HK1223360B - Novel indolizine derivatives, method for the production thereof and pharmaceutical compositions containing same - Google Patents
Novel indolizine derivatives, method for the production thereof and pharmaceutical compositions containing same Download PDFInfo
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- HK1223360B HK1223360B HK16111561.8A HK16111561A HK1223360B HK 1223360 B HK1223360 B HK 1223360B HK 16111561 A HK16111561 A HK 16111561A HK 1223360 B HK1223360 B HK 1223360B
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Description
The present invention relates to new derivatives of indolizine, their preparation process and the pharmaceutical compositions containing them.
The compounds of the present invention are novel and have pharmacological characteristics of great interest in the field of apoptosis and oncology.
Apoptosis, or programmed cell death, is a crucial physiological process for embryonic development and tissue homeostasis.
Apoptotic cell death causes morphological changes, such as nucleus condensation, DNA fragmentation, and biochemical events, such as activation of caspases, which will degrade key structural components of the cell to induce disassembly and death. Regulation of the apoptosis process is complex and involves activation or suppression of several intracellular signaling pathways (Cory S. et al., Nature Cancer Review, 2002, 2, 647-656).
In contrast, impairments in the execution of apoptosis play an important role in the development of cancers and their chemoresistance, autoimmune diseases, inflammatory diseases and viral infections. Thus, escape from apoptosis is one of the phenotypic signatures of cancer (Hanahan D. Cell et al., 2000, 100, 57-70).
Bcl-2 family anti-apoptotic proteins are associated with many diseases. The involvement of Bcl-2 family proteins is described in many types of cancer, such as colorectal cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma. A therapeutic need for compounds inhibiting the anti-apoptotic activity of Bcl-2 family proteins. Among the Bcl-2 family inhibitors known in the literature, the compounds 2-(1,2,3,3-tetrahydroquinoline-2-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbonyl-carbony
The compounds of the present invention, apart from being novel, exhibit pro-apoptotic properties which allow their use in pathologies involving a defect in apoptosis, such as in the treatment of cancer, autoimmune diseases and the immune system.
The present invention relates in particular to compounds of formula (I):
- What?
in which:
◆ X and Y represent a carbon atom or a nitrogen atom, it being understood that they cannot simultaneously represent two carbon atoms or two nitrogen atoms,◆ the Het part of the group
- What?
is a cyclic compound, whether or not aromatic, consisting of 5, 6 or 7 chains, and may contain, in addition to the nitrogen represented by X or Y, one to three heteroatoms independently selected from oxygen, sulphur and nitrogen, provided that the nitrogen in question may be replaced by a hydrogen group, a linear or branched alkyl group (C1-C6) or a -C(O) -O-Alk group in which Alk is a linear or branched alkyl group (C1-C6),◆ T represents a hydrogen atom, a linear or branched alkyl (C1-C6) possibly substituted by one to three halogen atoms, an alkyl group ((C2-C4) -NR1R2, or an alkyl group ((C1-C4) -OR6,◆ R1 and R2 independently represent a linear or branched hydrogen atom or alkyl group (C1-C6),
or R1 and R2 form with the nitrogen atom which carries them a heterocycloalkyl,◆ R3 is a linear alkyl (C1-C6), aryl or heteroaryl group, the latter two groups being substitutable by one or three groups chosen from halogen, linear or branched alkyl (C1-C6), linear or branched alkoxy (C1-C6), linear or branched cyano and linear or branched heterocycloalkyl-alkyl (C1-C6),Whereas one or more carbon atoms of the preceding groupings, or of their possible substituents, may be deuterized,◆ R4 represents a 4-hydroxyphenyle grouping, whereas one or more carbon atoms of the preceding grouping, or of its possible substituents, may be deuterized,◆ R5 represents a hydrogen or halogen atom, a linear or branched alkyl grouping (C1-C6), or a linear or branched alkoxy grouping (C1-C6),◆ R6 represents a linear or branched hydrogen atom or alkyl grouping (C1-C6),◆ and RaD each represents a hydrogen atom (R and R, respectively) with the carbon atoms together containing a group 1,Err1:Expecting ',' delimiter: line 1 column 360 (char 359)Err1:Expecting ',' delimiter: line 1 column 95 (char 94)Err1:Expecting ',' delimiter: line 1 column 227 (char 226)
Among the pharmaceutically acceptable acids, the following are to be included, but are not limited to, hydrochloric, bromic, sulphuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, sulphonic, camphoric, etc.
The pharmaceutically acceptable bases include but are not limited to sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.
The group has an advantage:
- What?
represents one of the following groups: 5,6,7,8-tetrahydroindolizine possibly substituted by an amino group; indolizine; 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine possibly substituted by a methyl; pyrrolo[1,2-a]pyrimidine.
In the preferred compounds of the invention, T represents a hydrogen atom, a methyl group (and more specifically a (R) -methyl), a 2- (morpholine-4-yl) ethyl group, 3- (morpholine-4-yl) propyl, -CH2-OH, 2-aminoethyl, 2- (difluoropiperin-1-yl) ethyl, 2- (difluoropiperin-1-yl), 2- (difluoroethyl) amino]ethyl or 2- (difluoroethyl) ethyl.
Preferably, Ra and Rd each represent a hydrogen atom and (Rb,Rc) together with the carbon atoms that carry them form a 1,3-dioxolane group, or else Ra, Rc and Rd each represent a hydrogen atom and Rb represents a halogen.
In the preferred compounds of the invention, R3 represents a heteroaryle group chosen from the following group: 1H-indole, 2,3-dihydro-1H-indole, 1H-indazole, pyridine, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazole, imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyridine, [1,2,4]triazole[1,5-a]pyrimidine, and 1H-pyrazolo[3,4-b]pyridine, all of which may be substituted by a linear or branched alkyl group (C1-C6).
The compounds of preference according to the invention are included in the following group:
The following substances are to be classified in the immediate vicinity of the place of dispatch: - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of a mixture of ethyl alcohols, - in the form of ethyl alcohols, - in the form of an ethyl alcohol - in the form of an ethyl alcohol - in the form of an ethyl alcohol - in the form of an ethyl alcohol - in the form of an ethyl alcohol - in the form of an ethyl alcohol - in the form of an ethyl alcohol - in the form of an ethyl alcohol - in the form of an ethyl alcohol - in the form of an ethyl alcohol - in the form of an ethyl alcohol - in the form of an ethyl alcohol - in the form of an ethyl alcohol - in the form of an ethyl alcohol - in the form of ethyl alcohol - in the form of ethyl alcohol - in the form of ethyl alcohol - in the form of ethyl alcohol - in the form of ethyl alcohol - in the form of ethyl alcohol - in the form of ethyl alcohol - in the form of ethyl alcohol - in the form of ethyl alcohol - in the form of ethyl alcohol - in the form of ethyl alcohol - in the form of ethyl alcohol - in the form of ethyl alcohol - in the form of ethyl
their enantiomers and diastereoisomers, and their salts of addition to an acid or a pharmaceutically acceptable base.
The invention also extends to the process of preparation of compounds of formula (I) characterized by the use of the compound of formula (II) as the starting product:
- What?
in which Ra, Rb, Rc and Rd are as defined in formula (I), a compound of formula (II) which undergoes a Heck reaction in an aqueous or organic medium in the presence of a palladium catalyst, a base, a phosphine and the compound of formula (III):
- What?
where the groups X, Y and Het are as defined in formula (I),
For the preparation of the compound of formula (IV):
- What?
wherein Ra, Rb,Rc, Rd, X, Y and Het are as defined in formula (I),
a purity of 99,99% or more but not more than 99,99% of propylene glycol,
wherein Ra, Rb, Rc, Rd, X, Y and Het are as defined in formula (I),
a formula (V) which is then peptidically coupled to a formula (VI):
- What?
where T and R5 are as defined in formula (I),
for use in the manufacture of compounds of formula (VII):
- What?
wherein Ra, Rb, Rc, Rd, T, R5, X, Y and Het are as defined in formula (I),a compound of formula (VII) with the ester function hydrolysed to the corresponding carboxylic acid or carboxylate, which can be converted to an acid derivative such as acyl chloride or the corresponding anhydride, before being coupled with an amine NHR3R4, where R3 and R4 have the same meanings as in formula (I), to give the compound of formula (I),
a compound of formula (I) which can be purified by a conventional separation technique, transformed, if desired, into its salts of addition to an acid or a pharmaceutically acceptable base and the isomers of which may be separated by a conventional separation technique,- What?
It is understood that at any time deemed appropriate during the process described above, certain groups (hydroxy, amino, etc.) of the synthesis reagents or intermediates may be protected and then unprotected for the purposes of synthesis.
In particular, when one of the R3 or R4 groups of the NHR3R4 amine is replaced by a hydroxy function, the latter may be subjected to a protective reaction prior to coupling with the carboxylic acid of the formula (VII) compound, or with any of the corresponding acid derivatives, the resulting protected formula (I) compound undergoes a deprotection reaction and is then possibly converted into one of its additive salts to a pharmaceutically acceptable acid or base.
The compounds of formulae (II), (III), (VI) and the amine NHR3R4 are either commercially available or available to the professional by conventional chemical reactions and described in the literature.
The pharmacological study of the derivatives of the invention showed that they possess pro-apoptotic properties. The ability to reactivate the apoptotic process in cancer cells is of major therapeutic interest in the treatment of cancers, autoimmune diseases and the immune system.
In particular, the compounds of the invention will be useful in the treatment of chemoradiation- or radiation-resistant cancers, as well as malignant hemopathies and small cell lung cancer.
Treatments for cancer include, but are not limited to, bladder, brain, breast, uterine, chronic lymphocytic leukemia, colorectal, esophageal, liver, lymphocytic leukemia, non-Hodgkin lymphoma, melanoma, malignant hemorrhagic disease, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer. Non-Hodgkin lymphomas include, but are not limited to, follicular lymphomas, diffuse lymphomas of the mantle, marrow lymphomas, large B cells and small B cell lymphomas of the lymphatic zone.
The present invention also covers pharmaceutical formulations containing at least one compound of formula (I) in combination with one or more pharmaceutically acceptable excipients.
The pharmaceutical formulations of the invention may include, in particular, those for oral, parenteral, nasal, percutaneous, rectal, perlingual, ocular or respiratory administration, including single or double-blind tablets, sublingual tablets, sachets, packets, capsules, glossets, tablets, suppositories, creams, ointments, dermal gels, and ampoules for drinking or injection.
The dose varies according to the patient' s sex, age and weight, route of administration, nature of the therapeutic indication, or any associated treatments and ranges from 0.01 mg to 1 g per 24 hours in one or more doses.
In addition, the present invention also concerns the combination of a compound of formula (I) with an anticancer agent selected from among genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors, or antibodies, as well as pharmaceutical formulations containing this type of combination and their use in the manufacture of drugs useful in the treatment of cancer.
The compounds of the invention may also be used in combination with radiotherapy in the treatment of cancer.
Finally, the compounds of the invention may be bound to monoclonal antibodies or to fragments thereof or may be bound to scaffold proteins which may or may not be related to monoclonal antibodies.
Antibody fragments are Fv, scFv, Fab, F(ab') 2, F(ab'), scFv-Fc, or diabodies, which generally have the same binding specificity as the antibody from which they are derived. According to the present invention, the antibody fragments of the invention may be obtained from antibodies by methods such as digestion by enzymes such as pepsin or papain, and/or cleavage of disulfide bridges by chemical reduction.Alternatively, the antibody fragments of the present invention may be obtained by techniques of genetic recombination also well known to the professional or by synthesis of peptides by means of automatic peptide synthesizers e.g. such as those provided by Applied Biosystems etc.
