WO2012007625A1 - Composés utiles comme véhicules à travers la barrière hémato-encéphalique et constructions véhicule-charge - Google Patents

Composés utiles comme véhicules à travers la barrière hémato-encéphalique et constructions véhicule-charge Download PDF

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Publication number
WO2012007625A1
WO2012007625A1 PCT/ES2011/070513 ES2011070513W WO2012007625A1 WO 2012007625 A1 WO2012007625 A1 WO 2012007625A1 ES 2011070513 W ES2011070513 W ES 2011070513W WO 2012007625 A1 WO2012007625 A1 WO 2012007625A1
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Prior art keywords
equiv
resin
dmf
conh
amino acid
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PCT/ES2011/070513
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English (en)
Spanish (es)
Inventor
Ernest GIRALT LLEDÓ
Meritxell TEIXIDÓ TURÀ
Morteza Malakoutikhah
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Universitat De Barcelona
Institut De Recerca Biomèdica De Barcelona
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Publication of WO2012007625A1 publication Critical patent/WO2012007625A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Useful compounds such as shuttles across the blood-brain barrier and shuttle-cargo constructions
  • This invention relates to the fields of medicine, research and diagnosis, and more specifically to new compounds that act as shuttles through the blood brain barrier (BBB) for the release of substances that cannot cross the BBB by themselves. It also refers to BBB shuttle-cargo constructions and their use as medications.
  • BBB blood brain barrier
  • brain treatment includes neurodegenerative diseases such as Parkinson's and Alzheimer's disease, but also
  • Central nervous system diseases such as schizophrenia, epilepsy and bipolar disorder.
  • brain cancer human immunodeficiency virus (HIV) and even certain aspects of obesity can be included as pharmacological targets located within the brain.
  • HIV human immunodeficiency virus
  • the BBB is a natural filter inside the body that only allows certain substances to pass from the blood to the brain. It is a natural defense mechanism designed to keep harmful substances out of the brain. It controls the composition of the extracellular fluid of the brain independent of fluctuations within the blood. It is also waterproof for many environmental compounds and medications.
  • the brain could serve as a hidden reservoir for HIV viral replication. HIV in the brain and in the cerebrospinal fluid could be particularly resistant to chemotherapy due to the failure of anti-retroviral drugs to penetrate the BBB.
  • the virus can cross the BBB during primary infection or at a late stage. The resulting infection leads to a number of central nervous system disorders such as AIDS-related dementia complex and HIV encephalopathy. Brain cancer can be counted among the most deadly and intractable diseases.
  • the treatment of brain cancer consists of surgery, radiotherapy using high-energy x-rays or other types of radiation and chemotherapy using anticancer or cytotoxic drugs.
  • anticancer drugs can reach cancer cells where they are in the body, but in the case of brain tumors, not all chemotherapeutic drugs are appropriate, because most chemotherapeutic drugs cannot cross the blood brain barrier (cf. D. Fort ⁇ n et al. ., "Enhanced chemotherapy delivery by intraarterial infusion and blood brain barrier disruption in malignant brain tumors", Cancer 2005, vol. 103, pp. 2606-15).
  • Schizophrenia affects almost 1% of the population. Although anti-psychotic medications are being used, there is a need to find new and better medications without the unwanted side effects of existing ones. In the search for these novel medicines, the BBB is the barrier that the medicine will need to cross to reach its target site.
  • Parkinson's disease is one of the biggest neurodegenerative disorders, affecting 3% of the population over 65 years old There is currently no preventive therapy for
  • Parkinson's disease Current treatment is to improve motor symptoms by supplementation of the dopamine deficient neurotransmitter. Since dopamine does not cross the BBB, a dopamine precursor, L-dopa, has been used since the 1960s in the treatment of Parkinson's disease. However, severe side effects are frequently observed after a few years of L-dopa therapy. L-dopa crosses the BBB using the amino acid transporter and once inside it is transformed to dopamine by the aromatic L-amino acid decarboxylase.
  • Some methods of administering medications to the brain for therapy or diagnosis are invasive techniques, such as administration
  • Another approach is administration by conjugation to a biological carrier.
  • These strategies use monoclonal antibodies (“Monoclonal anti-bodies", Mab) that bind to the transferrin receptor and undergo receptor-mediated endocytosis as molecular Trojan horses of compounds with therapeutic use that cannot cross the BBB by themselves.
  • Another approach comprises a strategy mediated by a peptide vector in which untranslated drugs bind peptides that have the ability to cross the BBB.
  • this conjugation even increased the solubility of the drug and bordered P-glycoprotein, consequently ruling out the need for solubilizers, which can cause side effects, and P-gp inhibitors, which limit the clinical application of drugs.
  • WO 2008/025867 describes several diketopiperazine compounds that act as vehicles for the delivery of pharmaceutical active ingredients through the BBB because they have the ability to passively diffuse drugs to the brain without the ability to pass the BBB. It also describes the shuttle constructs for the release of charges that transport drugs, for example, through the PAMPA membrane, an in vitro model of BBB. Finally, M. Malakoutikhah et al., In J. Med. Chem. 2008, vol. 51, pp.
  • GABA 4-aminobutanoic acid
  • Nip nipecotic acid
  • ALA 5-aminolevulinic acid
  • shuttle compounds which have the ability to cross the BBB and are capable of introducing into the brain drugs or other substances useful for diagnosis, to which it is made. reference as “charges”, which cannot cross the BBB by themselves.
