US20170298070A1 - Novel chiral synthesis of n-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines - Google Patents
Novel chiral synthesis of n-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines Download PDFInfo
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- US20170298070A1 US20170298070A1 US15/512,919 US201515512919A US2017298070A1 US 20170298070 A1 US20170298070 A1 US 20170298070A1 US 201515512919 A US201515512919 A US 201515512919A US 2017298070 A1 US2017298070 A1 US 2017298070A1
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- JCZPKWYLAIALPV-SNVBAGLBSA-N [C-]#[N+]C1=CC=C(C(=O)N2CCN3C(C4=NC(C)=NS4)=NN=C3[C@H]2C)C=C1 Chemical compound [C-]#[N+]C1=CC=C(C(=O)N2CCN3C(C4=NC(C)=NS4)=NN=C3[C@H]2C)C=C1 JCZPKWYLAIALPV-SNVBAGLBSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates to a novel chiral synthesis of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines of Formula I, avoiding the use of protection/deprotection steps.
- N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines is disclosed in the literature, comprising a) the synthesis of (3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine intermediates, followed by b) a classical N-acylation (Scheme 1):
- step a) of the synthesis of chiral (3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine intermediates are known in the literature.
- the below examples and experimental conditions of relevant approaches provided are illustrative only.
- the [1,2,4]triazolopyrazine core IIIa(i) is formed by acetylation of 2-hydrazidopyrazine (step 1) followed by a cyclodehydration reaction (step 2), using procedures familiar to those skilled in the art.
- This methodology was initially developed by Nelson and Potts ( J. Org. Chem. 1962, 27, 3243-3248). Subsequent reduction of the pyrazine ring with H 2 /Pd affords the [1,2,4]triazolo[4,3-a]piperazine (step 3).
- This method is well described in the literature and has been used, for example, in the Merck synthesis of Sitagliptin (Hansen et al., Org. Process Res. Dev. 2005, 9, 634-639 and references therein).
- Method A(ii) (cf. Scheme 3) is a variation on Method A(i) whereby the reduction of R 1 ⁇ H substituted [1,2,4]triazolopyrazine substrates is circumvented.
- step 1 Addition of acetylhydrazide to piperazinoimidate (step 1) is followed by cyclodehydration to form the fused triazolo ring (step 2).
- step 2 This method is well documented in the literature although exemplified only through racemic or achiral structures; e.g.: McCort and Pascal, Tetrahedron Lett., 1992, 33, 4443-4446; Brockunier et al. WO 03/082817 A2; Chu-Moyer et al. U.S. Pat. No. 6,414,149 B1; Banka et al. WO2009/089462 A1. To the best of his knowledge, the Applicant is unaware of any published reports of the application of this method for obtaining chiral products by starting from chiral piperazinones (Ic in Scheme 5).
- Boc-protected ketopiperazine 1.2 was prepared and then converted to iminoether 1.3 by using the Meerwein reagent (e.g. Et 3 OBF 4 ). Cyclodehydration reaction between the acyl hydrazide 1.4 and the iminoether aforementioned was conducted either under forcing thermal reflux conditions, or by applying excessive microwave irradiation in a sealed tube typically for rather protracted reaction times (often days). When using microwave irradiation, N-Boc deprotection occurred during the said cyclodehydration step; thus, a deprotection step was typically not necessary to conduct (i.e., 1.3+1.4 ⁇ 1.6 in Scheme 6). However, when thermal cyclodehydration conditions were applied, Boc-deprotection step was required (i.e., 1.3+1.4 ⁇ 1.5 ⁇ 1.6).
- steps 2 and 3 have shortcomings that significantly limit the application of the said procedure for uses wherein generation of chiral intermediates or products are required in a reproducible fashion, as with the preparation of pharmaceutically active ingredient, for instance.
- Step 2 is the piperazinoimidate formation (i.e., 1.2 ⁇ 1.3) and step 3 is the cyclodehydration step between the said imidate and acetylhydrazide (i.e., 1.3+1.4 ⁇ 1.5).
- This method is a variation on the method depicted in Scheme 6: the Boc protective group of Scheme 6, which is a N-Csp 2 protective group, was replaced by a N-Csp 3 protective group, preferably a benzylic protective group such as DMB, PMB or TMB.
- N-Csp 3 protective group was observed to provide 5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine chiral intermediates with a good enantiomeric excess and in a reproducible fashion. Retention of stereochemistry was observed with minimal if any racemization.
