Patent Application
20130131034
The instant invention relates to derivatives of aminoindanes, to their preparation and to their application in therapeutics.
Transient receptor potential cation channel, subfamily C, member 6, also known as TRPC6, is a human gene encoding a protein of the same name. TRPC6 has been associated with fibrotic disorders, such as focal segmental glomerulosclerosis (a) Winn et al, Science 2005, 308, 1801-1804. b) Hsu et al., Biochim. Biophys. Acta, Molec. Basis of Disease 2007, 1772, 928-936. c) Kriz, Trends Molec. Med. 2005, 11, 527-530. d) Winn et al, J. Amer. Soc. Nephrol. 2005, 17, 378-387), skeletal muscle dysfunction (Millay et al., PNAS 2009, 106, 19023-19028), renal failure, atherosclerosis, heart failure (Kuwahara et al., J. Clin. Invest. 2006, 116, 3114-26), cancer (e.g. oesophageal cancer, breast cancer) (a) Aydar et al., Cancer Cell Int. 2009, 9, 23. b) Cai et al., Int. J. Cancer. 2009, 125, 2281-2287. c) Shi et al., Gut 2009, 58, 1443-1450), chronic obstructive pulmonary disease (Sel et al., Clin. Exp. Allergy. 2008, 38, 1548-1558), pain (Alessandri-Haber et al., J. Neurosci. 2009, 29, 6217-6228), pulmonary hypertension (Yu et al., Circulation 2009, 119, 2313-2322), ischemic stroke, myocardial infarction (Varga-Szabo et al., J. Thromb. and Haemost. 2009, 7, 1057-1066), inflammation or peripheral arterial occlusive disease.
It is thus desirable to provide novel TRPC6 inhibitors for the prevention or treatment of these pathologies.
The compounds according to the instant invention respond to the general formula (I):
in which
6 to 10 membered aryl radicals,
of 5 to 10 membered heteroaryl radicals,
of 3 to 10 membered cycloalkyl radicals,
of 9 to 14 membered cycloalkylaryl radicals,
of 8 to 14 membered cycloalkylheteroaryl radicals,
of 3 to 10 membered cycloheteroalkyl radicals,
of 9 to 14 membered cycloheteroalkylaryl radicals and
of 8 to 14 membered cycloheteroalkylheteroaryl radicals,
(═O), Cl, Br, I and R10;
6 to 10 membered aryl radicals,
of 5 to 10 membered heteroaryl radicals,
of 3 to 10 membered cycloalkyl radicals,
of 9 to 14 membered cycloalkylaryl radicals,
of 8 to 14 membered cycloalkylheteroaryl radicals,
of 3 to 10 membered cycloheteroalkyl radicals,
of 9 to 14 membered cycloheteroalkylaryl radicals and
of 8 to 14 membered cycloheteroalkylheteroaryl radicals,
(═O), Cl, Br, I and R10;
The compounds of formula (I) can comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.
The compounds of formula (I) can be provided in the form of a free base or in the form of addition salts with acids, which also form part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids, but salts with other acids, useful for example for the purification or for the isolation of the compounds of formula (I), also form part of the invention.
The compounds of formula (I) can also be provided in the form of an hydrate or of a solvate, i.e. in the form of associations or combinations with one or more water or solvent molecules. Such hydrates and solvates also form part of the invention.
According to the present invention, the terms below have the following meanings:
(C1-C9)-Heteroaryl radicals are aromatic ring compounds in which one or more ring atoms are oxygen atoms, sulfur atoms or nitrogen atoms, e.g. 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms or a combination of various heteroatoms. This also applies when they carry substituents or occur as substituents of other radicals. The heteroaryl radicals may be attached by all positions. Heteroaryl means for example furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and cinnolinyl.
Preferred heteroaryl radicals are 2- or 3-thiophenyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-oxadiazol-2-yl or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl.
Particularly preferred heteroaryl radicals are pyrazolyl, isoxasolyl, benzotriazolyl;
A cycloheteroalkyl corresponds to a cyclic group comprising between 3 and 19 carbon atoms and between 1 and 3 heteroatoms, preferably nitrogen atoms.
The compounds of the invention advantageously respond to the general formula (II):
in which:
in the form of a free base or of an addition salt with an acid, as well as in the form of an hydrate or of a solvate as appropriate.
The compounds of the invention advantageously respond to the general formula
in which A, B′, B″, T, T′, T″, R1, R3, R4, R5, X, L and q are as defined above for compounds of formula (II), in the form of a free base or of an addition salt with an acid, as well as in the form of an hydrate or of a solvate.
Among the compounds of formula (I) according to the instant invention, the following compounds may be cited, in the same order as for the compounds depicted in the table hereafter, illustrating some examples of compounds:
A protecting group Pg, as mentioned hereafter, corresponds to a group which enables, on the one hand, the protection of a reactive function such as an hydroxy or an amine during a synthesis step and, on then other hand, to recover the intact reactive function at the end of the synthesis step. Examples of protecting groups, as well as methods for protecting and deprotecting various functional groups, are given in <<Protective Groups in Organic Synthesis>>, Green et al., 2nd Edition (John Wiley & Sons, Inc., New York).
