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EP2125863A1 - Procédé de formation de ponts disulfure - Google Patents

Procédé de formation de ponts disulfure

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Publication number
EP2125863A1
EP2125863A1 EP07857071A EP07857071A EP2125863A1 EP 2125863 A1 EP2125863 A1 EP 2125863A1 EP 07857071 A EP07857071 A EP 07857071A EP 07857071 A EP07857071 A EP 07857071A EP 2125863 A1 EP2125863 A1 EP 2125863A1
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
hydrogen
alkyl
group
radical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07857071A
Other languages
German (de)
English (en)
Inventor
Karsten Knorr
Marco Emgenbroich
Carsten BÜNGENER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AplaGen GmbH
Original Assignee
AplaGen GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/EP2006/012526 external-priority patent/WO2007076993A1/fr
Application filed by AplaGen GmbH filed Critical AplaGen GmbH
Priority to EP07857071A priority Critical patent/EP2125863A1/fr
Publication of EP2125863A1 publication Critical patent/EP2125863A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/496—Triazoles or their condensed derivatives, e.g. benzotriazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4966—Triazines or their condensed derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/04—Preparations for permanent waving or straightening the hair
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/113—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides without change of the primary structure
    • C07K1/1133—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides without change of the primary structure by redox-reactions involving cystein/cystin side chains
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/02—Preparations for cleaning the hair
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/06—Preparations for styling the hair, e.g. by temporary shaping or colouring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/12—Preparations containing hair conditioners

