt=−11.6 min.
The preparation was effected analogously to Example 3 from N-(4-cyano-3-trifluoromethylphenyl)-2-cyclohexyl-2-oxoacetamide (prepared analogously to N-(3-chloro-4-cyanophenyl)-2-cyclohexyl-2-oxoacetamide, see above) and benzylmagnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.05-1.40 (m, 5H), 1.65-2.05 (m, 6H), 2.15 (s, 1H), 2.92 (d, 1H), 3.41 (d, 1H), 7.16 (m, 2H), 7.24 (m, 3H), 7.73 (d, 1H), 7.81 (dd, 1H), 7.86 (d, 1H), 8.63 (s, 1H).
The racemic mixture obtained was separated into the enantiomers 20a and 20b by preparative chiral HPLC (column: Chiralpak AD 250×10 mm).
Example 20a: [α]D20=−129.4° (MeOH, c=1.01) Example 20b: [α]D20=+132.7° (MeOH, c=1.00)
The preparation was effected analogously to Example 20 with 3-methylbenzyl-magnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.2-1.5 (m, 5H), 1.6-2.1 (m, 6H), 2.20 (s, 1H), 2.28 (s, 3H), 2.94 (d, 1H), 3.42 (d, 1H), 7.0-7.3 (m, 4H), 7.85 (m, 3H), 8.68 (s, 1H).
The preparation was effected analogously to Example 20 with 4-methylbenzyl-magnesium chloride. 1H NMR (ppm, DMSO-D6, 400 MHz): 1.0-1.3 (m, 5H), 1.4-1.8 (m, 6H), 2.12 (s, 1H), 2.23 (s, 3H), 2.84 (d, 1H), 2.98 (d, 1H), 7.0-7.3 (m, 4H), 7.97 (d, 1H), 8.11 (dd, 1H), 8.23 (d, 1H), 9.90 (s, 1H).
The preparation was effected analogously to Example 20 with 4-methoxybenzyl-magnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.10-1.45 (m, 5H), 1.65-2.05 (m, 6H), 2.19 (s, 1H), 2.90 (d, 1H), 3.42 (d, 1H), 3.79 (s, 3H), 6.84 (d, 2H), 7.12 (d, 2H), 7.79 (d, 1H), 7.88 (dd, 1H), 7.94 (d, 1H), 8.71 (s, 1H).
The resulting racemic mixture was separated by preparative chiral HPLC (column: Chiralpak AD 250×10 mm) into enantiomers 23a and 23b.
Example 23a: Rt=5.41 min
(Chiralpak IA 5μ 150×4.6, 80% hexane/20% 2-propanol, 1 ml/min)
Example 23b: Rt, =6.36 min
(Chiralpak Ia 5μ 150×4.6, 80% Hexane/20% 2-Propanol, 1 ml/min)
The preparation was effected analogously to Example 3 with 4-methoxybenzyl-magnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.0-2.0 (m, 11H), 2.88 (d, 1H), 2.97 (d, 1H), 3.56 (s, 3H), 5.44 (s, 1H), 6.58 (m, 1H), 6.74 (m, 2H), 7.00 (dd, 1H), 8.17 (dd, 1H), 8.27 (d, 1H), 9.92 (s, 1H).
The preparation was effected analogously to Example 18 using 2-iodobenzylzinc bromide. 1H NMR (ppm, CDCl3, 400 MHz): 1.0-1.4 (m, 5H), 1.6-2.0 (m, 6H), 2.03 (s, 1H), 2.85 (d, 1H), 3.27 (d, 1H), 6.97 (dd, 1H), 7.12 (d, 1H), 7.36 (dd, 1H), 7.55 (m, 3H), 7.79 (s, 1H), 8.46 (s, 1H).
The preparation was effected analogously to Example 25 using 3-iodobenzylzinc bromide. 1H NMR (ppm, CDCl3, 400 MHz): 1.05-1.40 (m, 5H), 1.60-2.05 (m, 6H), 2.06 (s, 1H), 2.86 (d, 1H), 3.27 (d, 1H), 6.96 (m, 1H), 7.12 (m, 1H), 7.55 (d, 2H), 7.76 (m, 2H), 7.87 (s, 1H), 8.58 (s, 1H).
The racemic mixture obtained was separated into the enantimers 26a and 26b by preparation chiral HPLC (column Chiralpak 1A 5μ 250×20 mm, eluent hexane/ethanol 95:5).
Example 26a: Rt, =15.1-17.4 min
Example 26b:
The preparation was effected analogously to Example 19 using the compound prepared in Example 25. 1H NMR (ppm, DMSO-D6, 400 MHz): 0.90-1.25 (m, 5H), 1.45-1.80 (m, 6H), 2.57 (s, 3H), 3.01 (d, 1H), 3.13 (d, 1H), 5.49 (s, 1H), 7.04 (dd, 1H), 7.17 (m, 2H), 7.39 (d, 2H), 7.91 (d, 2H), 8.00 (m, 2H), 8.05 (m, 1H), 8.26 (d, 1H), 10.07 (s, 1H).