  • the shuttle compounds are biodegradable and biocompatible, have no intrinsic toxicity or antigenicity, since they are made of amino acids.
  • the shuttles of the present invention show good water solubility. This property allows to improve the administered dose, since the amount of solution contained in the construction to be administered will be less.
  • a first aspect of the present invention relates to providing shuttle compounds of formula (I), or their pharmaceutically acceptable salts, including stereoisomers or mixtures of stereoisomers,
  • R- ⁇ , R 2 and R3 are independently selected from the group consisting of: H and (CH 2 ) q -R6;
  • R 4 is a C-radical derived from one of the known ring systems with 1-4 rings; the rings being saturated, partially unsaturated or aromatic; the rings being isolated or partially / fully fused and having 5-6 members; each member being independently selected from C, CH, CH 2 , N, NH, O and S; the hydrogen atoms of these members being optionally substituted by substituents selected from (Ci-C 6 ) -alkyl, (CrC 6 ) -alkoxy and halogen;
  • R 5 is H or CH 3 CO-;
  • R 6 is a C-radical derived from one of the known ring systems with 1-2 rings; the rings being saturated, partially unsaturated or aromatic; the rings being isolated or partially / fully fused and having 5-6 members; each member being independently selected from C, CH, CH 2 , N, NH, O and S; the hydrogen
  • the compounds of formula (I) or their salts may exist in solvated form, as well as in non-solvated forms, including hydrated forms. Thus, they may contain stoichiometric amounts of solvent in the case of solvates, or of water in the case of hydrates. It should be understood that this invention encompasses all solvated, as well as non-solvated forms. Obtaining solvates and hydrates depends on the solvent used and the crystallization conditions that can be determined by the person skilled in the art.
  • the compounds of formula (I) are those where n is an integer from 2 to 6, more preferably from 2 to 5, and even more preferably from 2 to 4.
  • the compounds of formula (I) are those where Y is -NH 2 , -OH or -NHR 7 . In another more preferred embodiment, the compounds of formula (I) are those where Y is -NH 2 .
  • the compounds of formula (I) are those where the ring members in R 6 , R 4 , or both R 6 and R 4 are selected from C, CH and CH 2 .
  • the compounds of formula (I) are those where R 6 is a C-radical derived from one of the ring systems
  • the compounds of formula (I) are those where Ri, R 2 and R 3 are independently selected from the group consisting of H, phenyl, cyclohexyl, and 2-naphthyl.
  • the compounds of formula (I) are those where Ri and R 2 are H, and R 3 is a radical (CH 2 ) q -R 6 .
  • the compounds of formula (I) are those where R 3 is phenyl, cyclohexyl or 2-naphthyl.
  • the compounds of formula (I) are those where R 3 is phenyl.
  • the compounds of formula (I) are those where R 4 is selected from the group consisting of phenyl, cyclohexyl and 2-naphthyl.
  • Preferred compounds of formula (I) of those mentioned above are those where R 4 is cyclohexyl or 2-naphthyl.
  • the compounds of formula (I) are selected from those mentioned above where m is 1. In another particular embodiment, the compounds of formula (I) are selected from among the
  • the compounds of formula (I) are those where k is 0 or 1.
  • the most preferred compounds of formula (I) are those that are selected from the following list: Ac-PhPro- (PhPro) 3 -CONH 2 ;
  • the compounds of formula (I) have the ability to transport substances to the brain, referred to as charges, which cannot pass through the BBB themselves.
  • Another aspect of the invention relates to the use of these compounds of formula (I) as BBB-shuttles.
  • the use of these compounds makes it possible, for example, that the investigation of new drugs is not limited only to compounds that can pass through the BBB themselves.
  • the compounds of formula (I) are better BBB shuttles than those closest to the prior art.
  • the mechanism of transport through the BBB of the compounds of formula (I) is by passive diffusion, and this mechanism is independent of the L or D configuration of the amino acids.
  • one of the main advantages of the compounds of formula (I) is that they can be prepared from L or D amino acids or even racemic mixtures. This increases the half-life of constructions in the body, preventing degradation by different peptidases in the blood or associated with brain microvessels.
  • the compounds of formula (I) have appropriate functional groups for the covalent union of charges maintaining the original activity of the charge, until it reaches the place of action.
  • another aspect of the present invention is to provide constructs of formula (II), or pharmaceutically acceptable salts thereof, including any stereoisomer or mixtures of
  • Ri, R 2 , R 3 , R 4 , X, Y, k, m, and n are as defined above; and Z is a radical derived from a substance capable of forming an amide bond or an ester bond or a disulfide bond with X, said substance being unable to cross the blood brain barrier (BBB) by itself.
  • BBB blood brain barrier
  • the substances from which the Z radical derives include a wide variety of substances that have pharmacological or diagnostic utility. These substances may be pharmaceutical active ingredients, in particular antiretroviral agents, anticancer agents, anti-psychotic agents, antineurodegenerative agents or antiepileptic agents. Examples of pharmaceutical active ingredients are nipecotic acid and dopamine. Dopamine is a Key neurotransmitter in the central nervous system, in particular, the decrease in striatal dopamine is associated with clinical conditions of parkinsonism. Nipecotic acid is one of the most potent GABA reuptake inhibitors and also a GABA receptor agonist. However, the BBB does not penetrate.
  • the substances from which Z is derived also include other substances that would be interesting to transport to the brain but that do not do so properly alone, for example contrast agents for nuclear magnetic resonance ("Magnetic Resonance Imaging", MRI).
