US20160207957A1 - Amino diacids containing peptide modifiers - Google Patents

Amino diacids containing peptide modifiers Download PDF

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US20160207957A1
US20160207957A1 US14/914,374 US201414914374A US2016207957A1 US 20160207957 A1 US20160207957 A1 US 20160207957A1 US 201414914374 A US201414914374 A US 201414914374A US 2016207957 A1 US2016207957 A1 US 2016207957A1
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formula
group
integer
resin
mmol
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Kleomenis Barlos
Dimitrios GATOS
Kostas K. Barlos
Zoi Vasileiou
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Chemical and Biopharmaceutical Laboratories of Patras SA
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Chemical and Biopharmaceutical Laboratories of Patras SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • 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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    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
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    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • 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
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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
    • C07K1/1077—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 residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
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    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
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    • C07K14/505—Erythropoietin [EPO]
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    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • C07K14/695—Corticotropin [ACTH]
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    • C08F112/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring
    • C08F112/02—Monomers containing only one unsaturated aliphatic radical
    • C08F112/04—Monomers containing only one unsaturated aliphatic radical containing one ring
    • C08F112/14—Monomers containing only one unsaturated aliphatic radical containing one ring substituted by hetero atoms or groups containing heteroatoms
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Definitions

  • the present invention relates to peptide modifiers with applications in the synthesis of modified peptide derivatives.
  • Peptides are widely used as pharmaceuticals and their application is expected to increase in future. They can be produced by recombinant DNA technology or by conventional chemical synthesis.
  • Native peptides or analogues thereof generally have a high clearance, which is problematic if a prolonged period of biological activity is desired.
  • Pharmaceutical peptides which have a high clearance include, for example, ACTH, angiotensin, calcitonin, insulin, glucagon-like peptide-1, glucagon-like peptide-2, insulin like growth factor-1, insulin-like growth factor-2, growth hormone releasing factor, thrombopoietin, erythropoietin, hypothalamic releasing factors, prolactin, PTH and related peptides, endorphins, enkephalins and other opioids, vasopressin, oxytocin, fuzeon, and the like.
  • Amino acid side chain or amino terminus modifications are usually performed after the synthesis of the linear peptide by selective deprotection of the distinct amino acid side chain and adding the modification reagent, followed by the steps of peptide deprotection and purification.
  • modification of insulin, GLP-1 and chlorotoxin is carried out after the completion of the synthesis of the linear peptide.
  • the modifiers are diacid derivatives such as glutamic acid, aspartic acid etc. and the modified function is an amino function which can be a side chain amino function of a diamino acid or the N-terminal function of the peptide.
  • the peptide modifiers can be of any kind, including peptides, amino acids such as glutamic acid and its derivatives, cysteine and its derivatives, and complex molecules such as sugars, polyethylene glycols, lypophilic acids, lypophilic hydrocarbons, chromophores for diagnostic reasons and antigens for raising antibodies and developing vaccines. As the complexity of the modifiers increase, so does their synthesis.
  • Amino diacids have proved to be suitable linkers between peptides and peptide modifiers.
  • Representative examples are the insulin degludec, and the modified insulin like peptides Liraglutide and Semaglutide, where glutamic acid bound on the side chain of a lysine with its gama-carboxyl function is used as a linker of the peptide with lypophilic groups.
  • Such modifications are advantageous because the remaining free alpha-carboxyl function increases the water solubility of the modified peptide.
  • the peptide modification is performed post-synthetically.
  • the modification can be introduced after the assembly of the peptide chain on a suitable resin, the selective removal of the side chain amino protecting group of a diamino acid contained in the peptide sequence (such as lysine) followed by on-resin introduction of the modifying agent.
  • the present invention seeks to provide new peptide modifiers and methods for the preparation thereof.
  • the peptide modifiers of the invention have applications in the synthesis of peptide derivatives, particularly those for use in therapy.
  • the invention relates to a compound of Formula 1, or a salt thereof,
  • a is an integer from 1 to 10, more preferably from 1 to 4, or 1 to 3; b is an integer from 0 to 7; Z is a terminal group selected from: (a) a group of Formula 2
  • a second aspect of the invention relates to a resin conjugate of Formula 18
  • R 1 is NH 2 or OR 3 , where R 3 is selected from H, alkyl, aryl and aralkyl r is an integer from 1 to 12, more preferably from 2 to 6; Resin is an acid sensitive resin which allow the cleavage of compounds from the resin selectively in the presence of groups of the t Bu-type; b is an integer from 0 to 7; Z is a terminal group selected from: (a) a group of Formula 2
  • a third aspect of the invention relates to a compound (intermediate) of formula:
  • b is an integer from 0 to 7;
  • Z is a terminal group selected from: (a) a group of Formula 2
  • another aspect of the invention relates to the use of a compound as described above in the preparation of a peptide, or a fragment thereof, or a variant thereof.