A leaving group, as mentioned hereafter, corresponds to a group which may easily be cleaved from a molecule by breaking a heterolytic bond, with departure of electronic pair. This group may then easily be replaced by another functional group during a substitution reaction, for example. Such leaving groups may consist in halogen atoms or activated hydroxy groups, such as mesylate, tosylate, triflate or acetyl groups, etc. Examples of leaving groups, as well as references relating to their preparation, are given in <<Advances in Organic Chemistry>>, J. March, 3rd Edition, Wiley Interscience, p. 310-316.
General processes suitable for preparing compounds of the general formula I are described below. The compounds of the formula I can in this connection be prepared by different chemical processes. The groups and radicals A, B, L, X, R1, R2, R3, R4 and R5 and index p mentioned in the following methods have the abovementioned meaning unless they are explicitly defined otherwise.
Abbreviations:
HPLC high performance liquid chromatography
LC liquid chromatography
Rt retention time
THF tetrahydrofuran
TFA trifluoroacetic acid
DMSO dimethyl sulfoxide
DMF dimethylformamide
AcN acetonitrile
RT room temperature
min. minutes
h hour(s)
ES=ESI electrospray ionization
MS Mass Spectroscopy
HCl Hydrochloric acid
EtOAc Ethyl acetate
m multiplet
bs broad singlet
s singlet
Method A:
For example, as shown in scheme A that starting from epoxides of the formula II which initially, after epoxide ring opening with an amine of the formula HNR3R4, afford a corresponding 1-amino 2-ol intermediate of the formula III, which is subsequently subjected to a Mitsunobu reaction with an aryl or heteroaryl compounds B—OH which may be substituted one or more times by R5. Phenols are preferably employed in this reaction. It is also possible alternatively to employ aryl or heteroaryl thiols B—SH or aryl- or heteroarylcarboxylic acids B—CO2H which may be substituted one or more times by R5 in order to obtain the corresponding —S— or —CO2H— bridged derivatives. Mitsunobu reactions are, as is known, carried out in the presence of a phosphine, e.g. such as triphenylphosphine and of azodicarboxylic esters such as, for example, diisopropyl azodicarboxylate in inert solvents such as acetonitrile, CH2Cl2 or tetrahydrofuran. In the case of 1-amino 2-ols of the formula III, this entails migration of the amine residue NR3R4 into position 2 of the basic structure (J. Org. Chem. 1991, 56, 670-672).
in which L is a covalent bond, —C(═O)— and X is O,
or L is a covalent bond and X is S.
It is possible in this way to prepare a large number of compounds I, preferably those in which the two substituents are in a trans configuration relative to one another. If one of the radicals R3 and R4 of the amine substituent is to be replaced by a further functional group such as, for example, a hydroxy group or an amino group, care must be taken where appropriate to protect such groups during the Mitsunobu reaction. This can take place for example by trialkyl or triarylsilyl groups in the case of OH groups or by the BOC protective groups in the case of amino groups. After the Mitsunobu reaction, the protective group is then removed again, for example by treatment with hydrochloric acid or trifluoroacetic acid, to obtain the compounds of the formula I. After deprotection, these functional groups can be further modified where appropriate, for example by alkylation with an alkylating agent or by acylation and subsequent reduction in order to obtain further compounds I.
The starting materials employed in scheme A, such as the epoxides of the formula II, the amine NHR3R4, and the hydroxyaryls or hydroxyheteroaryls or the thiol derivatives thereof are either commercially available, known from the literature or can be synthesized easily in analogy to compounds known from the literature. A few suitable synthetic schemes for such starting materials are reproduced by way of example in the experimental section.
Method B:
A further method for preparing compounds of the formula I is depicted in scheme B.
In this process, 2-bromo 1-one compounds of the formula IV are reacted with amines of the formula R3-NH—R4 to give the corresponding amino ketones V. The keto group is then reduced to the 1-hydroxy group, resulting in the intermediates of the formula VI. It is possible in this connection for products VI with both the cis and the trans configuration with regard to centers 1 and 2 to be produced. The resulting intermediates of the formula VI are then arylated by nucleophilic aromatic substitution on aryl or heteroaryl compounds B—Y, where B may be substituted one or more times by R5, using a strong base such as, for example, sodium hydride or powdered NaOH in an inert solvent such as DMSO. Y is in this connection a suitable leaving group such as, for example, fluorine, chlorine or trifluoromesyloxy. If the radicals R3 and R4 are substituted for example by amino or hydroxy groups, these should be protected where appropriate by base-stable protective groups such as, for instance, alkyl- or aryl-substituted silyl groups.
It is also possible with this process to have recourse to a large extent to known or commercially available bromo ketones IV or can easily be obtained for example by bromination under standard conditions from the appropriate ketones.
Method C:
A further process relates to those compounds of the formula I in which the amine group NR3R4 is linked via a carbon-containing bridge to position 2, that is q is 1 in general formula I.
In this case, ketones of the formula VII are reacted with formamide acetals, preferably N,N-dimethylformamide dimethyl acetal, in order to obtain the corresponding dimethylaminomethylene compounds of the formula VIII. The dimethylamino group can be replaced in the next stage by other amino groups to give aminomethylene compounds of the formula IX. This can take place for example by heating compounds of the formula VIII in DMF in the presence of excess amine HNR3R4. Subsequent reduction, for example by sodium borohydride in methanol, ordinarily affords mixtures of stereoisomeric amine alcohols of the formula X which can, where appropriate after separation into the individual components, be arylated in analogy to the illustration in scheme B to give the compounds I of the invention.