By structure proteins which may or may not be related to monoclonal antibodies, we mean a protein which may or may not include an immunoglobulin fold and which delivers a binding capacity similar to that of a monoclonal antibody.it is known that, to be selected, such a structure should have several characteristics as follows (Skerra A., J. Mol. Recogn. 13, 2000, 167-187): good phylogenetic conservation, a robust architecture with a well-known three-dimensional molecular organization (such as crystallography or MRI, for example), small size, no or little post-translational modification (s), ease of production, expression and purification. Such a structure may be, but is not limited to, a structure chosen from the group consisting of fibronectin and preferably the tenth type III domain of fibronectin (FN10), lipocalcin,Err1:Expecting ',' delimiter: line 1 column 257 (char 256)
The following preparations and examples illustrate the invention and do not in any way limit it.
All reagents and anhydrous solvents are commercial and have been used without further purification or drying. Flash chromatography was performed on an ISCO CombiFlash Rf 200i device with pre-packaged cartridges filled with silica gel (SiliaSepTM F60 (40-63μm), 60Å). Thin-film chromatographies were performed on 5 x 10 cm plates coated with Merck Type 60 F254 silica gel.
The compounds of the invention were characterized by high performance liquid chromatography coupled with mass spectrometry (HPLC-MS) either on a high resolution Agilent HP 1200 apparatus coupled with a 6140 multi-modal source mass detector (range m/z 150 to 1000 atomic mass units or uma) or on an Agilent HP1100 apparatus coupled with a 1946D electrospray ionization source mass detector (range m/z 150 to 1000 uma). The conditions and methods listed below are identical for both machines.
Detection: UV detection at 230, 254 and 270 nm.
Injection volume: 2 μL or less
The test chemical is a chemical that is used to determine the concentration of a substance in a solution.
The column is: Gemini 5μm, C18, 30 mm x 4.6 mm (Phenomenex).Temperature: 35°C.
| 0 | 95 | 5 | 2 |
| 0,25 | 95 | 5 | 2 |
| 2,50 | 95 | 5 | 2 |
| 2,55 | 5 | 95 | 3 |
| 3,60 | 5 | 95 | 3 |
| 3,65 | 5 | 95 | 2 |
| 3,70 | 95 | 5 | 2 |
| 3,75 | 95 | 5 | 2 |
The column is: Gemini 5μm, C18, 30 mm x 4.6 mm (Phenomenex).Temperature: 35°C.
| 0 | 95 | 5 | 1,1 |
| 0,12 | 95 | 5 | 1,1 |
| 1,30 | 5 | 95 | 1,1 |
| 1,35 | 5 | 95 | 1,7 |
| 1,85 | 5 | 95 | 1,7 |
| 1,90 | 5 | 95 | 1,1 |
| 1,95 | 95 | 5 | 1,1 |
The solution is then agitated at room temperature overnight, the reaction medium is cooled to 0 °C, hydrolysed by the addition of 250 mL of water, and agitated for half an hour at 0 °C before being dried. The resulting oil is then re-absorbed into 200 mL of dried concentrated methanol. The product is obtained as a 98% oil with no other efficiency.
RMN 1H: δ (400 MHz; dmso-d6 ; 300K) : 13.0 (m, 1H OH); 8.0-8.05 (2s, 1H aldehyde) ; 4.9-4.5 (2d, 1H α of N and COOH) ; 4.1-2.6 (m, 2H in α of N); 2.2-1.2 (m, 6H piperidine)
IR ν: -OH: 2000-3000 cm-1 acid; ν: >C=O 1703 cm-1 broadband
To a 10 g solution of carboxylic acid obtained at Stage A (63.6 mmol) in 65 mL dichloromethane, 13.4 g tosyl chloride (70.4 mmol), 11.5 mL methyl 2-chloroacrylate (113.5 mmol) and then, by drip, 17.8 mL N,N,N-triethylamine (127.2 mmol) are added successively to a 10 g solution of carboxylic acid obtained at Stage A (63.6 mmol). The reaction medium is then brought to the reflux site for 1 h 30.
The reaction medium is then diluted with methylene chloride,The organic phase is then dried to MgSO4, filtered, concentrated dry, and purified by silica gel chromatography (heptane/AcOEt gradient). The titer product is obtained in the form of an oil.
The following is a list of the active substances in the active substance:
To a 6.4 g solution of the ester obtained at Stage B (35.7 mmol) in 12 mL N,N-dimethylacetamide, 12.3 g of 6-bromo-1,3-benzodioxole-5-carbaldehyde (53.6 mmol), 7 g of potassium acetate (71.4 mmol) are successively added, and the whole is agitated under argon for 20 minutes. 1.3 g of palladium PdCl2PPh3) catalyst is then added (1,8 mmol). The reaction medium is then heated to 130 °C for one hour before adding 139 μL of H2O. The medium is kept at this temperature overnight.The organic phase is then washed with water, dried on magnesium sulphate and dried in a concentrated form. The resulting raw product is purified on silica gel (heptane/ACOEt gradient).
The following is a list of the active substances in the active substance:
A solution containing 3.37 g of the Stage C compound (10.3 mmol) is prepared in 9.3 mL acetone and 8.8 mL (80.24 mmol) 2-methyl-2-butene, which is placed at 0 °C. 9.3 mL of an aqueous solution containing a mixture of 3.3 g NaClO2 (36.05 mmol) and 3.6 g Na2PO4 (25.75 mmol) is added, drop by drop. The mixture is then agitated at room temperature for 7 hours. The reaction medium is then concentrated to remove the acetone. The resulting solid is filtered, washed with water and dried at 40 °C overnight.
The mean value of the measurement is calculated as the sum of the values of the measurements of the two samples taken together.
The following is a list of the active substances:
The mixture is agitated at room temperature for 2 hours. Then a mixture of 32 g of 1,3-piperazine decarboxylate of 1-tert-butyl and 3-methyl ether (130 mmol) and 18 mL of trielamine (130 mmol) is added to a solution of 520 mL of CH2Cl2 in a solution of 520 mL of pentafluorophenol at 0°C. 49 g of 1-ethyl-3-(3'-dimethylaminopropyl) -carbodiimide (286 mmol) are added successively per serving and 12 mL of formic acid (312 mmol). The mixture is agitated at room temperature for 2 hours.
The following is the list of the substances which are to be used in the preparation of the product:
To a 28 g solution of the Stage A (103 mmol) compound in 515 mL dioxane, add 4.8 g LiOH (113 mmol) in solution in 100 mL H2O. The set is agitated at room temperature for 4 h. The reaction medium is then concentrated dry and then co-evaporated several times with ethyl acetate. The titer product is obtained as a solid and is used directly for the next cycling step.
The following is the list of active substances in the active substance:
IR ν: C=O: 1650 cm-1 and 2800 cm-1
The reaction mixture is agitated at the reflux for 2 hours. After cooling, the reaction mixture is diluted with ethyl acetate and the organic phase is washed with a neutral NaCl solution. After drying on SO4, saturation and dry filtration, the MgE product is isolated by silica gel chromatography (petroleum ether gradient: Ac/Oether 0-20%) as a solid.
The following is a list of the active substances in the active substance:
The following is the list of the substances which are to be classified in the Annex to this Regulation:
Follow the procedure described in Stages C and D of Preparation 1 by replacing the 6-bromo-1,3-benzodioxole-5-carbaldehyde used in Stage C with 2-bromo-4-chlorobenzaldehyde.
Follow the procedure of Preparation 1 by replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Stage C with 2-bromo-4-chlorobenzaldehyde.
The procedure described in Stages A-C of Preparation 2 shall be followed.
The following is a list of the active substances in the active substance:
The following is the list of the substances which are to be classified in the Annex to this Regulation:
The procedure described in Stages C and D of Preparation 1 is followed by replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Stage C with 7-bromo-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde.
The solution of 16.2 mL (200 mmol) pyridine in 120 mL ethyl acetate is then mixed with 27.8 g (200 mmol) bromoacetic acid in portions, stirred at room temperature overnight, filtered and washed with cold ethyl acetate, and then dried to produce a powder that is used directly for the next step.
The following is a list of the active substances in the active substance:
The following is a list of the components of the product:
To a 6.55 g suspension of pyridinium salt obtained at Stage A (30 mmol) in 240 mL toluene, 16.7 mL methyl acrylate (150 mmol), 4.2 mL triethylamine (30 mmol) are added successively, followed by 20.9 g portions of MnO2 (240 mmol). The whole is then heated to 90°C for 3 h. After cooling, the reaction medium is filtered on a cellite cake and concentrated dry. The product is then isolated by purification on silica gel (heptane/AcOEt gradient: 0-10%) in the form of a cold crystallizing h.
The following is the list of substances that are to be classified as 'substances' in Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council:
The following is a list of the substances which are to be used:
Follow the procedure described in Stages C and D of Preparation 1 by replacing the 6-bromo-1,3-benzodioxole-5-carbaldehyde used in Stage C with 2-bromo-4-chlorobenzaldehyde.
Follow the procedure described in Preparation 2 by replacing the 2-bromo-4-chlorobenzaldehyde used in Stage D with 2-bromo-4-fluorobenzaldehyde.
Follow the procedure described in Preparation 2 by replacing the 2-bromo-4-chlorobenzaldehyde used in Stage D with 6-bromo-1,3-benzodioxole-5-carbaldehyde.
The reaction medium is evaporated dry and taken up into the ethyl acetate. The organic phase is then successively washed with a solution of NaOH 1 N, water, then with a saturated solution of NH4Cl until it reaches a neutral pH. It is then dried on magnesium sulfate, filtered and concentrated in dry oil. The purified medium is then flash chromatography (a chromatography obtained by heptanol/acetyl heptanol).
RMN 1H: δ (400 MHz; dmso-d6; 300K): 8.15 (s, 1H, CHO); 5.0-4.75 (m, 1H, tertiary H) ; 4.3-3.7 (m, 5H, 4H ethylene dioxy + 1H aliphatic piperidine) ; 3.70 (s, 3H, Me) ; 3.4-2.9 (2m, 1H, aliphatic piperidine H) ; 2.3-1.75 (m, 2H, aliphatic piperidine H) ; 1.7-1.5 (m, 2H, aliphatic piperidine H)
15.25 g of the Stage A compound (62.7 mmol) is dissolved in 160 ml of dioxane. A 125 mL solution of KOH 1M is added drop by drop and the whole is stirred at room temperature for 1 h. 125 mL of HCl 1 M is then added and the compound is extracted with dichloromethane. The organic phase is dried to MgSO4, filtered and concentrated dry. The titer product is obtained as a powder.
RMN 1H: δ (400 MHz; dmso-d6 ; 300K) 13.5-12 (m, 1H, OH) ; 8.1 + 8.0 (2s, 1H, CHO); 4.9 + 4.6 (2m, 1H, tertiary H) ; 4.0-3.8 (m, 4H, ethylene dioxy) ; 4.2 + 3.7 (2ms, 1H, H aliphatic piperidine) ; 3.4 + 2.9 (2m, 1H, H aliphatic piperidine) ; 2.4-1.5 (m, 4H, H aliphatic piperidine)
IR: ν: OH: 3500-2000 cm-1; -C=O (acid + aldehyde) :1731 + 1655 cm-1
The reaction medium is then filtered on cellite. The filtrate is then washed with a saturated solution of NaHCO3 and then with a saturated solution of NH4Cl. The organic Mg is dried on SO4, filtered and dried in a concentrated form. The oil is obtained by flash chromatography (heptadiene/acetate) and the resulting product is obtained as a solid.
The following substances are considered to be toxic if they are used in the manufacture of the active substance:
IR: ν :-C=O (ester): 1689 cm-1
The procedure is as described in Step C of Preparation 1.