  • Another aspect of the invention relates to the use of a resin conjugate as described above in the preparation of a peptide, or a fragment thereof, or a variant thereof.
  • Another aspect relates to a method of preparing a peptide, or a fragment thereof, or a variant thereof, which comprises using a process according to the invention.
  • a further aspect of the invention relates to a peptide, or a fragment thereof, or a variant thereof, wherein at least one amino acid residue in said peptide or fragment thereof is modified by side chain attachment of a peptide modifier derived from Z—(Y) b —OH.
  • the invention relates to a peptide of Formula 38, or a fragment or variant thereof,
  • a, b, Z and Y are as defined above; Q 1 and Q 2 are each independently a terminal group; and Aaa x Aaa y . . . Aaa z and Aaa 1 Aaa 2 . . . Aaa n are each independently a natural or synthetic peptide comprising 1 to 100 natural or unnatural amino acid residues, each of which is optionally protected.
  • Another aspect of the invention relates to a peptide, or a fragment thereof, or a variant thereof, as described herein for use in medicine, or for use as a medicament.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a peptide, or a fragment thereof, or a variant thereof, as described herein admixed with a pharmaceutically acceptable excipient, diluent or carrier.
  • alkyl includes both saturated straight chain and branched alkyl groups which may be substituted (mono- or poly-) or unsubstituted.
  • the alkyl group is a C 1-20 alkyl group, more preferably a C 1-15 , more preferably still a C 1-12 alkyl group, more preferably still, a C 1-6 alkyl group, more preferably a C 1-3 alkyl group.
  • Particularly preferred alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.
  • Suitable substituents include, for example, one or more groups selected from OH, O-alkyl, halogen, NH 2 , NH-alkyl, N-(alkyl) 2 , CF 3 , NO 2 , CN, COO-alkyl, COOH, CONH 2 , CO—NH-alkyl, CO—N(alkyl) 2 , SO 2 -alkyl, SO 2 NH 2 and SO 2 —NH-alkyl.
  • aryl refers to a C 6-12 aromatic group which may be substituted (mono- or poly-) or unsubstituted. Typical examples include phenyl and naphthyl etc.
  • Suitable substituents include, for example, one or more groups selected from OH, O-alkyl, halogen, NH 2 , NH-alkyl, N-(alkyl) 2 , CF 3 , NO 2 , CN, COO-alkyl, COOH, CONH 2 , CO—NH-alkyl, CO—N(alkyl) 2 , SO 2 -alkyl, SO 2 NH 2 and SO 2 —NH-alkyl.
  • aralkyl is used as a conjunction of the terms alkyl and aryl as given above.
  • the invention includes, where appropriate all enantiomers and tautomers of the compounds of the invention.
  • the man skilled in the art will recognise compounds that possess optical properties (one or more chiral carbon atoms) or tautomeric characteristics.
  • the corresponding enantiomers and/or tautomers may be isolated/prepared by methods known in the art.
  • Some of the compounds of the invention may exist as stereoisomers and/or geometric isomers—e.g. they may possess one or more asymmetric and/or geometric centers and so may exist in two or more stereoisomeric and/or geometric forms.
  • the present invention contemplates the use of all the individual stereoisomers and geometric isomers of those compounds, and mixtures thereof.
  • the terms used in the claims encompass these forms.
  • the present invention also includes all suitable isotopic variations of the compounds or pharmaceutically acceptable salts thereof.
  • An isotopic variation of an agent of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, respectively.
  • isotopic variations of the agent and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the agent of the present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.
  • salts of the compounds of the invention include suitable acid addition or base salts thereof.
  • suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g.
  • sulphuric acid, phosphoric acid or hydrohalic acids with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C 1 -C 4 )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid.