- the new chiral synthetic procedure of the present invention first involves an N-acylation step followed by the building of the [1,2,4]triazolo[4,3-a]pyrazine core (Scheme 7):
- the new synthetic procedure of the present invention presents the distinct advantage of furnishing final desired targets with very high chiral purity while obviating the need of additional protection/deprotection steps that will advantageously impact production costs.
- the invention relates to a process of preparing chiral N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine of general Formula I:
- R 1 is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, preferably R 1 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; more preferably R 1 is methyl;
- R 2 is alkyl, alkoxyalkyl or haloalkyl, preferably R 2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl; more preferably R 2 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; even more preferably R 2 is methyl;
- Ar is a phenyl group, optionally substituted by one or more substituent(s) selected from H, halo, alkyl, alkoxy, haloalkyl, nitrile and thiophen-2-yl; preferably Ar is a phenyl group, optionally substituted by one or more substituent(s) selected from H, F, Cl, methyl, methoxy, trifluoromethyl, nitrile and thiophen-2-yl; more preferably Ar is a phenyl group substituted by H or F;
- X 1 is N and X 2 is S or O; or X 1 is S and X 2 is N;
- R 1 is as defined above;
- Ar is as defined above; and Y is hydroxyl or halo, wherein halo is preferably F or Cl; more preferably Y is hydroxyl or Cl, even more preferably Y is Cl;
- the reaction of each step is carried out under controlled mild experimental conditions. Especially, the reaction is carried out at a temperature equal to or below boiling point of the organic solvent, preferably at room temperature.
- the process does not use any protecting group.
- the process proceeds with the retention of stereochemistry with respect to the starting material.
- the process according to the present invention preferably provides the (R)-enantiomer of compounds of Formula I.
- the invention also refers to synthesis of chiral intermediates.
- the process provides chiral compounds of Formula C:
- compound C has Formula C-b2:
- the invention also refers to compounds of Formula D:
- compound D has Formula D-1:
- Preferred compounds of Formula C and Formula D are those wherein the stereoisomer obtained is the (R)-enantiomer.
- the invention also relates to the use of the compounds provided by the process or solvate thereof, for the manufacture of a medicament, a pharmaceutical composition or a pharmaceutically active ingredient.
- the invention relates to a novel chiral synthesis of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine compounds avoiding use of protection/deprotection steps and thus, allowing achieving high chiral purity while improving cost-effectiveness.
- the invention relates to a process of preparing N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine compounds of Formula I:
- the process is carried out under controlled mild experimental conditions.
- Amide coupling step a) of the process as defined above is advantageously carried out in an organic, preferably anhydrous, solvent, selected from dichloromethane, acetonitrile preferably in dichloromethane.
- the reaction is advantageously carried out at a temperature equal to or below boiling point of the organic solvent, preferably at room temperature.
- room temperature means a temperature comprised between 10° C. and 30° C., preferably 20 ⁇ 5° C.
- the reaction is carried out in the presence of a base selected from the group consisting of di-iso-propylethylamine, N-methylmorpholine, triethylamine, preferably N-methylmorpholine.
- a base selected from the group consisting of di-iso-propylethylamine, N-methylmorpholine, triethylamine, preferably N-methylmorpholine.
- the reaction is carried out on an activated anhydride, ester, acylurea derivative of the latter said compounds—formed through conventional amide bond forming reagent(s) involving the use of so-called activating groups, such as isobutylchloroformate, DIC, DCC, HOBt, HATU, HBTU, DEPBT under reaction conditions known to those skilled in the art.
- Y is a halo in compounds of Formula B and the reaction is carried out in the presence of a base selected from the group consisting of di-iso-propylethylamine, N-methylmorpholine, triethylamine, preferably N-methylmorpholine.
- Intermediates of Formula C may be optionally purified by silica gel flash chromatography or silica gel chromatography, and/or precipitation, and/or trituration, and/or filtration, and/or recrystallization.
- step b is the conversion of the ketopiperazine compounds of Formula C to iminoether compounds of Formula D.
- Step b) proceeds without significant loss of chirality resulting in the corresponding products of good enantiomeric purity as defined herein.
- the procedure involves a tri(C1-C2 alkyl)oxonium salt (Meerwein-type reagents), or (C1-C2)alkylsulfate, or (C1-C2)chloroformate, or use of PCl 5 /POCl 3 /(C1-C2)hydroxyalkyl, preferably tri(C1-C2 alkyl)oxonium salt (Meerwein-type reagents), or (C1-C2)alkylsulfate, more preferably tri(C1-C2 alkyl)oxonium salt, and even more preferably a tri(C2 alkyl)oxonium salt, such as Et 3 OBF 4 .