The procedure for Stage D of Preparation 1 is followed.
The procedure described in Preparation 5 is followed by replacing the 2-bromo-4-chlorobenzaldehyde used in Stage C with 6-bromo-1,3-benzodioxole-5-carbaldehyde.
The procedure described in Preparation 1 is followed by replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Stage C with 2-bromo-4-methylbenzaldehyde.
The procedure described in Preparation 1 is followed by replacing the 6-bromo-1,3-benzodioxole-5-carbaldehyde used in Stage C with 2-bromo-benzaldehyde.
The solution of 6.2 g of 2-pyrimidine-2-methylylacetate (40.75 mmol) in 250 mL acetone is successively treated with 14.04 g (167 mmol) of NaHCO3 powder, 13.2 mL (203.75 mmol) of chloroacetaldehyde, and then 3.54 g (40.75 mmol) of lithium bromide. The solution is heated to 60 °C for 24 h. The reaction medium is then dried, concentrated with ethyl acetate, washed with water, dried on MgSO4, filtered on dried concentrate.
The mass spectrum is given by the formula: C8H8N2O2LC/MS: m/z = [M+H]+ = 177
The reaction medium is heated to 130°C for 16 hours in an inert atmosphere. After drying, the residue is taken back into dichloromethane, a solid cake of silicon is filtered onto the wire, washed with water, and MgSO4 and NOCH2 are concentrated on the product. The result is a 5% gel of silicon (OH2O2).
The mass spectrum is given by the formula: C17H12N2O3LC/MS: m/z = [M+H]+ = 325
To a 2.91 g (8.97 mmol) solution of aldehyde obtained at Stage B in 140 mL acetone cooled to 0°C, 2-methylbutene is added, then a mixture of 2.8 g (17.94 mmol) NaH2PO4.2H2O and 2.84 g (31.4 mmol) NaClO2 in solution in 30 mL water is dripped into the solution. The mixture is stirred at room temperature for 4 h. The reaction medium is then concentrated under vacuum to remove the acetone, placed at 0°C and then acidified to pH = 2-3 by adding a drop of 5N HCl solution. A precipitate is observed, which is filtered, vacuumed with water, then with diethyl ether and diethyl ether.
The following is the list of substances that are to be classified as 'sodium nitrate' in the Annex to Regulation (EC) No 1907/2006 of the European Parliament and of the Council:
The following is a list of the main components of the system:
The procedure described in Preparation 1 is followed by replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Stage C with 2-bromo-4-methoxybenzaldehyde.
The procedure described in Preparation 1 is followed by replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Stage C with 2-bromo-5-methoxybenzaldehyde.
Follow the procedure of Preparation 1 by replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Stage C with 7-bromo-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde.
Follow the procedure of Preparation 5 by replacing the 2-bromo-4-chlorobenzaldehyde used in Stage C with 2-bromo-benzaldehyde.
Follow the procedure of Preparation 5 by replacing the 2-bromo-4-chlorobenzaldehyde used in Stage C with 2-bromo-4-fluorobenzaldehyde.
Follow the procedure of Preparation 1 by replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Stage C with 2-bromo-4-fluorobenzaldehyde.
The reaction medium is then agitated at room temperature for 20 h. It is then diluted with dichloromethane, washed successively with HCl 1M, a saturated solution of NaHCO3, a saturated solution of NaCl to neutrality. The organic phase is sequestered to MgSO4, then filtered to dry. The crystal is then obtained in the form of a minimum volume of dichloromethane, then pre-filtered with the product, and then the resulting solution is obtained in the form of a cyclohexane.
RMN 1H: δ (400 MHz ; dmso-d6 ; 300K) : 7.75 (d, 2H , aromatic H, ortho-O-tosyl); 7.6 (d, 2H , aromatic H, ortho-N-tosyl); 7.5 (d, 2H , aromatic H, meta-O-tosyl); 7.3 (d, 2H , aromatic H, meta-N-tosyl); 7.15-6.9 (m, 4H, aromatic H, tetrahydro isoquinoline); 4.4-4.15 (dd, 2H, aliphatic H, tetrahydroisoquinoline); 4.25 (m, 1H, aliphatic H, trahydroisoquinoline); 4.0 (28dd, 2H, aliphatic H, CH2-O-tosyl) (2, 2.7dd, 2H, aliphatic H, trahydroquinoline; 2.3-H, CH2-SO, CH2-SO, CH2-SO, CH3-SO, CH2-SO, CH3-SO, CH3-SO, CH3-SO, CH2-SO, CH3-SO, CH3-SO, CH2-SO, CH3-SO, CH3-SO, CH2-SO, CH3-SO, CH3-SO, CH2-SO, CH3-SO, CH3-SO, CH2-SO, CH3-SO, CH3-SO, CH3-SO, CH2-SO, CH3-SO, CH3-SO, CH2-SO, CH3-SO, CH3-SO, CH3-SO, CH2-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH2-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH2-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH3-SO, CH
IR ν: -SO2: 1339 to 1165 cm1
To a suspension of 8.15 g (214.8 mmol) LiAlH4 in 800 mL methyl tert-butyl ether (MTBE), add 101.2 g of the ditosyl derivative obtained at Stage A (214.8 mmol) in solution in 200 mL MTBE. The set is then heated to 50°C for 2 hours. Cool and set at 0°C, then add 12 mL of a NaOH 5N solution, drop by drop. The set is agitated at room temperature for 45 minutes. The resulting solid is then filtered, washed with MTBE with dichloromethane. The filter is then dried and concentrated. The product is then obtained in the form of a solid.
RMN 1H: δ (400 MHz ; dmso-d6 ; 300K) : 7.70 (d, 2H , aromatic H, ortho N-tosyl); 7.38 (d, 2H , aromatic H, meta N-tosyl); 7.2-7.0 (m, 4H, aromatic H, tetrahydroisoquinoline); 4.4 (m, 2H, aliphatic H, tetrahydroisoquinoline); 4.3 (m, 1H, aliphatic H, tetrahydroisoquinoline); 2.85-2.51 (2dd, 2H, aliphatic H, tetrahydroquinoline); 2.35 (s, 3H, N-Ph-SO-CH3); 0.90 (d, 3H, tetrahydroisoquinoline CH3)
IR ν: -SO2: 1332 to 1154 cm1
The reaction medium is then filtered and the solid is washed several times with methanol. The filtrate is then concentrated dry. After chromatographic column purification on silica gel (dichloromethane/Et/OHNH4OH), the titer product is obtained in the form of an oil.
RMN 1H: δ (400 MHz; dmso-d6; 300K): 7.05 (m, 4H, aromatic H, tetrahydroisoquinoline); 3.90 (m, 2H, aliphatic H, tetrahydroisoquinoline); 2.85 (m, 1H, aliphatic H, tetrahydroisoquinoline); 2.68-2.4 (2dd, 2H, aliphatic H, tetrahydroisoquinoline); 1.12 (d, 3H, tetrahydroisoquinoline-CH3); 2.9-2.3 (m, wide, 1H, HN))
IR: ν: -NH: 3248 cm-1
The solution of 14.3 g (97.20 mmol) of the compound obtained in Stage C in 20 mL anhydrous ethanol is added, drop by drop, 100 mL of a solution of 1M hydrochloride ether. The set is agitated at room temperature for 1 hour, then filtered. The resulting crystals are washed with ethyl ether.
RMN 1H: δ (400 MHz; dmso-d6 ; 300K): 9.57 (m wide, 2H, NH2+ ((tetrahydro isoquinoline)).7.22 (m, 4H, aromatic H, tetrahydroisoquinoline); 4.27 (s, 2H, aliphatic H, tetrahydroisoquinoline); 3.52 (m, 1H, aliphatic H, tetrahydroisoquinoline); 3.03--2.85 (2dd, 2H, aliphatic H, tetrahydroisoquinoline); 1.39 (d, 3H, tetrahydroquinoline-CH3)
The following is a list of the substances which are to be used:
To a solution of 3 g (10.30 mmol) of acetic acid [(3S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-yl]acetic acid in 100 mL of dichloromethane, add 1.10 mL (11.32 mmol) of morpholine, still 4.3 mL (30.9 mmol) of triethylamine, 2.20 g (12.40 mmol) of 1,2-dichloromethane, and 1.70 g (1,68 mmol) of hydroxybenzotriazole. The set is agitated at room temperature for 15 h. The reaction is then diluted with dichloromethane, then successively washed with a saturated solution of 1 HM, a saturated phase of NaOH, a saturated solution of NaCl, and then a neutral solution of MgCl/Cl4 is obtained. After purification, the solution is filtered to the organic medium and then dried in a concentrated form.
RMN 1H: δ (400 MHz; dmso-d6; 300K): 7.20-7.10 (m, 4H, aromatic H, tetrahydroisoquinoline); 4.70 (m, 1H, aliphatic H, CH tetrahydroisoquinoline); 4.75-4.20 (2m, 2H, aliphatic H, CH2 in alpha of N tetrahydroisoquinoline); 3.60 (m, 8H, aliphatic H, morpholine); 3.00 and 2.70 (2dd, 2H, aliphatic H, tetrahydroquinoline); 2.50-2.20 (2d, 2H, aliphatic H, CH2CO); 1.40 (s, 9H, tBu)
The following is a list of the main types of products:
To a 2.88 g (7.18 mmol) solution of the Stage A compound in 16 mL dichloromethane, 80 mL (80 mmol) of a 1M solution of hydrochloride ether is added drop by drop. The set is agitated at room temperature for 15 h, then the suspension is filtered and the precipitate washed with ether.
RMN 1H: δ (400 MHz ; dmso-d6 ; 300K) : 9.80-9.50 (m, 2H, NH2+); 7.30-7.10 (m, 4H, aromatic H, tetrahydroisoquinoline); 4.30 (m, 2H, aliphatic H, CH2 in alpha of N tetrahydroisoquinoline); 3.80 (m, 1H, aliphatic H, CH tetrahydroisoquinoline); 3.70-3.40 (2m, 8H, aliphatic H, morpholine); 3.15 and 2.8 (m, 4H, aliphatic H, CH2 tetrahydroisoquinoline and CH2CO)
The following is a list of the substances which are to be used:
The solution of 2.2 g (7.44 mmol) of the Stage B compound is prepared in 22 mL MTBE and 5 mL dichloromethane. After cooling in an ice bath at 0 °C, 15 mL (15 mmol) of a solution of 1M LiAlH4 in tetrahydrofuran is added to the solution by drip. The solution is then agitated at room temperature for 6 h. It is placed at 0 °C, then 1 mL of a solution of NaOH 5N is added by drip. The solution is agitated at room temperature for 45 minutes. The solid is then filtered and washed with MTBE, then with dichloromethane and the filler is dried in this way. The crystals are diluted to the desired temperature and dichloromethane is added.
RMN 1H: δ (400 MHz ; dmso-d6 ; 300K) : 11.35 + 9.80 (2m, 2H, NH2+); 10.00 (m, H, NH+); 7.20 (m, 4H, H aromatic, tetrahydroisoquinoline); 4.30 (s, 2H, H aliphatic, CH2 in alpha of N tetrahydroisoquinoline); 4.00 + 3.85 (2m, 4H, H aliphatic, CH2 in alpha of N morpholine); 3.70 (m, 1H, H aliphatic, CH tethrahydroisoquinoline); 3.55-3.30 (m, 4H, H aliphatic, CH in alpha of morpholine and CH2-Morpholine); 3.15 (m, 1H, H aliphatic, CH2 in alpha of N tetrahydroisoquinoline); 3.10 (m, 4H, H aliphatic, CH2 in alpha of morpholine; 2H, H 2H, CH2 in alpha of morpholine; 2.15 (m, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H
IR ν: NH+ / -NH2+: between 3500 and 2250 cm-1; ν: C=C: weak 1593 cm-1; ν: aromatic C-H: 765 cm-1
The compound of the title is obtained from the acid (3S)-2-[benzyl) carbonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid based on a protocol from the literature (Jinlong Jiang et al Bioorganic & Medicinal Chemistry Letters, 14, 1795, 2004).
