WO2016110822A1 - Dérivé de créatine biacyl carboxylique, utilisations et procédé de synthèse associés - Google Patents

Dérivé de créatine biacyl carboxylique, utilisations et procédé de synthèse associés Download PDF

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Publication number
WO2016110822A1
WO2016110822A1 PCT/IB2016/050085 IB2016050085W WO2016110822A1 WO 2016110822 A1 WO2016110822 A1 WO 2016110822A1 IB 2016050085 W IB2016050085 W IB 2016050085W WO 2016110822 A1 WO2016110822 A1 WO 2016110822A1
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Prior art keywords
formula
creatine
salts
saturated
compound
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PCT/IB2016/050085
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English (en)
Inventor
Patrizia GARBATI
Enrico Millo
Maurizio Balestrino
Annalisa Salis
Enrico ADRIANO
Gianluca Damonte
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DIMES Dipartimento di Medicina Sperimentale Universita degli Studi di Genova
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DIMES Dipartimento di Medicina Sperimentale Universita degli Studi di Genova
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Publication of WO2016110822A1 publication Critical patent/WO2016110822A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines

Definitions

  • Carboxylic biacyl creatine derivative uses and method of synthesis thereof
  • the present invention relates to novel biacyl creatine derivatives, methods of synthesis and therapeutic uses thereof.
  • Creatine or methyl-guanidino-acetic acid, is an amino acid of which 95% is found in skeletal muscle, and 5% is distributed between heart, testes, brain and retina.
  • the creatine present in blood is transported against the concentration gradient into target cells by means of the saturable, sodium- and chlorine-dependent creatine transporter (SLC6A8, CrTl, CT1 or CrT) that crosses the plasma membrane.
  • SLC6A8, CrTl, CT1 or CrT saturable, sodium- and chlorine-dependent creatine transporter
  • the expression of the creatine transporter is present in almost all tissues, but is much higher in tissues with high energy requirements (skeletal muscle, heart, brain, retina) or with creatine uptake function.
  • Creatine is a polar molecule that is not capable of crossing biological barriers in the absence of its specific transporter (Ohtsuki S, Tachikawa M, Takanaga H, Shimizu H, Watanabe M, Hosoya K, Terasaki T. (2002)
  • the blood-brain barrier creatine transporter is a major pathway for supplying creatine to the brain. J Cereb Blood Flow Metab 22:1327- 35). Even in the presence of such a transporter, it crosses slowly and only partially the blood-brain barrier and cell membranes.
  • Deficiency of the creatine transporter is a rare genetic disease due to the absence, or failure, of the protein that constitutes the mechanism designed for creatine transport through the blood-brain barrier and cell membranes.
  • Creatine administered systemically is not capable, in the absence of the transport mechanism, of crossing biological barriers and for this reason the disease is currently incurable.
  • Deficiency of the creatine transporter (OMIM number 300352) is the most frequent inborn error of creatine metabolism, as well as one of the most common causes of X-linked mental retardation. This is a disease that affects infants in the perinatal period, but it is also not infrequent to detect learning and/or behaviour disorders in carriers. Learning disabilities of various degrees were found in about 50% of female carriers.
  • a form of creatine capable of crossing cell membranes and the blood-brain barrier independently from the creatine transporter could represent a therapeutic tool. This might in fact restore the creatine content inside nerve cells.
  • other diseases due to primary shortage of brain creatine as the deficiencies of arginine glycine amidinotransferase (AGAT, EC 2.1.4.1) and guanidinoacetate methyl transferase GAMT (EC 2.1.1.2), which are the two enzymes that lead to formation of creatine from arginine, glycine and methionine, could benefit from a more bioavailable form of creatine.
  • Creatine esters are mostly lipophilic, but their enzymatic cleavage provides creatinine (Lunardi G, Parodi A, Perasso L, Pohvozcheva AV, Scarrone S, Adriano E, Florio T, Gandolfo C, Cupello A, Burov SV, Balestrino M. (2006)
  • the creatine transporter mediates the uptake of creatine by brain tissue, but not the uptake of two creatine-derived compounds.
  • An object of the present invention is thus to overcome the above shortcomings of the state of the art by providing a creatine derivative that is capable of crossing biological barriers by diffusion and therefore without the aid of the creatine transporter.
  • Another object of the present invention is to provide a creatine derivative that is effective in the treatment of diseases caused by deficiency of cerebral creatine.
  • R and Ri are independently selected from the group consisting of substituted or unsubstituted, saturated or unsaturated aliphatic chains having from 1 to 18 carbon atoms, saturated or unsaturated aliphatic cycles, saturated or unsaturated heterocycles, aromatic and heteroaromatic rings, and wherein R is selected from the group consisting of substituted or unsubstituted, saturated or unsaturated aliphatic chains having from 1 to 18 carbon atoms, saturated or unsaturated aliphatic cycles, saturated or unsaturated heterocycles, aromatic and heteroaromatic rings, biomolecules, such as for example amino acids, vitamins, carbohydrates and lipids.