Method D:
A further process for preparing compounds of the formula I is depicted in scheme D. Benzoic esters I which are synthesized as in scheme A are hydrolyzed in a known manner to give compounds of the general formula VI. This takes place for example in solvents such as acetone/water mixtures and using suitable bases such as sodium hydroxide. Compounds of the formula VI are then reacted with suitable alkylating agents such as, for example, benzyl bromides in solvents such as, for example, THF in the presence of suitable bases such as sodium hydride. The compound I obtained in this way is available where appropriate for further manipulations.
in which L is an alkylene bridge.
If the compounds I contain further functional groups such as, for example, alcohols or amines, these can be reacted further in a known manner as in scheme E. Suitable examples are acylations, alkylations or acylation/reduction sequences. The procedure is described in the experimental section by means of exemplary embodiments.
Method E:
A further process relates to those compounds of the formula I in which one or two substituents R3 or R4 at the amine group NR3R4 equals hydrogen, that is R3=H or R3=R4=H in general formula I.
In this process, allyl amines XI, which for example can be synthesized following method A, are deprotected using nucleophiles, e.g. such as thiosalicylic acid or dimethylbarbituric acid, in inert solvents such as CH2Cl2 or THF. The reaction is catalyzed by Pd. Suitable Pd sources are for example Pd(PPh3)4 or Pd(dba)2 in the presence of stabilizing ligands such as bis(diphenylphosphino)butane. In case of bisallyl amines (R3=R4=allyl) both allyl groups can be cleaved using at least 2 equivalents of a suitable nucleophile and prolonged reaction times. Compounds of the general formula I, which are synthesized following method F, are available for further manipulations e.g. acylation or alkylation.
The following examples describe the synthesis of some compounds according to the invention. These examples are not intended to be limitative and only illustrate the present invention. The numbers of the exemplified compounds refer to those in the table given later, which illustrate the chemical structures and the physical properties of a number of compounds according to the invention.
LC/MS spectra were recorded according to the following methods.
A mixture of 1.00 eq. (20.2 mmol, 4.79 g) 2-bromo-5-chloro-indane-1-one, 1.20 eq. (24.2 mmol, 5.00 g) (R)-3-N-Boc-aminopiperidine and 1.60 eq. (32.0 mmol, 4.47 g) potassium carbonate in 150 ml acetone is stirred at RT for 2 h. After addition of 100 ml of water and 100 ml of EtOAc the layers are separated and the aqueous layer is extracted with EtOAc. The combined organic layers are dried with anhydrous MgSO4, filtered, concentrated under reduced pressure and the residue is used in the next step without further purification.
[(R)-1-(cis-5-chloro-1-keto-indan-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester is dissolved in 150 ml dry THF and 1.50 eq. (30.0 mmol, 30.0 ml of 1 M solution) of L-selectride is added at 0° C. with stirring. The mixture is allowed to warm up to RT and stirring is continued for 2 days. 150 ml water and 150 ml EtOAc are added, the layers are separated and the aqueous layer is extracted with EtOAc. After drying, filtering and concentrating under reduced pressure the combined organic layers, the residue is dissolved in 100 ml THF at 0° C. and 5 ml H2O2 (35%) and NaOH (10 ml, 4N) are added. After 2 h at 0° C., water (100 ml) and EtOAc (100 ml) are added. The aqueous layer is extracted with EtOAc. The combined organic layers are dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue is purified via chromatography on silica gel (EtOAc as eluent) to yield the title compound.
[(R)-1-(cis-5-chloro-1-hydroxy-indan-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester (0.1 mmol), 1-chloro-2-(chloromethyl)-4-fluorobenzene (0.2 mmol) and Ag2O (0.5 mmol) are stirred in 2.5 ml dry toluene for 3 h at 85° C. The cooled reaction mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is dissolved in DMF and subjected to preparative HPLC purification.
The purified product is taken up in 1 ml TFA/CH2Cl2 (1/9) and shaken for 1 h at RT, then evaporated (12 mbar, 40° C. over night in a drying cabinet) to afford the desired product: LCMS (ESI) M+ 409.2537.
In a three-neck round bottom flask is introduce NaOCl (50.4 ml, 0.31 eq., 2N). The flask is then flushed with argon and cooled to 0° C. A solution of (R,R)—N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride (2.06 g, 0.01 eq.) and 4-(3-phenylpropyl)pyridine-N-oxide (2.08 g, 0.03 eq.) in CH2Cl2 (166 ml) is added. The suspension is stirred for 15 min. To the cooled solution is added simultaneously via two addition funnels NaOCl (152 ml, 0.93 eq., 2N) and a solution of indene (37.85 g, 1 eq.) in CH2Cl2 (107 ml). The mixture is then stirred at 0° C. for 1 h and the temperature is let warmed up to RT over night. The suspension is diluted with water and CH2Cl2 and filtered through Celite®. The aqueous layer is separated and extracted three times with CH2Cl2. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 18.64 g (43%) of the desired compound as a yellow oil, used in the next step without further purification.
To a solution of (1aR,6aS)-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (6 g, 1.00 eq.) in AcN (122 ml) is added tert-butyl (3R)-piperidin-3-ylcarbamate (12.27 g, 1.35 eq.). The solution is brought to reflux and heated overnight. After cooling, the solvents are evaporated under reduced pressure and the residue is purified by column chromatography (Heptane/EtOAc, 100/0 to 70/30) to afford 12.3 g (82%) of the desired product as a solid.