  • MRI Magnetic Resonance Imaging
  • Contrast agents can be used as diagnostic methods for diseases of the central nervous system such as Alzheimer's disease, brain cancer, or as a tool for a pre-operative MRI scan that will guide the surgeon. In all these cases the contrast agent used needs to pass through the BBB.
  • contrast agents include magnetic nanoparticles such as iron oxide nanoparticles.
  • diagnostic agents include fluorescent dyes or probes such as carboxyfluorescein and derivatives, lucifer yellow, rhodamine or Texas red.
  • the shuttle compounds of formula (I) may be formed by natural and non-natural amino acids and / or their derivatives.
  • the compounds of formula (I) and the shuttle-cargo constructions of formula (II) can be generated totally or partially by chemical synthesis. Appropriate amino acids for the preparation of compounds of formula (I) are available
  • the compounds of formula (I) and the constructs of formula (II) can be easily prepared, for example, according to liquid phase synthesis or, preferably, solid phase peptide synthesis methods, of which general descriptions are widely available ( cf. eg M. Amblard, et al., "Methods and protocols of modern solid phase peptide synthesis. Molecular Biotechnoloqy 2006, vol. 33, pp. 239-254); or they can be prepared in solution by phase methods liquid or by any combination of solid phase, liquid and chemical phase in solution, for example, first completing the BBB-shuttle portion and then after removing any of the protecting groups if present, by introduction of the solution charge.
  • shuttle-cargo constructs of formula (II) together with appropriate amounts of pharmaceutically acceptable excipients or carriers will choose the appropriate route of administration by usual methods.
  • the speed and time of administration will depend on the nature and severity of what is being treated.
  • the precise nature of the carrier or other excipients will depend on the route of administration, which may be oral, nasal or by injection, eg cutaneous, subcutaneous or
  • terapéuticaally effective amount refers to the amount of a compound that, when administered, is sufficient to prevent the development of, or relieve to some degree, one or more of the symptoms of the disease a The one that goes.
  • the particular dose of compound administered according to this invention will of course be determined by the particular conditions surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations.
  • pharmaceutical composition refers to a mixture of a compound described herein with other chemical components, such as diluents or bearers The pharmaceutical composition facilitates the administration of the compound to an organism.
  • pharmaceutically acceptable excipients or carriers refer to pharmaceutically acceptable material, composition or vehicle. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with tissues or organs of humans and animals without too much toxicity, irritation, allergic response, immunogenicity or other problems or complications in accordance with a reasonable benefit / risk ratio.
  • composition comprising a construction according to the present invention can be administered alone or in combination with others.
  • Another aspect of the present invention relates to the constructions of the present invention for use as a medicament.
  • Another aspect of the invention relates to the constructs of formula (II) where Z is a dopamine radical for use in the treatment of Parkinson's disease.
  • This aspect can also be formulated as the use of the constructions of formula (II) where Z is a dopamine radical for the preparation of a medicament for the treatment of Parkinson's disease. Therefore, this aspect is also related to a method of treatment and / or prophylaxis of a mammal, including a human, who suffers or is susceptible to Parkinson's disease, said method comprising the administration of a therapeutically effective amount of a compound of formula (II) with Z derived from dopamine, together with pharmaceutically acceptable excipients or carriers.
  • Another aspect of the invention relates to the constructions of formula (II) where Z is a radical of the nipecotic acid for use as an anticonvulsant.
  • Anticonvulsants are drugs used in the treatment of
  • This aspect can also be formulated as the use of the constructions of formula (II) where Z is a radical of the nipecotic acid for the preparation of a medicament for the treatment of seizures or diseases that cause seizures. Therefore, this aspect is also related to a method of treatment and / or prophylaxis of a mammal, including a human, who suffers or is susceptible to seizures, said method comprising administering to a patient a therapeutically effective amount of a compound of formula (II) with Z derived from nipecotic acid, together with pharmaceutically acceptable excipients or carriers.
  • the DCM was passed through a column of AI 2 O 3 .
  • the DMF was stored on a 4A molecular sieve and nitrogen was bubbled to remove volatile agents.
  • DIEA V-diisopropylethylannine
  • PVDF Millipore Polyvinylidine Difluoride
  • TBME tert-butyl methyl ether
  • NMP V-methyl pyrrolidone
  • the De Clercq test is performed by first washing a small sample of the resin (approx. 1 mg) with DMF (4x1 minutes) and DCM (4x1 minutes). Ten drops of reagent solution (0.002 M p-nitrophenyl ester of red dispersed 1 in MeCN) is added to the resin and the resulting mixture is heated at 70 ° C for 10 minutes. The solution is then decanted and the resin washed with DMF until a clear supernatant is obtained. The presence of secondary amines is indicated by red resin balls.
  • Protocols used during the synthesis of the constructs of formula (II) They were synthesized on a scale of 100 ⁇ using the following methods and protocols;
  • N-terminal amino acid acetylation In some cases, acetylation was performed in solid phase using a standard protocol of Ac 2 O (50 equiv) and DIEA (50 equiv) for 20 min.
  • the protected amino acid derivative of the second amino acid was coupled to the first amino acid already anchored to the resin using the following protocol:
  • the protected amino acid was sequentially added (Fmoc-PhPro-OH, 4 equiv., 400 ⁇ , 165 mg), PyBOP (4 equiv., 400 ⁇ , 208 mg) and HOAt (12 equiv., 1 .2 mmols, 163 mg) dissolved in DMF (1-3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ _).