  • the compounds of formula (I) of the present invention and the pharmaceutically acceptable salts thereof solve the above mentioned technical problem as these are molecules that are more lipophilic compared to creatine and also because the two acyl groups on the guanidine group protect the molecule from enzymatic cleavage into creatinine.
  • the ester bond is the first one to be hydrolysed because of its reduced stability, while the amide bond is more stable and therefore the guanidine group will be made available later for phosphorylation by the enzyme creatine kinase.
  • the compound of formula (A) of the state of the art is a less lipophilic derivative compared to the compounds forming the subject of the present invention in so far as: (i) the anhydride on the carboxyl group is less stable - in aqueous media in comparison with the esters present in the compounds that are the subject of the present invention, (ii) the unsubstituted nitrogen atom represents a polar moiety capable of increasing the hydrophilicity of the molecule, (iii) the partition coefficient (log Pow) calculated for the compound of formula (A) of the state of the art is -0.6862, while the molecule of formula (IA) shown here below, which is one of the less lipophilic molecules among those falling within formula (I) of the present invention, exhibits a partition coefficient of -0.0972.
  • Pow is indicated on a base-10 logarithmic scale, i.e. as log Pow:
  • R and Ri in the formula (I) are independently selected from methyl, ethyl and propyl.
  • R 2 is selected from methyl, ethyl and propyl.
  • a pharmaceutically acceptable salt is a salt of the compounds according to the present invention that has no toxicity or an acceptable degree of toxicity, obtained by addition of inorganic or organic acids or bases.
  • the following examples are to be understood as illustrative and by no means limitative of the salts that can be prepared from the carboxylic biacyl creatine derivative of formula (I) on the basis of the specific structure accomplished: ammonium salts, hydrochlorides, hydrobromides, sulfates, hydrogen sulfates, dihydrogen phosphates, citrates, malates, fumarates, tosylates, mesylates, phosphates, salicylates, tartrates, lactates, citrates, benzoates, succinates, acetates, trifluoroacetates, 2-naphthalenesulfonates, p- toluenesulfonates, potassium salts, sodium salts, lithium salts, calcium salts, magnesium salts, zinc
  • the carboxylic biacyl creatine derivative of formula (I) forming the subject of the present invention is synthesized through an extremely simple process, which contemplates the use as a precursor of a commercially available (e.g. from Sigma Aldrich) carboxylic creatine derivative of formula (II), wherein R 2 has the meanings indicated above in relation to formula (I), which is converted into the carboxylic biacyl creatine derivative of formula (I).
  • the conversion of the carboxylic creatine derivative of formula (II) into the carboxylic biacyl creatine derivative of formula (I) is obtained by the use of an acylating agent on both of the nitrogen atoms of the guanidine group, which allows for the direct synthesis thereof.
  • the carboxylic creatine derivative of formula (II) is preferably creatine ethyl ester.
  • acetic anhydride (CAS 108-24- 7) or butyric anhydride (CAS 106-31-0) is used as the acylating agent.
  • CAS 108-24- 7 acetic anhydride
  • butyric anhydride (CAS 106-31-0) is used as the acylating agent.
  • the yields obtained with these two acylating agents are similar.
  • a compound of formula (I) according to the present invention can be obtained according to the following reaction scheme, in which, in a first step, an alkyl thiourea of formula (III), wherein R4 is a short- chain alkyl (preferably a C 1 -C4 alkyl, such as for example methyl), is acylated by reaction with an acylating agent of formula (IV), wherein R and R ⁇ are as defined above, to give an intermediate compound of formula (V), which, in a second step, is esterified by reaction with a sarcosine ester of formula (VI), wherein R 2 is as defined above, to obtain the compound of formula (I) of the invention:
  • acylating agent of formula (IV) used in the synthesis method described above is also employed in the synthesis method previously described in which the carboxylic creatine derivative of formula (II) is used as the precursor.
  • the carboxylic biacyl creatine derivative of formula (I) of the present invention is capable of crossing biological barriers and the blood-brain barrier independently from the creatine transporter and is also protected from enzymatic cleavage into creatinine. It is therefore effective in the therapeutic treatment of pathologies due to deficiency of cerebral creatine, such as creatine transporter deficiency, AGAT deficiency, and GAMT deficiency.
  • a further aspect of the present invention is therefore the carboxylic biacyl creatine derivative of formula (I),, as defined above, for use in the therapeutic treatment of pathologies due to deficiency of cerebral creatine, such as creatine transporter deficiency, AGAT enzyme deficiency and GAMT enzyme deficiency.