  • Natural amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
  • non-natural amino acid includes alpha and alpha-disubstituted amino acids, N-alkyl amino acids, lactic acid, halide derivatives of natural amino acids such as trifluorotyrosine, p-Cl-phenylalanine, p-F-phenylalanine, p-Br-phenylalanine, p-NO 2 -phenylalanine, phenylglycine, sarcosine, penicillamine, D-2-methyltryptophan, phosphoserine, phosphothreonine, phosphotyrosine, p-I-phenylalanine, L-allyl-glycine, ⁇ -alanine, ⁇ -aspartic acid, ⁇ -cyclohexylalanine, citrulline, homoserine, homocysteine, pyroglutamic acid, L- ⁇ -amino butyric acid, L- ⁇ -amino butyric acid,
  • the compounds of the present invention may comprise amino acids in the L or D form, i.e. one or more residues, preferably all the residues may be in the L or D form.
  • Suitable protecting groups for amino acids will be familiar to the person skilled in the art (see for example, Chem. Rev. 2009, 109, 2455-2504). These protecting groups can be separated into three groups, as follows:
  • Suitable amino protecting groups are described in “Fmoc Solid Phase Peptide Synthesis—A Practical Approach” W. C. Chan & P. D. White. Oxford University Press, 2000, reprinted 2004.
  • Suitable hydroxy protecting groups are described in Green T., “Protective Groups in Organic Synthesis”, Chapter 1, J. Wiley & Sons, Inc., 1991, 10-142.
  • peptide fragment refers to an amino acid sequence (or variant thereof) derived from a full length protein.
  • the peptide fragment has one or more amino acid residues deleted from the full length protein.
  • the peptide fragment has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues deleted from the full length protein.
  • the peptide fragment comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% of the full length sequence.
  • the term “variant” includes any variation wherein; (a) one or more amino acid residues are replaced by a naturally or non-naturally occurring amino acid residue (b) the order of two or more amino acid residues is reversed, (c) both (a) and (b) are present together, (d) a spacer group is present between any two amino acid residues, (e) one or more amino acid residues are in peptoid form, (f) the (N—C—C) backbone of one or more amino acid residues of the peptide has been modified, or any of (a)-(f) in combination.
  • the variants arise from one of (a), (b) or (c).
  • one or two amino acids residues are substituted by one or more other amino acid residues. Even more preferably, one amino acid residue is substituted by another amino acid residue. Preferably, the substitution is homologous.
  • Homologous substitution substitution and replacement are both used herein to mean the interchange of an existing amino acid residue, with an alternative residue
  • substitution and replacement may occur i.e. like-for-like substitution such as basic for basic, acidic for acidic, polar for polar etc.
  • Non-homologous substitution may also occur i.e.
  • ornithine hereinafter referred to as Z
  • B diaminobutyric acid ornithine
  • 0 norleucine ornithine
  • pyridylalanine thienylalanine
  • naphthylalanine phenylglycine
  • amino acids are classified according to the following classes:
  • homologous substitution is used to refer to substitution from within the same class, whereas non-homologous substitution refers to substitution from a different class or by an unnatural amino acid.
  • Suitable spacer groups that may be inserted between any two amino acid residues of the carrier moiety include alkyl groups such as methyl, ethyl or propyl groups in addition to amino acid spacers such as glycine or ⁇ -alanine residues.
  • alkyl groups such as methyl, ethyl or propyl groups in addition to amino acid spacers such as glycine or ⁇ -alanine residues.
  • type (e) involving the presence of one or more amino acid residues in peptoid form, will be well understood by those skilled in the art.
  • the peptoid form is used to refer to variant amino acid residues wherein the ⁇ -carbon substituent group is on the residue's nitrogen atom rather than the ⁇ -carbon.
  • amino acid variation preferably of type (a) or (b), to occur independently at any position.
  • more than one homologous or non-homologous substitution may occur simultaneously. Further variation may occur by virtue of reversing the sequence of a number of amino acid residues within a sequence.
  • the replacement amino acid residue is selected from the residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
  • the replacement amino acid residue may additionally be selected from unnatural amino acids.
  • Non-natural amino acid derivatives that may be used in the context of the present invention include alpha* and alpha-disubstituted* amino acids, N-alkyl amino acids*, lactic acid*, halide derivatives of natural amino acids such as trifluorotyrosine*, p-Cl-phenylalanine*, p-Br-phenylalanine*, p-I-phenylalanine*, L-allyl-glycine*, ⁇ -alanine*, L- ⁇ -amino butyric acid*, L- ⁇ -amino butyric acid*, L- ⁇ -amino isobutyric acid*, L- ⁇ -amino caproic acid # , 7-amino heptanoic acid*, L-methionine sulfone # *, L-norleucine*, L-norvaline*, p-nitro-L-phenyla
  • the present invention relates to a compound of Formula 1,
  • the introduction into the peptide chain of the derivatives of Formula 1 can be performed by any method known in the art.