- step b) is carried out in the presence of a base.
- step b) Use of at least 2 equivalents of tri(C1-C2 alkyl)oxonium salt with respect to the 3-substituted-piperazin-2-one of Formula C was required to aid towards a more complete conversion when step b) was carried out without a mild base additive, such as Na 2 CO 3 , as further discussed hereunder.
- a mild base additive such as Na 2 CO 3
- the base is advantageously selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate, preferably the base is sodium carbonate.
- the tri(C1-C2 alkyl)oxonium salt is advantageously selected from the group consisting of trimethyloxonium tetrafluoroborate, triethyloxonium tetrafluoroborate, preferably the tri(C1-C2 alkyl) oxonium salt is triethyloxonium tetrafluoroborate.
- the tri(C1-C2 alkyl) oxonium salt is triethyloxonium tetrafluoroborate.
- between 1 and 2 preferably about 1.25, mole equivalents of tri(C1-C2 alkyl)oxonium salt is used, with respect to the 3-substituted-piperazin-2-one.
- the iminoether synthesis step b) is advantageously carried out in an organic, preferably anhydrous, solvent, preferably dichloromethane.
- the reaction is advantageously carried out at a temperature equal to or below the boiling point of the organic solvent; preferably the reaction is carried out at room temperature.
- Intermediates of Formula D may optionally be purified by flash or column chromatography on silica gel.
- step c is the preparation of triazolopiperazine compounds of Formula I by condensation between an iminoether of Formula D and an acylhydrazide of Formula E or a salt or solvate thereof.
- Step c) is generally carried out at a temperature comprised between 50° C. and 135° C., preferably between 50° C. and 90° C.; more preferably the temperature is about 70° C.
- Compounds of Formula I may optionally be purified by silica gel flash chromatography or silica gel chromatography, and/or precipitation, and/or trituration, and/or filtration, and/or recrystallization.
- the process of the invention provides compounds of Formula I or solvate thereof having good enantiomeric excess of up to 97% and possibly more in a reproducible fashion.
- the process of the invention proceeds with the retention of stereochemistry with respect to the starting material except to the extent that racemization occurs as a minor side-reaction; thus the configuration at position 8 of the ring is defined by the configuration of the aforesaid chiral starting material.
- the process of the invention provides access to N-acyl-(3-substituted)-(8-substituted)-5 ,6-dihydro-[1,2,4]triazolo [4,3-a]pyrazines by minimizing any intervening racemization during the process.
- the process of invention provides compounds of Formula I; preferably said compounds are the (R)-enantiomer.
- preferred compounds of Formula I are those of Formula I′:
- preferred compounds of Formula I are those of Formula Ia:
- preferred compounds of Formula Ia are those of Formula Ia′:
- preferred compounds of Formula Ia and Ia′ and pharmaceutically acceptable solvates thereof are those wherein:
- preferred compounds of Formula I are those of Formula Ia-1:
- preferred compounds of Formula Ia-1 are those of Formula Ia-1′:
- preferred compounds of Formula Ia are those of Formula Ia-2:
- R a , R a′ , R b , R b′ , R c and R 2 are as defined in Formula I′.
- preferred compounds of Formula Ia-2 are those of Formula Ia-2′:
- R a , R a′ , R b , R b′ , R c and R 2 are as defined in Formula I′.
- preferred compounds of Formula Ia-2 and Ia-2′ and pharmaceutically acceptable solvates thereof are those wherein:
- preferred compounds of Formula Ia are those of Formula Ia-3:
- R a , R a′ , R b , R b′ , R c and R 1 are as defined in Formula I′.
- preferred compounds of Formula Ia-3 are those of Formula Ia-3′:
- R a , R a′ , R b , R b′ , R c and R 1 are as defined in Formula I′.
- preferred compounds of Formula I are those of Formula Ib:
- compounds of Formula Ib do not comprise compound wherein R c is thiophen-2-yl when R 2 is methyl.
- preferred compounds of Formula Ib are those of Formula Ib′:
- preferred compounds of Formula Ib′ are those wherein R c is F when R 2 is methyl.
- preferred compounds of Formula Ib′ are those of Formula Ib-1:
- preferred compounds of Formula I are those of Formula Ic:
- R a , R a′ , R b , R b′ , R c , R 1 and R 2 are as defined in Formula I′.