The reaction medium is then stirred at room temperature for 2 hours. The product is then hydrolyzed by slowly adding water. The product is extracted several times with CH2Cl2. The organic phases are then grouped and successively treated with a solution of HCl 1N, a saturated solution of NaCl, a saturated solution of NaCO3 and a saturated solution of NaCO3 until neutral. They are dried and concentrated on Mg4 and Mg4. After purification, they are obtained in the form of a chromium-Other (Other) gel.
The following information shall be provided for each test chemical:
To a 15.4 g solution of the derivative obtained at Stage B (41.02 mmol) in 250 mL anhydrous DMSO, 22 g (449 mmol) of sodium cyanide is added. The set is then heated to 60 °C for 12 h. The set is allowed to cool, then the reaction medium is diluted by adding ethyl acetate. It is then hydrolyzed with a saturated solution of NaHCO3. After 2 further extractions with ethyl acetate, the organic phases are grouped, purified with H2O, seeded to MgSO4 and concentrated to dry. After purification by silicon gel chromatography (Ethexane/O 7/3), the desired product is obtained in the form of an oil.
The following information shall be provided for each test chemical:
The reaction medium is then gradually brought back to room temperature and then stirred for 14 hours. The reaction medium is then hydrolyzed by slow addition of a saturated solution of NH4Cl. After 2 extractions with ethyl acetate, the organic phases are grouped and dried on MgSO4. After dried concentration, the desired product is obtained in the form of a foam which is used directly without purification for the next protective step.
To a solution of 15.6 g of the derivative obtained in Stage D (50.3 mmol) in 670 mL of CH2Cl2, 13.2 g (60.36 mmol) of Boc2O per pellet, triethylamine 14 mL (100.6 mmol) and DMAP in catalytic quantity are added successively. The whole is agitated at room temperature for 5 h. The reaction medium is then hydrolyzed with water and extracted 2 times with CH2Cl2.
The following information shall be provided for each test chemical:
The reaction medium is then filtered and concentrated dry. The desired product is obtained as a solid which is incorporated into a pentane/Et2O (90/10), crushed and filtered mixture. After drying, the product is obtained as a solid.
RMN 1H: δ (400 MHz; dmso-d6; 300K): 7.1-6.98 (m, 4H, aromatic H, tetrahydroisoquinoline); 6.83 (m, 1H, CH2NHBoc); 3.85 (s, 2H, aliphatic H, tetrahydroisoquinoline); 3.09 (q, 2H, CH2NHBoc); 2.73 (m, 1H, aliphatic H, tetrahydroisoquinoline); 2.70 and 2.39 (2m, 2H, aliphatic H, tetrahydroisoquinoline); 1.63 (m , 2H, aliphatic H) 1.38 (s, 9H, NHCOBu);
The following is a list of the substances which are to be used in the preparation of the product:
The procedure is identical to that of Step A of Preparation 1'.
A solution of 5 g of tert-butyl 3-morpholino-3-oxopropanoate (21.81 mmol) is added to a suspension of 1 g NaH (60%) (25.08 mmol) in 30 mL MTBE by dripping a solution of 5 g of tert-butyl 3-morpholino-3-oxopropanoate (21.81 mmol) in 20 mL anhydrous MTBE. This suspension is agitated at room temperature for 1 h, then the resulting Stage A compound is added as a powder. The set is agitated at 60 °C for 30 h. A solution of 100 mL saturated ammonium chloride is added. This solution is extracted from dichloromethane. The organic phase is then concentrated on MgSO4, filtered and dried.The product obtained is an oil.
The frequency range of the signal is defined as the frequency range of the signal at which the signal is transmitted.
A 9.5 g (17.97 mmol) solution of the compound obtained in Stage B in 40 mL of dioxane is added to the solution of dioxane by adding 20 mL of a 4M solution of hydrochloric acid in the solution.
The frequency of the signal is measured at a frequency of 1 Hz (400 MHz, dmso-d6) δ ppm: 12.75 (m, 1 H), 7.6 (2*d, 2 H), 7.3 (2*d, 2 H), 7.1/6.95 (2*m, 4 H), 4.7-4.2 (d, 2 H), 4.25/4.12 (2*m, 1 H), 3.9-3.3 (m, 9 H), 2.55 (d, 2 H), 2.3 (2*s, 3 H), 1.8 (t, 2 H)
IR (ATR) cm-1: v: -OH: 3500 to 2000; ν: >C=O: 1727 (acid) ν: >C=O: 1634 (amide); v: -S02: 1330 to 1155
The reaction medium is then diluted with dichloromethane, washed successively with a saturated lithium chloride solution, then a saturated NaCl solution. The organic phase is then dried to MgSO4, filtered, dry-concentrated. After chromatographic column purification on silica gel (cyclohexane/ethyl acetate), the product is obtained in the form of a hendu.
The frequency of the signal is measured at a frequency of 1 Hz (400 MHz, dmso-d6) δ ppm: 7.65 (d, 2 H), 7.3 (d, 2 H), 7.15/7 (2 m, 4 H), 4.6 (d, 1 H), 4.25 (d, 1 H), 4.2 (m, 1 H), 3.5 (m, 4 H), 3.4 (2 m, 4 H), 2.6 (2 dd, 2 H), 2.35 (s, 3 H), 2.3 (m, 2 H), 1.5 (quad, 2 H)
The following is a list of the main components of the IRR:
The solution is then diluted with MTBE and dichloromethane. The suspension is filtered and the precipitate is washed with MTBE and dichloromethane. The organic phase is dried to MgSO4, then filtered and concentrated to MgSO4. After purification by chromatographic gel of 5 M (OH/OH) chloride on a silicone gel, the resulting product is obtained as MgSO4.
The frequency of the signal is measured at a frequency of 1 Hz (400 MHz, dmso-d6) δ ppm: 7.68 (d, 2 H), 7.32 (d, 2 H), 7.1 (massive, 4 H), 4.65/4.23 (AB, 2 H), 4.2 (m, 1 H), 3.55 (t, 4 H), 2.7/2.6 (ABx, 2 H), 2.35 (s, 3 H), 2.25 (t, 4 H), 2.2 (t, 2 H), 1.4/1.3 (2m, 4 H).
(IRATR) cm-1: ν: -S02: 1333-1158 The number of units of measurement is given in the table below.
The reaction medium is then filtered, the solid is washed several times with methanol, and the filtrate is concentrated dry. After chromatographic column purification on silica gel (dichloromethane /EtOH /NH4OH), the desired product is obtained in the form of an oil.
The frequency of the signal is measured at a frequency of approximately 1 Hz (400 MHz, dmso-d6) δ ppm: 7.3 (d, 2 H), 7.1 (t, 2 H), 7.1 (d+t, 3 H), 7 (d, 2 H), 3.9 (s, 2 H), 3.55 (t, 4 H), 2.75 (m, 1 H), 2.72/2.45 (dd, 2 H), 2.35 (t, 4 H), 2.25 (t, 2 H), 1.6 (m, 2 H), 1.45 (m, 2 H)
The following is the list of the substances which are to be used in the preparation of the product:
High resolution mass (ESI+-/FIA/HR):Raw formula: C16 H24 N2 O[M+H]+ calculated: 261.1961[M+H]+ measured: 261.1959
The preparation 2' procedure is followed by replacing the morpholine used in Stage A with 3,3-difluoro-1-piperin.
RMN 1H: δ (400 MHz ; dmso-d6 ; 300K) : 11.3 (m, 1H, NH+) ; 10.2-9.8 (m, 2H, NH2+); 7.25 (m, 4H, aromatic H, tetrahydroisoquinoline); 4.3 (wide s, 2H, aliphatic H, CH tetrahydroisoquinoline); 4.0-3.3 (m, 7H, aliphatic H) 3.15-2.95 (dd, 2H, aliphatic H, CH ; tetrahydroisoquinoline); 2.4-1.9 (m, 6H, aliphatic H, H 3,3-fluoro-1-pipyridine)
The following is a list of the main types of products:
The preparation 2' procedure is followed by replacing the morpholine used in Stage A with 3-methoxyazetin.
The mean value of the measurement is calculated as the sum of the values of the measurements of the two samples of the test chemical and the measurements of the measurements of the test chemical and the measurements of the measurements of the test chemical.
Follow the procedure of Preparation 1 by replacing the [(3S)-1,2,3,4-tetrahydroisoquinoline-3-yl]methanol used in Stage A with [(3R)-1,2,3,4-tetrahydroisoquinoline-3-yl]methanol.
The compound of the title is obtained from 4-aminophenol in the THF in the presence of imidazole and tert-butyl ((dimethyl) silyl chloride according to the protocol described in the literature (S. Knaggs et al, Organic & Biomolecular Chemistry, 3(21), 4002-4010; 2005).RMN 1H: δ (400 MHz ; dmso-d6 ; 300K) : 6.45-6.55 (dd, 4H, H ; aromatics); 4.60 (m, 2H, NH2-Ph) 0.90 (s, 9H, Si (CH2) 2CH3) 2); 0.10 (s, 6H, Si (CH2) 2CH3)
The following is the list of the products covered by the exemption:
To a 30.8 g (0.137 mol) solution of the Stage A compound in 525 mL anhydrous toluene, 29.8 g of sodium tert-butylate (0.310 mol), 4.55 g of Pd2 ((dba) 3 (also called tris ((dibenzylideneacetone) dipalladium))) (4.96 mmol), 4.81 g of 2-di-tert-butylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl (9.91 mmol) and 12.8 mL of 4-bromo-1-methyl-1H-pyrazole (0.124 mol) are successively added. The whole is then heated to 30 mn argon gas and then cooled for 3 h. The reaction is reconcentrated, in the dichlorinated medium, then filtered on the product to provide a new concentrated solid in the form of dichlorinated dichlorinated chloride, then purified in a gel (O2Cl2) The product is then released into the liquid crystalline.
The following is a list of the most commonly used methods of measuring the concentration of hydrocarbons in the atmosphere:
The following is a list of the main types of water:
Err1:Expecting ',' delimiter: line 1 column 91 (char 90)
After 20 minutes of agitation at 0°C, the hydrochloride of 4- (((2-chloroethyl) morpholine (10.4 g; 56 mmol) is added in 1 hour's time. After a night of agitation at room temperature, the reaction medium is placed for 5 hours at 80°C. It is then poured over a mixture of aqueous sodium bicarbonate and dicholoethane. The aqueous phase is extracted from the dichloromethane. The organic phase is concentrated on MgSO4, dried to the residue and purified by chromatography on a gel of silicon (OH2/Cl2Me) to provide the desired product.
The following are the values of the frequency bands: δ (400 MHz; CDCl3 ; 300K) :7.75 (d, 1H) ; 7.30 (dd, 1H) ; 7.20 (d, 1H) ; 7.15 (d, 1H) ; 6.40 (d, 1H) ; 4.20 (t, 2H) ; 3.70 (m, 4H) ; 2.75 (t, 2H) ; 2.45 (m, 4H)
Err1:Expecting ',' delimiter: line 1 column 91 (char 90)
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The solution of 12 g of 4-anilinephenol (64.7 mmol) in 200 mL of acetonitrile is then dried on magnesium sulfate, then filtered and evaporated dry. The resulting product is then chromatographed on a silica gel (oil ether/dichloromethane gradient). The product is then obtained in the form of a powder.