  • a pharmaceutical composition comprising as the active ingredient the carboxylic biacyl creatine derivative of formula (I), as defined above, is also included within the scope of the present invention.
  • Such a pharmaceutical composition also contains additional ingredients such as pharmaceutically acceptable carriers, excipients and/or diluents known per se to those of ordinary skill in the art.
  • the pharmaceutical composition is formulated into any suitable form, such as tablets, solutions, suspensions, aerosols, or any other appropriate form for administration of the active ingredient.
  • the administration may for example take place by intravenous, subcutaneous or intramuscular injection, or orally, ophthalmologically, nasally, buccally, rectally, even if the parenteral administration is preferred.
  • the amount of the active principle When used for treating the pathologies mentioned above, the amount of the active principle will be chosen by the attending physician considering various factors such as, for example, the specific disease to be treated, the severity of the disease, the age, weight and state of health of the patient. For instance, but without limitation, there is administered an amount of active principle which is suitable to provide a blood concentration of the active ingredient in the range between 0.1 and 10 mM (millimolar). Also the frequency and the duration of the treatment will be chosen taking into account various factors related to the specific disease to be treated, the patient's status, the toxicity and the effectiveness of the active ingredient. The person of average skill in the art is able to select the correct amount of active ingredient to be administered and the correct administration regimen.
  • a solution of DMF, acetic anhydride and triethylamine in a 9:0.5:0.5 ratio is added to a solution of creatine ethyl ester (1 equivalent) in anhydrous N,N-dimethylformamide (DMF).
  • DMF N,N-dimethylformamide
  • TLC thin layer chromatography
  • the reaction times range from 3 to 24 hours.
  • the reaction mixture is evaporated to minimum volume and subsequently freeze-dried in order to remove the solvents.
  • the oil thus obtained is taken up in ether and subsequently crystallized to obtain the final product.
  • a 5M NaOH solution is added to a solution of methylisothiourea (1 equivalent) in cold deionized water and maintained in an ice bath.
  • acetic anhydride (3 equivalents) and a 1M aqueous sodium carbonate solution.
  • the pH is then maintained at 6 with 1 N NaOH.
  • the suspension is kept under stirring in an ice bath until the reaction is completed, as monitored by TLC.
  • the resulting suspension is filtered and washed twice with cold water.
  • the aqueous filtrate is then evaporated, taken up in ethyl acetate and washed with water.
  • the organic layer thus obtained is then evaporated and subsequently freeze-dried.
  • the freeze-dried organic phase is dissolved in anhydrous ⁇ , ⁇ -dimethylformamide (DMF).
  • DMF ⁇ , ⁇ -dimethylformamide
  • 1 equivalent of sarcosine ethyl ester, 3 equivalents of triethylamine and 1.1 equivalents of HgCl 2 is added.
  • the reaction is kept under stirring at room temperature until completion, as monitored by TLC.
  • the reaction mixture is taken up in an organic solvent (ether or ethyl acetate according to the type of sarcosine ester used) with the formation of an abundant white precipitate. This precipitate is filtered under vacuum. The filtrate is washed with deionized water and the organic layer is evaporated to minimum volume and subsequently freeze-dried to obtain the final product.
  • biacetyl creatine ethyl ester is able to abolish the negative effects of GPA, which instead creatine is not able to do, thereby protecting the nervous tissue from damage.
  • the effect of biacetyl creatine ethyl ester is statistically significant, as shown in figure 1 (the P-value is indicated for the analysis of variance, ANOVA).
  • Figure 2 shows that this compound is able to increase the content of phosphocreatine in mouse hippocampus slices in the presence of a blockage of the creatine transporter induced in this case by using a chlorine-free incubation medium.
  • the creatine transporter works with a sodium-chlorine symport mechanism, therefore it does not work in the absence of chlorine (Dai W, Vinnakota S, Qian X, Kunze DL, Sarkar H . (1999) Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes. Arch Biochem Biophys 361 :75-84).
  • Figure 3 shows the effects of biacetyl creatine ethyl ester in hippocampus slices subjected to electrophysiology experiments carried out in the presence of GPA to mimic the creatine transporter deficiency disease.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un nouveau dérivé de créatine, le dérivé de créatine biacyl carboxylique de formule (I) et des sels pharmaceutiquement acceptables de celui-ci, des procédés de synthèse et l'utilisation de celui-ci dans le traitement de pathologies dues à un déficit en créatine cérébrale, tel que le déficit en transporteur de la créatine, le déficit en enzymes AGAT et le déficit en enzymes GAMT.
PCT/IB2016/050085 2015-01-09 2016-01-08 Dérivé de créatine biacyl carboxylique, utilisations et procédé de synthèse associés Ceased WO2016110822A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
ITTO20150013 2015-01-09
ITTO2015A000013 2015-01-09
ITTO2015A000116 2015-02-20
ITTO20150116 2015-02-20

