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WO2011011865A1 - Agents anticancéreux à base de dérivés d’acides aminés - Google Patents

Agents anticancéreux à base de dérivés d’acides aminés Download PDF

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Publication number
WO2011011865A1
WO2011011865A1 PCT/CA2010/001125 CA2010001125W WO2011011865A1 WO 2011011865 A1 WO2011011865 A1 WO 2011011865A1 CA 2010001125 W CA2010001125 W CA 2010001125W WO 2011011865 A1 WO2011011865 A1 WO 2011011865A1
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Prior art keywords
compound
tyr
cancer
formula
chl
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Gervais Berube
Caroline Descoteaux
Eric Asselin
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3R VALO SEC
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3R VALO SEC
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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—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
    • 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

Definitions

  • This disclosure relates to the field of amino acid derivatives as active agents. More particularly, this dicslosure relates to amino acid derivatives which are usefull as anticancer agents for treating cancer such as melanoma, breast cancer, uterine cancer and ovarian cancer.
  • Scheme 1 Structures of major classes of alkylating agents [0004] There are four bis(chloroethyl)amines used clinically; mechlorethamine (Mustargen ) ' , cyclophosphamide (Cytoxan ) ' , melphalan (Alkeran ) ' and chlorambucil (Leukeran ) ' (scheme 2). Mechlorethamine is effective in Hodgkin's disease. 4 Cyclophosphamide is active orally which is a great advantage over other alkylating agents. It is active against multiple myeloma, chronic lymphocytic leukemia, and acute leukemia in children.
  • 4 Melphalan is used against multiple myeloma and ovarian cancers.
  • 4 Chlorambucil is a slow acting nitrogen mustard which can be administered orally. It is mainly used in chronic lymphocytic leukemia and primary macro globulinemia. It is also useful in treating lymphosarcoma and Hodgkin's disease. 4 All nitrogen mustard anticancer drugs can be used as a single agent or in combination therapy with other antineoplastic agents.
  • alkylating agents are both mutagenic and genotoxic. 5
  • the alkylating agents form adducts with DNA, inhibiting protein synthesis in fast replicating malignant cells. However, they also form adducts with RNA and protein and this is likely to contribute to the overall cytotoxicity. 5
  • T is L or -A-NH-C(O)-L-;
  • L is -(CH 2 ) H - or -(CH 2 ) P -Z- ;
  • A is -(CH 2 ) m - or an alkyl component of a naturally occurring amino acid
  • R is -CO 2 R 1 , -CH 2 OH,
  • Ri is H or is C 1 -Ci 2 alkyl
  • X is -OH, -OSO 2 R 2 , -Cl, -Br, or -I;
  • R 2 is Ci-C 12 alkyl or -CF 3 ;
  • Z is phenyl or naphthyl
  • n is an integer having a value of 1 to 20;
  • n is an integer having a value of 1 to 20;
  • p is an integer having a value of 1 to 20, or enantiomers, diastereoisomers or tautomers of the compounds of formula I in any ratio, or pharmaceutically acceptable salts, solvates or prodrugs of the compounds of formula I or enantiomers, diastereoisomers or tautomers of the compounds of formula I in any ratio, or mixtures of any of the above.
  • composition comprising a pharmaceutically acceptable carrier and at least one compound of the present disclosure.
  • a method for treating cancer or at least one cancer chosen from breast cancer, uterine cancer and ovarian cancer comprising administering to a subject in need thereof an effective amount of at least one compound of the present disclosure.
  • a method for reducing the risks of developing cancer or for reducing the risk of developingat least one cancer in a subject comprising administering to the subject an effective amount of at least one compound of the present disclosure.
  • a method for inhibiting cancer cell growth comprising administering to a subject in need thereof an effective amount of at least one compound of the present disclosure.
  • the cancer can be chosen from melanoma, breast cancer, uterine cancer and ovarian cancer.
  • At least one compound of the present disclosure for treating cancer or for treating at least one cancer chosen from melanoma, breast cancer, uterine cancer and ovarian cancer.
  • At least one compound of the present disclosure for reducing the risks of developing cancer or for reducing the risks of developing at least one cancer chosen from melanoma, breast cancer, uterine cancer and ovarian cancer.
  • At least one compound of the present disclosure in the manufacture of a medicament for treating cancer or for treating at least one cancer chosen from melanoma, breast cancer, uterine cancer and ovarian cancer.