Tert-butyl {(3R)-1-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]piperidin-3-yl}carbamate (3.0 mmol), 2-(2H-benzotriazol-2-yl)-4-methylphenol (3.3 mmol) and triphenylphosphin (5.2 mmol) are dissolved in THF under Argon, then diisopropylazodicarboxylate (4.5 mmol) is added and the mixture is stirred over night at RT. After evaporation of the solvent, the crude product is stirred in 15% TFA in DCM at RT over night. The solvent is evaporated under reduced pressure and the residue is purified by preparative HPLC to afford the desired compound: 1H NMR (500 MHz, DMSO-d6) δ 8.20 (bs, 2H), 8.05-7.90 (m, 2H), 7.65-7.40 (m, 5H), 7.35-7.15 (m, 4H), 6.25 (s, 1H), 3.90 (s, 1H), 3.40-2.95 (m, 5H), 2.85-2.55 (m, 2H), 2.38 (s, 3H), 2.00-1.83 (m, 2H), 1.70-1.55 (m, 1H), 1.52-1.40 (m, 1H); LCMS (ESI) M+ 440.2551.
The title compound is prepared following the method used for example 2.
The title compound is prepared following the method used for example 2.
Tert-butyl {(3R)-1-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]piperidin-3-yl}carbamate (0.10 mmol), 3-chloro-4-hydroxybenzonitrile (0.12 mmol) and polymer-bound PPh3 (Argonaut, 0.25 mmol) in 2.5 ml THF are treated with di-isopropyl azodicarboxylate (0.2 mmol). The mixture is stirred over night at RT then filtered on Celite®. The filter is washed with CH2Cl2. The filtrate is evaporated under reduced pressure. The residue is purified by column chromatography (CH2Cl2/methanol, 100/0 to 90/10) and then dissolved in CH2Cl2 and treated with HCl (1 ml, 2N in Et2O). The precipitate is filtered and dried under reduced pressure to afford the desired compound as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.50 (bs, 2H), 8.18 (s, 1H), 8.05-7.95 (m, 1H), 7.83-7.75 (m, 1H), 7.50-7.40 (m, 2H), 7.32-7.28 (m, 1H), 7.15-7.12 (m, 1H), 6.75 (bs, 1H), 4.18-4.12 (m, 1H), 3.45-3.40 (m, 7H), 1.94-1.90 (m, 4H); LCMS (ES) M+ 368; [αD]=−215.5° (CH3OH); mp=221.3° C.
To a cooled solution (0° C.) of 6-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (2.50 g, 1 eq.) in THF (48 ml) and methanol (10 ml) is added sodium borohydride (0.89 g, 2 eq.) portionwise. The suspension is stirred at RT overnight. The mixture is diluted with water. The aqueous layer is extracted with CH2Cl2. The organic layer is dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 1.99 g (79%) of the desired product as a white solid, used in the next step without further purification.
In a round bottom flask equipped with a dean starck is introduced a solution of 6-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (2 g, 1 eq.) in toluene (85 ml). Para-toluenesulfonic acid (0.02 g, 0.01 eq.) is added and the mixture is brought to reflux. The solution is heated for 7 h. After cooling, the mixture is diluted with CH2Cl2. The organic layer is washed with saturated aqueous NaHCO3 and water. The organic layer is dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (CH2Cl2/methanol, 100/0 to 95/5) to afford 0.54 g (30%) of the desired product as a white solid.
In a three-neck round bottom flask is introduce NaOCl (0.43 ml, 0.31 eq., 2N). The flask is then flushed with argon and cooled to 0° C. A solution of (R,R)—N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride (0.02 g, 0.01 eq.) and 4-(3-phenylpropyl)pyridine-N-oxide (0.02 g, 0.03 eq.) in CH2Cl2 (1 ml) is added. The suspension is stirred for 15 min. To the cooled solution is added simultaneously via two addition funnels NaOCl (1.3 ml, 0.93 eq., 2N) and a solution of 1H-inden-5-yl methyl sulfone (0.55 g, 1 eq.) in CH2Cl2 (0.7 ml). The mixture is then stirred at 0° C. for 1 h and the temperature is let warmed up to RT over night. The suspension is diluted with water and CH2Cl2 and filtered through Celite®. The aqueous layer is separated and extracted three times with CH2Cl2. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 0.51 g (86%) of the desired compound as a brown oil, used in the next step without further purification.
To a solution of (1aR,6aS)-3-(methylsulfonyl)-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (0.5 g, 1.00 eq.) in AcN (7 ml) is added tert-butyl (3R)-piperidin-3-ylcarbamate (0.69 g, 1.45 eq.). The solution is brought to reflux and heated overnight. After cooling, the solvents are evaporated under reduced pressure and the residue is purified by column chromatography (CH2Cl2/methanol, 100/0 to 95/5) to afford 0.73 g (75%) of the desired product as a greenish foam.