The following is a list of the active substances in the active substance:
IR v: >NH: 3403 cm-1; >Ar: 1597 cm-1
A solution of 4-hydroxy-N-phenylenyl-aniline (30 g; 162 mmol) in acetonitrile (400 mL) is added 58 g of Cs2CO3 (178 mmol) and stirred for 15 minutes at room temperature. Benzyl bromide (22.5 mL; 178 mmol) is then added by drip and the reaction medium is heated at the backflow for 4 h. After filtration and rinsing with acetonitrile, the filtrate is concentrated and chromatographed on silica gel (petroleum ether gradient / AcOEt).
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To a solution of 4-bromobenzaldehyde (500 mg; 2.7 mmol) in 12 mL dichloromethane, 3,3-difluoropiperidine hydrochloride (470 mg; 3 mmol), sodium triacethoxyborohydride (860 mg; 4 mmol) and acetic acid (0.17 mL; 3 mmol) are added in this order. After 1 h agitation at room temperature, the reaction medium is poured over a mixture of aqueous sodium bicarbonate and dichloromethane. The aqueous phase is extracted from the dichloromethane. The organic phase is dried on MgS04, concentrated in a dry solution and the residual is purified by chromatography on silica gel (OH2/Cl2Me) to provide the desired product in the form of oil.
The following is a list of the most commonly used parameters:
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To a solution of 4-bromophenyllacetic acid (4 g; 18.6 mmol) and 3,3-difluoropiperidine hydrochloride (2,5 g; 20.4 mmol) in dichloromethane (190 mL) add EDC (3,8 g; 22.3 mmol), HOBt (3 g; 22.3 mmol) and triethylamine (1,3 mL; 593 mmol). The reaction medium is agitated for 17 h at room temperature and then poured over a mixture of aqueous sodium bicarbonate and ethyl acetate. The aqueous phase is extracted from the solid ethyl acetate. The organic phase is washed with hydrochloric acid 0,1 g, water, and then the residual product is washed over the purified petroleum gel to provide a concentrated solution of N4 Mg/mol of ethyl silicate.
The frequency range of the signal is defined as the frequency range of the signal, and the frequency range of the signal is defined as the frequency range of the signal.
The reaction medium is heated to 80°C for 3 hours, then the solvent is evaporated at reduced pressure. The residue is treated with methanol (50 mL), then with 5N HCl (5.8 mL). After a night of agitation at ambient temperature and 3 hours at reflux, the pH of the reaction medium is adjusted to 8 by a saturated solution of sodium bicarbonate, then in the dry phase is extracted to dichromethane. The organic residue is chlorinated to MgS04, and the residual is purified to a chromium chloride gel to provide the expected product of H2OH (Me2OH) in the form of a silicon.
The following is a list of the most commonly used parameters:
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The NHR3R4 amines containing a hydroxy substituent which are used to synthesize the compounds of the invention include: 4- ((4-toluidino) phenol, 4- ((4-chloroanilino) phenol, 4- ((3-fluoro-4-methylanilino) phenol, 4- ((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((
The hydroxy function (s) of the secondary amines listed above are pre-protected by a suitable protective grouping prior to any coupling to an acid derivative of the compound of formula (VII) as defined in the previous general process.
To a 2 g solution of Preparation 1 in 20 mL dichloromethane, add at room temperature 5.5 mL N,N,N triethylamine (6.96 mmol), the Preparation compound l (6.96 mmol), then 0.94 g hydroxybenzotriazole (HOBT) and 1.34 g 1-ethyl-3-(3'-dimethylaminopropyl) -carbodiimide (EDC) (6.96 mmol) to a solution of Preparation 1. The reaction medium is then agitated at room temperature for 1 night, then poured on a solution of ammonium chloride and extracted with Othyle Acetate. The organic phase is then dried on magnesium sulphate, filtered and evaporated. The raw product is then obtained by heptanol/ silicon heptanol gel.- What?
RMN1H: δ (400 MHz; dmso-d6; 300K): 7.2-6.8 (m, 4H, aromatic H, tetrahydroisoquinoline H) ; 7.10 (s, 1H, aromatic H, benzodioxole) ; 6.92 (s, 1H, aromatic H, benzodioxole) ; 6.25 (m, 1H, H tetrahydroindolizine); 6.10 (s, 2H, aliphatic H, OCH2O) ; 4.80 (m, 1H, aliphatic H, tetrahydroquinoline H) ; 4.20 (m, 1H, aliphatic H, tetrahydroisoquinoline H) ; 4.1-3.5 (m, 3H, 3H) ; 3.60 (s, 3H, 1H, aromatic H, benzodioxole) ; 2.90 (m, 2H, 2H, H trahydrahydrolizine; 2.45 (m, 2H, aliphatic H, tetrahydroquinoline H, 2H, 3H, CO), 1.80 (m, 3H, 3H) ; 2.90 (m, 2H, 3H, 3H, 3H, 3H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 4H, 5H, 5H
A solution of lithium hydroxide (675 mg, 16.1 mmol) is added to a solution containing 8.26 mmol of the Stage A compound in 24 mL of dioxane. The solution is placed in a microwave oven at 140 W, 100 °C for 2 hours. The reaction medium is then filtered and evaporated. The resulting solid is dried at 40 °C in a furnace in the presence of P2O5.
Err1:Expecting ',' delimiter: line 1 column 503 (char 502)
The solution is then diluted in dichloromethane and washed successively with HCl 1N solution, a saturated NaHCO3 solution, then a saturated NaCl solution until a neutral pH is reached. The organic phase is dried on magnesium sulfate, filtered and evaporated. The resulting raw product is then silica-based (dichloromethane/ethanol gradient) and lyophilised to provide the desired product.
High resolution mass (ESI+) :Raw formula: C42H38CN4O5[M+H]+ calculated: 679.2920[M+H]+ measured: 679.2908
Following the silica gel purification step (see Step D), the solid is then solubilised in dichloromethane and 2 mL of 1N hydrochloride ether is added. The whole is agitated for 1 hour and then evaporated dry. The resulting hydrochloride is dissolved in a water/acetonite mixture until total solubilisation and then lyophilised.
Basic microanalysis: (% theoretical: measured)
The following table shows the number of units of the test chemical:
Err1:Expecting ',' delimiter: line 1 column 451 (char 450)
Err1:Expecting ',' delimiter: line 1 column 244 (char 243)
The following data are available for the analysis of the data:
Err1:Expecting ',' delimiter: line 1 column 247 (char 246)
Sodium cyanoborohydride (900 mg; 15 mmol) is added at room temperature to a 1.3 g (1.45 mmol) solution of the Stage A compound in 13 mL acetic acid. After 2 h agitation, the reaction medium is concentrated dry, then diluted with methanol (8 mL) and treated with a molar potassium solution in methanol (6.3 mL; 6.3 mmol). After 1 h at room temperature, the reaction medium is concentrated dry, then chromatographed on silica gel (dichloromethane/methanol gradient), then lyophilized to give the desired product in the form of a powder.
Basic microanalysis: % measured (theoretical)
The number of persons employed in the sector is estimated at approximately 78,5 million.
The process is similar to that described for Example 7 by substituting the compound from Preparation 4 for the compound from Preparation 2 at Step A.
Basic microanalysis: (% theoretical: measured)
The following table shows the number of units of the test chemical:
Err1:Expecting ',' delimiter: line 1 column 216 (char 215)
A solution of the Stage A compound (1.1 g; 1.25 mmol) in methanol (6 mL) is to be treated with a solution of 1M potassium in methanol (6.2 mL; 6.2 mmol). After 2 h at room temperature, the methanol is evaporated under vacuum and the residue is collected in a mixture of dichloromethane and a saturated sodium bicarbonate solution. The combined organic phases are dried in MgSO4 and dried in a dry concentrated form. The resulting residue is purified by silica gel chromatography (gradient CH2Cl2/OH) to give the desired product in solid form.
IR: v: NH: 3450 cm-1; v: CO: 1745 to 1620 cm-1
Add triethylamine (0.2 mL; 1.39 mmol) and pivaloyl chloride (0.11 mL; 0.93 mmol) at room temperature to a solution of the Stage B compound (0.7 g; 0.93 mmol) in dichloromethane (7 mL). After 2 hours of stirring at room temperature, the reaction medium is washed with water, brine, dried on MgSO4 and dried. The resulting residue is used as is for the next step without analysis.
After 15 hours of stirring at room temperature, a saturated sodium bicarbonate solution is slowly added to the reaction medium, and the phases are then separated. The aqueous phase is extracted from the dichloromethane. The organic phases are purified on MgSO4 and concentrated dry. The resulting residue is chromatographed on silica gel (gradient CH2Cl2/OH) to give the desired product in the form of a solid.
The following information shall be provided for each test chemical:
Formaldehyde (48 μL; 1.74 mmol) and then sodium triacetatoxyborohydride (161 mg; 0.76 mmol) are added at room temperature to a solution of the previous stage compound (0.41 g; 0.54 mmol) in dichloromethane (2 mL). After 2 h of stirring at room temperature, the reaction medium is diluted in dichloromethane and then washed with a saturated solution of sodium bicarbonate. The organic phase is purified with MgSO4 and dried in dry concentrate. The residue is obtained by silica gel chromatography (gradient CH2Cl2/MeOH).
The following information is provided for the purposes of this Regulation:
A solution of lithium hydroxide (27 mg; 0.65 mmol) is added to a solution of the previous stage compound (0.25 g; 0.32 mmol) in dioxane (1 mL) in water (1 mL). After 5 h of stirring at room temperature, the reaction medium is concentrated and diluted by a saturated solution of sodium bicarbonate. The aqueous phase is extracted to CH2Cl2. The organic phase is dried on MgSO4 and dried. The resulting residue is purified by silica gel chromatography (gradient CH2Cl2/MeOH). The desired product is then obtained as a solid.
Theoretical %: measured
The number of employees in the company is not known.
The following data are available for the analysis of the data:
Err1:Expecting ',' delimiter: line 1 column 245 (char 244)
Err1:Expecting ',' delimiter: line 1 column 244 (char 243)
Err1:Expecting ',' delimiter: line 1 column 244 (char 243)
Err1:Expecting ',' delimiter: line 1 column 244 (char 243)
The following data are available for the analysis of the data:
The following data are available for the analysis of the following data:
Follow the step A protocol in Example 1 by replacing the compound in Preparation 1 with the compound in Preparation 8.
4.47 mmol of the Stage A compound in solution in 75 mL of THF is agitated in the presence of 37 mL of HCl 1 M at the reflux for 15 h. 100 mL of water and 100 mL of ethyl acetate are added to the reaction medium. 4 g of NaHCO3 (4.7 mmol) is then added as a powder until a basic pH is reached. The compound is extracted with ethyl acetate, the organic phase is dried on MgSO4, filtered and dry concentrated.
The reaction medium is agitated for 1 hour at room temperature. 50 mL of HCl 1M is then added and the methanol is evaporated. The aqueous phase is then neutralized with NaHCO3, then extracted with dichloromethane. The organic phase is successively washed with H2O, dried on MgSO4, filtered and concentrated dry. The oil thus obtained is chromatographically purified (dichlorothenate/thanomethane-ammonia gradient) to lead to the desired product.
A 331 mg (8.26 mmol) suspension of sodium hydride in 15 mL anhydrous THF cooled to 0°C is added to 4.13 mmol of the compound obtained in Stage C. This suspension is agitated for 15 min at 0°C, then a 790 μL (9.1 mmol) solution of allyl bromide in 10 mL THF is added slowly (over 15 min). The reaction medium is agitated for 1 h at 0°C, then 15 h at room temperature. This solution is hydrolysed with a saturated solution of NH4Cl. The compound is extracted with ethyl acetate; the organic phase is dried on MgSO4, filtered and concentrated. The purified heat is then obtained by flash chromatography (acetyl cycloate) to produce the desired product.