  • At least one compound of the present disclosure in the manufacture of a medicament for reducing the risks of developing cancer or for reducing the risks of developing at least one cancer chosen from melanoma, breast cancer, uterine cancer and ovarian cancer.
  • the cancer can be chosen from melanoma, breast cancer, uterine cancer and ovarian cancer.
  • the use of at least one compound of the present disclosure in the manufacture of a medicament for inhibiting cancer cell growth can be chosen from melanoma, breast cancer, uterine cancer and ovarian cancer.
  • T is L or -A-NH-C(O)-L-;
  • L is -(CH 2 ) n - or -(CH 2 ) P -Z- ;
  • A is -(CH 2 ) In - or an alkyl component of a naturally occurring amino acid
  • R is -CO 2 R 11 -CH 2 OH
  • R 1 is H or is C 1 -C 12 alkyl
  • X is -OH, -OSO 2 R 2 , -Cl, -Br, or -I;
  • R 2 is C 1 -C 12 alkyl or -CF 3 ;
  • Z is phenyl or naphthyl
  • n is an integer having a value of 1 to 20;
  • n is an integer having a value of 1 to 20;
  • p is an integer having a value of 1 to 20
  • E is -NH 2 , or -NH 3 + X 1 " ;
  • Xf is a suitable counter anion
  • R 5 is a C 1 -C 5 alkyl;
  • R, T, and X are as previously defined for formula I,
  • Xf is a suitable counter anion
  • R 5 is a Ci-C 5 alkyl
  • R, A, L and X are as previously defined for formula I,
  • sufficient amount of a compound of the present disclosure is a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, including clinical results, and, as such, an "effective amount” or synonym thereto depends upon the context in which it is being applied. For example, in the context of treating cancer, for example, it is an amount of the compound sufficient to achieve such treatment of the cancer as compared to the response obtained without administration of the compound.
  • the amount of a given compound of the present disclosure that will correspond to an effective amount will vary depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
  • a “therapeutically effective amount” , “effective amount” or a “sufficient amount” of a compound of the present disclosure is an amount which inhibits, suppresses or reduces a cancer (e.g., as determined by clinical symptoms or the amount of cancerous cells) in a subject as compared to a control.
  • subject includes all members of the animal kingdom including human. According to one embodiment, the subject is a human.
  • alkyl as used herein means straight and/or branched chain, saturated alkyl groups containing from one to n carbon atoms and includes (depending on the identity of n) methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t- butyl, 2,2-dimethylbutyl, n-pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-hexyl and the like, wherein n is the maximum number of carbon atoms in the group.
  • an alkyl component of a naturally occurring amino acid refers to the portion of a naturally occurring amino acid that is comprised between the carbon of the carbonyl group of the amino acid and the nitrogen atom of the amino acid.
  • the expression "compound(s) of the present disclosure” as used in the present document refers to compounds of formulae I, II, Ha, III, Ilia, IV, IVa, V, Va, VI, Via, VII, Vila, VIIb, and VIIc, presented in the present disclosure, isomers thereof, such as stereoisomers (for example, enantiomers, diastereoisomers, including racemic mixtures) or tautomers, or to pharmaceutically acceptable salts, solvates, hydrates and/or prodrugs of these compounds, isomers of these latter compounds, or racemic mixtures of these latter compounds.
  • the expression “compound(s) of the present disclosure” also refers to mixtures of the various compounds or variants mentioned in the present paragraph.
  • the compounds of the disclosure may have at least one asymmetric centre. Where the compounds according to the present document possess more than one asymmetric centre, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present disclosure. It is to be understood that while the stereochemistry of the compounds of the present disclosure may be as provided for in any given compound listed herein, such compounds of the disclosure may also contain certain amounts (for example less than 30%, less than 20%, less than 10%, or less than 5%) of compounds of the present disclosure having alternate stereochemistry.
  • suitable reaction conditions means that the selection of the particular group or conditions would depend on the specific synthetic manipulation to be performed and the identity of the molecule but the selection would be well within the skill of a person trained in the art. All process steps described herein are to be conducted under conditions suitable to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so. [0027]
  • pharmaceutically acceptable means compatible with the treatment of subjects such as animals or humans.
  • pharmaceutically acceptable salt means an acid addition salt or basic addition salt which is suitable for or compatible with the treatment of subjects such as animals or humans.