The racemic mixture obtained was separated into the enantimers 27a and 27b by preparation chiral HPLC (column Chiralpak OD-H5μ 250×20 mm, eluent hexane/2-propanoll 98:15).
Example 27a: Rt=8.1-10.4 min
Example 27b: Rt=10.8-13.4 min
The preparation was effected analogously to Example 19 using the compound prepared in Example 26. 1H NMR (ppm, CDCl3, 400 MHz): 1.05-1.45 (m, 5H), 1.65-2.10 (m, 6H), 2.22 (s, 1H), 2.63 (s, 3H), 3.01 (d, 1H), 3.44 (d, 1H), 7.20 (m, 1H), 7.35 (m, 1H), 7.44 (m, 1H), 7.50 (d, 2H), 7.69 (m, 3H), 7.90 (m, 1H), 7.95 (d, 2H), 8.64 (s, 1H).
The racemic mixture obtained was separated into the enantimers 28a and 28b by preparation chiral HPLC (column Chiralpak 1A5μ 250×20 mm, hexane/ethanol 8:2).
Example 28a: [α]D20=−49.6° (MeOH, c=1.0)
Example 28b: [α]D20=???° (MeOH, c=1.0)
2-Oxo-2-cyclohexylacetic acid (200 mg) was reacted with 6-amino-4-methyl-2,3-benzoxazin-1-one and thionyl chloride in N,N-dimethylacetamide in analogy to Example d. After column chromatography, 360 mg of product were obtained.
1H NMR (ppm, CDCl3, 400 MHz): 1.23-1.51 (5H), 1.73-1.98 (5H), 2.61 (3H), 3.45-3.53 (1H), 7.84 (1H), 8.36 (1H), 8.39 (1H), 9.19 (1H).
6-[2-Cyclohexyl-2-oxoethanoylamino]-4-methyl-2,3-benzoxazin-1-one (200 mg) was reacted with phenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 160 mg of product were obtained.
1H NMR (ppm, DMSO-d6, 400 MHz): 1.00-1.32 (5H), 1.58-1.77 (4H), 1.93-2.02 (2H), 2.47 (3H), 6.86 (1H), 7.34-7.43 (5H), 8.19 (1H), 8.37-8.41 (2H), 10.50 (1H).
The preparation was effected analogously to Example 3 using the keto amide described in Example 29a and benzylmagnesium chloride. 1H NMR (ppm, DMSO-D6, 400 MHz): 1.00-1.35 (m, 5H), 1.45-1.85 (m, 5H), 1.95 (m, 1H), 2.40 (s, 3H), 2.90 (d, 1H), 3.06 (d, 1H), 5.48 (s, 1H), 7.00-7.25 (m, 5H), 8.06 (m, 1H), 8.10 (s, 1H), 8.25 (dd, 1H), 9.81 (s, 1H).
The resulting racemic mixture was separated by preparative chiral HPLC (column: Chiralpak AD 250×10 mm) into enantiomers 30a and 30b.
Example 30a: [α]D20=−119.4° (DMSO, c=0.54)
Example 30b: [α]D20=+113.5° (DMSO, c=0.57)
The preparation was effected analogously to Example 30 using 4-methoxybenzyl-magnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.12-1.47 (m, 5H), 1.55-2.14 (m, 6H), 2.23 (s, 1H), 2.64 (s, 3H), 2.92 (d, 1H), 3.44 (d, 1H), 3.86 (s, 3H), 6.83 (d, 2H), 7.14 (d, 2H), 7.62 (dd, 1H), 8.25 (d, 1H), 8.31 (d, 1H), 8.81 (s, 1H).
The compound was obtained analogously to Example 3 by reacting N-(3-chloro-4-cyanophenyl)-2-cyclopentyl-2-oxoacetamide (obtained analogously to the corresponding cyclohexyl compound, 1H NMR (ppm, CDCl3, 400 MHz): 1.71 (m, 4H), 1.82 (m, 2H), 2.01 (m, 2H), 3.85 (m, 1H), 7.60 (dd, 1H), 7.68 (d, 1H), 8.03 (d, 1H), 9.01 (s, 1H)) with benzylmagnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.45-1.95 (m, 8H), 2.50 (m, 1H), 2.84 (d, 1H), 3.50 (d, 1H), 7.16 (m, 2H), 7.27 (m, 3H), 7.37 (dd, 1H), 7.55 (d, 1H), 7.82 (d, 1H), 8.52 (s, 1H).
The preparation was effected analogously to Example 32 with 4-methylbenzyl-magnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.45-1.75 (m, 7H), 1.87 (m, 1H), 2.15 (s, 1H), 2.29 (s, 3H), 2.48 (m, 1H), 2.79 (d, 1H), 3.48 (d, 1H), 7.06 (m, 4H), 7.39 (dd, 1H), 7.56 (d, 1H), 7.83 (d, 1H), 8.55 (s, 1H).