  • one preferred embodiment of the invention relates to a process for preparing a peptide derivative of Formula 22, said process comprising the steps of:
  • the first step in the above process involves a coupling reaction using DIC/HOBt.
  • Z is a group of Formula 2.
  • Z is a group of Formula 4.
  • Z is a group of Formula 5.
  • Z is a group of Formula 6.
  • Z is a group of Formula 7.
  • Z is a group of Formula 8.
  • Z is a group of Formula 37.
  • Z is a group of Formula 10.
  • Z is a group of Formula 11.
  • Z is a group of Formula 12.
  • Y is a group of Formula 2′.
  • Y is a group of Formula 6′.
  • Y is a group of Formula 7′.
  • Y is a group of Formula 8′.
  • Y is a group of Formula 10′.
  • Y is a group of Formula 11′.
  • Y is a group of Formula 12′.
  • the diamino acid derivative is of Formula 13
  • Pr is a protecting group, and a, r and R are as defined above.
  • Pr represents a very acid sensitive group of the trityl-type.
  • Pr represents trityl (Trt) or 2-chlorotrityl and R tBu. These new diacid derivatives can be easily introduced into peptide chains similar to 1.
  • R 1 is O-alkyl, more preferably, O t Bu.
  • b is 1 or 2 or 3, more preferably 1 or 2, even more preferably 2.
  • b is 0, i.e. Y is absent.
  • a is an integer from 1 to 5, more preferably 2 or 3 or 4, even more preferably 2. In one highly preferred embodiment, a is 4.
  • Z is a group selected from Formulae 2, 4, 5, 6, 7, 8, 9, 11 and 12.
  • Z is a group selected from Formulae 2, 5, 6, 7, 8, 9, 11 and 12.
  • each Y is independently a group selected from Formulae 2′, 11′ and 12′.
  • each Y is independently a group selected from Formulae 11′ and 12′.
  • One preferred embodiment of the invention relates to a compound of Formula 1, or a salt thereof, but with the proviso that when a is 4, b is 1, Y is of Formula 2′, where r is 2 and R 1 is OR 3 , R 3 is alkyl and Z is of Formula 4, k is other than 11 to 19.
  • One preferred embodiment of the invention relates to a compound of Formula 1, or a salt thereof, but with the proviso that when a is 4, b is 1, Y is of Formula 2′, where r is 2 and R 1 is OR 3 , and Z is of Formula 4, k is other than 11 to 19.
  • One preferred embodiment of the invention relates to a compound of Formula 1, or a salt thereof, but with the proviso that when a is 4, b is 1, Y is of Formula 2′, where r is 2 and R 1 is O t Bu, and Z is other than —C(O)—C 12-20 -alkyl.
  • One preferred embodiment of the invention relates to a compound of Formula 1, or a salt thereof, but with the proviso that when a is 4, b is 1, Y is of Formula 2′, where r is 2 and R 1 is O t Bu, and Z is other than —C(O)—C 15 H 33 .
  • the compound of Formula 1 is selected from the following:
  • One aspect of the invention relates to a process for preparing a compound of Formula 1 as defined above (see examples 1 and 2), said process comprising reacting a compound of Formula 19 with a compound of Formula Z—(Y) b —OH.
  • compounds of Formula 13 are prepared by the coupling of the new amino diacid derivatives of formula 14 with diamino acid derivatives as shown below.
  • one embodiment of the invention relates to a process for the preparation of a compound of Formula 13, said process comprising the steps of:
  • Pr is an acid sensitive protecting group which can be selectively removed in the presence of t Bu-type groups.
  • Pr is selected from the trityl-type groups, even more preferably Trt or Clt.
  • the compound of the invention is of Formula 16
  • compounds of Formula 16, where Y is an amino diacid are prepared according to the scheme below.
  • one embodiment of the invention relates to a process for the preparation of a compound of Formula 16, said process comprising the steps of:
  • the groups Z—Y are introduced on the N ⁇ -function of the amino diacid of Formula 15 starting from the resin-bound aminodiacid where the side chain carboxyl function of the diacid is bound on a very acid sensitive resin and the side chain carboxyl group is protected as OR′ or is NH 2 where R′ is alkyl, aryl or aralkyl.