  • pharmaceutically acceptable acid addition salt means any non-toxic organic or inorganic salt of any compound of the present disclosure, or any of its intermediates.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
  • mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sul
  • the acid addition salts of the compounds of the present disclosure are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection of the appropriate salt will be known to one skilled in the art.
  • Other non-pharmaceutically acceptable salts e.g. oxalates, may be used, for example, in the isolation of the compounds of the present disclosure, for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt, hi embodiments of the present disclosure, the pharmaceutically acceptable acid addition salt is the hydrochloride salt.
  • compositions of the invention include any non-toxic organic or inorganic base addition salt of any acid compound of the invention, or any of its intermediates.
  • Acidic compounds of the invention that may form a basic addition salt include, for example, where R is CO 2 H.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.
  • Other non- pharmaceutically acceptable basic addition salts may be used, for example, in the isolation of the compounds of the invention, for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • a desired compound salt is achieved using standard techniques. For example, the neutral compound is treated with an acid or base in a suitable solvent and the formed salt is isolated by filtration, extraction or any other suitable method.
  • solvate means a compound of the present disclosure, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate”.
  • solvates of the compounds of the present disclosure will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions.
  • prodrugs include prodrugs.
  • prodrugs will be functional derivatives of these compounds which are readily convertible in vivo into the compound from which it is notionally derived.
  • Prodrugs of the compounds of the present disclosure may be conventional esters formed with available hydroxy, or amino group.
  • an available OH or nitrogen in a compound of the present disclosure may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine).
  • esters which have been utilized as prodrugs are phenyl esters, aliphatic (Cg-C 24 ) esters, acyloxymethyl esters, carbamates and amino acid esters, hi certain instances, the prodrugs of the compounds of the present disclosure are those in which one or more of the hydroxy groups in the compounds is masked as groups which can be converted to hydroxy groups in vivo.
  • Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985.
  • Compounds of the present disclosure include radiolabeled forms, for example, compounds labeled by incorporation within the structure 2 H, 3 H, 14 C, 15 N, or a radioactive halogen such as 125 I.
  • a radiolabeled compound of the compounds of the present disclosure may be prepared using standard methods known in the art.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment or “treating” can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • “Palliating" a disease or disorder means that the extent and/or undesirable clinical manifestations of a disorder or a disease state are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the disorder.
  • derivative thereof when referring to a compound of formula (XI) means a derivative of the compound of formula (XI) that has a similar reactivity and that could be used as an alternative to the compound of formula (XI) in order to obtain the same desired result i.e. formation of a compound of formula (I) when reacting this derivative with a compound of formula (X) or a derivative thereof under conditions to form the compound of formula I.
  • Coupled reagent refers to a reagent effective for coupling together an amine or a derivative thereof and an organic acid or a derivative thereof in order to obtain an amide.