The procedures described in Steps B and C of Example 1 shall be followed using appropriate reagents.
The allyl group is then de-protected in the presence of 1,3-dimethylpyrimidine-2,4,6 ((1H,3H,5H) -trione (also called dimethylbarbiturate) and tetrakis (triphenylphosphine) palladium in a mixture of methanol and dichloromethane.
After 20 minutes of agitation, the reaction medium is concentrated dry and then diluted in 10 mL of DMSO. 470 mg of NaN3 powder (7.2 mmol) is added. The reaction medium is left at room temperature for 20 h, then 20 h at 50°C. It is poured over a mixture of dichloromethane and water. The organic phase is washed 3 times in SO3, then in brine, then dried on Mg4, then dried to give the desired product in the following concentration.
After 15 hours of agitation under 1 bar of hydrogen, the reaction medium is filtered on Whatman and concentrated dry. After chromatographic column purification on silica gel (dichloromethane/methanol gradient), the solid is then solubilised in dichloromethane and 2 mL of 1N hydrochloride ether are added. The whole is agitated for 1 hour and then evaporated dry. The hydrochloride is dissolved in a water/acetyl sulphate until total solubilisation, and lyophilisate is then compounded to lead to the desired powder form.
Basic microanalysis: (% theoretical: measured)
The following table shows the number of units of the test chemical:
Follow the procedure in Step A of Example 1 using (3S)-1,2,3,4-tetrahydroisoquinoline-3-ylmethanol.
After 1 hour of agitation, add allyl bromide (1.7 mL; 19 mmol). The reaction medium is agitated for 48 h at room temperature, then poured over a mixture of ethyl acetate and water. The organic phase is concentrated 3 times with water, with a saturated LiOH solution, dried on MgSO4, dry chromatography. After purification by silica gel on silica (dichloromethane/methanol gradient), the desired product is obtained in the form of a solid.
The following is a list of the most commonly used parameters for the calculation of the value of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement
Err1:Expecting ',' delimiter: line 1 column 169 (char 168)
After 15 hours of agitation at 45°C, the reaction medium is poured over a mixture of ethyl acetate and water. The organic phase is washed 2 times with water, treated with SO4, concentrated dry and diluted in Mg (5 mL). The whole is agitated for 24 hours under hydrogen in the presence of Pd/C (100 mg/dL). The reaction medium is then filtered for a second time, then concentrated in the form of dichlorophenol/methyl chloride, and finally produced in the form of a gel (chromophilus) and a silicone.
Basic microanalysis: % measured (theoretical)
The number of persons employed in the service sector is estimated at approximately 72,800.
The following data are available for the analysis of the following data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the following data:
The following is a list of the main components of the test chemical:
The following data are available for the analysis of the following data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the following data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the following data:
The following table shows the results of the analysis:
The following data are available for the analysis of the following data:
The following formula is used for the calculation of the CO2 savings:
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the following data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the following data:
The following data are available for the analysis of the following data:
To a 2 g solution of Preparation 1 in 20 mL dichloromethane, add at room temperature 5.5 mL N,N,N triethylamine (6.96 mmol), the compound of Preparation 3' (6.96 mmol), then 0.94 g hydroxybenzotriazole (HOBT) and 1.34 g 1-ethyl-3-(3'-dimethylaminopropyl) -carbodiimide (EDC) (6.96 mmol) to a solution of Preparation 1 in 20 mL dichloromethane. The reaction medium is then agitated at room temperature for 1 night, then poured over a solution of ammonium chloride and extracted with Othyle Acetate. The organic phase is then dried on magnesium sulphate, filtered and evaporated. The raw product is then obtained by heptanol (heptanol) and then purified on a heptanol gel.- What?
RMN1H: δ (400 MHz; dmso-d6 ; 300K): 7.2-6.8 (m, 4H, aromatic H, tetrahydroisoquinoline H) ; 7.15-6.90 (m, 4H, aromatic H, tetrahydroisoquinoline H) ; 7.00-6.80 (m, 2H, aromatic H, benzodioxole) ; 6.68+6.55+6.25 (m, 1H, NH); 6.50-6.05 (m, 1H, aromatic H, tetrahydroindolizine H); 6.12 (m, 2H, aliphatic H, OCH2O) ; 4.95+4.20+4.10 (m, 2H, aliphatic H, CH2N tetrahydroisoquinoline H); 4.85+4.78+3.80 (m, 1H, aliphatic H, trahydrozoquinoline H); 1.68+6.55+6.25 (m, 1H, NH); 4.50-6.05 (m, 1H, aromatic H, tetrahydrozolizine H); 2.50-2.50 (m, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2The following substances are considered to be toxic if they are used in the manufacture of the active substance:
A solution of lithium hydroxide (675 mg, 16.1 mmol) is added to a solution containing 8.26 mmol of the Stage A compound in 24 mL of dioxane. The solution is placed in a microwave oven at 140 W, 100 °C for 2 hours. The reaction medium is then filtered and evaporated. The resulting solid is dried at 40 °C in a furnace in the presence of P2O5.
Err1:Expecting ',' delimiter: line 1 column 503 (char 502)purified by silica gel chromatography (dichloromethane/methanol gradient) to lead to the expected product.
RMN1H: δ (400 MHz; dmso-d6; 300K): 7.0 (m, 11H, aromatic H, Ph + 4H, tetrahydroisoquinoline + 2H, PhO) ; 6.80-6.65 (m, 2H, aromatic H, PhO) ; 6.95-6.85 (m, 2H, aromatic H, benzodioxole); 6.70+6.40 (3tl, 1H, NH); 6.10 (m, 2H, aliphatic H, OCH2O) ; 5.25-4.85 (m, 1H, aromatic Hindo, tetrahydrolizine); 5.00+4.00 (m, 2H, aliphatic H, CH2N, trahydroisoquinoline) ; 4.90-3.60 (m, 1H, aliphatic H, trahydroquinoline; CH3.10; 4.40; 2.40; 3.40; 2.50; 2.00; 2.50; 2.50; 2.50; 2.50; 3.00; 2.50; 2.50; 2.50; 2.50; 3.00; 2.50; 2.50; 3.00; 2.50; 3.00; 2.50; 3.00; 2.50; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.00; 3.The following substances are to be classified as chemicals with a specific active substance: CH2CH tetrahydroindolizine); 3.00-2.50 (m, 2H, aliphatic H, CH2NHBoc); 1.80-1.50 (m, 4H, aliphatic H, CH2CH2 tetrahydroindolizine); 1.50-1.30 (m, 2H, aliphatic H, CH2CH2NHBoc); 1.35 (2s, 9H, aliphatic H, tBu); 0.90 (s, 9H, aliphatic H, tBu-Si); 0.10 (m, 6H, aliphatic H, tBu-Si);
After 3 hours of stirring at room temperature, the reaction medium is treated with a solution of HCl 4M in 6 mL of dioxane. After 2 hours of stirring at room temperature, the reaction medium is concentrated and treated with a saturated aqueous solution of NaHCO3 and extracted with methylene chloride. The organic phase is then dried on magnesium sulfate, then filtered and dry evaporated. The resulting raw product is then chromatographically purified on silica gel (dichloromethane/methylene dichloromethane gradient).The compound is then dissolved in 5 mL of dichloromethane and 2.5 mL of 1M hydrochloride ether is added.
Basic microanalysis: (% theoretical: measured)
The following table shows the number of units of the test chemical:
High resolution mass (ESI+) :Raw formula: C40H38N4O5[M+H]+ calculated: 655.2915[M+H]+ measured: 655.2915RMN1H : δ (400 MHz ; dmso-d6 ; 300K) : 9.55+9.45 (2s, 1H, OH); 7.80+7.75 (2s, 3H, NH3+); 7.46-6.55 (m, 11H, aromatic H, Ph + 4H, tetrahydroisoquinoline + 2H, PhO); 6.90-6.55 (m, 2H, aromatic H, PhO); 7.00-6.70 (plus several s, 2H, aromatic H, benzodiole); 5.The following are the active substances which may be used in the manufacture of the active substance: 35-5.00 (multiple s, 1H, aromatic H, tetrahydroindolizine); 6.10 (multiple s, 2H, aliphatic H, OCH2O); 5.00-3.35 (multiple m, 4H, aliphatic H, CH2N tetrahydroisoquinoline + CH2N tetrahydroindolizine); 4.85+4.75+3.60 (multiple m, 1H, aliphatic H, CH tetrahydroisoquinoline); 2.85-2.45 (multiple m, 2H, aliphatic H, CH2NH2); 3.00-2.45 (multiple m, 2H, aliphatic H, CH2C tydroindolizine); 3.05+2.30 (multiple m, 2H, aliphatic H, CH2CH); 1.85-1.40 m (multiple m, 2H, aliphatic H, CH2H, CH2, aliphatic H, CH2, CH2, CH2, H1, CH2, CH2, H1, CH2, CH2, H1, CH2, H1, CH2, CH2, H2, H2, CH2, H2, CH2, H2, H2, H2, H2, H2, H2, H3, H4, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H5, H
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the following data:
The following data are available for the analysis of the following data:
The process is similar to that described in Step A of Example 37.
A 337 mg NaH (60%) (8.41 mmol) suspension in 13 mL dimethylformamide is dripped with a 1.01 g (1.68 mmol) solution of the Stage A compound in 13 mL dimethylformamide. This suspension is stirred at room temperature for 15 min, then 1.08 g (5.04 mmol) of 2,2-difluoroethyl trifluoromethanesulfonate is added to 13 mL dimethylformamide. The set is stirred at room temperature for 2 h. A 20 mL solution of saturated ammonium chloride is added. The solution is extracted from the acetylated cycloacetate. The organic phase is then dried on Mg4, filtered to concentrate.The product obtained is an oil.
High resolution (ESI+):Raw formula: C37H43CN3O7[M+H]+ calculated: 680.3142[M+H]+ measured: 680.3145RMN1H: δ (400 MHz; dmso-d6; 300K): 7.25-6.90 (m, 4H, H aromatic, tetrahydroisoquinoline); 7.10-6.75 (m, 2H, H aromatic, benzodioxole); 6.40-6.05 (m, 1H, H aromatic, tetrahydroindolizine); 6.10 (m, 2H, H aliphatic, OCH2O); 6.25-5.90 (m, 1H, H aliphatic, CHF2); 4.95-4.10 (m, 2H, H aliphatic, CHCH2N); 3.80-3.75 (m, 2H, H aromatic, CH2N); 3.80-2.60 (m, 2H, CH2N; 2.60-2.02-H aliphatic, CH2N; 3.80-2.02-H aliphatic, CH2N; 3.80-2.02-H aliphatic, CH2N; 2.60-2.02-H aliphatic, CH2N; 3.80-2.02-H aliphatic, CH2N; 2.60-2.02-H (m, 2H aliphatic, CH2N; 2.60-2.02-H, CH2N; 3.80-2.02-H, CH2N; 2.60-2, CH2N; 2.60-2, H aliphatic, CH2N; 2.60-2, CH2N; 2.5-H, 2.60-2, H aliphatic, CH2N; H2N; 2.60-2, H aliphatic, CH2N; 2.0); H2H, H, H2H, H aliphatic, H, H2N; 4.02-H, H, H, H, H2H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H,The following are the main components of the test:
The process is similar to that described in Steps B and C of Example 37.