  • one embodiment of the invention relates to a process for preparing a compound of Formula 15, wherein r is an integer from 1 to 12, more preferably from 2 to 6, said process comprising the steps of:
  • step (i) comprises reacting the compound of Formula 24 with a resin in DCM or THF.
  • step (ii) is carried out in the presence of a base and more preferably in the presence of DIPEA.
  • Step (iii) may be carried out in multiple steps, or a single reaction step.
  • step (iv) is carried out in the presence of a weak acid.
  • the resin is a TFA-cleavable resin of the diphenylmethyl or of the trityl type.
  • the resin is selected from trityl, 2-chloro-trityl, 4-methyl-trityl and 4-methoxy-trityl resins as shown below, wherein Q can be absent, or is a linker between the trityl-group and the polymer matrix P, such as a carboxyl group.
  • Another aspect of the invention relates to compounds (or “resin conjugates”) of Formula 19
  • the acid sensitive resin is selected from trityl, 2-chloro-trityl, 4-methyl-trityl and 4-methoxy-trityl resin, more preferably 2-chlorotrityl resin.
  • the compound of Formula 18 is selected from the following:
  • Another aspect of the invention relates to a compound (or “intermediate”) of formula Z—(Y) b —OH as defined above.
  • Another aspect of the invention relates to the use of a compound as described above in the preparation of a peptide, or a fragment thereof, or a variant thereof.
  • Another aspect of the invention relates to the use of a resin conjugate as described above in the preparation of a peptide, or a fragment thereof, or a variant thereof.
  • Another aspect relates to a method of preparing a peptide, or a fragment thereof, or a variant thereof, which comprises using a process according to the invention.
  • Another aspect relates to a peptide, or a fragment thereof, or a variant thereof, wherein at least one amino acid residue in said peptide or fragment thereof is modified by side chain attachment of a peptide modifier derived from Z—(Y) b —OH, wherein Z, Y and b are as defined above.
  • a peptide modifier derived from Z—(Y) b —OH is attached via the side chain of a lysine residue.
  • the peptide, or a fragment or variant thereof is of Formula 38
  • a, b, Z and Y are as defined above; Q 1 and Q 2 are each independently a terminal group; and Aaa x Aaa y . . . Aaa z and Aaa 1 Aaa 2 . . . Aaa n are each independently a natural or synthetic peptide comprising 1 to 100 natural or unnatural amino acid residues, each of which is optionally protected.
  • Q 1 is H or a protecting group.
  • Q 2 is OH or NH 2 .
  • the peptide or fragment thereof is selected from the following:
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a peptide, or a fragment thereof, or a variant thereof, as described herein admixed with a pharmaceutically acceptable excipient, diluent or carrier.
  • the peptides of the present invention can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent, particularly for human therapy.
  • a pharmaceutical carrier excipient or diluent
  • the pharmaceutical compositions may be for human or animal usage in human and veterinary medicine.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like.
  • suitable diluents include ethanol, glycerol and water.
  • compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).
  • Suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol.
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • compositions of the present invention may be adapted for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal or sublingual routes of administration.
  • compositions of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders.
  • transdermal administration is by use of a skin patch.
  • compositions may be formulated in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose.
  • a person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject without undue experimentation.
  • a physician will determine the actual dosage which will be most suitable for an individual patient and it will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • the dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Trt-Glu-OtBu in the syrup form 44.0 g were dissolved in 125 g THF and cooled to 10° C. Then 20.6 g DCC in 125 ml THF were added and the solution was stirred for 3 h at RT. Then 0.5 g AcOH and 0.5 ml H 2 O were added and the mixture was stirred for additional 1 h and filtered. The obtained solution was concentrated in the RE. A yellowish solid precipitated by the addition of DEE/hexane, filtered and dried in vacuum.
  • the water layer was extracted one more time with DEE and to the obtained water phase solid sodium carbonate and solid NaCl were added until the formed (9H-fluoren-9-yl)methyl 3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy) propylcarbamate was separated as a yellowish oil which was extracted in DCM.
  • the obtained DCM solution was then concentrated in the RE and the oily residue was dissolved in 750 ml DMF. Then 58.5 g (0.5 Mol) of 1,4-dioxane-2,6-dione (glycolic acid anhydride) and 130 g DIPEA were added and the mixture was warmed to 60° C. and stirred for 3 h.
  • the water layer was extracted one more time with DEE and to the obtained water phase solid sodium carbonate and solid NaCl were added until the formed (9H-fluoren-9-yl)methyl 3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy) propylcarbamate was separated as a yellowish oil which was extracted in DCM.