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111417620A (zh) * 2017-12-01 2020-07-14 奥特吉尼克斯制药公司 肌酸前药、其组合物以及使用方法
EP3771709A1 (fr) * 2014-12-22 2021-02-03 Farmington Pharma Development Promédicaments de la créatine, compositions en contenant et leurs procédés d'utilisation
US11021501B2 (en) 2015-03-30 2021-06-01 Farmington Pharma Development Creatine phosphate analog prodrugs, compositions and methods of use thereof

Citations (1)

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WO2015069699A1 (fr) * 2013-11-05 2015-05-14 Ultragenyx Pharmaceutical Inc. Analogues de créatine et leur utilisation

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WO2015069699A1 (fr) * 2013-11-05 2015-05-14 Ultragenyx Pharmaceutical Inc. Analogues de créatine et leur utilisation

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Title
ALEXANDRA TROTIER-FAURION ET AL: "Synthesis and Biological Evaluation of New Creatine Fatty Esters Revealed Dodecyl Creatine Ester as a Promising Drug Candidate for the Treatment of the Creatine Transporter Deficiency", JOURNAL OF MEDICINAL CHEMISTRY, vol. 56, no. 12, 27 June 2013 (2013-06-27), US, pages 5173 - 5181, XP055222476, ISSN: 0022-2623, DOI: 10.1021/jm400545n *
BERGMANN M., ZERVAS L.: "Synthese des Kreatins aus Sarkosin und Arginin. Neue Synthese des Methylguanidins", HOPPE-SEYLER´S ZEITSCHRIFT FÜR PHYSIOLOGISCHE CHEMIE, vol. 173, 1928, pages 80 - 83, XP008177289, ISSN: 0018-4888, DOI: 10.1515/bchm2.1928.173.1-2.80 *
PATRIZIA GARBATI ET AL: "A new method to synthesize creatine derivatives", AMINO ACIDS, vol. 45, no. 4, 7 June 2013 (2013-06-07), pages 821 - 833, XP055137064, ISSN: 0939-4451, DOI: 10.1007/s00726-013-1525-x *
PATRIZIA GARBATI ET AL: "Effects of Amide Creatine Derivatives in Brain Hippocampal Slices, and Their Possible Usefulness for Curing Creatine Transporter Deficiency", NEUROCHEMICAL RESEARCH, vol. 39, no. 1, 1 January 2014 (2014-01-01), pages 37 - 45, XP055209170, ISSN: 0364-3190, DOI: 10.1007/s11064-013-1188-8 *

