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  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
  • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
  • C07K1/1075—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of amino acids or peptide residues
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Definitions

• the present invention relates to cyclic amino acid molecules and methods of preparing the same.
• Peptides play vital roles by mediating a wide range of biological processes, acting as hormones, antibiotics, and signaling molecules. Due to the highly specific interaction with their biological targets, peptides have been widely used in medicine. However, the enormous therapeutic potential of peptides is not always easy to realize due to their low bioavailability. This shortcoming is a consequence of the degradation of peptides by endo- and exopeptididases, which results in poor in vivo stability of peptides. Compared to their linear counterparts, cyclic peptides are more resistant to degradation. There are two main reasons for this stability. Firstly, exopeptidases cannot cleave the cyclic peptide at its (non-existent) ends.
• cyclic peptides especially those with a small-to- medium ring size, are protected against endopeptidases because the constrained cyclic peptide backbone prevents the adaptation of the required extended conformation during proteolysis.
• the reduced charge and intramolecular hydrogen bonding within cyclic peptides facilitate passive membrane permeability, which contributes to their enhanced bioavailability.
• conformational constraints imposed on the amino acid sequence by the cyclic topology maximize enthalpic interactions between cyclic peptides and their biochemical targets while ensuring favourable entropy of binding.
• R 1 , R 2 , R 3, R 4 , R 5 and R 6 are each independently selected from the group consisting of a protecting group; H; lower alkyl; aryl; heteroaryl; alkenyl; heterocyde; acids of the formula -C(0)OH; esters of the formula -C(0)OR 3 ⁇ 4 herein
• R* is selected from alkyl and aryl; amides of the formula ⁇ C(0)NR**R***, wherein R * * and R*** are independently selected from H, alkyl and aryl; -CH2C(0)R, wherein R is selected from -OH, lower alkyl, aryl, - loweralkyl-aryl, or -NRaRb, where Ra and Rb are independently selected from H, lower alkyl, aryl or -loweralkyl-aryl; -C(0)Rc, wherein Rc is selected from lower alkyl, aryl or - lower alkyl-aryl; or -lower alkyl-
• R 9 and R 9 are independently selected from the amino acid side chains of a proteinogenic or a non-proteinogenic amino acid having, the N-terminus thereof being the N-R 7 , or may form a cyclic side chain with R 7 ; and R 10 is H, a protecting group, a resin, lower alkyl, allyl, tert-butyl, or benzyl; stereocentres 1*, 2* and 3 * are each independently selected from R and S; and n is 1 , 2, 3, or 4 and where n is 2-4, each R e and each R g are independent of each other.
• R 5 or R s is a carboxamide
• R 1 , R 3 , R 4 , R 5 and R B are each independently selected from the group consisting of H; lower alkyl; aryl; heteroaryl; alkenyl; heterocycle; acids of the formula -C(0)OH, esters of the formula -C(0)OR * wherein R* is selected from alkyl and aryl; amides of the formula -C(0)NR**R***, wherein R** and R*** are independently selected from H, alkyl and aryl; -CH 2 C(0)R, wherein R is selected from -OH, lower alkyl, aryl, -loweralkyl-aryl, or -NRaRb, where Ra and Rb are independently selected from H, lower alkyl, aryl or - loweralkyl-aryl; -C(0)Rc, wherein Rc is selected from lower alkyl, aryl or -lower al
• R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from the group consisting of a protecting group; H; lower alkyl; aryl; heteroaryl; alkenyl; heterocycle; acids of the formula -C(0)OH; esters of the formula -C(0)OR* wherein R* is selected from alkyl and aryl; amides of the formula -C(0)NR**R***, wherein R** and R*** are independently selected from H, alkyl and aryl; -CH 2 C(0)R, wherein R is selected from -OH, lower alkyl, aryl, - loweralkyl-aryl, or -NRaRb, where Ra and Rb are independently selected from H, lower alkyl, aryl or -loweralkyl-aryl; -C(0)Rc, wherein Rc is selected from lower alkyl, aryl or - lower alkyl-aryl; or -lower alkyl-ORd, wherein
• R 7 is H, a protecting group, lower alkyl, benzyl, alkenyl, lower alkyloxy; aryl; heteroaryl; heterocycle; -C(0)R****, wherein R** + * is independently selected from alkyl, aryl, heteroaryl, amino, aminoalky!, aminoaryl, aminoheteroaryl, alkoxy, aryloxy, heteroaryloxy; -CH 2 C(0)R; -C(0)Rc; all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents; or, along with R 8 or R 9 , a cyclic side chain of a proteinogenic or a non- proteinogenic alpha-amino acid having, the N-terminus thereof being the N-R 7 ;
• a compound of formula (III)