  • Non-limitative examples of such coupling reagents include DCC (dicyclohexylcarbodiimide), CDI (N,N'- carbonyldiimidazole), BOP (benzotriazole- 1 -yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate), DEPBT (3-(diethoxy-phosphoryloxy)-3H- benzo[d][l,2,3] triazin-4-one), EDCHCl (l-ethyl-3-(3- dimethyllaminopropyl)carbodiimide hydrochloride), HATU (2-(lH-7- azabenzotriazol- 1 -yl) ⁇ 1,1,3 ,3 -tetramethyl ur
  • R is -CO 2 Ri or -CH 2 OH
  • L is -CH 2 CH 2 CH 2 -C 6 H 4 - or -(CH 2 V;
  • X is -OH, -OSO 2 R 2 or -Cl
  • R 1 is chosen from H, straight alkyl group having from 1 to 5 carbon atoms, and branched alkyl group having from 3 to 5 carbon atoms;
  • R 2 is -CH 3 or -CF 3 ;
  • n 1, 2, 3, 4, 5, 6, 7 or 8
  • R is -CO 2 R 1 or -CH 2 OH
  • L is -CH 2 CH 2 CH 2 -C 6 H 4 - or -(CH 2 ),,-;
  • A is -(CH 2 ) m -;
  • X is -OH, -OSO 2 R 2 or -Cl
  • Ri is chosen from H, straight alkyl group having from 1 to 5 carbon atoms, and branched alkyl group having from 3 to 5 carbon atoms;
  • R 2 is -CH 3 or -CF 3 ;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10
  • L is -CH 2 CH 2 CH 2 -C 6 H 4 - or -(CH 2 ),,-;
  • X is -OH, -OSO 2 R 2 or -Cl
  • R 2 is -CH 3 or -CF 3 ;
  • n 1, 2, 3, 4, 5, 6, 7 or 8
  • L is -CH 2 CH 2 CH 2 -C 6 H 4 - or -(CH 2 ),,-;
  • A is -(CH 2 ) m -;
  • X is -OH, -OSO 2 R 2 or -Cl
  • R 2 is -CH 3 or -CF 3 ;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10
  • R is -CO 2 R 1 or -CH 2 OH
  • L is -CH 2 CH 2 CH 2 -C 6 H 4 - or -(CH 2 V;
  • X is -OH, -OSO 2 R 2 or -Cl
  • R 1 is chosen from H, straight alkyl group having from 1 to 5 carbon atoms, and branched alkyl group having from 3 to 5 carbon atoms;
  • R 2 is -CH 3 or -CF 3 ;
  • n 1, 2, 3, 4, 5, 6, 7 or 8
  • R is -CO 2 R 1 or -CH 2 OH
  • L is -CH 2 CH 2 CH 2 -C 6 H 4 - or -(CH 2 V;
  • A is -(CH 2 ) m -;
  • X is -OH, -OSO 2 R 2 or -Cl
  • R 1 is chosen from H, straight alkyl group having from 1 to 5 carbon atoms, and branched alkyl group having from 3 to 5 carbon atoms;
  • R 2 is -CH 3 or -CF 3 ;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10
  • L is -CH 2 CH 2 CH 2 -C 6 H 4 - or -(CH 2 V;
  • X is -OH, -OSO 2 R 2 or -Cl
  • R 2 is -CH 3 or -CF 3 ;
  • n i, 2, 3, 4, 5, 6, 7 or 8
  • L is -CH 2 CH 2 CH 2 -C 6 H 4 - or -(CH 2 ) n -;
  • A is -(CHa) 1n -;
  • X is -OH, -OSO 2 R 2 or -Cl
  • R 2 is -CH 3 or -CF 3 ;
  • n 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10
  • L is -CH 2 CH 2 CH 2 -C 6 H 4 -, or enantiomers or tautomers of the compounds of formula VII in any ratio, or pharmaceutically acceptable salts, solvates or prodrugs of the compounds of formula VII or enantiomers or tautomers of the compounds of formula VII in any ratio, or mixtures of any of the above.
  • L is -CH 2 CH 2 CH 2 -C 6 H 4 -, or enantiomers or tautomers of the compounds of formula VIIb in any ratio, or pharmaceutically acceptable salts, solvates or prodrugs of the compounds of formula VIIb or enantiomers or tautomers of the compounds of formula VIIb in any ratio, or mixtures of any of the above.
  • A is the alkyl component of a hydrophobic naturally occurring amino acid.
  • the naturally occuring amino acid is chosen from alanine, phenylalanine, leucine, isoleucine, tryptophan, valine and proline.
  • non natural amino acids are also used to make derivatives of formula Ha, Ilia, IVa, Va, Via, Vila, VIIb, and VIIc.
  • A is chosen from
  • L is -CH 2 CH 2 CH 2 -
  • L is -CH 2 CH 2 CH 2 -
  • L is -CH 2 CH 2 CH 2 -
  • A is -(CH 2 V-, X is -Cl and R is ⁇ CO 2 CH 3 .
  • L is -CH 2 CH 2 CH 2 -
  • A is -(CH 2 V-, m is 5 or 10, X is -Cl and R is -CO 2 CH 3 .
  • L is -CH 2 CH 2 CH 2 -
  • A is -(CH 2 V-, X is -Cl and R is -CH 2 OH.
  • L is -CH 2 CH 2 CH 2 -
  • A is -(CH 2 V-, m is 5 or 10, X is -Cl and R is -CH 2 OH.
  • L is -CH 2 CH 2 CH 2 -
  • L is -CH 2 CH 2 CH 2 -
  • L is -CH 2 CH 2 CH 2 -
  • the conditions to form a compound of formula I comprise the presence of at least one coupling reagent and a base.