  • the obtained DCM solution was then concentrated in the RE and the oily residue was dissolved in 750 ml DMF. Then 50.0 g (0.5 Mol) of 1, dihydrofuran-2,5-dione (succinic acid anhydride) and 130 g DIPEA were added and the mixture was warmed to 60° C. and stirred for 3 h.
  • the compounds of the general Formula 26 were obtained according to the scheme below starting from resin-bound mercapto acids.
  • N-Mercaptoacyl-amino acids or peptide esters of Formula 25 which were obtained according to (Spyros Mourtas, Dimitrios Gatos, Manolis Karavoltsos, Christina Katakalou and Kleomenis Barlos, Resin - bound mercapto acids: synthesis and application , Tetrahedron Letters 43 (2002) 3419-3421) were dissolved as 1 N-solutions in DMF and treated with a 1.2 molar excess of a bromoalcanoic acid for 1-4 h at RT. Then a 4 molar excess of cysteamine was added and the mixture was stirred for additional 1 h at RT.
  • the resin was filtered and washed 3 ⁇ DMF and 6 ⁇ DCM. The resin was then treated 6 ⁇ with 5 ml of 1.5% TFA in DCM and the combined filtrates were extracted with water and brine and the DCM solution was concentrated in the RE.
  • the obtained oil was dissolved in 5 ml DMF and to the obtained solution 260 mg DIPEA and 195 mg 6-bromohexanoic acid in 5 ml DMF were added at 5° C. The mixture was stirred for additional 1 h at 5° C. and 3 h at RT. Then 260 mg DIPEA and 254 mg 3-aminopropane-1 thiol hydrochloride (cysteamine hydrochloride) were added and the mixture was stirred for additional 2 h at RT.
  • the compounds of the general Formula 26 were obtained according to the scheme below starting from resin-bound halogeno acids (CBL-Patras, Merck).
  • the compounds of the general Formula 27 were obtained according to the scheme below starting from resin-bound oligoethylene glycol derivatives of the Formula 11-1 (CBL-Patras) and acids of the general Formula 26 obtained as described above in the Example 63.
  • the coupling and the cleavage of 27 from the resin were performed according to the standard procedures. Yield 80-95%.
  • CTC-Cl 2-Chlorotrityl chloride resin (CTC-Cl) (100 g; loading 1.6 mmol/g) of CBL-Patras, was placed in a 2 L peptide synthesis reactor and swelled with 700 mL dichloromethane (DCM) for 30 min at 25° C. The resin was filtered and a solution of 100 mmol Fmoc-amino acid and 300 mmol diisopropylethylamine (DIEA) in 500 mL DCM was added. The mixture was stirred under nitrogen for 2 hours at 25° C. Then, the remaining active sites of 2-CTC resin were neutralised by adding 10 mL of methanol (MeOH) and reacting for 1 hour.
  • MeOH methanol
  • the resin was filtered and washed twice with 400 mL DMF.
  • the resin was filtered and treated twice with 500 mL 25% by volume of piperidine in DMF for 30 min.
  • the resin was then washed four times with 500 mL DMF.
  • the resin was unswelled with 3 washes with 500 mL of isopropanol (IPA).
  • IPA isopropanol
  • MBH-Br resin (100 g; 190 mmol) was placed in a 2 L peptide synthesizer and swollen with 700 mL DCM for 30 min at 25° C. The resin was filtered and then a solution of Fmoc-amino acid and DIEA in 500 mL DCM was added. The mixture was stirred under nitrogen for 6 h at 25° C. Then the remaining active sites of the MBH resin were bound by adding 10 mL MeOH and stirring for 24 h. The resin was then filtered and washed twice with 400 mL DMF. The resin was filtered and reacted twice with 500 mL of a solution of 25% by volume of piperidine in DMF for 30 min.
  • the resin was then washed four times with 500 mL DMF.
  • the resin was diswelled with three washes with 500 mL IPA.
  • the resin was then dried to constant weight under vacuum (15 torr, 25° C.). 60-90% of the mmol of the used amino acid were bound onto the resin.
  • the solid-phase synthesis was performed at 24° C., with 1.0 g amino acid esterified to the CTC or MBH resin as described in Part A of Example 1. During the whole synthesis the following protocol was used.
  • the resin was placed in a 15 ml reactor and treated twice with 7 mL NMP, followed by filtration.