RMN1H: δ (400 MHz ; dmso-d6 ; 300K) : 7.30-6.60 (m, 9H, aromatic H, 4H tetrahydroisoquinoline + Ph); 6.90-6.70 (m, 2H, aromatic H, benzodiazole); 6.80-6.60 (m, 4H, PhO); 6.10 (m, 2H, aliphatic H, OCH2O); 6.20-5.90 (m, 1H, aliphatic H, CHF2); 5.50-4.80 (4s, 1H, aromatic H, tetrahydrolizine); 5.20-4.00 (m, 2H, aliphatic H, CH2N, t-hydroquinoline) ; 4.80+4.70+3.50 (3m, 1H, aliphatic H, t-hydroquinoline); 1.0.1-0.3m; 1.0.3-0.3m; 1.0.2-0.2m; 2.0.2-0.2 (H, 2.0, 2.0, 2.0, 2.0, 2.0, 2.0, 2.0, 3.0, 2.0, 2.0, 2.0, 3.0, 2.0, 2.0, 2.0, 3.0, 2.0, 2.0, 2.0, 3.0, 2.0, 2.0, 2.0, 2.0, 3.0, 2.0, 2.0, 2.0, 3.0, 2.0, 2.0, 2.0, 3.0, 2.0, 2.0, 2.0, 3.0, 3.0, 3.0, 3.0, and 2.0, and 2.
After 3 hours of stirring at room temperature, the reaction medium is treated with a solution of 4M HCl in 6 mL of dioxane. After 2 hours of stirring at room temperature, the reaction medium is concentrated and treated with a saturated aqueous solution of NaHCO3, then extracted with methylene chloride. The organic phase is then dried on magnesium sulfate, then filtered and evaporated to dry. The resulting crude product is then chromatographically purified on silica gel (dichloromethane/methanol gradient) to give the desired product in the form of::: a foam: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: a solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid: solid:
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The maximum value of the test chemical is calculated as the sum of the maximum values of the test chemical and the maximum values of the test chemical.
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following table shows the data for the calculation of the average of the data for the period from 1 January to 31 December:
The following data are available for the analysis of the following data:
The following table shows the data for the calculation of the average of the data for the period from 1 January to 31 December:
The following data are available for the analysis of the following data:
The following data are available for the analysis of the following data:
The following data are available for the analysis of the data:
High resolution mass (ESI+) :Raw formula: C39H32N4O6[M+H]+ calculated: 653.2395[M+H]+ measured: 653.2385
The following data are available for the analysis of the data:
The following data are available for the analysis of the following data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following data are available for the analysis of the data:
The following formula is used for the calculation of the CO2 savings:
The following are the basic parameters:
The following formula is used for the calculation of the CO2 savings:
The following data are available for the analysis of the data:
The following formula is used for the calculation of the CO2 savings:
The following data are available for the analysis of the data:
The following formula is used:
Err1:Expecting ',' delimiter: line 1 column 164 (char 163)
A similar procedure is followed to that described in Step D of Example 1. The resulting product is subjected to a salification step in the presence of hydrochloric ether.
IR (ATR) cm-1: 2500 to 3000 v-OH, 1614 ν > C=O amides, 1236 ν > C-O-C<, 740 γ > CH-Ar
Basic microanalysis: % measured (theoretical)
The Commission has also received information from the Member States on the progress of the implementation of the programme.
High resolution mass (ESI+) :Raw formula: C40H32N6O5[M+H]+ calculated: 677.2507[M+H]+ measured: 677.2510
The compound in Example 21 (311 mg, 0.5 mmol) is dissolved in dichloromethane and washed with an aqueous solution saturated with sodium hydrocarbonate. After drying the organic phase with magnesium sulfate and dry evaporation, the residue is dissolved in ethanol (30 mL). Methyl iodide (45 μL, 0.7 mmol) is then added and the reaction medium is heated to 40 °C. The resulting solution is purified dry. The reaction crude is purified on a silica gel column using dichloromethane and methanol as solvents.
The frequency of the signal is measured at a frequency of approximately 1 Hz, and the frequency of the signal is measured at a frequency of approximately 1 Hz.
The previous stage compound (320 mg, 0.42 mmole) is dissolved in methanol (20 mL), then silver carbonate (173 mg, 0.628 mmole) is added in portions over 10 minutes. This suspension is stirred for 1 hour at room temperature; the precipitate is filtered and washed with methanol. The filtrate is concentrated dry, then treated by 50 mL of a 2N hydrochloric acid solution, heated at 60°C for 30 minutes and then evaporated in water.
IR (ATR) cm-1: 3388 v -OH phenol, 1650 + 1627 ν > C=O amides
High resolution mass (ESI+) :Raw formula: C39H33N4O5[M]+ calculated = 637.2445[M]+ measured = 637.2431
The compounds in Examples 72, 73, 77, 78-80, 84 and 85 are synthesised in the process described in Example 3 using the acid from Preparation 7, 1,2,3,4-tetrahydroisoquinoline or the appropriate derivative obtained from one of Preparations 1 to 7', and the appropriate NHR3R4 amine.Example 72.N- (((((Hydroxyphenyl) N-methyl-indoxy-66-[[[3R) -3-methyl-3-dihydroxybenzyl-benzyl-2-hydroxy-2H) -methoxybenzyl-carbonyl-methyl-5-MS-MS-B5-hydroxybenzyl-benzyl-5-hydroxybenzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzy
LC/MS (C34H42N4O4) 571 [M+H]+; RT 1.79 (Method B) Example 79.N-Butyl-N-(4-hydroxyphenyle)-6-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H) -yl]carbonyl}-1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydropyrrolol[1,2-a]pyrazine-8-carboxamide
The following is the list of active substances which are to be classified in the additive:
LC/MS (C34H33N3O5) 564 [M+H]+; RT 2.48 (Method A) Example 82.N- ((4-Hydroxyphenyle) -N-methyl-3-(6-{[(3S) -3-methyl-3,4-dihydroisoquinoline-2(1H) -yl]carbonyl}-1,3-benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxyamideLC/MS (C34H33N3O5) 564 [M+H]+; RT 2.55 (Method A) Example 83. 3-[6-3,4-Hydroxyphenyle) -N-methyl-3-methyl-3-methyl-3-methyl-3-methyl-carbonyl- (((3-H) -3-methyl-3-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-
Err1:Expecting ',' delimiter: line 1 column 429 (char 428)
A similar procedure is followed to that described in Step D of Example 1. The resulting product is subjected to a salification step in the presence of hydrochloric ether.
IR (ATR) cm-1: 2500 to 3000 ν-OH, 1614 ν >C=O amides, 1236 ν >C-O-C<,
740 γ > CH-Ar
The total number of samples of the product shall be calculated as follows:
The fluorescence polarization tests were performed in microplates (384 wells). The labeled Bcl-2 protein (histag-Bcl-2 as Bcl-2 corresponds to the primary UniProtKB® sequence number: P10415) at the final concentration of 2.50.10-8M is mixed with a fluorescent peptide (Fluorescein-REIGAQLRRMADDLNAQY) at the final concentration of 1.00. 10-8M in a buffer solution (Hepes 10 mM, NaCl 150 mM, Tween20 0.05%, pH 7.4), in the presence or absence of increasing concentrations of test compounds. After incubation for 2 hours, fluorescence polarization is measured.
The results are expressed in IC50 (compound concentration that inhibits fluorescence polarization by 50%) and are shown in Table 1 below.
The results show that the compounds of the invention inhibit the interaction between the Bcl-2 protein and the fluorescent peptide described above.
Cytotoxicity studies were performed on the RS4 leukaemia tumor line; 11. The cells were broken into microplates and exposed to the test compounds for 48 hours.
The results are expressed as IC50 (compound concentration that inhibits 50% cell viability) and are presented in Table 1 below.
The results show that the compounds of the invention are cytotoxic.
| 17,9 | 11,3 | 19,0 | 163 | ||
| 17,0 | 36 | 10,4 | 52,3 | ||
| 33,6 | 66,5 | 5,4 | 13,7 | ||
| 56,4 | 251 | 5,0 | 32,7 | ||
| 55,9 | 416 | 4,6 | 6,33 | ||
| 60,3 | 161 | 5,6 | 27,3 | ||
| 46,4 | 108 | 15,1 | 62,2 | ||
| 24,5 | 20,5 | 12,6 | 49,7 | ||
| 40,6 | 780 | 2,9 | 24,7 | ||
| 24,7 | 439 | 4,6 | 9,52 | ||
| 10,9 | 83,7 | 4,6 | 26,3 | ||
| 10,4 | 116 | 6,0 | 49 | ||
| 5,8 | 33,65 | 41,5 | 294 | ||
| 3,7 | 7,6 | 5,1 | 57,6 | ||
| 5,7 | 166 | 4,8 | 26 | ||
| 7,5 | 252 | 2,9 | 8,56 | ||
| 3,4 | 11,8 | 3,8 | 63,8 | ||
| 7,5 | 47,7 | 4,1 | 27,9 | ||
| 8,0 | 235 | 4,3 | 90,1 | ||
| 11,1 | 205 | 3,6 | 24,7 | ||
| 4,6 | 25,3 | 3,7 | 84,7 | ||
| 12,9 | 263 | 2,2 | 28,2 | ||
| 3,8 | 9,99 | 4,8 | 68,8 | ||
| 6,2 | 28,4 | 7,9 | 20,9 | ||
| 7,9 | 30 | 5,4 | 70,9 | ||
| 16,6 | 300 | 6,6 | 45 | ||
| 7,7 | 44,1 | 5,5 | 22,8 | ||
| 8,8 | 112 | 4,7 | 36,7 | ||
| 21,2 | 282 | 90,2 | 1520 | ||
| 6,4 | 68,5 | 83,6 | 1320 | ||
| 4,0 | 21,2 | 68,7 | 1340 | ||
| 5,4 | 60,3 | 67,7 | 1360 | ||
| 7,0 | 61,3 | 77,6 | 1630 | ||
| 5,6 | 96,6 | 25,1% @10 µM | 1880 | ||
| 6,2 | 25,4 | 823,3 | 1880 | ||
| 7,8 | 282 | 99,1 | 1010 | ||
| 5,3 | 62,8 | 299,3 | 1880 | ||
| 4,7 | 42 | 12,1 | 778 | ||
| ND | ND | 42% @10 µM | 1880 | ||
| 8,3 | 82,4 | 35,8 | 1500 | ||
| 4,6 | 1,38 | 524,9 | ND | ||
| 5,2 | 6,17 | 242,7 | ND | ||
| 49 | ND | 5 | 20,1 |
| ND : non déterminé |
For partial inhibitors, the percentage of inhibition of fluorescence polarization for a given concentration of the test compound is given, so 25.1% @10 μM means that 25.1% inhibition of fluorescence polarization is observed for a concentration of test compound equal to 10 μM.
The ability of the compounds of the invention to activate caspase 3 is evaluated in an RS4 xenograph model of leukaemic cells;
The results of the study were published in the Journal of Clinical Immunology in the journal Physiology and Immunology in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology and Medicine in the journal Physiology in the journal Physiology and Medicine in the journal Physiology in the journal Physiology and Medicine in the journal Physiology in the journal Physiology and Medicine in the journal Physiology in the journal Physiology in the journal of Medicine in the journal Physiology and Medicine in the journal Physiology in the journal Physiology and Medicine in the journal of Medicine in the journal Physiology in the journal Physiology in the journal of Physiology and Medicine in the journal of Physiology in the journal of Physiology in the journal of Physiology and Medicine in the journal of Physiology in the University of Physiology in the University of Physiology in the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University of the University
This enzymatic measurement is achieved by measuring the occurrence of a fluorinated cleavage product (DEVDase activity, Promega) and is expressed as an activation factor corresponding to the ratio of the two caspase activities: the one for the treated mice divided by the one for the control mice.
The results show that the compounds of the invention are capable of inducing apoptosis in RS4 tumour cells; 11 in vivo.