To a solution of 3-chloro-4-hydroxybenzonitrile (0.23 g, 1.25 eq.) in CH2Cl2 (7 ml) is added polymer-bound PPh3 (1 g, 3 mmol/g, 2.50 eq.) and tert-butyl {(3R)-1-[(1S,2S)-2-hydroxy-6-(methylsulfonyl)-2,3-dihydro-1H-inden-1-yl]piperidin-3-yl}carbamate (0.50 g, 1 eq.). The suspension is cooled to 0° C. and a solution of di-tert-butyl azodicarboxylate (0.56 g, 2 eq.) in CH2Cl2 (3 ml) added dropwise. The mixture is stirred over night at RT, then filtered on Celite®. The filter is washed twice with CH2Cl2. The filtrate is evaporated under reduced pressure and the residue is purified by column chromatography (CH2Cl2/methanol, 100/0 to 95/5) to yield 0.66 g (quantitative) of a white foam. The residue is then dissolved in ethanol (1 ml) and HCl (0.6 ml, 2N in Et2O) is added. The precipitate is filtered and dried under reduced pressure to afford 0.12 g of the desired compound as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.38 (bs, 2H), 8.15 (s, 1H), 8.02-8.00 (m, 1H), 8.00-7.98 (m, 1H), 7.88-7.85 (m, 1H), 7.75 (s, 1H), 7.76-7.74 (m, 1H), 6.28 (s, 1H), 3.92-3.88 (m, 1H), 3.35-3.10 (m, 4H), 3.11 (s, 3H), 2.81-2.75 (m, 1H), 2.70-2.51 (m, 2H), 1.95-1.80 (m, 2H), 1.65-1.50 (m, 2H); LCMS (ES) M+ 446; [αD=−187.1° (CH3OH); mp=162° C.
The title compound is prepared following the method used for example 2.
To a solution of (1aR,6aS)-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (0.34 g, 1.00 eq.) in AcN (7 ml) is added tert-butyl[2-(azetidin-3-yl)propan-2-yl]carbamate (0.92 g, 1.45 eq.). The solution is brought to reflux and heated overnight. After cooling, the solvents are evaporated under reduced pressure and the residue is purified by column chromatography (CH2Cl2/methanol, 100/0 to 90/10) to afford 0.47 g (53%) of the desired product.
To a solution of 3-chloro-4-hydroxybenzonitrile (0.26 g, 1.25 eq.) in CH2Cl2 (10 ml) is added polymer-bound PPh3 (1.12 g, 3 mmol/g, 2.50 eq.) and tert-butyl (2-{1-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]azetidin-3-yl}propan-2-yl)carbamate (0.47 g, 1 eq.). The suspension is cooled to 0° C. and a solution of di-isopropyl azodicarboxylate (0.63 g, 2 eq.) in CH2Cl2 (4 ml) is added dropwise. The mixture is stirred over night at RT, then filtered on Celite®. The filter is washed twice with CH2Cl2. The filtrate is evaporated under reduced pressure and the residue is purified by column chromatography (cyclohexane/EtOAc, 100/0 to 70/30) to yield 0.10 g (15%) of the product. The residue is then dissolved in ethanol (2 ml) and HCl (1 ml, 1N in Et2O) is added. The precipitate is filtered and dried under reduced pressure to afford 0.03 g of the desired compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.25 (bs, 2H), 8.10 (s, 1H), 7.94-7.90 (m, 1H), 7.76-7.74 (m, 1H), 7.46-7.43 (m, 1H), 7.43 (s, 1H), 7.32-7.28 (m, 1H), 7.22-7.19 (m, 1H), 6.45 (s, 1H), 4.80-4.68 (m, 1H), 4.58-4.00 (m, 5H), 1.40-1.25 (m, 2H), 1.20 (s, 6H); LCMS (ES) M+ 382; mp=93° C.
The title compound is prepared following the method used in example 3.
To a solution of tert-butyl {(3R)-1-[(1R,2R)-1-(2-chloro-4-cyanophenoxy)-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl}carbamate (0.23 g, 1 eq.) in DMF (1 ml) is added water (10 μl) and sodium hydride (0.13 g, 60% in mineral oil, 7 eq.) at 0° C. After stirring for 1 h at 0° C., methyl iodide (0.09 g, 1.50 eq.) is added and the mixture is stirred at RT overnight. The mixture is then diluted with CH2Cl2 (40 ml) and water (5 ml). The aqueous layer is separated and extracted with CH2Cl2. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (CH2Cl2/EtOAc, 80/20). The product is dissolved in CH2Cl2 and treated with HCl (0.10 ml, 4N in dioxane). The precipitate is then filtered and dried under vacuum to afford 35 mg of the desired product as a beige powder: 1H NMR (400 MHz, DMSO-d6) δ 9.00 (bs, 1H), 8.00 (s, 1H), 7.90-7.82 (m, 1H), 7.79-7.71 (m, 1H), 7.42-7.40 (m, 1H), 7.40 (s, 1H), 7.30-7.20 (m, 2H), 6.40 (s, 1H), 4.02-3.90 (m, 1H), 3.70-3.20 (m, 4H), 2.92-2.80 (m, 3H), 2.60 (s, 3H), 2.06-1.60 (m, 4H); LCMS (ES) M+ 382; [αD]=−197.7° (CH3OH).