• R , R 3 , R 4 , R 5 and R 6 are each independently selected from the group consisting of H; lower alkyl; aryl; heteroaryl; alkenyl; heterocycle; acids of the formula -C(0)OH; esters of the formula -C(Q)OR* wherein R* is selected from alkyl and aryl; amides of the formula -C(0)NR**R***, wherein R** and R*** are independently selected from H, alkyl and aryl; -CH 2 C(0)R, wherein R is selected from -OH, lower alkyl, aryl, -loweralkyl-aryl, or -NRaRb, where Ra and Rb are independently selected from H, lower alkyl, aryl or - loweralkyl-aryl; -C(0)Rc, wherein Rc is selected from lower alkyl, aryl or -lower alkyl-aryl; or -lower alkyl-ORd, wherein Rd is
• R , R ! , R 3 , R 4 , R 5 and R 3 are each independently selected from the group consisting of a protecting group; H; lower aikyl; aryl; heteroaryl; alkenyl; heterocycle; acids of the formula -C(0)OH; esters of the formula -C(0)OR* wherein R* is selected from alkyi and aryl; amides of the formula -C(0)NR**R***, wherein R** and R" 1 ⁇ 2 are independently selected from H, alkyi and aryl; -CH2C(0)R, wherein R is selected from -OH, lower alkyi, aryl, - loweralkyl-aryl, or -NRaRb, where Ra and Rb are independently selected from H, lower alkyi, aryl or -loweralkyl-aryl; -C(0)Rc, wherein Rc is selected from lower alkyi, aryl or - lower alkyl-aryl; or -lower alkyl-
• R 7 is H, a protecting group, lower alkyi, benzyl, alkenyl, lower alkyloxy; aryl; heteroaryl; heterocycle; -C(0)R****, wherein R**** is independently selected from alkyi, aryl, heteroaryl, amino, aminoalkyl, aminoaryl, aminoheteroaryl, alkoxy, aryloxy, heteroaryloxy; -CH 2 C(0)R; -C(0)Rc; all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents or along with R or R , a cyclic side chain of a proteinogenic or a non- proteinogenic amino acid having, the N-terminus thereof being the N-R 7 , wherein the proteinogenic or a non-proteinogenic amino acid can be substituted with a suitable substituent; R B and R 9 are independently selected from the amino acid side chains of a proteinogenic or a non-proteinogenic amino acid having, the N-terminus thereof being the N-R 7
• R 10 is H, a protecting group, a resin, lower alkyl, allyl, tert-butyl, or benzyl; stereocentres 1*, 2* and 3* are each independently selected from R and S; and n is 1 , 2, 3, or 4 and where n is 2-4, each R s and each R 9 are independent of each other.
• a protecting group or protective group is a substituent introduced into a molecule to obtain chemoselectivity in a subsequent chemical reaction.
• Many protecting groups are known in the art and a skilled person would understand the kinds of protecting groups that would be incorporated and could be used in connection with the methods described herein.
• protecting group based peptide synthesis typically solid phase peptide synthesis, the desired peptide is prepared by the step-wise addition of amino acid moieties to a building peptide chain.
• the two most widely used protocols, in solid-phase synthesis employ tert- butyloxycarbonyi (Boc) or 9-fluorenylmethoxycarbonyl (Fmoc) as amino protecting groups.
• Amino protecting groups generally protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Greene, T. W. et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons (1999).
• Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, .alpha.- chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like, sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyl
• Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle.
• amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
• amino acid refers to molecules containing an amine group, a carboxylic acid group and a side chain that varies.
• Amino acid is meant to include not only the twenty amino acids commonly found in proteins but also non-standard amino acids and unnatural amino acid derivatives known to those of skill in the art, and .therefore includes, but is not limited to, alpha, beta and gamma amino acids.
• Peptides are polymers of at least two amino acids and may include standard, non-standard, and unnatural amino acids.
• suitable substituen as used in the context of the present invention is meant to include independently H; hydroxyl; cyano; alkyl, such as lower alky!, such as methyl, ethyl, propyl, n-butyl, t-butyl, hexyl and the like; alkoxy, such as lower alkoxy such as methoxy, ethoxy, and the like; aryloxy, such as phenoxy and the like; vinyl; alkenyl, such as hexenyl and the like; alkynyl; formyl; haloalkyl, such as lower haloalkyl which includes CF 3 , CCI3 and the like; halide; aryl, such as phenyl and napthyl; heteroaryl, such as thienyl and furanyl and the like; amide such as C(0)NR a R b , where R a and R b are independently selected from lower alkyl, aryl or benzy
• lower alkyl as used herein either alone or in combination with another substituent means acyclic, straight or branched chain alkyl substituent containing from one to six carbons and includes for example, methyl, ethyl, 1-methylethyl, 1 -methyIpropyl, 2-methylpropyl, and the like.
• lower alkoxy as used herein includes methoxy, ethoxy, f-butoxy.