The ability of the compounds of the invention to activate caspase 3 is evaluated in an RS4 xenograph model of leukaemic cells;
1.107 RS4 cells;11 are transplanted subcutaneously into immunosuppressed mice (SCID strain). 25 to 30 days after transplantation, the animals are treated orally with the various compounds. After treatment, the tumor masses are recovered (after a T time), lysed and the cleaved (activated) form of caspase 3 is quantified in tumor lysates.
This quantification is performed using the Meso Scale Discovery (MSD) ELISA platform assay which specifically doses the cleaved form of caspase 3. It is expressed as an activation factor corresponding to the ratio of the amount of caspase 3 cleaved in treated mice divided by the amount of caspase 3 cleaved in control mice.
The results show that the compounds of the invention are capable of inducing apoptosis in RS4 tumour cells; 11 in vivo.
| Composé testé | Temps au bout duquel est prélevé la tumeur (T) | Facteur d'activation ± SEM (versus contrôle) |
| 6 h | 14,6 (50 mg/kg) | |
| 2 h | 23,1 (50 mg/kg) | |
| 2 h | 15,3 (50 mg/kg) | |
| 2 h | 24,8 ± 1,4 (50 mg/kg) | |
| 2 h | 54,4 ± 2,8 (25 mg/kg) | |
| 2 h | 31,1 ± 10,8 (25 mg/kg) | |
| 2 h | 27,5 ± 2,6 (25 mg/kg) | |
| 2 h | 34,1 ± 2,4 (25 mg/kg) | |
| 2 h | 77,5 ± 4,8 (25 mg/kg) | |
| 2 h | 45,2 ± 3,9 (25 mg/kg) | |
| 2 h | 10,3 ± 4,2 (25 mg/kg) |
The anti-tumor activity of the compounds of the invention is evaluated in an RS4 xenograph model of leukaemic cells;
1,107 RS4 cells;11 are transplanted subcutaneously into immunocompromised mice (SCID strain).25 to 30 days after transplantation, when the tumor mass has reached approximately 150 mm3, the mice are treated orally with the different compounds in 2 different regimens (daily treatment for five days a week for two weeks, or two treatments a week for two weeks).Tumor mass is measured twice a week from the start of treatment.
The results obtained therefore show that the compounds of the invention are capable of inducing significant tumour regression during the treatment period.
| 1000 comprimés dosés à 5 mg d'un composé choisi parmi les exemples 1 à 86 | 5 g |
| Amidon de blé | 20 g |
| Amidon de maïs | 20 g |
| Lactose | 30 g |
| Stéarate de magnésium | 2 g |
| Silice | 1 g |
| Hydroxypropylcellulose | 2 g |
Claims (16)
- Compound of formula (I): wherein:◆ X and Y represent a carbon atom or a nitrogen atom, it being understood that they may not simultaneously represent two carbons atoms or two nitrogen atoms,◆ the Het moiety of the group represents an optionally substituted, aromatic or non-aromatic ring composed of 5, 6 or 7 ring members, which may contain, in addition to the nitrogen represented by X or by Y, from one to 3 hetero atoms selected independently from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (C1-C6)alkyl group or a group -C(0)-0-Alk wherein Alk is a linear or branched (C1-C6)alkyl group,◆ T represents a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted by from one to three halogen atoms, a group (C2-C4)alkyl-NR1R2, or a group (C1-C4)alkyl-OR6,◆ R1 and R2 independently of one another represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, or R1 and R2 form with the nitrogen atom carrying them a heterocycloalkyl,◆ R3 represents a linear (C1-C6)alkyl group, an aryl group or a heteroaryl group, it being possible for the last two groups to be substituted by from one to three groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy and cyano, it being understood that one or more of the carbon atoms of the preceding groups, or of their possible substituents, may be deuterated,◆ R4 represents a 4-hydroxyphenyl group, it being understood that one or more of the carbon atoms of the preceding group, or of its possible substituents, may be deuterated,◆ R5 represents a hydrogen or halogen atom, a linear or branched (C1-C6)alkyl group, or a linear or branched (C1-C6)alkoxy group,◆ R6 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,◆ Ra and Rd each represent a hydrogen atom and (Rb,Rc) form together with the carbon atoms carrying them a 1,3-dioxolane group or a 1,4-dioxane group, or Ra, Rc and Rd each represent a hydrogen atom and Rb represents a hydrogen, a halogen, a methyl or a methoxy, or Ra, Rb and Rd each represent a hydrogen atom and Rc represents a hydroxy group or a methoxy group,it being understood that:- "aryl" means a phenyl, naphthyl, biphenyl or indenyl group,- "heteroaryl" means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 4 hetero atoms selected from oxygen, sulphur and nitrogen (including quaternary nitrogens),- "cycloalkyl" means any mono- or bi-cyclic, non-aromatic, carbocyclic group containing from 3 to 10 ring members,- "heterocycloalkyl" means any mono- or bi-cyclic, non-aromatic, condensed or spiro group composed of 3 to 10 ring members and containing from 1 to 3 hetero atoms selected from oxygen, sulphur, SO, SO2 and nitrogen,it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the groups alkyl, alkenyl, alkynyl and alkoxy to be substituted by from 1 to 3 groups selected from linear or branched (C1-C6)alkyl, (C3-C6)spiro, linear or branched (C1-C6)alkoxy, (C1-C6)alkyl-S-, hydroxy, oxo (or N-oxide where appropriate), nitro, cyano, -COOR', -OCOR', NR'R", linear or branched (C1-C6)polyhaloalkyl, trifluorornethoxy, (C1-C6)alkylsulphonyl, halogen, aryl, heteroaryl, aryloxy, arylthio, cycloalkyl, heterocycloalkyl optionally substituted by one or more halogen atoms or alkyl groups, it being understood that R' and R", each independently of the other, represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, it being possible for the Het moiety of the group defined in formula (I) to be substituted by from one to three groups selected from linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, NR1'R1" and halogen, it being understood that R1' and R1" are as defined for the groups R' and R" mentioned hereinbefore, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
- Compound of formula (I) according to claim 1, wherein the group represents one of the following groups: 5,6,7,8-tetrahydroindolizine optionally substituted by an amino group; indolizine; 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine optionally substituted by a methyl; pyrrolo[1,2-a]pyrimidine.
- Compound of formula (I) according to claim 1 or 2, wherein T represents a hydrogen atom, a methyl group, a group 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, -CH2-OH, 2-aminoethyl, 2-(3,3-difluoropiperidin-1-yl)ethyl, 2-[(2,2-difluoroethyl)amino]ethyl or 2-(3-methoxyazetidin-1-yl)ethyl.
- Compound of formula (I) according to one of claims 1 to 3, wherein R3 represents a heteroaryl group selected from the following group: 1H-indole, 2,3-dihydro-1H-indole, 1H-indazole, pyridine, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazole, imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, and 1H-pyrazolo-[3,4-b]pyridine, all of which may be substituted by a linear or branched (C1-C6)alkyl group.
- Compounds of formula (I) according to claim 1, selected from the following group:- N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}-1,3-benzodioxol-5-yl)-N-{1-[2-(morpholin-4-yl)ethyl]-1H-indol-5-yl}-5,6,7,8-tetrahydroindolizine-1-carboxamide,- N-(4-hydroxyphenyl)-3-(6-{[(3S)-3-[2-(moipholin-4-yl)ethyl]-3,4-dihydroiso-quinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide,- N-{3-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}-N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)indolizine-1-carboxamide,- N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(pyridin-4-yl)indolizine-1-carboxamide,- N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}-1,3 benzodioxol-5-yl)-N-(2-methylpyridin-4-yl)indolizine-1-carboxamide,- N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pynolo[2,3-b]pyridin-5-yl)-indolizine-1-carboxamide,- N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-[3-(morpholin-4-yl)propyl]-3,4-dihydro-isoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide,- N-(2,6-dimethylpyridin-4-yl)-N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)indolizine-1-carboxamide,- N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}-1,3-benzodioxol-5-yl)-N-(pyridin-4-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide,- 3-(5-chloro-2-{[(3R}-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)indolizine-1-carboxamide,- N-(4-hydroxyphenyl)-N-(2-methoxypyridin-4-yl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)indolizine-1-carboxamide,their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
- Process for the preparation of compounds of formula (I) according to claim 1, characterised in that there is used as starting material the compound of formula (II): wherein Ra, Rb, Rc and Rd are as defined for formula (I), which compound of formula (II) is subjected to a Heck reaction, in an aqueous or organic medium, in the presence of a palladium catalyst, of a base, of a phosphine and of the compound of formula (III): wherein the groups X, Y and Het are as defined for formula (I), to obtain the compound of formula (IV): wherein Ra, Rb, Rc, Rd, X, Y and Het are as defined for formula (I), the aldehyde function of which compound of formula (IV) is oxidised to a carboxylic acid to form the compound of formula (V): wherein Ra, Rb, Rc, Rd, X, Y and Het are as defined for formula (I), which compound of formula (V) is then subjected to peptide coupling with a compound of formula (VI): wherein T and R5 are as defined for formula (I), to yield the compound of formula (VII): wherein Ra, Rb, Rc, Rd, T, R5, X, Y and Het are as defined for formula (I), the ester function of which compound of formula (VII) is hydrolysed to yield the corresponding carboxylic acid or carboxylate, which may be converted into an acid derivative such as the corresponding acyl chloride or anhydride before being coupled with an amine NHR3R4 wherein R3 and R4 have the same meanings as for formula (I), to yield the compound of formula (I), which compound of formula (I) may be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional separation technique, it being understood that, at any time considered appropriate in the course of the above-described process, certain groups (hydroxy, amino...) of the reagents or intermediates of synthesis may be protected and then deprotected according to the requirements of synthesis.
- Process according to claim 6 for the preparation of a compound of formula (I) wherein one of the groups R3 or R4 is substituted by a hydroxy function, characterised in that the amine NHR3R4 is subjected beforehand to a reaction protecting the hydroxy function prior to any coupling with the carboxylic acid formed from the compound of formula (VII), or with a corresponding acid derivative thereof, the resulting protected compound of formula (I) subsequently undergoes a deprotection reaction and is then optionally converted into one of its addition salts with a pharmaceutically acceptable acid or base.
- Pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 5 or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.
- Pharmaceutical composition according to claim 8 for use as a pro-apoptotic agent.
- Pharmaceutical composition according to claim 8 for use in the treatment of cancers, auto-immune diseases and diseases of the immune system.
- Pharmaceutical composition according to claim 8 for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the oesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer.
- Compound of formula (I) according to one of claims 1 to 5, or an addition salt thereof with a pharmaceutically acceptable acid or base, for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the oesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer.
- Association of a compound of formula (I) according to any one of claims 1 to 5 with an anti-cancer agent selected from genotoxic agents, mitotic poisons, antimetabolites, proteasome inhibitors, kinase inhibitors and antibodies.
- Pharmaceutical composition comprising an association according to claim 13 in combination with one or more pharmaceutically acceptable excipients.
- Association according to claim 13 for use in the treatment of cancers.
- Compound of formula (I) according to any one of claims 1 to 5 for use in association with radiotherapy in the treatment of cancers.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1357265 | 2013-07-23 | ||
| FR1357265A FR3008976A1 (en) | 2013-07-23 | 2013-07-23 | "NOVEL INDOLIZINE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM" |
| PCT/FR2014/051885 WO2015011397A1 (en) | 2013-07-23 | 2014-07-22 | Novel indolizine derivatives, method for the production thereof and pharmaceutical compositions containing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1223360A1 HK1223360A1 (en) | 2017-07-28 |
| HK1223360B true HK1223360B (en) | 2018-06-08 |
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