The preparation was effected analogously to Example 32 with 3-methylbenzyl-magnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.45-1.73 (m, 7H), 1.85 (m, 1H), 2.17 (s, 1H), 2.25 (s, 3H), 2.49 (m, 1H), 2.79 (d, 1H), 3.48 (d, 1H), 6.95 (m, 2H), 7.05 (d, 1H), 7.16 (m, 1H), 7.38 (dd, 1H) 7.56 (d, 1H), 7.82 (d, 1H), 8.53 (s, 1H).
The preparation was effected analogously to Example 32 with 4-methoxybenzyl-magnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.46-1.79 (m, 7H), 1.91 (m, 1H), 2.17 (s, 1H), 2.52 (m, 1H), 2.81 (d, 1H), 3.50 (d, 1H), 3.80 (s, 3H), 6.85 (m, 2H), 7.12 (m, 2H), 7.44 (dd, 1H), 7.61 (d, 1H), 7.89 (d, 1H), 8.61 (s, 1H).
The preparation was effected analogously to Example 32 with 3-methoxybenzyl-magnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.46-1.72 (m, 7H), 1.87 (m, 1H), 2.20 (s, 1H), 2.49 (m, 1H), 2.80 (d, 1H), 3.50 (d, 1H), 3.69 (s, 3H), 6.75 (m, 3H), 7.19 (m, 1H), 7.40 (dd, 1H), 7.56 (d, 1H), 7.84 (d, 1H), 8.58 (s, 1H).
The preparation was effected analogously to Example 18, except using 3-fluorobenzyl-zinc chloride solution and N-(3-chloro-4-cyanophenyl)-2-cyclopentyl-2-oxoacetamide (see Example 32). 1H NMR (ppm, CDCl3, 400 MHz): 1.40-1.75 (m, 7H), 1.87 (m, 1H), 2.10 (s, 1H), 2.51 (m, 1H), 2.84 (d, 1H), 3.45 (d, 1H), 6.93 (m, 3H), 7.21 (m, 1H), 7.38 (m, 1H), 7.56 (d, 1H), 7.81 (d, 1H), 8.53 (s, 1H).
The preparation was effected analogously to Example 37 using 3-chlorobenzylzinc chloride solution. 1H NMR (ppm, CDCl3, 400 MHz): 1.41-1.75 (m, 7H), 1.89 (m, 1H), 2.09 (s, 1H), 2.52 (m, 1H), 2.81 (d, 1H), 3.40 (d, 1H), 7.04 (m, 1H), 7.19 (m, 3H), 7.39 (m, 1H), 7.56 (m, 1H), 7.80 (d, 1H), 8.51 (s, 1H).
The compound was obtained analogously to Example 32 by reacting N-(4-cyano-3-trifluoromethylphenyl)-2-cyclopentyl-2-oxoacetamide (obtained analogously to the corresponding compound with Cl substitents, 1H NMR (ppm, CDCl3, 400 MHz): 1.60-1.87 (m, 7H), 1.99 (m, 1H), 3.84 (m, 1H), 7.84 (d, 1H), 7.99 (dd, 1H), 8.16 (d, 1H), 9.12 (s, 1H)) with benzylmagnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.45-1.75 (m, 7H), 1.89 (m, 1H), 2.16 (s, 1H), 2.52 (m, 1H), 2.85 (d, 1H), 3.50 (d, 1H), 7.17 (dd, 2H), 7.28 (m, 3H), 7.74 (d, 1H), 7.82 (dd, 1H), 7.88 (d, 1H), 8.65 (s, 1H).
The preparation was effected analogously to Example 33. 1H NMR (ppm, CDCl3, 400 MHz): 1.48-1.72 (m, 7H), 1.89 (m, 1H), 2.18 (s, 1H), 2.28 (s, 3H), 2.49 (m, 1H), 2.81 (d, 1H), 3.48 (d, 1H), 7.06 (m, 4H), 7.75 (d, 1H), 8.86 (m, 2H), 8.67 (s, 1H).
The preparation was effected analogously to Example 34. 1H NMR (ppm, CDCl3, 400 MHz): 1.45-1.75 (m, 7H), 1.89 (m, 1H), 2.19 (s, 1H), 2.24 (s, 3H), 2.51 (m, 1H), 2.80 (d, 1H), 3.47 (d, 1H), 6.96 (m, 2H), 7.05 (d, 1H), 7.16 (m, 1H), 7.75 (d, 1H) 7.83 (dd, 1H), 7.88 (d, 1H), 8.66 (s, 1H).
The preparation was effected analogously to Example 35. 1H NMR (ppm, CDCl3, 400 MHz): 1.50-1.75 (m, 7H), 1.93 (m, 1H), 2.21 (s, 1H), 2.53 (m, 1H), 2.83 (d, 1H), 3.51 (d, 1H), 3.79 (s, 3H), 6.85 (m, 2H), 7.13 (d, 2H), 7.79 (d, 1H), 7.90 (dd, 1H), 7.95 (d, 1H), 8.73 (s, 1H).
The preparation was effected analogously to Example 36. 1H NMR (ppm, CDCl3, 400 MHz): 1.46-1.73 (m, 7H), 1.88 (m, 1H), 2.23 (s, 1H), 2.50 (m, 1H), 2.81 (d, 1H), 3.49 (d, 1H), 3.68 (s, 3H), 6.69-6.80 (m, 3H), 7.19 (dd, 1H), 7.74 (d, 1H), 7.84 (dd, 1H), 7.91 (d, 1H), 8.70 (s, 1H).