- preferred compounds of Formula Ic are those of Formula Ic′:
- Particularly preferred compounds of Formula I of the invention are those listed in Table 1 hereafter.
- the invention provides intermediates for the synthesis of compounds of Formula I, in particular according to the process of the invention.
- preferred compounds of Formula C or solvates thereof are those of Formula C-a:
- compound of Formula C is the (R)-enantiomer.
- preferred compounds of Formula C or solvates thereof are those of Formula C-b:
- R c and R 1 are as defined in Formula C-a.
- preferred compounds of Formula C and solvates thereof are those of Formula C-b′:
- R c and R 1 are as defined in Formula C-a.
- preferred compounds of Formula C and solvates thereof are those of Formula C-a-1:
- R a , R a′ , R b , R b′ and R c are as defined in Formula C-a.
- preferred compounds of Formula C and solvates thereof are those of Formula C-a-1′:
- R a , R a′ , R b , R b′ , and R c are as defined in Formula C-a.
- preferred compounds of Formula C and solvates thereof are those of Formula C-b1:
- R c is as defined in Formula C-a.
- preferred compounds of Formula C and solvates thereof are those of Formula C-b1′:
- R c is as defined in Formula C-a.
- preferred compounds of Formula C and solvates thereof are compound of Formula C-b2:
- preferred compounds of Formula C and solvates thereof are compound of Formula C-b2′:
- compound of Formula D is compound of Formula D-1 ((3-ethoxy-2-methyl-5,6-dihydropyrazin-1(2H)-yl)(4-fluorophenyl)methanone):
- compound of Formula D is the (R)-enantiomer.
- halo or “halogen” means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro.
- alkyl by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C n H 2n+1 wherein n is a number greater than or equal to 1.
- Cx-Cy-alkyl refer to alkyl groups which comprise from x to y carbon atoms.
- alkyl groups of this invention comprise from 1 to 4 carbon atoms (C1-C4), preferably from 1 to 3 carbon atoms (C1-C3), more preferably from 1 to 2 carbon atoms (C1-C2).
- Alkyl groups may be linear or branched. Suitable alkyl groups include but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
- haloalkyl alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.
- haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.
- alkoxy refers to any group —O-alkyl, wherein alkyl is as defined above. Suitable alkoxy groups include for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, f-butoxy, sec-butoxy, and n-pentoxy.
- alkoxyalkyl refers to any group -alkyl-O-alkyl, wherein alkyl is as defined above.
- hydroxyalkyl refers to any group -alkyl-OH, wherein alkyl is as defined above.
- (C1-C2)hydroxyalkyl refers to any (C1-C2)alkyl-OH.
- (C1-C2)alkylsulfate refers to any (C1-C2)alkyl-O—SO 3 ⁇ compound, wherein alkyl is as defined above.
- (C1-C2)chloroformate refers to any (C1-C2)alkyl-O—COCl compound, wherein alkyl is as defined above.
- tri(C1-C2 alkyl)oxonium salt refers to any salt of [C1-C2)alkyl] 3 -O + , wherein alkyl is as defined above.
- thiophen-2-yl as used herein means a group of formula
- esters or “esters” as used herein means a group selected the group consisting of unsubstituted C1-C4 alkyloxycarbonyl, unsubstituted phenyloxycarbonyl or unsubstituted phenyl(C1-C2 alkyl)oxycarbonyl.
- Suitable ester groups include methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, i-propyloxycarbonyl, n-butyloxycarbonyl, i-butyloxycarbonyl, s-butyloxycarbonyl, t-butyloxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl and phenethyloxycarbonyl, among which methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, i-propyloxycarbonyl, phenyloxycarbonyl, and benzyloxycarbonyl are preferred.
- protecting group refers to a suitable organic moiety used to protect a certain functional group in a chemical synthesis.
- protecting group refers to an organic moiety selected from 2,4-dimethoxybenzyl (DMB), 4-methoxybenzyl (PMB), tert-butoxycarbonyl (Boc), allyl, diphenyl-phosphiramide (DPP) and/or 2-trimethylsilylethanesulfonyl (SES).
- N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines of the invention is shown in the below:
- the compounds of Formula I and subformulae thereof contain a stereogenic carbon center at position 8 and thus may exist as (R)- and (S)-enantiomers.
- the use of a solid line to depict the bond between position 8 of the ring and R 1 , with a star next to position 8, (i.e. -*) indicates that the individual enantiomers are meant, thus excluding racemic mixtures thereof.