Cited By (18)

* Cited by examiner, † Cited by third party
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US11407722B2 (en) 2014-12-22 2022-08-09 Farmington Pharma Development Creatine prodrugs, compositions and methods of use thereof
EP3771709A1 (fr) * 2014-12-22 2021-02-03 Farmington Pharma Development Promédicaments de la créatine, compositions en contenant et leurs procédés d'utilisation
US11021501B2 (en) 2015-03-30 2021-06-01 Farmington Pharma Development Creatine phosphate analog prodrugs, compositions and methods of use thereof
AU2018375199B2 (en) * 2017-12-01 2023-03-30 Ultragenyx Pharmaceutical Inc. Creatine prodrugs, compositions and methods of use thereof
US11753369B2 (en) 2017-12-01 2023-09-12 Ultragenyx Pharmaceutical Inc. Creatine prodrugs, compositions and methods of use thereof
EP3717453A4 (fr) * 2017-12-01 2021-07-28 Ultragenyx Pharmaceutical Inc. Promédicaments à base de créatine, compositions et procédés d'utilisation associés
US11332438B2 (en) 2017-12-01 2022-05-17 Ultragenyx Pharmaceutical Inc. Creatine prodrugs, compositions and methods of use thereof
KR20200105833A (ko) * 2017-12-01 2020-09-09 울트라제닉스 파마수티컬 인코포레이티드 크레아틴 전구약물, 조성물과 이의 사용 방법
CN111417620A (zh) * 2017-12-01 2020-07-14 奥特吉尼克斯制药公司 肌酸前药、其组合物以及使用方法
CN111417620B (zh) * 2017-12-01 2023-08-25 奥特吉尼克斯制药公司 肌酸前药、其组合物以及使用方法
JP2021505537A (ja) * 2017-12-01 2021-02-18 ウルトラジェニクス ファーマシューティカル インク．Ｕｌｔｒａｇｅｎｙｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｉｎｃ． クレアチンプロドラッグ、組成物及びその使用方法
TWI815832B (zh) * 2017-12-01 2023-09-21 美商奧特吉尼克斯製藥公司 肌酸前藥、其組合物及使用方法
JP2024009811A (ja) * 2017-12-01 2024-01-23 ウルトラジェニクス ファーマシューティカル インク． クレアチンプロドラッグ、組成物及びその使用方法
JP7433226B2 (ja) 2017-12-01 2024-02-19 ウルトラジェニクス ファーマシューティカル インク． クレアチンプロドラッグ、組成物及びその使用方法
IL274701B1 (en) * 2017-12-01 2024-03-01 Ultragenyx Pharmaceutical Inc Creatine prodrugs, compositions and methods of use thereof
KR102678696B1 (ko) * 2017-12-01 2024-06-27 울트라제닉스 파마수티컬 인코포레이티드 크레아틴 전구약물, 조성물과 이의 사용 방법
IL274701B2 (en) * 2017-12-01 2024-07-01 Ultragenyx Pharmaceutical Inc Promote drugs, compositions and methods of their use
JP7542705B2 (ja) 2017-12-01 2024-08-30 ウルトラジェニクス ファーマシューティカル インク． クレアチンプロドラッグ、組成物及びその使用方法

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