  • the least one coupling reagent is chosen from DCC (dicyclohexylcarbodiimide), CDI (N 5 N'- carbonyldiimidazole), BOP (benzotriazole- 1 -yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate), DEPBT (3-(diethoxy-phosphoryloxy)-3H- benzo[d][l,2,3] triazin-4-one), EDCHCl (l-ethyl-3-(3- dimethyllaminopropyl)carbodiimide hydrochloride), HATU (2-(lH-7- azabenzotriazol- 1 -yl) ⁇ 1,1,3 ,3 -tetramethyl uronium hexafluorophosphate methanaminium), HOBt (1-hydroxybenzotriazole or N-hydroxybenzotriazole), HBTU (O-benzo
  • the conditions to form a compound of formula I comprise the presence of dicyclohexylcarbodiimide and N-hydroxybenzotriazole.
  • Xf is chosen from,
  • Schemes 3 to 5 represent examples of synthetic routes used for the preparation of the compounds of the present disclosure.
  • the reaction conditions of each step are presented directly in the schemes.
  • Scheme 3 illustrates the preparation of first generation tyrosine- nitrogen mustard hybrids of formulae types II, Ha, IV and IVa.
  • L-tyrosine (1) or D-tyrosine
  • thionyl chloride in methanol
  • derivative 2 100%
  • Compound 2 was transformed into tyrosine-nitrogen mustard 3 (81%) upon treatment with chlorambucil (CHL), 1-hydroxybenzotriazole (HOBt), dicyclohexylcarbodiimide (DCC) and triethylamine (TEA) in dimethylformamide (DMF).
  • CHL chlorambucil
  • HABt 1-hydroxybenzotriazole
  • DCC dicyclohexylcarbodiimide
  • TAA triethylamine
  • DMF dimethylformamide
  • Compound 3 was reduced to L- tyrosinol-nitrogen mustard derivative 4 with lithium borohydride (LiBH 4 ) in dry diethylether (Et 2 O) with 8
  • Boc-aa, m 5 or 10 (97%) performed with D-p-, DL-O- and L-m- the starting material.
  • Reagents (a) MeOH, SOCl 2 . ⁇ (100%); (b) Chlorambucil, HOBt, DCC, Et 3 N, DMF (81%); (c) LiBH 4 Et 2 O, O 0 C to 22 0 C (4, 88%; 7, 57%); (d) Boc-ON, 1,4-dioxane, Et 3 N, H 2 O (97%); (e) BocNH(CH 2 ) m CO 2 H, HOBt, DCC, Et 3 N, DMF (96%); (f) TFA, CH 2 Cl 2 10 min, (100%).
  • Scheme 5A illustrates the preparation of second generation tyrosine- nitrogen mustard hybrids of formulae types III, Ilia, V, Va, V, Va, VII, Vila, VIIb, and VIIc.
  • the final tyro sine-nitrogen mustard hybrids 15 were obtained in a two-step reaction sequence. First, derivative 13 was deprotected with TFA in dichloromethane to give the trifluoroacetic ammonium salt intermediate 14. Secondly, derivative 14 was coupled with chlorambucil using HOBt, DCC, triethylamine in DMF to give hybrid 15 with 19% yield.
  • Scheme 5A Synthesis of tyrosine-nitrogen mustard hybrids second generation.
  • the hybrids 15 were synthesized using a convergent and more efficient approach. 6-Amino caproic acid and 11 -amino undecanoic acid were initially coupled with chlorambucil as shown in scheme 5B to give 16 with 98% yield. This transformation was performed upon treatment of the amino acid with 1,1,1,3,3,3- hexamethyldisilazane (HMDS) in the presence trimethylchlorosilane (TMSCl) and catalytic sulfuric acid in DCM and TEA to give the sililated amino acid intermediate. The latter was then added to activated chlorambucil to produce derivative 16 with excellent yields.
  • HMDS 1,1,1,3,3,3- hexamethyldisilazane
  • TMSCl trimethylchlorosilane
  • DCM and TEA trimethylchlorosilane
  • Reagents (a) 1. HMDS, H 2 SO 4 cat., TMSCl, DCM, TEA; 2. CHL, HOBt, DCC, TEA, DMF (98%);
  • the derivatives of the first generation seen in scheme 3 can also be obtained by convergent synthesis. This was done for the first generation D- tyrosine series as described in the experimental section. Of note, solid phase synthesis can be used to make these tyrosine-nitrogen mustard hybrids.