The compound was obtained analogously to Example 32 by reacting 2-cyclopentyl-N-(4-methyl-1-oxo-1H-benzo[d][1,2]oxazin-6-yl)-2-oxoacetamide (obtained analogously to the corresponding cyclohexyl compound from Example 15a), 1H NMR (ppm, CDCl3, 400 MHz): 1.71 (m, 4H), 1.82 (m, 2H), 2.01 (m, 2H), 2.61 (s, 3H), 3.86 (m, 1H), 7.84 (dd, 1H), 8.35 (d, 1H), 8.38 (d, 1H), 9.21 (s, 1H)) with benzylmagnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.50-1.80 (m, 7H), 1.96 (m, 1H), 2.25 (s, 1H), 2.59 (m, 1H), 2.63 (s, 3H), 2.93 (d, 1H), 3.57 (d, 1H), 7.21-7.43 (m, 5H), 7.61 (dd, 1H), 8.25 (d, 1H), 8.32 (d, 1H), 8.79 (s, 1H).
7.0 g of ethyl acetoxy(diethoxyphosphoryl)acetate were initially charged in 25 ml of THF, 1.06 g of lithium chloride were added and the mixture was cooled to 0° C. 3.1 ml of N,N,N′,N′-tetramethylguanidine were added dropwise and the mixture was stirred for 15 min. 2.46 g of tetrahydro-4H-pyran-4-one, dissolved in 10 ml of THF, were then added dropwise. The mixture was allowed to come to room temperature and stirred for 18 h. The mixture was partitioned between ethyl acetate and water, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. The residue was chromatographed on silica gel. 3.37 g of the desired intermediate were obtained as a yellowish liquid. 1H NMR (ppm, CDCl3, 400 MHz): 1.28 (t, 3H), 2.21 (s, 3H), 2.36 (t, 2H), 2.98 (t, 2H), 3.75 (m, 4H), 4.21 (q, 2H).
870 mg of acetoxy(tetrahydropyran-4-ylidene)acetic acid ethyl ester were added to 8 ml of 1M sodium hydroxide solution in 2:1 ethanol/water. The mixture was left to stir at room temperature for 15 min, then diluted with cold water, acidified with hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. 540 mg of oxo(tetrahydropyran-4-yl)acetic acid were obtained as a colourless crystalline solid. 1H NMR (ppm, CDCl3, 400 MHz): 1.77 (m, 2H), 1.89 (m, 2H), 3.45 (m, 1H), 3.56 (m, 2H), 4.07 (m, 2H), 8.76 (br s, 1H).
The preparation was effected analogously to the corresponding cyclohexyl compound (see above) from oxo(tetrahydropyran-4-yl)acetic acid, 4-cyano-3-trifluoromethylaniline and thionyl chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.75 (m, 2H), 1.85 (m, 2H), 3.55 (m, 2H), 3.68 (m, 1H), 4.05 (m, 2H), 7.86 (d, 1H), 7.98 (dd, 1H), 8.17 (d, 1H), 9.08 (s, 1H).
The preparation was effected analogously to Example 20 from N-(4-cyano-3-trifluoromethylphenyl)-2-oxo-2-(tetrahydropyran-4-yl)acetamide and benzyl-magnesium chloride. 1H NMR (ppm, CDCl3, 400 MHz): 1.45-1.87 (m, 4H), 2.19 (m, 1H), 2.25 (s, 1H), 2.88 (d, 1H), 3.40 (m, 2H), 3.46 (d, 1H), 4.01 (dd, 1H), 4.10 (dd, 1H), 7.17 (m, 2H), 7.28 (m, 3H), 7.75 (d, 1H), 7.82 (d, 1H), 7.88 (d, 1H), 8.64 (s, 1H).
Analogously to example 27, using the method used in example 19, the following compounds were prepared. Separation into the corresponding enantiomers was effected, where appropriate, by chiral HPLC:
Analogously to example 26, using the method used in example 28, the following compounds were prepared:
570 mg of N-(4-cyano-3-trifluoromethylphenyl)-2-cyclohexyl-2-hydroxy-3-(3-iodo-phenyl)propionamide (example 26) were suspended in a glass pressure tube together with 75 mg of dichlorobis(triphenylphosphine)palladium and 0.32 ml of triethylamine in 17 ml of methanol and 1 ml of DMSO. The mixture was degassed and placed under a carbon monoxide atmosphere. The pressure tube was then closed and heated to 100° C. The mixture was stirred for 16 h and cooled, and the pressure vessel was opened. The mixture was concentrated and purified by chromatography. This afforded 293 mg (59%) of the target product.
170 mg of the product obtained in step a) were initially charged in 6 ml of THF at RT and admixed with 0.25 ml of 1M lithium aluminum hydride solution in THF and stirred for 2 h. The reaction was ended by adding water. The mixture was extracted with ethyl acetate, washed with NaCl solution, dried with sodium sulfate and concentrated. This afforded 156 mg (98%) of the desired product.