  • the mixture was allowed to react with intermittent manual stirring for 1.5 h.
  • the solvent was removed by suction, the resin was washed thoroughly and the coupling was repeated two more times.
  • the extension of the coupling was checked by the De Clercq test.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each.
  • Two additional treatments with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2 x 5 min) were performed to ensure the removal of the Fmoc group from secondary amines.
  • the same protocol was used to couple the third amino acid derivative.
  • the protected amino acid 4 equiv., 400 ⁇ (Fmoc-PhPro-OH, 165 mg) (Fmoc-Cha-OH, 157 mg) or (Fmoc-) was added sequentially 2Nal-OH, 175 mg), PyBOP (4 equiv., 400 ⁇ , 208 mg) and HOAt (12 equiv., 1 .2 mmols, 163 mg) dissolved in DMF (1 -3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ ). The mixture was allowed to react with intermittent manual stirring for 1.5 h. The solvent was removed by suction, the resin was washed thoroughly and the coupling was repeated two more times. The extension of the coupling was checked by the De test
  • the synthesis was performed on a 100 ⁇ scale.
  • the amino acid derivative of the first amino acid (Fmoc-PhPro-OH, 4 equiv., 400 ⁇ , 165 mg), PyBOP (4 equiv., Was sequentially added 400 ⁇ , 208 mg) and HOAt (12 equiv., 1, 2 mmols, 163 mg) dissolved in DMF (1 - 3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ ). The mixture was allowed to react with intermittent manual stirring for 1.5 h. The solvent was removed by suction, the resin was washed thoroughly.
  • the extent of the coupling was checked by the ninhydrin colorimetric assay.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each.
  • Two additional treatments with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2 x 5 min) were performed to ensure the removal of the Fmoc group from secondary amines.
  • the protected amino acid derivative of the second amino acid was coupled to the first amino acid already anchored to the resin using the following protocol:
  • the protected amino acid was sequentially added (Fmoc-PhPro-OH, 4 equiv., 400 ⁇ , 165 mg), PyBOP (4 equiv., 400 ⁇ , 208 mg) and HOAt (12 equiv., 1 .2 mmols, 163 mg) dissolved in DMF (1-3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ _).
  • the mixture was allowed to react with intermittent manual stirring for 1.5 h.
  • the solvent was removed by suction, the resin was washed thoroughly and the coupling was repeated two more times.
  • the extension of the coupling was checked by the De test
  • Fmocq The Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each. Two additional treatments were performed with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2.5 min) to ensure the removal of the Fmoc group from secondary amines. The same protocol was used to couple the third amino acid derivative.
  • the cleavage stage was performed by treating the resin with 2% TFA in DCM (6 x 3 min). The filtrate was collected and the DCM evaporated under N 2 . The residue was dissolved in H 2 O: MeCN (1: 1) and lyophilized.
  • the synthesis was performed on a 100 ⁇ scale.
  • the amino acid derivative of the first amino acid (Fmoc-PhPro-OH, 4 equiv., 400 ⁇ , 165 mg), PyBOP (4 equiv., Was sequentially added 400 ⁇ , 208 mg) and HOAt (12 equiv., 1, 2 mmols, 163 mg) dissolved in DMF (1 -3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ ). The mixture was allowed to react with intermittent manual stirring for 1.5 h. The solvent was removed by suction, the resin was washed thoroughly.
  • the extent of the coupling was checked by the ninhydrin colorimetric assay.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each. Two additional treatments were performed with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2.5 min) to ensure the removal of the Fmoc group from secondary amines.
  • the protected amino acid derivative of the second amino acid was coupled to the first amino acid already anchored to the resin using the following protocol:
  • the protected amino acid was sequentially added (Fmoc-PhPro-OH, 4 equiv., 400 ⁇ , 165 mg), PyBOP (4 equiv., 400 ⁇ , 208 mg) and HOAt (12 equiv., 1 .2 mmols, 163 mg) dissolved in DMF (1-3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ ).
  • the mixture was allowed to react with intermittent manual stirring for 1.5 h.
  • the solvent was then removed by suction, the resin washed thoroughly and the coupling was repeated two more times.
  • the extension of the coupling was checked by the De Clercq test.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each.
  • Two additional treatments with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2 x 5 min) were performed to ensure the removal of the Fmoc group from secondary amines.
  • the same protocol was used to couple the third amino acid derivative.
  • the cleavage stage was performed by treating the resin with 2% TFA in DCM (6 x 3 min). The filtrate was collected and the DCM evaporated under N 2 . The residue was dissolved in H 2 O: MeCN (1: 1) and lyophilized.
  • the synthesis was performed on a 100 ⁇ scale.
  • the amino acid derivative of the first amino acid (Fmoc-PhPro-OH, 4 equiv., 400 ⁇ , 165 mg), PyBOP (4 equiv., Was sequentially added 400 ⁇ , 208 mg) and HOAt (12 equiv., 1, 2 mmols, 163 mg) dissolved in DMF (1 - 3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ _). The mixture was allowed to react with intermittent manual stirring for 1.5 h.
  • the solvent was removed by suction, the resin was washed thoroughly. The extent of the coupling was checked by the ninhydrin colorimetric assay.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each. Two additional treatments with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2 x 5 min) were performed to ensure the removal of the Fmoc group from secondary amines.
  • the protected amino acid derivative of the second amino acid was coupled to the first amino acid already anchored to the resin using the following protocol:
  • the protected amino acid was sequentially added (Fmoc-PhPro-OH, 4 equiv., 400 ⁇ , 165 mg), PyBOP (4 equiv., 400 ⁇ , 208 mg) and HOAt (12 equiv., 1 .2 mmols, 163 mg) dissolved in DMF (1-3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ ).