  • the amino acid (3.0 equiv.) and 1-hydroxybenzotriazol (4.0 equiv.) was weighted and dissolved in a reactor with 2.5 their volume in NMP and cooled to 0° C. DIC was then added (3.0 equiv.) and the mixture was stirred for 15 min.
  • the solution which was prepared in B2 was then added to the B1 reactor.
  • the reactor was washed once with one volume of DCM and was added to the reactor which was stirred for 1-3 h at 25°-30° C.
  • the Kaiser Test was performed to determine the completion of the reaction. If the coupling reaction was not completed after 3 h (positive Kaiser Test), the reaction mixture was filtered and recoupled with a fresh solution of activated amino acid. After completion of the coupling the reaction mixture was filtered and washed 4 times with NMP (5 volumes per wash).
  • the resulting resin in B3 was filtered and then treated for 30 min with 5 mL of a solution which contained 25% by volume of piperidine. The resin is then washed three times with 5 mL NMP.
  • Fmoc-amino acids Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Val-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Mmt)-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(Trt)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Thr(Trt)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-T
  • the resin-bound peptide or peptide segment which was produced as described above in B1-B5 and was protected at a specific Lys, Orn, or any other diamino acid side chain with Mmt or Mtt or was substituted at a specific Lys, Orn, or any other diamino acid side chain with Trt-Glu-OR, Trt-Asp-OR or any other Trt-Aaa-OH was washed 4 times with 5 mL NMP, 3 times with 5 ml IPA and finally 5 times with 7 ml DCM to remove completely any residual NMP or other basic components.
  • the resin was then cooled to 0° C., filtered from DCM and was treated six times with a solution of 10 mL 1.0-1.5% TFA in DCM/TES (95:5) at 5° C. The mixture was then stirred 20 min at 0° C. and filtered. The resin is then washed three times with 10 mL DCM. Pyridine is then added to the filtrates (1.3 equiv. relative to TFA) to neutralize the TFA. The cleavage solution in DCM was then mixed with an equal volume of water. The resulting mixture was distilled at reduced pressure to remove DCM (350 torr at 28° C.). The peptide or peptide segment precipitated after the removal of DCM. The resulting peptide was washed with water and ether and dried at 30-35° C. under 15 Torr vacuum. Alternatively DCM was removed in vacuum and the partially protected peptide was precipitate by the addition of ether.
  • the partially protected peptide obtained as described above (0.01-0,005 mmol) was treated with 10 mL TFA/TES/thioanisol/water (85:5:5:5) or TFA/DTT/water (90:5:5 for 3 h at 5° C. and for 1 h at 15° C.
  • the resulting solution was concentrated in vacuum and then the deprotected peptide was precipitated by the addition of DEE or diisopropylether and washed three times with 10 mL DEE or diisopropylether.
  • the resulting solid was dried in vacuum (25° C., 1-10 Torr) until constant weight.
  • Fmoc-Ala-OH, Fmoc-Ala-OH and Fmoc-Gln(Trt)-OH were coupled sequentially using a five fold molar excess on amino acid, DIC and HOBt. After removal of the Fmoc-group the resin-bound peptide was coupled sequentially with 1.25 and 1.5 molar excess of 1. Fmoc-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(tBu)-Val-Ser(tBu)- ⁇ Ser-Tyr(tBu)-Leu-Glu(tBu)-Gly-OH and 2.
  • the obtained mixture was concentrated in vacuum and the thioester was then perecipitated by the addition of DEE and washed 4 ⁇ with DEE and dried in vacuum to constant weight.
  • the crude protected thioester obtained was then deprotected by treatment with 50 ml of TFA/TES/DCM (90/5/5) for 4 h at RT.
  • the deprotection solution was then concentrated in vacuum and the deprotected thioester was precipitated by the addition of DEE, washed with DEE and dried in vacuum. Yield: 3.13 g (96.4%) crude thioester of 82% purity determined by HPLC.
  • the synthesis was performed in the 1.0 mmol scale according to the general procedures.
  • the Lys 20 residue already modified with a Glu residue was introduced using 1.6 g (2.0 mmol) 14-(tert-butoxycarbonyl)-1-(9H-fluoren-9-yl)-3,11-dioxo-16,16,16-triphenyl-2-oxa-4,10,15-triazahexadecane-5-carboxylic acid according to the sheme below. Palmitic acid was activated with EDAC/HOSu. Yield: 1.51 g (44.9%).