To a cooled solution (0° C.) of 6-methoxyindanone (4 g, 1 eq.) in THF (100 ml) and methanol (23 ml) is added sodium borohydride (1.86 g, 2 eq.) portionwise. The suspension is stirred at RT overnight. The mixture is diluted with water. The aqueous layer is extracted with CH2Cl2. The organic layer is dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 4.0 g (98%) of the desired product as a yellow oil, used in the next step without further purification
In a round bottom flaky equipped with a dean starck is introduced a solution of 6-methoxy-2,3-dihydro-1H-inden-1-ol (4 g, 1 eq.) in toluene (121 ml). Para-toluenesulfonic acid (0.05 g, 0.01 eq.) is added and the mixture is brought to reflux. The solution is heated for 7 h. After cooling, the mixture is diluted with CH2Cl2. The organic layer is washed with saturated aqueous NaHCO3 and water. The organic layer is dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (heptane/EtOAc, 100/0 to 50/50) to afford 2.69 g (75%) of the desired product as acolorless oil.
In a three-neck round bottom flask is introduce NaOCl (2.8 ml, 0.31 eq., 2N). The flask is then flushed with argon and cooled to 0° C. A solution of (R,R)—N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride (0.12 g, 0.01 eq.) and 4-(3-phenylpropyl)pyridine-N-oxide (0.12 g, 0.03 eq.) in CH2Cl2 (9.5 ml) is added. The suspension is stirred for 15 min. To the cooled solution is added simultaneously via two addition funnels NaOCl (12.5 ml, 0.93 eq., 2N) and a solution of 1H-inden-5-ylmethyl ether (2.69 g, 1 eq.) in CH2Cl2 (5.8 ml). The mixture is then stirred at 0° C. for 1 h and the temperature is let warmed up to RT over night. The suspension is diluted with water and CH2Cl2 and filtered through Celite®. The aqueous layer is separated and extracted three times with CH2Cl2. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2.90 g (97%) of the desired compound as a brown oil, used in the next step without further purification.
To a solution of (1aR,6aS)-3-methoxy-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (0.70 g, 1.00 eq.) in AcN (16 ml) is added tert-butyl (3R)-piperidin-3-ylcarbamate (1.25 g, 1.45 eq.). The solution is brought to reflux and heated overnight. After cooling, the solvents are evaporated under reduced pressure and the residue is purified by column chromatography (CH2Cl2/methanol, 100/0 to 95/5) to afford 0.85 g (85%) of the desired product as a brown foam.
To a solution of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (0.40 g, 1.25 eq.) in CH2Cl2 (11 ml) is added polymer-bound PPh3 (1.31 g, 3 mmol/g, 2.50 eq.) and tert-butyl {(3R)-1-[(1S,2S)-2-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl]piperidin-3-yl}carbamate (0.85 g, 1 eq.). The suspension is cooled to 0° C. and a solution of di-tert-butyl azodicarboxylate (0.92 g, 2 eq.) in CH2Cl2 (6.7 ml) is added dropwise. The mixture is stirred over night at RT, then filtered on Celite®. The filter is washed twice with CH2Cl2. The filtrate is evaporated under reduced pressure and the residue is purified by column chromatography (CH2Cl2/methanol, 100/0 to 90/10) to yield 0.43 g (43%) of an orange foam. The residue is then dissolved in CH2Cl2 (5 ml) and HCl (0.82 ml, 2N in Et2O) is added. The precipitate is filtered and dried under reduced pressure to afford 0.25 g of the desired compound as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.30 (bs, 2H), 7.21-7.15 (m, 1H), 6.95 (s, 1H), 6.90-6.75 (m, 3H), 6.60 (s, 1H), 6.05 (s, 1H), 3.94-3.80 (m, 1H), 3.62 (s, 3H), 3.55-2.96 (m, 7H), 2.85-2.75 (m, 2H), 2.40-2.35 (m, 2H), 1.98-1.85 (m, 1H), 1.85-1.70 (m, 2H), 1.65-1.50 (m, 1H); LCMS (ES) M+ 408; mp=145.6° C.
The title compound is prepared following the method used in example 2.
To a solution of 6-hydroxy-7-chloro-3,4-dihydroquinolin-2(1H)-one (0.26 g, 1.25 eq.) in CH2Cl2 (7 ml) is added polymer-bound PPh3 (0.69 g, 3 mmol/g, 2.50 eq.) and tert-butyl {(3R)-1-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]piperidin-3-yl}carbamate (0.35 g, 1 eq.). The suspension is cooled to 0° C. and a solution of di-tert-butyl azodicarboxylate (0.48 g, 2 eq.) in CH2Cl2 (3 ml) is added dropwise. The mixture is stirred over night at RT, then filtered on Celite®. The filter is washed twice with CH2Cl2. The filtrate is evaporated under reduced pressure and the residue is purified by column chromatography (CH2Cl2/methanol, 100/0 to 92/8) to yield 0.36 g (67%) of the product. The residue is then dissolved in CH2Cl2 (5 ml) and HCl (0.7 ml, 2N in Et2O) is added. The precipitate is filtered and dried under reduced pressure to afford 0.18 g of the desired compound as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.45 (bs, 2H), 7.42-7.38 (m, 1H), 7.35 (s, 1H), 7.32-7.18 (m, 3H), 7.00 (s, 1H), 6.18 (s, 1H), 4.10-4.00 (m, 1H), 3.60-3.20 (m, 11H), 2.09-2.78 (m, 3H), 1.72-1.60 (m, 1H); LCMS (ES) M+ 412; mp=183.7° C.