  • the mixture was allowed to react with intermittent manual stirring for 1.5 h.
  • the solvent was removed by suction, the resin was washed thoroughly and the coupling was repeated two more times.
  • the extension of the coupling was checked by the De Clercq test.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each.
  • Two additional treatments were performed with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2.5 min) to ensure the removal of the Fmoc group from secondary amines.
  • the same protocol was used to couple the third and fourth amino acid derivative.
  • Example 5 Preparation of the compound of formula (II) with Z derived from Levodopa: L-Dopa-PhPro- (PhPro) 3 -CONH ? (lid) The synthesis was performed on a 100 ⁇ scale.
  • the following protocol was used: The amino acid derivative of the first amino acid (Fmoc-PhPro-OH, 4 equiv., 400 ⁇ , 165 mg), PyBOP (4 equiv., Was sequentially added 400 ⁇ , 208 mg) and HOAt (12 equiv., 1, 2 mmols, 163 mg) dissolved in DMF (1 -3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ ). The mixture was allowed to react with intermittent manual stirring for 1.5 h. The solvent was removed by suction, the resin was washed thoroughly.
  • the extension was checked by the ninhydrin colorimetric assay.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each. Two additional treatments were performed with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2.5 min) to ensure the removal of the Fmoc group from secondary amines.
  • the protected amino acid derivative of the second amino acid was coupled to the first amino acid already anchored to the resin using the following protocol:
  • the protected amino acid was sequentially added (Fmoc-PhPro-OH, 4 equiv., 400 ⁇ , 165 mg), PyBOP (4 equiv., 400 ⁇ , 208 mg) and HOAt (1 2 equiv., 1 .2 mmols, 1 63 mg) dissolved in DMF (1 -3 ml / g resin) to the resin followed by DIEA (1 2 equiv., 1 .2 mmols, 204 ⁇ _).
  • the mixture was allowed to react with intermittent manual stirring for 1.5 h.
  • the solvent was then removed by suction, the resin washed thoroughly and the coupling repeated two more times.
  • the extension of the coupling was checked by the De Clercq test.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each.
  • Two additional treatments with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2 x 5 min) were performed to ensure the removal of the Fmoc group from secondary amines.
  • the same protocol was used to couple the third and fourth amino acid derivative.
  • the cleavage stage was performed by treating the resin with 2% TFA in DCM (6 x 3 min). The filtrate was collected and the DCM evaporated under N 2 . The residue was dissolved in H 2 O: MeCN (1: 1) and lyophilized.
  • Product characterization Reverse phase HPLC: linear gradient from 30 to 60% MeCN in 8 minutes using a Sunfire Ci 8 column (100 x 4.6 mm x 3.5 ⁇ , 100 ⁇ , Waters), L-Dopa-PhPro- (PhPro) 3 -CONH 2 tr: 3.5-6.9 min (diastereomers).
  • the synthesis was performed on a 100 ⁇ scale.
  • the amino acid derivative of the first amino acid (Fmoc-PhPro-OH, 4 equiv., 400 ⁇ , 165 mg), PyBOP (4 equiv., Was sequentially added 400 ⁇ , 208 mg) and HOAt (12 equiv., 1, 2 mmols, 163 mg) dissolved in DMF (1 - 3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ _). The mixture was allowed to react with intermittent manual stirring for 1.5 h.
  • the solvent was removed by suction, the resin was washed thoroughly. The extent of the coupling was checked by the ninhydrin colorimetric assay.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each. Two additional treatments with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2 x 5 min) were performed to ensure the removal of the Fmoc group from secondary amines.
  • the protected amino acid derivative of the second amino acid was coupled to the first amino acid already anchored to the resin using the following protocol:
  • the protected amino acid was sequentially added (Fmoc-PhPro-OH, 4 equiv., 400 ⁇ , 165 mg), PyBOP (4 equiv., 400 ⁇ , 208 mg) and HOAt (12 equiv., 1 .2 mmols, 163 mg) dissolved in DMF (1-3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ ).
  • the mixture was allowed to react with intermittent manual stirring for 1.5 h.
  • the solvent was removed by suction, the resin was washed thoroughly and the coupling was repeated two more times.
  • the extension of the coupling was checked by the De Clercq test.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each.
  • Two additional treatments were carried out with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2 5 min) to ensure the removal of the Fmoc group from secondary amines.
  • the same protocol was used to couple the third amino acid derivative.
  • the cleavage stage was performed by treating the resin with 2% TFA in DCM (6 x 3 min). The filtrate was collected and the DCM evaporated under N 2 . The residue was dissolved in H 2 O: MeCN (1: 1) and lyophilized.
  • the synthesis was performed on a 100 ⁇ scale.
  • the amino acid derivative of the first amino acid (Fmoc-PhPro-OH, 4 equiv., 400 ⁇ , 165 mg), PyBOP (4 equiv., Was sequentially added 400 ⁇ , 208 mg) and HOAt (12 equiv., 1, 2 mmols, 163 mg) dissolved in DMF (1 -3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ _). The mixture was allowed to react with intermittent manual stirring for 1.5 h. The solvent was removed by suction, the resin was washed thoroughly.
  • the extent of the coupling was checked by the ninhydrin colorimetric assay.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each. Two additional treatments were performed with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2.5 min) to ensure the removal of the Fmoc group from secondary amines.