  • the synthesis performed as shown below was started with 1.00 g (0.25 mmol) of H-Gly-O-CTC-resin.
  • the Lys residue was introduced with 2 equivalents Fmoc-Lys(Trt-Glu-OtBu)-OH.
  • the partially protected peptide was modified in solution using 190 mg modifier activated with EDAC/HOSu. Yield 1.34 g (88.5%).
  • the synthesis was performed in the 1.00 mmol scale.
  • the modifier was introduced with 2.6 g (2.0 mmol) tert-butyl 5-acetyl-34-(tert-butoxycarbonyl)-1-(9H-fluoren-9-yl)-52-isopropyl-3,11,15,31,36,50-hexaoxo-2,13,20,23,26-pentaoxa-42-thia-4,10,16,30,35,51-hexaazatripentacontan-53-oate. Yield: 1.65 g (33.3%).
  • the synthesis was performed on the 1.0 mmol scale.
  • the modifier was introduced using 2.4 g (2.0 mmol) 50-(((9H-fluoren-9-yl)methoxy)carbonylamino)-41-(tert-butoxycarbonyl)-2,2-dimethyl-4,21,30,39,44-pentaoxo-3,25,28,34,37-pentaoxa-22,31,40,45-tetraazahenpentacontan-51-oic acid. Yield: 1.06 g (22.3%).
  • the synthesis was performed in the 10 mmol scale on the Fmoc-Ser(CTC-resin)-NH 2 .
  • the modifier was introduced using 16.0 g (20.0 mmol) tert-butyl 5-acetyl-1-(9H-fluoren-9-yl)-28-isobutyl-3,11,26-trioxo-2-oxa-4,10,27-triazanonacosan-29-oate.
  • the Leu w -Ser 11 residues were introduced with the corresponding pseudoproline. Yield: 29.7 g (31.4%).
  • the synthesis was performed in the 1.0 mmol scale.
  • the modifier was introduced using two equivalents of 51-(((9H-fluoren-9-yl)methoxy)carbonylamino)-42-carboxy-5-isopropyl-2,2-dimethyl-4,7,21,37,41,45-hexaoxo-3,26,29,32,39-pentaoxa-15-thia-6,22,36,46-tetraazadopentacontan-52-oic acid (2.46 g) activated with EDAC and pentafluorophenol. Yield 1.56 g (42%).
  • the synthesis was performed in a 1.0 mmol scale.
  • the modifier was introduced using 23,35-di-tert-butyl 1-perfluorophenyl 39,39-dimethyl-4,20,25,37-tetraoxo-2,9,12,15,38-pentaoxa-33-thia-5,19,24,36-tetraazatetracontane-1,23,35-tricarboxylate produced in situ using pentafluorophenol and EDAC as the activating agents. Yield: 2.01 g (36.5%).
  • the modified Lys at position 18 was introduced using 34-(tert-butoxycarbonyl)-1-(9H-fluoren-9-yl)-55,55-dimethyl-3,11,15,31,36,53-hexaoxo-2,13,20,23,26,54-hexaoxa-44-thia-4,10,16,30,35-pentaazahexapentacontane-5-carboxylic acid
  • Fragment 1 N-acetyl-Tyr(tBu)-Thr(tBu)-Ser(tBu)-Leu-Ile-His(Trt)-Ser(tBu)-Leu-Ile-Glu (tBu)-Glu(tBu)-Ser(tBu)-Gln(Trt)-Asn(Trt)-Gln(Trt)-Gln-OH
  • Fragment 3 Fmoc-Asp(tBu)-Lys(Boc)-Trp(Boc)-Ala-Ser(tBu)-Leu-Trp(Boc) Asn(Trt)-Trp (Boc)-Phe-NH 2 .

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US11338018B2 (en) 2016-12-19 2022-05-24 Harrow Ip, Llc Adrenocorticotropic hormone-based pharmaceutical formulations and methods for fabricating and using thereof
US11534481B2 (en) 2016-12-19 2022-12-27 Harrow Ip, Llc Adrenocorticotropic hormone-based pharmaceutical formulations and methods for fabricating and using thereof
WO2020150262A1 (en) * 2019-01-17 2020-07-23 Harrow Ip, Llc Adrenocorticotropic hormone-based pharmaceutical formulations and methods for fabricating and using thereof
CN115504893A (zh) * 2022-11-18 2022-12-23 成都普康生物科技有限公司 一种L-谷氨酸-α-叔丁脂的合成方法

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