To a solution of 6,7-dihydro-5H-cyclopenta[b]pyridine (5 g, 1 eq.) in acetic acid (25 ml) is added H2O2 (2.51 g, 50% in water, 0.88 eq.). The solution is warmed to 70° C. After 3 hours, further H2O2 (2.51 g, 50% in water, 0.88 eq.) is added and the mixture is stirred at 70° C. over night. After cooling down, the solvent is evaporated under reduced pressure and water (20 ml) is added to the residue. Solid K2C03 is then added to have pH=9. The aqueous layer is separated and extracted three times with CH2Cl2. The combined organic layers are dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to yield 5.55 g (97%) of the desired compound, used in the next step without further purification.
To a solution of acetic anhydride (44 g, 10.50 eq.) and water (0.42 g, 0.50 eq.) is added 6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (5.55 g, 1 eq.). After stirring for 1 h at RT, the mixture is heated gently to 80° C. The temperature is monitored in order not to rise above 95° C. When the exothermy is over, the Brownish red solution is heated to 100° C. for 3 h. After cooling to RT, water (150 ml) and Et2O (300 ml) are added. The aqueous layer is separated and extracted three times with Et2O. The combined organic layers are dried over Na2SO4, filtered and evaporated under reduced pressure to yield 3.75 g (87%) of the desired compound, used in the next step without further purification.
Concentrated sulphuric acid (20.5 ml, 6.63 eq.) is added to 6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (5.3 g, 1 eq.). The mixture is stirred at 130° C. for 1 h then stirred at RT overnight. Ice is added, followed by sodium hydroxide (25 ml, 35%) and water (120 ml). The aqueous layer is extracted 3 times with CH2Cl2. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain 3.2 g (95%) of a 65:35 mixture of the 2 regioisomers as a black oil, used in the next step without further purification.
In a three-neck round bottom flask is introduce NaOCl (7.1 ml, 1 eq., 2N). The flask is then flushed with argon and cooled to 0° C. A solution of (R,R)—N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride (0.17 g, 0.01 eq.) and 4-(3-phenylpropyl)pyridine-N-oxide (0.17 g, 0.03 eq.) in CH2Cl2 (8 ml) is added. The suspension is stirred for 15 min. Simultaneous addition of NaOCl (10 ml, 1.2 eq., 2N) and a solution of 5H-cyclopenta[b]pyridine and 7H-cyclopenta[b]pyridine (3.3 g, 1 eq.) in CH2Cl2 (8 ml) via two addition funnel follows. The mixture is then stirred at 0° C. for 1 h and the temperature is let warmed up to RT over night. The suspension is diluted with water and CH2Cl2 and filtered through Celite®. The aqueous layer is separated and extracted three times with CH2Cl2. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 3.70 g (quantitative) of a 65:35 mixture of the 2 desired regioisomers, used in the next step without further purification.
To a solution of (1aR,6aS)-6,6a-dihydro-1aH-oxireno[4,5]cyclopenta[1,2-b]pyridine and (1aS,6aR)-2,6b-dihydro-1aH-oxireno[3,4]cyclopenta[1,2-b]pyridine (3.70 g, 1 eq.) in AcN (70 ml) is added tert-butyl (3R)-piperidine-3-yl carbamate (7.98 g, 1.43 eq.). The solution is brought to reflux and heated over night. After cooling, the mixture is evaporated under reduced pressure and the resulting residue is purified by column chromatography (CH2Cl2/methanol, 100/0 to 90/10) to afford 3.08 g of tert-butyl {(3R)-1-[(5S,6S)-6-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl]piperidin-3-yl}carbamate and 1.85 g of tert-butyl {(3R)-1-[6S,7S)-6-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]piperidin-3-yl}carbamate.
To a solution of 3-chloro-4-hydroxybenzonitrile (0.48 g, 1.05 eq.) in THF (36 ml) is added polymer-bound PPh3 (2.36 g, 3 mmol/g, 3 eq.) and tert-butyl {(3R)-1-[(5S,6S)-6-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl]piperidin-3-yl}carbamate (1 g, 1 eq.). The suspension is cooled to 0° C. and a solution of di-isopropyl azodicarboxylate (1.82 g, 3 eq.) in THF (3 ml) is added dropwise. The mixture is stirred over night at RT, then filtered on Celite®. The filter is washed twice with CH2Cl2. The filtrate is evaporated under reduced pressure and the residue is purified by column chromatography (CH2Cl2/methanol, 100/0 to 95/5) to yield 0.2 g of the desired product. The residue is then dissolved in CH2Cl2 (1.4 ml) and HCl (0.5 ml, 4N in Et2O) is added. The precipitate is filtered and dried under reduced pressure to afford 0.10 g of the desired compound as light grey solid: 1H NMR (400 MHz, DMSO-d6) δ 8.60-8.55 (m, 1H), 8.32 (bs, 2H), 8.02 (s, 1H), 7.92-7.88 (m, 1H), 7.83-7.79 (m, 1H), 7.65-7.60 (m, 1H), 7.37-7.28 (m, 1H), 6.56 (s, 1H), 4.25-4.15 (m, 1H), 3.58-3.35 (m, 4H), 3.12-3.00 (m, 1H), 3.00-2.80 (m, 2H), 2.06-1.60 (m, 4H); LCMS (ES) M+ 369; [αD]=−113° (CH3OH); mp=172° C.