  • the protected amino acid derivative of the second amino acid was coupled to the first amino acid already anchored to the resin using the following protocol:
  • the protected amino acid was sequentially added (Fmoc-PhPro-OH, 4 equiv., 400 ⁇ , 165 mg), PyBOP (4 equiv., 400 ⁇ , 208 mg) and HOAt (12 equiv., 1 .2 mmols, 163 mg) dissolved in DMF (1-3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ ).
  • the mixture was allowed to react with intermittent manual stirring for 1.5 h.
  • the solvent was then removed by suction, the resin washed thoroughly and the coupling repeated two more times.
  • the extension of the coupling was checked by the De Clercq test.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each.
  • Two additional treatments with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2 x 5 min) were performed to ensure the removal of the Fmoc group from secondary amines.
  • the same protocol was used to couple the third amino acid derivative.
  • the mixture was allowed to react with intermittent manual stirring for 2 h.
  • the cleavage stage was performed by treating the resin with 2% TFA in DCM (6 x 3 min). The filtrate was collected and the DCM evaporated under N 2 . The residue was dissolved in H 2 O: MeCN (1: 1) and lyophilized.
  • the synthesis was performed on a 100 ⁇ scale.
  • the following protocol was used for coupling the first amino acid to the Sieber resin:
  • the amino acid derivative of the first amino acid (Fmoc-N-MePhe-OH, 4 equiv., 400 ⁇ , 161 mg), PyBOP (4 equiv. ., 400 ⁇ , 208 mg) and HOAt (12 equiv., 1 .2 mmols, 163 mg) dissolved in DMF (1 -3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols , 204 ⁇ ).
  • the mixture was allowed to react with intermittent manual agitation for 1.5 h.
  • the solvent was removed by suction, the resin was washed thoroughly. The extent of the coupling was checked by the ninhydrin colorimetric assay.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each. Two additional treatments were performed with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2.5 min) to ensure the removal of the Fmoc group from secondary amines.
  • the protected amino acid derivative of the second amino acid was coupled to the first amino acid already anchored to the resin using the following protocol:
  • the protected amino acid (Fmoc-N-MePhe-OH, 4 equiv., 400 ⁇ , 161 mg), PyBOP was added sequentially (4 equiv., 400 ⁇ , 208 mg) and HOAt (12 equiv., 1.2 mmols, 163 mg) dissolved in DMF (1-3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ _). The mixture was allowed to react with intermittent manual stirring for 1.5 h. The solvent was removed by suction, the resin was washed thoroughly and the coupling was repeated two more times.
  • the extension of the coupling was checked by the De Clercq test.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each.
  • Two additional treatments were performed with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2.5 min) to ensure the removal of the Fmoc group from secondary amines.
  • the same protocol was used to couple the third and fourth amino acid derivative. Acetylation was performed in solid phase using a standard protocol of
  • the synthesis was performed on a 1,00 ⁇ scale.
  • the amino acid derivative of the first amino acid (Fmoc-Pro-OH, 4 equiv., 400 ⁇ , 1 35 mg), PyBOP (4 equiv. , 400 ⁇ , 208 mg) and HOAt (1 2 equiv., 1 .2 mmols, 1 63 mg) dissolved in DMF (1 -3 ml / g resin) to the resin followed by DIEA (1 2 equiv., 1. 2 mmols, 204 ⁇ _). The mixture was allowed to react with intermittent manual stirring for 1.5 h. The solvent was removed by suction, the resin was washed thoroughly.
  • the extent of the coupling was checked by the ninhydrin colorimetric assay.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each. Two additional treatments were performed with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2.5 min) to ensure the removal of the Fmoc group from secondary amines.
  • the protected amino acid derivative of the second amino acid was coupled to the first amino acid already anchored to the resin using the following protocol:
  • the protected amino acid (Fmoc-Pro-OH, 4 equiv., 400 ⁇ , 135 mg), PyBOP (4 were sequentially added equiv., 400 ⁇ , 208 mg) and HOAt (1 2 equiv., 1 .2 mmols, 163 mg) dissolved in DMF (1 -3 ml / g resin) to the resin followed by DIEA (1 2 equiv., 1 .2 mmols, 204 ⁇ ).
  • the mixture was allowed to react with intermittent manual stirring for 1.5 h.
  • the solvent was removed by suction, the resin was washed thoroughly and the coupling was repeated two more times.
  • the extent of the coupling was checked by the De Clercq test.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each. Two additional treatments were performed with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2.5 min) to ensure the removal of the Fmoc group from secondary amines.
  • Acetylation was performed in solid phase using a standard protocol of Ac 2 O (50 equiv., 5 mmols, 471 ⁇ ) and DIEA (50 equiv., 5 mmols, 850 ⁇ ) for 20 min.
  • the cleavage stage was performed by treating the resin with 2% TFA in DCM (6 x 3 min). The filtrate was collected and the DCM evaporated. under N 2 . The residue was dissolved in H 2 O: MeCN (1: 1) and lyophilized. To remove salts, a desalting step was performed using the DOWEX MR-3 Mixed Bed resin overnight.
  • the synthesis was performed on a 100 ⁇ scale.
  • the following protocol was used for coupling the first amino acid to the sieber resin:
  • the amino acid derivative of the first amino acid (Fmoc-N-MePhe-OH, 4 equiv., 400 ⁇ , 161 mg), PyBOP (4 equiv. ., 400 ⁇ , 208 mg) and HOAt (12 equiv., 1 .2 mmols, 163 mg) dissolved in DMF (1 - 3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols , 204 ⁇ _).