156 mg of the product obtained in step b) were dissolved in 5 ml of dichloromethane and, at 0° C., 222 mg of Dess-Martin periodinane were added. After stirring for 2 h, the mixture was added to 1:1 sodium hydrogencarbonate solution/sodium thiosulfate solution and extracted with ethyl acetate, and the organic phases were washed with NaCl solution, dried with sodium sulfate and concentrated. This afforded 160 mg of crude product, which was converted further directly.
The product obtained in step c) was initially charged in 6 ml of dichloromethane, 60 μl of N,N,N′-trimethylethylenediamine were added and, after stirring at RT for 15 min, 170 mg of trisacetoxyborohydride were added in portions. After stirring for 16 h, the mixture was admixed with sodium hydrogencarbonate solution admixed (pH 9) and extracted with ethyl acetate, and the organic phases were washed with water and NaCl solution, dried with sodium sulfate and concentrated. This afforded 170 mg of crude product, which was purified by chromatography. The resulting purified racemate was separated into the enantiomers by means of chiral HPLC (Chiralcel OD-H 5μ, 250×20 mm, 99:1 hexane (0.1% DEA)/ethanol, 25 ml/min).
Example 79a: Rt=17.5-21.4 min
Example 79b: Rt=23.0-27.4 min
1H NMR (ppm, d6-DMSO, 400 MHz): 1.02-1.29 (m, 3H), 1.45 (m, 1H), 1.58 (m, 1H), 1.65 (m, 1H), 1.76 (m, 2H), 1.92 (m, 1H), 2.05 (m, 6H), 3.23 (m, 3H), 2.87 (d, 1H), 2.99 (d, 1H), 3.23 (m, 2H), 5.44 (s, 1H), 6.96 (m, 1H), 7.06 (m, 3H), 7.95 (d, 1H), 8.06 (dd, 1H), 8.80 (d, 1H), 9.89 (s, 1H). LCMS (ESI+): m/z=531 (M+1).
This reaction sequence can be carried out analogously beginning with the corresponding 2-iodo or 4-iodo compounds.
Analogously to example 79, a multitude of different amines can be used in the reductive amination in step d). The following example compounds were prepared:
a) 250 mg of the methyl ester obtained in example 79a) were dissolved in 5 ml of 1:1 THF/water and 125 mg of LiOH were added. The mixture was stirred at RT for 16 h, water was added, and the mixture was adjusted to pH 4 with 2M HCl, extracted with ethyl acetate, washed with NaCl solution, dried with sodium sulfate and concentrated. The crude product was recrystallized from dichloromethane and converted further directly.
b) 50 mg of the acid obtained in a), 30 mg of benzoylpiperazine and 0.05 ml of triethylamine were dissolved in 6 ml of DMF, and 46 mg of the coupling reagent HATU were added. The mixture was stirred at RT for 16 h, water was added, and the mixture was extracted with ethyl acetate, washed with NaCl solution, dried with sodium sulfate and concentrated. The crude product was chromatographed on amino phase. This afforded 20 mg of the desired product.
LCMS: ES+: m/z=633 (M+1), ES−: m/z=631 (M−1)
Analogously, further examples can be prepared using various amine components.
1.2 g of 1-methyl-1H-pyrrole-2-carbonitrile were dissolved in 7 ml of acetic anhydride. At 0° C., a mixture of 1 ml of fuming nitric acid and 2 ml of acetic anhydride was added dropwise at such a rate that the internal temperature did not rise above 1° C. After 2 h, the mixture was added to 25 ml of ice-water, extracted with diethyl ether and ethyl acetate, dried with sodium sulfate and concentrated. The crude product was purified by chromatography. This afforded 170 mg of the desired isomer: 1H NMR (ppm, d6-DMSO, 400 MHz): 3.98 (s, 3H), 7.12 (d, 1H), 7.27 (d, 1H); and 260 mg of 4-nitro-1-methyl-1H-pyrrole-2-carbonitrile 1H NMR (ppm, d6-DMSO, 400 MHz): 3.79 (s, 3H), 7.67 (s, 1H), 8.31 (s, 1H).
200 mg of 5-nitro-1-methyl-1H-pyrrole-2-carbonitrile were dissolved in 6 ml of ethyl acetate, 140 mg of palladium (10% on activated carbon) were added and hydrogenation was effected at RT and 1 atm of hydrogen pressure. The catalyst was filtered off and the solution was concentrated. This afforded 160 mg of the desired product. 1H NMR (ppm, CDCl3, 400 MHz): 2.85 (s br, 2H), 3.65 (s, 3H), 6.29 (d, 1H), 6.35 (d, 1H);
116 mg of cyclohexyloxoacetic acid and 90 mg of 5-amino-1-methyl-1H-pyrrole-2-carbonitrile were converted analogously to the preparation of N-(3-chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (see above) to N-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-cyclohexyl-2-oxoacetamide. Yield 125 mg (65%).