To a solution of 3-chloro-4-hydroxybenzonitrile (0.72 g, 1.05 eq.) in THF (53 ml) is added polymer-bound PPh3 (3.54 g, 3 mmol/g, 3 eq.) and tert-butyl {(3R)-1-[(6S,7S)-6-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]piperidin-3-yl}carbamate (1.50 g, 1 eq.). The suspension is cooled to 0° C. and a solution of di-isopropyl azodicarboxylate (2.73 g, 3 eq.) in THF (3 ml) is added dropwise. The mixture is stirred over night at RT, then filtered on Celite®. The filter is washed twice with CH2Cl2. The filtrate is evaporated under reduced pressure and the residue is purified by column chromatography (CH2Cl2/methanol, 100/0 to 95/5) to yield 0.5 g of the desired product. The residue is then dissolved in CH2Cl2 (3.9 ml) and HOI (1.5 ml, 4N in Et2O) is added. The precipitate is filtered and dried under reduced pressure to afford 0.18 g of the desired product as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.45-8.40 (m, 1H), 8.35 (bs, 2H), 7.99 (s, 1H), 7.90-7.80 (m, 3H), 7.42-7.38 (m, 1H), 6.45 (s, 1H), 4.25-4.15 (m, 1H), 3.58-3.35 (m, 2H), 3.35-3.20 (m, 2H) 3.15-2.80 (m, 3H), 2.06-1.60 (m, 4H); LCMS (ES) M+ 369; [αD]=−245.9° (CH3OH); mp=180° C.
The following table illustrates the chemical structures and the physical properties of some examples of compounds according to the present invention. In this table, in the <<salt>> column, <<->> represents a compound as a free base, whereas “TFA” represents a compound in the form of a trifluoroacetic acid salt, <<HCl>> represents a compound in the form of a hydrochloride, the ratio in parentheses being the acid to base ratio.
The compounds of the invention underwent pharmacological studies which demonstrated their ability to inhibit TRCP6. The method for testing the TRPC6 inhibitory activity of the compounds of the invention is as described in the patent application WO 2006/074802.
The IC50 of the compounds of the invention are lower than 10 μM, demonstrating their value as therapeutically active substances. More specifically, the IC50 values of the compounds described in table 1 are comprised between 0.001 μM and 1 μM. For example, compounds 8 and 63 display IC50 of 1.20×10−8 and 8.11×10−7 μM, respectively.
The compounds according to the invention therefore display inhibition activity towards TRPC6.
The compounds of formula (I) are inhibitors of TRCP6, and are therefore useful for the prevention and treatment of fibrotic disorders, such as focal segmental glomerulosclerosis, skeletal muscle dysfunction, renal failure, atherosclerosis, heart failure, cancer (e.g. oesophageal cancer, breast cancer), chronic obstructive pulmonary disease, pain, pulmonary hypertension, ischemic stroke, myocardial infarction, inflammation or peripheral arterial occlusive disease.
The invention also relates to a medicament, comprising a compound of formula (I) as defined above, or an addition salt of said compound to a pharmaceutically acceptable salt, or an hydrate or solvate of said compound.
The invention also relates to compounds of formula (I) as drugs.
The compounds according to the invention can indeed be useful for the preparation of drugs, specifically of medicaments inhibiting TRCP6, in particular medicaments for the prevention and the treatment of fibrotic disorders, such as focal segmental glomerulosclerosis, skeletal muscle dysfunction, renal failure, atherosclerosis, heart failure, cancer (e.g. oesophageal cancer, breast cancer), chronic obstructive pulmonary disease, pain, pulmonary hypertension, ischemic stroke, myocardial infarction, inflammation or peripheral arterial occlusive disease.
The invention also relates to a pharmaceutical composition, comprising a compound of formula (I) as defined above, or an addition salt of said compound to a pharmaceutically acceptable salt, or an hydrate or solvate of said compound, as active principle, and at least one pharmaceutically acceptable excipient.
These pharmaceutical compositions comprise an effective dose of at least one compound according to the invention, or an addition salt thereof with a pharmaceutically acceptable salt, or an hydrate or solvate of the latter, and at least one pharmaceutically acceptable excipient.
Said excipients are chosen according to the pharmaceutical form and the administration route desired, among usual excipients known of one of skill in the art.
In the pharmaceutical compositions according to the invention for the oral, sublingual, sub-cutaneous, intramuscular, intra-venous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, its salt, solvate or hydrate, can be administered as a unitary dosage form, in blend with usual pharmaceutical excipients, to animals and human beings for the prevention or for the treatment of diseases mentioned above.
The appropriate unitary dosage forms comprise the oral forms, such as tablets, hard or soft gelatin capsules, powders, granules and oral solutions or suspensions, the sublingual, buccal, intratracheal, intraocular, intranasal forms, by inhalation, the topical, transdermal, sub-cutaneous, intramuscular or intra-venous forms, the rectal forms and the implants. For the topical application, the compounds of the invention may be used as creams, gels, ointments or lotions.
As an example, a unitary dosage form for a compound according to the invention, in the form of a tablet, can comprise the following ingredients:
The present invention, according to another of its aspects, also relates to a method for the treatment or prevention of the above pathologies, which comprises the administration to a patient of an effective dose of a compound according to the invention, or a salt with a pharmaceutically acceptable salt thereof, or an hydrate or a solvate thereof.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10305207.2 | Mar 2010 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP11/53024 | 3/1/2011 | WO | 00 | 1/14/2013 |