  • the compounds of the present disclosure may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the compounds of the present disclosure may contain one or more asymmetric carbon atoms and thus may occur as racemates and racemic mixtures, single enantiomer, diastereomeric mixtures and individual diastereoisomers. All such isomeric forms of these compounds are expressly included in the present disclosure.
  • Each stereo genie carbon may be of the R or S configuration.
  • the infrared spectra were taken on a Nicolet Impact 420 FT-IR. Mass spectral assays were obtained using a MS model 6210, Agilent technology instrument. The high resolution mass spectra (HRMS) were obtained by TOF (time of flight) using ESI (electrospray ionization) using the positive mode (ESI+). (Plateforme analytique pour molecules organiques de l'Universite du Quebec a Montreal).
  • Multiplicities are described by the following abbreviations: s for singlet, d for doublet, dd for doublet of doublets, t for triplet, dt for doublet of triplets, q for quartet, dq for doublet of quartets, m for multiplet, #m for several multiplets, br for a broad signal.
  • Triethylamine (3.62 mmol) and isobutylchloroformate (3.62 mol) were added and the mixture was kept at 0°c for 1 h. Then, the chlorambucil solution was added to the activated amino acid solution and the mixture was stirred at room temperature for 4 h. Work-up was done by diluting with ethyl acetate and by washing the organic phase with HCl 10% solution (2x) and with a saturated sodium chloride solution (2x). The organic phase was dried with anhydrous magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography (hexanes: acetone, 7:3) to give the desired material in 98 % yield.
  • NCH 2 CH 2 Cl 41.0 (2x C, 2x NCH 2 CH 2 Cl), 39.1, 35.6, 34.3, 33.6, 29.4, 27.9, 26.5,
  • Step A Synthesis of L-p-tyrosine-methyl ester hydrochloride (2) and various isomers of (2) (D-p-tyr, DL- ⁇ -tyr, L-m-fyr))
  • Step B Synthesis of N-chlorambucil-L-p-tyrosine methyl ester (3) and various isomers of (3) (D-p-tyr, DL- ⁇ -tyr, h-m-tyr))
  • Step A Synthesis of N-((iV-Boc-amino)alcanoyl)-L-p-tyrosine methyl ester
  • Step A Synthesis of J /V-(( ⁇ / -chlorambucilamino)alcanoyl) ⁇ tyrosine methyl ester (isomers of 6, made with D-p-tyr, DL- ⁇ -tyr, and L-m-tyr) [00100]
  • the tyrosine methyl ester hydrochloride 2 (0.41 mmol) was dissolved in dimethylformamide and triethylamine (0.41 mmol). The latter was added in order to neutralize the hydrochloride salt.
  • NCH 2 CH 2 Cl 38.7, 37.4, 35.4 (2C), 34.0, 27.7, 26.1, 25.1, (1C hidden).
  • NCH 2 CH 2 Cl 38.8, 37.4, 35.5, 35.3, 34.0, 29.6, 29.2, 29.1, 28.9, 27.7, 26.7, 25.4,
  • Step B Synthesis of ⁇ / -(( ⁇ r -chlorambuciIamino)alcanoyl-tyrosinol (isomers of 7, made with D-/»-tyr, DL- ⁇ -tyr, and L-m-tyr)
  • Step B Synthesis of iV-chlorambucil-hydroxyphenyl-L-p-tyrosinaniide (11)
  • N-Boc-hydroxyphenyl-L-p-tyrosinamide 10 (0.16 mmol) was dissolved in dichloromethane and trifluoro acetic acid (1.60 mmol) was added. The solution was stirred at room temperature for 24 h. After evaporation, the resulting trifluoroacetic salt was dissolved in dimethylformamide and neutralized with triethylamine (0.16 mmol). Simultaneously, chlorambucil (0.24 mmol) was dissolved in dimethylformamide, and DCC (0.25 mmol) followed by HOBt (0.25 mmol) were added.
  • Step A Synthesis of iV-ffiV-Boc-amino)alcanoyl)-/7-hydroxyphenyl-L-p- tyrosinamide (13)
  • N-Boc-p-hydroxyphenyl-L-p-tyrosinamide derivative 10 (0.57 mmol, see example 6) was dissolved in dichloromethane and trifluoroacetic acid (5.70 mmol) was added. The solution was stirred at room temperature for 29 h. After evaporation, the resulting trifluoroacetic salt was dissolved in dimethylformamide and neutralized with triethylamine (0.57 mmol).