• alkyl encompasses lower alkyl, and also includes alkyl groups having more than six carbon atoms, such as, for example, acyclic, straight or branched chain alkyl substituents having seven to ten carbon atoms.
• aryl as used herein, either alone or in combination with another substituent, means an aromatic monocyclic system or an aromatic polycyclic system.
• aryl includes a phenyl or a napthyl ring, and may also include larger aromatic polycyclic systems, such as fluorescent (eg. anthracene) or radioactive labels and their derivatives.
• heteroaryl as used herein, either alone or in combination with another substituent means a 5, 6, or 7-membered unsaturated heterocycle containing from one to 4 heteroatotns selected from nitrogen, oxygen, and sulphur and which form an aromatic system.
• heteroaryl also includes a polycyclic aromatic system comprising a 5, 6, or 7-membered unsaturated heterocycle containing from one to 4 heteroatoms selected from nitrogen, oxygen, and sulphur.
• cycloalkyl 1 ' as used herein, either alone or in combination with another substituent, means a cycloalkyl substituent that includes for example, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• cycloalkyl-alkyl- as used herein means an alkyl radical to which a cycloalkyl radical is directly linked; and includes, but is not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, cyc!ohexylmethyl, 1-cycIohexylethyl and 2-cyclohexylethyl.
• alkyl or “lower alkyl” terms is to be understood for aryl-alkyl-, aryl-lowera!kyl- (eg.
• aryl-alkyl- means an alkyl radical, to which an aryl is bonded.
• aryl-alkyl- include, but are not limited to, benzyl (phenylmethyl), 1-phenyIethyl, 2-phenylethyl and phenylpropyl.
• heterocycle either alone or in combination with another radical, means a monovalent radical derived by removal of a hydrogen from a three- to seven-membered saturated or unsaturated (including aromatic) cyclic compound containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur.
• heterocycles include, but are not limited to, aziridine, epoxide, azetidine, pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, thiophene, hydantoin, diazepine, imidazole, isoxazole, thiazole, tetrazole, piperidine, piperazine, homopiperidine, homopiperazine, 1 ,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-N-oxide or pyrimidine, and the like.
• alkenyl as used herein, either alone or in combination with another radical, is intended to mean an unsaturated, acyclic straight chain radical containing two or more carbon atoms, at least two of which are bonded to each other by a double bond.
• examples of such radicals include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl.
• alkynyl as used herein is intended to mean an unsaturated, acyclic straight chain radical containing two or more carbon atoms, at least two of which are bonded to each other by a triple bond. Examples of such radicals include, but are not limited to, ethynyl, -propynyl, 2-propynyl, and 1-butynyl.
• alkoxy as used herein, either alone or in combination with another radical, means the radical -0-(C-i.
• alkyl is as defined above containing 1 or more carbon atoms, and includes for example methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1 ,1-dimethylethoxy.
• n is 1 to 6
• lower alkoxy applies, as noted above
• aryloxy as used herein alone or in combination with another radical means -O-aryl, wherein aryl is defined as noted above.
• a peptide is a polymer of two or more amino acids.
• one and only one of R 1 and R 2 is a protecting group.
• R 1 and R 2 are both H.
• R 3 and R 4 are each independently selected from the group consisting of amino acid chains of a proteinogenic or a non-proteinogenic alpha-amino acids, preferably CH 3) H, isobutyl, and -CH2-S-R*****, wherein R***** is selected from lower alkyl; lower amino alkyl; aryl; heteroaryl; alkenyl; or heterocycle; all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents; preferably R ** *** is phenyl or phenyl substituted with lower alkyl, halogen, or lower amino alkyl.
• the proteinogenic or non-proteinogenic alpha- amino acid is a primary amino acid.
• the proteinogenic or non- proteinogenic alpha-amino acid is a secondary amino acid, preferably proline.
• R 5 and R s are either (i) H and a carboxamide, the carboxamide preferably being -C(0)NH-tert-butyl; or (ii) H and H respectively.
• R 7 and either R 5 or R 9 are selected to form proline, the N-terminus thereof being the N-R 7 .
• R 10 is selected from the group consisting of CH 3 and H.
• R , R 2 , R 3 , R 4 , R 5 and R 6 are an acid of the formula - C(0)OH.
• R 7 is H, a protecting group, lower alkyl, benzyl, or alkenyl.
• R 5 or R 6 is a carboxamide
• this method is performed in the presence of at least one of: 0
• the peptide is bound to the compound of Formula (I).
• the peptide is 2-8 amino acids in length.
• two or more fragment compounds described herein are bound to each other using the protecting group based peptide synthesis.