107 mg of the keto amide obtained in step c) were reacted analogously to example 20 with benzylmagnesium chloride. This afforded 97 mg (90%) of the desired product. 1H NMR (ppm, CDCl3, 400 MHz): 1.10-1.36 (m, 5H), 1.65-1.86 (m, 5H), 1.99 (m, 1H), 2.87 (d, 1H), 3.42 (d, 1H), 3.73 (s, 3H), 6.42 (m, 1H), 7.16 (m, 2H), 7.26 (m, 3H), 7.41 (m, 1H), 8.13 (s, 1H).
Analogously to example 97, the sequence can also be carried out with the 4-nitro-1-methyl-1H-pyrrole-2-carbonitrile obtained in step a) of example 97. 1H NMR (ppm, CDCl3, 400 MHz): 1.10-1.39 (m, 5H), 1.60-2.03 (m, 5H), 2.23 (m, 1H), 2.85 (d, 1H), 3.35 (d, 1H), 3.74 (s, 3H), 5.95 (m, 1H), 6.70 (d, 1H), 6.80 (m, 3H), 7.21 (m, 1H), 7.26 (m, 1H), 8.10 (s, 1H).
26.15 g of ethyl acetoxy(diethoxyphosphoryl)acetate were initially charged in 130 ml of THF, 3.93 g of lithium chloride were added and the mixture was cooled to 0° C. 12 ml of N,N,N′,N′-tetramethylguanidine were added dropwise and the mixture was stirred for 15 min. Then 14 g of 1-(tert-butyloxycarbonyl)-4-piperidinone, dissolved in 60 ml of THF, were added dropwise. The mixture was allowed to come to room temperature and was stirred for 18 h. The mixture was partitioned between ethyl acetate and water, and the phases were separated and extracted with ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated. The residue was chromatographed on silica gel. This afforded 22.5 g of the desired intermediate as a colorless oil. 1H NMR (ppm, CDCl3, 400 MHz): 1.27 (t, 3H), 1.45 (s, 9H), 2.20 (s, 3H), 2.32 (dt, 2H), 2.91 (dt, 2H), 3.47 (m, 4H), 4.20 (q, 2H).
22.5 g of tert-butyl 4-(acetoxyethoxycarbonylmethylene)piperidine-1-carboxylate were added to 140 ml of 1M sodium hydroxide solution in 2:1 ethanol/water. The mixture was left to stir at room temperature for 30 min, then diluted with 1.4 l of cold water, acidified with hydrochloric acid (pH 3-4), extracted with ethyl acetate and with dichloromethane/methanol, then acidified to pH 2-3 and extracted again with dichloromethane/methanol. The combined organic phases were dried with sodium sulfate and concentrated. This afforded 16.9 g of tert-butyl 4-oxalylpiperidine-1-carboxylate as a colorless solid. LCMS: m/z (ES−)=256 (M−1).
16.9 g of tert-butyl 4-oxalylpiperidine-1-carboxylate were initially charged in 500 ml of dimethylacetamide and 8.6 ml of thionyl chloride were added dropwise at 0° C. After 30 min, 12.23 g of 5-amino-2-cyanobenzotrifluoride were added and the mixture was stirred at RT for 18 h. The mixture was added slowly and with vigorous stirring to 1.8 l of water and stirred for a further 2.5 h. The crystals were filtered off and dried in a vacuum drying cabinet. This afforded 21.5 g of the desired keto amide. 1H NMR (ppm, d6-DMSO, 400 MHz): 1.30 (m, 4H), 1.36 (s, 9H), 1.82 (m, 2H), 3.45 (m, 1H), 3.92 (m, 2H), 8.13 (d, 1H), 8.24 (dd, 1H), 8.48 (d, 1H), 11.22 (s, 1H).
4.2 g of tert-Butyl 4-(4-cyano-3-trifluoromethylphenylaminooxalyl)piperidine-1-carboxylate were initially charged in 129 ml of THF under Ar and, at 0° C., 14 ml of a 2 molar benzylmagnesium bromide solution in THF were added dropwise. The mixture was allowed to thaw to RT and stirred for a further 14 h. The reaction was ended by adding ammonium chloride solution. The mixture was partitioned between ethyl acetate and water, and the phases were separated and extracted with ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated. Recrystallization from dichloromethane afforded the desired product in approx. 70% yield. 1H NMR (ppm, CDCl3, 400 MHz): 1.45 (s, 9H), 1.57 (m, 2H), 1.91 (m, 1H), 2.29 (m, 1H), 2.70 (m, 2H), 2.88 (d, 1H), 3.48 (d, 1H), 4.22 (m, 2H), 4.71 (s, 1H), 7.15 (m, 3H), 7.28 (m, 2H), 7.74 (d, 1H), 7.79 (dd, 1H), 7.88 (d, 1H), 8.63 (s, 1H).
5 g of tert-butyl rac-4-[1-(4-cyano-3-trifluoromethylphenylcarbamoyl)-1-hydroxy-2-phenylethyl]piperidine-1-carboxylate were dissolved in 120 ml of dichloromethane, 20 ml of trifluoroacetic acid were added dropwise and the mixture was stirred for 16 h. The mixture was added to sodium carbonate solution/ice, adjusted to pH 8 with potassium carbonate and extracted with dichloromethane. The organic phases were dried with sodium sulfate and concentrated. This afforded 4.8 g of the racemic product, which was separated into the enantiomers by means of chiral HPLC (Chiralcel OD-H 5μ, 250×20 mm, 9:1 hexane/ethanol).