- a solid wedge ( ) for the bond between position 8 of the ring and R 1 is used to depict the (S)-enantiomer and a dotted wedge ( ) for the bond between position 8 of the ring and R 1 is used to depict the (R)-enantiomer.
- solvate is used herein to describe a compound in this invention that contain stoechiometric or sub-stoechiometric amounts of one or more pharmaceutically acceptable solvent molecule such as ethanol.
- solvent molecule such as ethanol.
- hydrate refers to when the said solvent is water.
- references to compounds of Formula I include references to solvates, multi-component complexes and liquid crystals thereof.
- the compounds of the invention include compounds of Formula I, Formula C and Formula D as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including tautomeric isomers) and isotopically-labeled compounds of Formula I.
- salts of the compounds of the invention in its broadest sense also included salts, which may for example be used in the isolation and/or purification of the compounds of the invention.
- salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula E above.
- TLC thin layer chromatography
- HPLC-MS spectra were typically obtained on an Agilent LCMS using electropsray ionization (ESI).
- the Agilent instrument includes an autosampler 1200 , a binary pump 1100 , an ultraviolet multi-wavelength detector 1100 and a 6100 single-quad mass-spectrometer.
- the chromatography column used was Sunfire 3.5 ⁇ m, C18, 3.0 ⁇ 50 mm in dimensions.
- Eluent typically used was a mixture of solution A (0.1% TFA in H 2 O) and solution B (0.1% TFA in MeCN).
- Gradient was applied at a flow rate of 1.3 mL per minute as follows: gradient A: held the initial conditions of 5% solution B for 0.2 min, increased linearly to 95% solution B in 6 min, held at 95% during 1.75 min, returned to initial conditions in 0.25 min and maintained for 2.0 min; gradient B: held the initial conditions of 5% solution B for 0.2 min, increased linearly to 95% in 2.0 min, held at 95% during 1.75 min, returned to initial conditions in 0.25 min and maintained for 2 min.
- chiral HPLC Determination of chiral purity was made using chiral HPLC that was performed on an Agilent 1100 (binary pump and a ultraviolet multi wavelength detector) with manual or automatic (Autosampler 1100 ) injection capabilities. Column used is CHIRALPAK IA 5 ⁇ m, 4.6 ⁇ 250 mm in isocratic mode. Choice of eluent was predicated on the specifics of each separation. Further details concerning the chiral HPLC methods used are provided below:
- Method A column CHIRALPAK IA 5 ⁇ m, 4.6 ⁇ 250 mm, eluent: DCM/EtOH (98:2 v/v) plus 0.1% of DEA, flow rate: 1.0 mL per minute; UV detection at 254 nm; column at RT, eluent was used as sample solvent.
- Method B column CHIRALPAK IA 5 ⁇ m 4.6 ⁇ 250 mm, eluent: MTBE plus 0.1% of DEA, flow rate: 1.0 mL per minute; UV detection at 254 nm, column at RT, eluent was used as sample solvent.
- Solvents, reagents and starting materials were purchased and used as received from commercial vendors unless otherwise specified.
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PCT/EP2015/072167 WO2016046398A1 (fr) | 2014-09-25 | 2015-09-25 | Nouvelle synthèse chirale de n-acyl-(3-substitué)-(8-substitué)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines |
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US16/361,737 Active US10787458B2 (en) | 2014-09-25 | 2019-03-22 | Chiral synthesis of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-A]pyrazines |
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US10624890B2 (en) | 2015-03-16 | 2020-04-21 | Ogeda Sa | NK-3 receptor antagonists for therapeutic or cosmetic treatment of excess body fat |
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RS54833B1 (sr) | 2011-10-03 | 2016-10-31 | Euroscreen Sa | Novi hiralni n-acil-5,6,7, (8-supstituisan)-tetrahidro-[1,2,4]triazolo [4,3-a]pirazini kao selektivni antagonisti nk-3 receptora, farmaceutsko jedinjenje, i postupci za upotrebu u nk-3 receptorom posredovanim poremećajima |