• R ⁇ R 3 , R R 6 and R 6 are each independently selected from the group consisting of H; lower alkyl; aryl; heteroaryl; alkenyl; heterocycle; acids of the formula -C(0)OH; esters of the formula -C(0)OR* wherein R* is selected from alkyl and aryl; amides of the formula -C(0)NR**R***, wherein R** and R*** are independently selected from H, alkyl and aryl; -CH 2 C(0)R, wherein R is selected from -OH, lower alkyl, aryl, -loweralkyl-aryl, or -NRaRb, where Ra and Rb are independently selected from H, lower alkyl, aryl or - loweralkyl-aryl; -C(0)Rc, wherein Rc is selected from lower alkyi, aryl or -lower alkyl-aryl
• the protecting group based peptide synthesis is performed on solid phase.
• the fragment compound described herein is bound to the solid phase.
• R R 2 , R 3 , R 4 , R 5 and R S are each independently selected from the group consisting of a protecting group; H; lower alkyi; aryl; heteroaryl; alkenyl; heterocycle; acids of the formula -C(0)OH; esters of the formula -C(0)OR* wherein R* is selected from alkyi and aryl; amides of the formula -C(0)NR**R***, wherein R** and R*** are independently selected from H, alkyl and aryl; -CH2C(0)R, wherein R is selected from -OH, lower alkyl, aryl, - loweralkyl-aryl, or -NRaRb, where Ra and Rb are independently selected from H, lower alkyl, aryl or -loweralkyl-aryl; -C(0)Rc, wherein Rc is selected from lower alkyl, aryl or - lower alkyl-aryl; or -lower alkyl-ORd, wherein Rd is
• R 7 is H, a protecting group, lower alkyl, benzyl, alkenyl, lower alkyloxy; aryl; heteroaryl; heterocycle; -C(0)R****, wherein R**** is independently selected from alkyl, aryl, heteroaryl, amino, aminoalkyl, aminoaryl, aminoheteroaryl, alkoxy, aryloxy, heteroaryloxy; -CH 2 C(0)R; -C(0)Rc; all of which are optionally substituted at one or more substitutabie positions with one or more suitable substituents or , along with R e or R 9 , a cyclic side chain of a proteinogenic or a non- proteinogenic alpha-amino acid having, the N-terminus thereof being the N-R 7 ;
• R 1 , R 3 , R 4 , R 5 and R 9 are each independently selected from the group consisting of H; lower alkyl; aryl; heteroaryl; alkenyl; heterocycle; acids of the formula -C(0)OH; esters of the formula -C(0)OR* wherein R* is selected from alkyl and aryl; amides of the formula -C(0)NR**R***, wherein R** and R*** are independently selected from H, alkyl and aryl; -CH2C(0)R, wherein R is selected from -OH, lower alkyl, aryl, -loweralkyl-aryl, or -NRaRb, where Ra and Rb are independently selected from H, lower alkyl, aryl or - loweralkyl-aryl; -C(0)Rc, wherein Rc is selected from lower alkyl, aryl or -lower alkyl-ary!; or -lower alkyl-ORd, wherein Rd is
• Lithium aluminum hydride powder (3.5 g, 92.1 mmol) was placed in a dry, 1 L flask.
• THF Sigma-Aldrich, 250 ppm of BHT, ACS reagent > 99.0 %, 200 mL
• the resulting slurry was cooled to -78 °C, with stirring.
• a solution of the crude Compound 1 (30 g; effective quantity estimated to be 21.7 g, 61.4 mmol) in THF (300 mL).
• the reaction vessel was transferred to an ice/water bath, and maintained at 0 "C for 1 h.
• the acid-mediated Ugi reaction produces a cleaner crude profile trace than the Ugi reaction conducted in the absence of an acid.
• Reaction Molarity 0.142 molar To a mixture of Compound 9 (2.7 g, 9.95 mmol) and Fmoc-OSu (3.69 g, 10.95 mmol) in DCM (70 ml) was added DIPEA (3.64 mL, 20.90 mmol) at 0 °C. The reaction mixture was stirred at 0 °C to room temperature for 2 h. LC-MS analysis showed that the reaction was complete. The mixture was diluted with EtOAc (300 mL), washed with 0.2 N HCI (2 x 80 mL) and brine (80 mL), dried and evaporated.
• a fully-deprotected fragment can be cyclized head-to-tail as part of a strategy to prepare piperazinones and facilitate determination of the stereochemical outcome of the Ugi reaction.
• the additional constraints in the resulting cyclic structure lend themselves to full structure determination by 2D NMR techniques.
• Compound 7A When treated with an acid to remove the N-Boc protecting group, can then be treated with a base to mediate cyclization by direct amidation from the free amine to the C-terminus methyl ester:
• DMSO-dg ⁇ 175.01, 174.93, 171.83, 170.18, 169.86, 169.03, 167.29, 150.18, 147.53, 140.74, 137.41, 134.85', 129.82, 126.64, 126.35, 24.45, 67.57, 65.63, 64.91, 57.77,

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