Example 100a: Rt=9.4-11.4 min; [α]D20=+70.50 (MeOH, c=0.46)
Example 100b: Rt=12.6-14.3 min; [α]D20=−74.0° (MeOH, c=0.47)
1H NMR (ppm, d6-DMSO, 400 MHz): 1.57 (m, 3H), 2.00 (m, 2H), 1.81 (m, 2H), 2.91 (d, 1H), 3.04 (d, 1H), 3.30 (m, 2H), 5.89 (s, 1H), 7.13 (m, 5H), 8.00 (d, 1H), 8.07 (dd, 1H), 8.27 (d, 1H), 10.02 (s, 1H).
180 mg of rac-N-(4-cyano-3-trifluoromethylphenyl)-2-hydroxy-3-phenyl-2-piperidin-4-ylpropionamide were initially charged at 0° C. in 9 ml of dichloromethane and admixed with 0.12 ml of triethylamine, and 0.06 ml of benzoyl chloride was added dropwise. The mixture was allowed to come to RT and was stirred for approx. 14 h. The reaction was ended by adding sodium hydrogencarbonate solution, the phases were separated, the aqueous phase was extracted with dichloromethane and the combined organic phases were dried with sodium sulfate and concentrated. The crude product was recrystallized from diisopropyl ether/dichloromethane/hexane. The resulting 90 mg of racemate were separated by means of chiral HPLC into the enantiomers (Chiralpak IA 5μ 250×20 mm, 8:2 hexane/ethanol, 25 ml/min).
Example 101a: Rt=9.9-11.4 min
Example 101b: Rt=11.6-14.2 min
1H NMR (ppm, CDCl3, 400 MHz): 1.58 (m, 3H), 2.00 (m, 1H), 2.25 (m, 1H), 2.90 (d, 1H), 2.90 (m, 2H), 3.30 (m, 1H), 3.35 (d, 1H), 3.88 (m, 1H), 7.14 (m, 2H), 7.22 (m, 3H), 7.37 (m, 5H), 7.70 (m, 2H), 7.80 (s, 1H), 8.61 (s, 1H).
Analogously, by reaction of N-(4-cyano-3-trifluoromethylphenyl)-2-hydroxy-3-phenyl-2-piperidin-4-ylpropionamide with the appropriate carbonyl chloride or sulfonyl chloride, the following compound were prepared and, where appropriate, separated into the enantiomers:
3.5 g of tert-butyl 4-(4-cyano-3-trifluoromethylphenylaminooxalyl)piperidine-1-carboxylate (for preparation see above) were dissolved under Ar at −75° C. in 150 ml of THF, then 50 ml of a 0.5 M solution of 3-iodobenzylzinc bromide in THF were added dropwise and the mixture was thawed overnight. The reaction was ended with ammonium chloride solution and diluted with ethyl acetate, the phases were separated, the aqueous phase was extracted with ethyl acetate, and the organic phases were washed with NaCl solution and dried with sodium sulfate. The crude product was purified by chromatography. This afforded 2.32 g of a pale yellowish solid, which was separated into the enantiomers by means of chiral HPLC (Chiralpak IA 5μ, 250×30 mm, 9:1 hexane/ethanol, 40 ml/min)
Example 127a: Rt=8.6-9.5 min; [α]D20=−38.0° (MeOH, c=1.03)
Example 127b: Rt=9.6-10.7 min; [α]D20=+19.4° (MeOH, c=0.48)
1H NMR (ppm, d6-DMSO, 400 MHz): 1.35 (s, 9H), 1.38 (m, 3H), 1.80 (m, 1H), 1.95 (m, 1H), 2.58 (m, 2H), 2.83 (d, 1H), 2.97 (d, 1H), 3.98 (m, 2H), 5.72 (s, 1H), 6.93 (m, 1H), 7.15 (d, 1H), 7.40 (d, 1H), 7.54 (s, 1H), 7.99 (d, 1H), 8.04 (d, 1H), 8.26 (s, 1H), 9.97 (s, 1H).
Analogously, by reaction with 2-iodobenzylzinc bromide or 4-iodobenzylzinc bromide, the corresponding ortho- and para-iodo compounds can be obtained:
The reaction was effected analogously to example 100. One hour of reaction time was sufficient.
LCMS: m/z=544 (ES+, M+1); 542 (ES−, M−1)
The corresponding 2-iodo and 4-iodo compounds are obtained analogously.
The reaction was effected analogously to example 101. 1.77 g of amine afforded 1.9 g (90%) of the desired product. 1.1 equivalents of benzoyl chloride were used.