US10183948B2 (en) | 2013-03-29 | 2019-01-22 | Ogeda Sa | N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines as selective NK-3 receptor antagonists |
JP6316932B2 (ja) | 2013-03-29 | 2018-04-25 | オゲダ エス.エー. | 選択的NK−3受容体拮抗薬としての新規なN−アシル−(3位置換)−(8位置換)−5,6−ジヒドロ−[1,2,4]トリアゾロ[4,3−a]ピラジン、医薬組成物、NK−3受容体媒介性障害における使用方法 |
JP2021014404A (ja) * | 2017-10-13 | 2021-02-12 | アステラス製薬株式会社 | トリアゾロピラジン誘導体の塩及び結晶 |
WO2022031773A1 (fr) | 2020-08-04 | 2022-02-10 | Teva Pharmaceuticals International Gmbh | Formes à l'état solide de fézolinétant et sels associés |
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JP3252483B2 (ja) | 1992-10-20 | 2002-02-04 | 東レ株式会社 | 3環性トリアゾロ誘導体の製造方法 |
SK13532001A3 (sk) | 1999-04-01 | 2003-02-04 | Pfizer Products Inc. | Aminopiridíny ako inhibítory sorbitoldehydrogenázy |
DE60316416T2 (de) | 2002-03-25 | 2008-06-26 | Merck & Co., Inc. | Heterocyclische beta-aminoverbindungen als inhibitoren der dipeptidylpeptidase zur behandlung bzw. prävention von diabetes |
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AR043443A1 (es) | 2003-03-07 | 2005-07-27 | Merck & Co Inc | Procedimiento de preparacion de tetrahidrotriazolopirazinas y productos intermedios |
DE602005008558D1 (de) | 2004-02-18 | 2008-09-11 | Astrazeneca Ab | Kondensierte heterocyclische verbindungen und deren verwendung als antagonisten des metabotropen reznkungen |
TWI378091B (en) | 2006-03-09 | 2012-12-01 | Eisai R&D Man Co Ltd | Multi-cyclic cinnamide derivatives |
JP5635910B2 (ja) | 2008-01-09 | 2014-12-03 | アレイ バイオファーマ、インコーポレイテッド | AKTタンパク質キナーゼ阻害剤としての5H−シクロペンタ[d]ピリミジン |
WO2009090055A1 (fr) | 2008-01-17 | 2009-07-23 | Grünenthal GmbH | Dérivés de sulfonamides substitués |
JP5654001B2 (ja) * | 2009-04-29 | 2015-01-14 | グラクソ グループ リミテッドGlaxo Group Limited | P2X7調節因子としての5,6,7,8−テトラヒドロ[1,2,4]トリアゾロ[4,3−a]ピラジン誘導体 |
WO2011007756A1 (fr) | 2009-07-13 | 2011-01-20 | 武田薬品工業株式会社 | Composé hétérocyclique et son utilisation |
BR112012025101B1 (pt) | 2010-04-02 | 2021-08-31 | Ogeda S.A. | Compostos antagonistas seletivos de receptor nk-3, composição farmacêutica e medicamento compreendendo os mesmos |
US10065960B2 (en) | 2010-04-02 | 2018-09-04 | Ogeda Sa | NK-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in NK-3 receptors mediated disorders |
RS54833B1 (sr) | 2011-10-03 | 2016-10-31 | Euroscreen Sa | Novi hiralni n-acil-5,6,7, (8-supstituisan)-tetrahidro-[1,2,4]triazolo [4,3-a]pirazini kao selektivni antagonisti nk-3 receptora, farmaceutsko jedinjenje, i postupci za upotrebu u nk-3 receptorom posredovanim poremećajima |
CA2907813C (fr) | 2013-03-29 | 2021-09-07 | Euroscreen Sa | Nouvelles n-acyl-(3-substitues)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines utilisees en tant qu'antagonistes selectifs des recepteurs nk-3, composition pharmaceutique, meth odes destinees a etre utilises dans des troubles medies par le recepteur nk-3 |
JP6316932B2 (ja) | 2013-03-29 | 2018-04-25 | オゲダ エス.エー. | 選択的NK−3受容体拮抗薬としての新規なN−アシル−(3位置換)−(8位置換)−5,6−ジヒドロ−[1,2,4]トリアゾロ[4,3−a]ピラジン、医薬組成物、NK−3受容体媒介性障害における使用方法 |
EP2989103B1 (fr) | 2013-03-29 | 2019-02-20 | Ogeda Sa | N-acyl-(3-substituées)-(8-méthyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines en tant qu'antagonistes sélectifs du récepteur nk-3, composition pharmaceutique et procédés pour utilisation dans les maladies à médiation par le récepteur nk-3 |
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US10624890B2 (en) | 2015-03-16 | 2020-04-21 | Ogeda Sa | NK-3 receptor antagonists for therapeutic or cosmetic treatment of excess body fat |
US11478472B2 (en) | 2015-03-16 | 2022-10-25 | Ogeda Sa | NK-3 receptor antagonists for therapeutic treatment of leptin-related disease |
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