  • the mixture was allowed to react with intermittent manual stirring for 1.5 h.
  • the solvent was removed by suction, the resin was washed thoroughly. The extent of the coupling was checked by the ninhydrin colorimetric assay.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each. Two additional treatments were carried out with DBU, toluene, piperidine, DMF (5%, 5%, 20%,
  • the protected amino acid derivative of the second amino acid was coupled to the first amino acid already anchored to the resin using the following protocol: the protected amino acid (Fmoc-N-MePhe-OH, 4 equiv., 400 ⁇ , 161 mg), PyBOP was added sequentially (4 equiv., 400 ⁇ , 208 mg) and HOAt (12 equiv., 1.2 mmols, 163 mg) dissolved in DMF (1-3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols, 204 ⁇ ). The mixture was allowed to react with intermittent manual stirring for 1.5 h. The solvent was removed by suction, the resin was washed thoroughly and the coupling was repeated two more times.
  • the protected amino acid Fmoc-N-MePhe-OH, 4 equiv., 400 ⁇ , 161 mg
  • PyBOP was added sequentially (4 equiv., 400 ⁇ , 208 mg) and HOAt (12
  • the extension of the coupling was checked by the De test Clercq.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each. Two additional treatments were performed with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2.5 min) to ensure the removal of the Fmoc group from secondary amines.
  • the same protocol was used to couple the third amino acid derivative.
  • Acetylation was performed in solid phase using a standard protocol of Ac 2 O (50 equiv., 5 mmols, 471 ⁇ ) and DIEA (50 equiv., 5 mmols, 850 ⁇ ) for 20 min.
  • the cleavage stage was performed by treating the resin with 2% TFA in DCM (6 x 3 min). The filtrate was collected and the DCM evaporated under N 2 . The residue was dissolved in H 2 O: MeCN (1: 1) and lyophilized. To remove salts, a desalting step was performed using the DOWEX MR-3 Mixed Bed resin overnight.
  • the synthesis was performed on a 100 ⁇ scale.
  • the amino acid derivative of the first amino acid (Fmoc-N-MePhe-OH, 4 equiv., 400 ⁇ , 161 mg), PyBOP (4 equiv. ., 400 ⁇ , 208 mg) and HOAt (12 equiv., 1 .2 mmols, 163 mg) dissolved in DMF (1 - 3 ml / g resin) to the resin followed by DIEA (12 equiv., 1 .2 mmols , 204 ⁇ _). The mixture was allowed to react with intermittent manual stirring for 1.5 h.
  • the solvent was removed by suction, the resin was washed thoroughly. The extent of the coupling was checked by the ninhydrin colorimetric assay.
  • the Fmoc group was eliminated with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each. Two additional treatments with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2 x 5 min) were performed to ensure the removal of the Fmoc group from secondary amines.
  • the protected amino acid derivative of the second amino acid was coupled to the first amino acid already anchored to the resin using the following protocol:
  • the protected amino acid (Fmoc-N-MePhe-OH, 4 equiv., 400 ⁇ , 161 mg), PyBOP was added sequentially (4 equiv., 400 ⁇ , 208 mg) and HOAt
  • Fmocq The Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each. Two additional treatments were performed with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2.5 min) to ensure the removal of the Fmoc group from secondary amines. The same protocol was used to couple the third amino acid derivative.
  • the solvent was removed by suction, the resin was washed thoroughly and the coupling was repeated two more times.
  • the extension of the coupling was checked by the De Clercq test.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each.
  • two additional treatments were performed with DBU, toluene, piperidine, DMF (5%, 5%, 20%, 70%) (2 x 5 min) to ensure the removal of the Fmoc group from the amines high schools.
  • the cleavage stage was performed by treating the resin with 2% TFA in DCM (6 x 3 min). The filtrate was collected and the DCM evaporated under N 2 . The residue was dissolved in H 2 O: MeCN (1: 1) and lyophilized.
  • Comparative Example 4a L-Dopa-N-MePhe- (N-MePhe) 3 - CONH 2 5.4%; Comparative Example 4b: L-Dopa-Cha- (N-MePhe) 3 -CONH 2 10.6%; Comparative Example 4c: L-Dopa-2Nal- (N-MePhe) 3 -CONH 2 26%.
  • the protected amino acid derivative of the second amino acid was coupled to the first amino acid already anchored to the resin using the following protocol:
  • the protected amino acid (Fmoc-N-MePhe-OH, 4 equiv., 400 ⁇ , 161 mg), PyBOP was added sequentially (4 equiv., 400 ⁇ , 208 mg) and HOAt (12 equiv., 1.2 mmols, 163 mg) dissolved in DMF (1 - 3 ml / g resin resin followed by DIEA (12 equiv., 1. 2 mmols, 204 ⁇ ) The mixture was allowed to react with intermittent manual stirring for 1.5 h.The solvent was removed by suction, the resin was washed thoroughly and the coupling was repeated two more times.
  • the Fmoc group was removed with 20% (v / v) piperidine in DMF using 2 treatments of 10 minutes each. Two additional treatments were performed with DBU, toluene, piperidine, DMF (5%, 5 %, 20%, 70%) (2 5 min) to ensure the removal of the Fmoc group from secondary amines.
  • the protocol was used to couple the third amino acid derivative.