LCMS: m/z=648 (ES+, M+1); 646 (ES−, M−1)
100 mg of 2-(1-benzoylpiperidin-4-yl)-N-(4-cyano-3-trifluoromethylphenyl)-2-hydroxy-3-(3-iodophenyl)propionamide and 26 mg of (3-aminocarbonylphenyl)boronic acid were initially charged in 2 ml of 1:1 toluene/ethanol, admixed with 0.15 ml of 2M sodium carbonate solution and 18 mg of tetrakis(triphenylphosphine)palladium and irradiated in a microwave at 150 W/120° C. for 30 min. Thereafter, the mixture was partitioned between water and ethyl acetate, filtered together and then the phases were separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were washed with sat. NaCl solution, dried with sodium sulfate and concentrated. The crude product was purified by chromatography. This afforded 37 mg (38%) of the desired product as a colorless solid.
1H NMR (ppm, CDCl3, 400 MHz): 1.45-1.70 (m, 3H), 1.83-2.02 (m, 1H), 2.29-2.39 (m, 1H), 2.73-2.87 (m, 1H), 2.98 (d, 1H), 2.96-3.09 (m, 1H), 3.18 (d, 1H), 3.75-3.90 (m, 1H), 4.72-4.89 (m, 1H), 6.21 (s br, 1H), 6.77 (s br, 1H), 7.12-7.20 (m, 2H), 7.36 (m, 5H), 7.39-7.44 (m, 1H), 7.48-7.72 (m, 6H), 7.78 (s, 1H), 8.05 (s, 1H), 8.85 (s, 1H).
LCMS: m/z=641 (ES+, M+1); 639 (ES−, M−1)
By reaction of N-(4-cyano-3-trifluoromethylphenyl)-2-hydroxy-3-(3-iodophenyl)-2-piperidin-4-ylpropionamide (example 130) with a multitude of carbonyl chlorides and sulfonyl chlorides, it was possible using the process described in example 131 to prepare appropriate starting compounds for Suzuki reactions, which were converted analogously to example 132. Alternatively, a changeover of the reaction sequence was also possible. In this case, the Suzuki reaction (analogously to example 132) was carried out on the Boc-protected intermediate (analogously to example 127), which was followed by Boc-deprotection (analogously to example 130) and acylation or sulfonamide formation analogously to example 131. The enantiomers, which were pure in each case, were obtained by preparative chiral HPLC of the end compound or by performing the reaction sequence with material already separated at the stage of example 127.
The following further example compounds were prepared.
The compound was prepared analogously to example 99, beginning with 4,4-difluoro-cyclohexanone and separated into the enantiomers by means of chiral HPLC (Chiralpak AD-H 5μ, 250×20 mm, 8:2 hexane/ethanol, 25 ml/min).
Example 198a: Rt=5.1-6.1 min
Example 198b: Rt=7.1-8.1 min
1H NMR (ppm, CDCl3, 400 MHz): 1.57-2.25 (m, 9H), 2.90 (d, 1H), 3.48 (d, 1H), 7.16 (m, 2H), 7.29 (m, 3H), 7.75 (d, 1H), 7.80 (dd, 1H), 7.88 (d, 1H), 8.63 (s, 1H).
The compound was prepared analogously to example 99, beginning with 4-trifluoromethylcyclohexanone and separated into the isomers by means of chiral HPLC (Chiralpak IA 5μ, 250×20 mm, 9:1 hexane/ethanol, 25 ml/min). LCMS (ESI+) m/z=485 (M+1).
300 mg of N-(4-cyano-3-trifluoromethylphenyl)-2-cyclohexyl-2-hydroxy-3-(3-methoxy-phenyl)propionamide (example 24) were dissolved in 20 ml of dichloromethane and, at −10° C., 2 ml of tribromoborane were added dropwise. The mixture was left to stir at RT for 16 h, then the mixture was added to ice-water, extracted with ethyl acetate, washed with water and NaCl solution, dried with sodium sulfate and concentrated. The crude product was purified by chromatography (yield: 150 mg, 52%). The racemate was separated into the enantiomers by means of chiral HPLC (Chiralpak IA 5μ, 250×20 mm, 85:15 hexane/ethanol, 25 ml/min).
Example 200a: Rt=7.6-8.8 min; [α]D20=+116.5° (CHCl3, c=0.34)
Example 200b: Rt=9.9-11.5 min; [α]D20=−122.5° (CHCl3, c=0.43)
1H NMR (ppm, CDCl3, 400 MHz): 1.14 (m, 2H), 1.29 (m, 3H), 1.68 (m, 2H), 1.78 (m, 1H), 1.88 (m, 2H), 1.99 (m, 1H), 2.85 (d, 1H), 3.37 (d, 1H), 5.14 (s, 1H), 6.69 (m, 3H), 7.13 (dd, 1H), 7.78 (d, 1H), 7.82 (dd, 1H), 7.89 (d, 1H), 8.69 (s, 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.
The entire disclosures of all applications, patents and publications, cited herein and of corresponding European application No. 07076093.9, filed Dec. 14, 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.
| Number | Date | Country | Kind |
|---|---|---|---|
| 07076093.9 | Dec 2007 | EP | regional |
This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 61/006,015 filed Dec. 14, 2007.
| Number | Date | Country | |
|---|---|---|---|
| 61006015 | Dec 2007 | US |