  • Step B Synthesis of ⁇ L (( ⁇ L chlorambucilamino)hexanoyl)-p- hydroxyphenyl-L-p-tyrosinamide (15)
  • Step A Synthesis of ⁇ r -(( ⁇ / -chlorambucilamino)alkaloyl)-hydroxyphenyl-L-
  • Table 1 Cell proliferation with the MTT assay on breast carcinomas obtained for L-tyrosine-nitrogen mustard hybrids and for chlorambucil (CHL).
  • Table 2 Cell proliferation with the MTT assay on breast, ovarian and uterine carcinomas obtained for L- or D-tyrosine-nitrogen mustard hybrids and for
  • NCI-60 DTP Human Tumor Cell Line Screen 11
  • CHL chlorambucil
  • GI 50 Growth inhibition of 50 %
  • the LC 50 concentration of drug resulting in a 50% reduction in the measured protein at the end of the drug treatment as compared to that at the beginning
  • the table gives the average value over all cell lines tested and the GI 5 0, TGI and LC 50 ratios CHL/6.
  • the compounds of the present disclosure are able to target cancers such as, for example, melanoma, breast, uterine and ovarian cancers, but also to display increased efficacy and overall decreased systemic toxicity. They are also active against various types of cancer cell lines.
  • the present disclosure comprises a novel class of nitrogen mustard anticancer compounds including their pharmaceutically acceptable derivatives. These molecules demonstrated in vitro cytotoxic activity on human breast cancer. Therefore, these compounds can be, for example, used to provide medicaments with anticancer activity against hormono-dependent breast, uterine, melanoma as well as ovarian cancers as well as various other types of cancer These compounds can be used, for example, alone or in combination with other therapeutic or prophylactic agents for the treatment of melanoma breast, uterine and ovarian cancers.

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Abstract

L’invention concerne des composés représentés par la formule (I) dans laquelle T représente L ou -A-NH-C(O)-L-; L représente -(CH2)n- ou -(CH2)p-Z-; A représente -(CH2)m- ou un composant alkyle d’un acide aminé naturel; R représente -CO2R1, -CH2OH, -C(O)NH(hydroxyphenyl) ou C(S)NH(hydroxyphenyl); R1 représente H ou C1-C12 alkyle; X représente -OH, OSO2R2, -Cl, -Br, ou –I; R2 représente C1-C12 alkyle ou -CF3 ; Z représente phényle ou naphthyle; m est un nombre entier compris entre 1 et 20; n est un nombre entier compris entre 1 et 20; et p est un nombre entier compris entre 1 et 20 ou représente un énantiomère, un diastéréoisomère, un mélange racémique, un sel pharmaceutiquement acceptable, un solvate ou un promédicament de celui-ci. Ces composés peuvent être utilisés comme agents anticancéreux.
PCT/CA2010/001125 2009-07-29 2010-07-16 Agents anticancéreux à base de dérivés d’acides aminés Ceased WO2011011865A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018123092A (ja) * 2017-02-01 2018-08-09 国立研究開発法人産業技術総合研究所 アミノ酸含有両親媒性分子および有機ナノチューブ

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096367A1 (fr) * 2000-06-13 2001-12-20 Oncopeptides Ab Derives de melphalan et leur utilisation comme produits chimiotherapeutiques contre le cancer

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2001096367A1 (fr) * 2000-06-13 2001-12-20 Oncopeptides Ab Derives de melphalan et leur utilisation comme produits chimiotherapeutiques contre le cancer

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Title
ASTIK, R. R. ET AL.: "Studies on Potential Anticancer Dmgs", JOURNAL OF THE INSTITUTION OF CHEMISTS, vol. 47, no. 5, 1975, INDIA, pages 188 - 190 *
DATABASE CAPLUS accession no. STN Database accession no. 1958:82371 *
DATABASE CAPLUS accession no. STN Database accession no. 1963:27571 *
DATABASE CAPLUS accession no. STN Database accession no. 1972:483636 *
VERTELYTE, L. ET AL.: "Synthesis and Biological Activity of N-[[p- [bis(2-chloroethyl) amino]phenyl]acet5-1]-O-benzyl-L-tyrosine", CHEMIJA, vol. 3, 1996, pages 58 - 59 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018123092A (ja) * 2017-02-01 2018-08-09 国立研究開発法人産業技術総合研究所 アミノ酸含有両親媒性分子および有機ナノチューブ

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