  • the cleavage stage was performed by treating the resin with 2% TFA in DCM (6 x 3 min). The filtrate was collected and the DCM evaporated under N 2 . The residue was dissolved in H 2 O: MeCN (1: 1) and lyophilized.
  • Comparative 5b Nip-Cha- (N-MePhe) 3 -CONH 2 91%; Comparative Example 5c: Nip-2Nal- (N-MePhe) 3 -CONH 2 75%.
  • Example 8 Evaluation of BBB transport using the parallel artificial membrane permeability test (PAMPA)
  • the evaluation method chosen to prove that the compounds of formula (I) of the invention are BBB-shuttles capable of crossing passive diffusion charges is the parallel artificial membrane permeability test (PAMPA), which allows predicting or evaluating only this transport mechanism
  • PAMPA parallel artificial membrane permeability test
  • the PAMPA method originally introduced by Kansy in Roche uses an artificial membrane in the form of phospholipid bilayers supported on a filter (cf. M. Kansy et al., "Physicochemical high throughput screening: Parallel artificial membrane permeability assay in the description of the absorption processes "J. Med. Chem. 1998, vol. 41, pp. 1007-1010).
  • the phospholipid membrane mimics the cell membrane, but does not have the means for active or paracellular transport of drug molecules. It is a very practical tool to evaluate the transport of compounds by passive diffusion. This technique allows the evaluation of pure, raw compounds and even mixtures of compounds.
  • the PAMPA test is used to determine the capacity of the
  • the effective permeability of the compounds was measured in triplicate at an initial concentration of 200 ⁇ .
  • the buffer solution was prepared from the concentrate sold by plON following its indications. The pH was adjusted to 7.4 using a 0.5M NaOH solution. The compound of interest was dissolved in buffer solution and 2-propanol (20% cosolvent) at
  • the PAMPA sandwich was separated and the donor well was filled with 200 ⁇ of the solution of the compound to be studied.
  • the acceptor plate was placed on the donor plate making sure that the bottom of the membrane was in contact with the buffer.
  • 4 ⁇ of phospholipid mixture (20 mg / mL) in dodecane was added to each well and 160 ⁇ of the buffer solution and 40 ⁇ L of 1-propanol were added to each acceptor well.
  • the plate was covered and incubated at room temperature in a humid atmosphere saturated for 4 hours under orbital agitation of 100 rpm.
  • composition phosphatidylcholine (PC) 12.6%, phosphatidylethanolamine (PE) 33.1%, phosphatidylserine (PS) 18.5%, phosphatidylinositol (Pl) 4.1%, phosphatidic acid 0.8% and 30.9% of other compounds.
  • Effective permeability was calculated using the following equation:
  • the different compounds were evaluated by PAMPA assay.
  • the PAMPA assay only measures passive diffusion transport, thus the positive transport measured for these compounds indicates that these compounds have a positive transport through the BBB in vivo by passive diffusion.
  • Tables 2, 3 and 4 it can be seen how the use of the BBB shuttle-cargo construction allows charges that do not cross by themselves, such as nipecotic acid and dopamine, can now cross the membrane by passive diffusion.

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Abstract

Les composés de formule (I), dans laquelle R1, R2 et R3 sont sélectionnés de manière indépendante parmi: H et (CH2)q-R6, R4 représente un radical C dérivé d'un des systèmes anneau connus à 1 à 4 anneaux; R5 représente H ou CH3CO-; R6 représente un radical C dérivé d'un des systèmes anneau connus à 1 ou 2 anneaux; X est sélectionné parmi -NH-(CH2)r-CO-, -CO(CH2)rCO-, -S-(CH2)r-, -S-(CH2).CO-, -O-(CH2)r- et -O-(CH2)r-CO-; Y représente -NH2, -OH, -OR7 ou -NHR7; k représente un entier de 0 à 1; m représente un entier de 0 à 1; n est un entier de 2 à 10; q est un entier de 0 à 1; r est un entier de 1 à 3; R7 représente un radical alkyle en (C1-C6); à condition qu'au moins un radical R sélectionné parmi R1, R2 et R3 représente (CH2)q-R6 et à condition que lorsque X représente -CO(CH2)rCO-, R5 représente H, sont utiles comme véhicules à travers la barrière hémato-encéphalique (BBB). Les constructions BBB-véhicule-charge sont utiles comme médicaments.
PCT/ES2011/070513 2010-07-13 2011-07-12 Composés utiles comme véhicules à travers la barrière hémato-encéphalique et constructions véhicule-charge WO2012007625A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013127829A1 (fr) 2012-02-27 2013-09-06 Universitat De Barcelona Composés résistant aux protéases utiles comme navettes à travers la barrière hémato-encéphalique et produit de construction navette-cargaison

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MALAKOUTIKHAH, M. ET AL.: "N-Methyl phenylalanine rich peptides as highly versatile blood brain barrier shuttles", J. MED. CHEM., vol. 53, 2010, pages 2354 - 2363 *
MORADI, M.: "A classical molecular dynamics investigation of the free energy and structurre of short polyproline conformers", JOURNAL OF CHEMICAL PHYSICS, vol. 133, no. 12, 2010, pages 125104/1 - 125104/18 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013127829A1 (fr) 2012-02-27 2013-09-06 Universitat De Barcelona Composés résistant aux protéases utiles comme navettes à travers la barrière hémato-encéphalique et produit de construction navette-cargaison
US9475840B2 (en) 2012-02-27 2016-10-25 Universitat De Barcelona Protease-resistant compounds useful as shuttles through the blood-brain barrier and shuttle-cargo constructs

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