Definitions

  • disulfide bridges are known in the art. For example, in a standard method of cyclizing peptides by forming intramolecular disulfide bridges, it is known to use K 3 [Fe (CN) e] as the oxidant. This reagent ensures clean cyclization products at high yields; Side reactions are avoided. In addition, cyclizations due to the influence of oxygen or iodine are still known. However, these methods have the disadvantage that they are either too slow or result in a large number of unwanted by-products.
  • Another known method for the cyclization of peptides is the use of immobilized Ellmann's reagent (5,5; -dithiobis (2-nitrobenzoic acid)) as the oxidant.
  • This method allows the complete oxidation of, for example, a linear peptide; Impurities caused by the reagent are avoided.
  • This approach has recently been extended to cross-linked ethoxylate-acrylate-resin (CLEAR) supports. These are compatible with both organic and aqueous solvent mixtures.
  • disulfide bridges are not only important for the peptide and protein chemistry, but also plays an important role in the cosmetic and therapeutic area, as well as the structure of keratin-containing structures such as skin, nails and hair by disulfide bridges Proteins are determined or influenced.
  • the outer skin is basically divided into 3 main layers: epidermis, dermis (dermis or corium) and subcutis (subcutis).
  • the epidermis or "epidermis” is one of the epithelial tissues, it is a multi-layered keratinizing squamous epithelium, which is usually between 0.03 to 0.05 millimeters, on the palms and soles but up to several millimeters thick. As the outermost layer of skin, it forms the actual protective cover against the environment. It is multi-layered and consists to 90 percent of keratinocytes, the actual epidermal cells, which are held together by so-called desmosomes. In the uppermost layers, the epidermis consists of keratinized squamous epithelial cells.
  • stratum corneum There are five different layers: the stratum corneum, the stratum lucidum, the stratum granulosum, the stratum spinosum, and the basal stratum.
  • stratum corneum the stratum corneum
  • stratum lucidum the stratum granulosum
  • stratum spinosum the stratum spinosum
  • basal stratum A typical property of the epidermis is its mechanosensitivity, e.g. due to the formation of calluses on hands and feet as a result of increased strain becomes visible.
  • Keratinocyte is the predominant (over 90 percent) cell type in the epidermis (epidermis). This cell type produces keratin and differentiates as it passes from the bottom layer of the epidermis to the top layers (ie, facing the outside world). In the so-called basal cell layer, proliferating cells are located directly on the basal membrane, providing a constant supply of new keratinocytes.
  • Keratin is a structural protein responsible for the stability and shape of the cells. Certain subgroups of this protein (the so-called trichocytic keratins) are also a major component of hair and nails.
  • the strength of these keratins is enhanced by fiber formation.
  • Next to the Structure-forming keratin is also included in keratin matrix as part of keratinization of squamous epithelium (epidermis) and in the development of keratin-based skin appendages (hair, nails), many other cellular molecules of the initially differentiating, later dying keratinocytes.
  • filaggrin An important protein is the so-called filaggrin, which is responsible for the cross-linking. While keratinocytes perish and produce large amounts of these proteins, massive cross-linking occurs in the upper layers of the skin (stratum lucidum and stratum corneum). A key chemical reaction that significantly affects the ultimate strength of the resulting keratin image is the closure of disulfide bridges between the sulfhydryl-rich proteins of the keratin matrix.
  • This covalent crosslinking via disulfide bridges imparts particular strength to the keratin formation.
  • Keratines in the ears, hair or nails are less pliable than the soft keratins from the skin.
  • ⁇ -keratins such as rhinoceros horns
  • up to 18% of the amino acids are involved in cross-linking via disulfide bridges.
  • the hair is also strongly keratinhaltig.
  • the hair can be roughly divided into three layers, cuticle, codex and medulla.
  • the outermost layer consists of flat, overlapping cells that are oriented similar to a pine cone to the tip of the hair. It consists of six to ten such cell layers.
  • the dandruff layer indicates the health of the hair. In healthy hair, the cuticle layer lies flat, resulting in a smooth, translucent surface. The light is optimally reflected and thus gives the healthy shine of the hair. Alkaline environment opens the scales, acidic environment closes them. The dandruff layer may be severely strained by cosmetic treatments such as dying or perming; The hair then becomes dull and brittle.
  • the cortex (“bark”), fiber layer or fiber trunk accounts for about 80% of the hair content, where all the relevant chemical processes that occur, for example, in cosmetic treatments take place.
  • the cortex consists of fiber bundles that consist of a large number of very fine keratin fibers
  • the connection between the two cells is made by the cell membrane complex, which can be thought of as a kind of cementitious substance, and the tear strength and elasticity of the hair are due to this cementation.
  • the medulla Inside the hair is the medulla (Hair medulla). It consists of cell walls, degradation products of cortex cells and fats.
  • the disulfide bridges in keratin described above are exploited in particular in cosmetic applications in order to deform keratin-containing structures, in particular hair.
  • the hair is usually first treated with a deforming agent based on a keratin-reducing compound, which causes an opening of the disulfide bridges of the hair keratin.
  • a deforming agent based on a keratin-reducing compound, which causes an opening of the disulfide bridges of the hair keratin.
  • Keratinreducing mercapto compounds such as, for example, salts or esters of mercaptocarboxylic acids, are generally used as shaping agents.
  • the hair is then brought into the desired shape, eg. By winding on curlers or smoothing the hair.
  • a second chemical modification is made, which is primarily to re-form disulfide bonds from the SH groups by oxidation. Due to the deformation imposed on the hair, the new bonds are formed elsewhere than the original bonds. This causes the strands of hair to be fixed in the imposed new shape and thus a permanent deformation is achieved.
  • Hydrogen peroxide is often used for the oxidation step to form new disulfide bridges.
  • hydrogen peroxide has the disadvantage that it attacks the hair and thus strained.
  • the present invention is therefore based on the object to provide an alternative method for generating disulfide bridges. It is another object of the present invention to provide an improved process for treating keratin-containing structures to form disulfide bridges.
  • This object is achieved by a method for forming disulfide bridges, which is characterized in that the reaction is carried out in a liquid or pasty mixture containing at least one heterocyclic compound having at least one nitrogen atom in the ring.
  • heterocyclic compounds are preferably added in catalytic amounts and remain unchanged during the reaction. You can also if necessary be removed after the reaction.
  • heterocyclic compounds are suitable, which are described in more detail below.
  • metal compounds such as metal ions or metal ion-containing or releasing compounds, such as metal salts or metal complexes can be used.
  • claim 1 relates to a process for forming disulfide bridges, characterized in that the reaction is carried out in a medium containing at least one compound which promotes the formation of disulfide bridges, said compound being selected from the group consisting of:
  • Hydroxy group is the heterocycle unsaturated
  • - is hydrogen, an optionally substituted alkyl radical, an optionally substituted aryl radical or a saturated or unsaturated Heterocyclyl having 3 to 10 ring members and 1 to 3 heteroatoms, such as nitrogen, oxygen and / or sulfur, wherein the heterocyclyl is unsubstituted or monosubstituted or polysubstituted by halogen, alkyl having 1 to 4 carbon atoms, cyano, nitro, cycloalkyl with 3 to 6 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms and / or
  • the above-defined heterocyclic compounds promote the formation of disulfide bridges and thus can act as a kind of catalyst in the reaction. Their effect is further enhanced by adding at least one metal compound according to the invention. It is therefore advantageous to add these compounds to the reaction mixture in order to promote the formation of disulfide bridges in the case of different SH group-carrying substances, in particular peptides and proteins, and keratin-containing structures.
  • the at least one metal compound may be a metal ion-containing or releasing compound. It is preferably selected from the group of metal salts, metal salt complexes and soluble metal compounds.
  • Metal compounds to be used according to the invention are therefore preferably ions or such releasing compounds or ionic complexes of metals. Even high-affinity chelating agents, such as ethylenediaminetetraacetate (EDTA), do not hinder the reinforcing properties of the metal-containing additives according to the invention and can be used as auxiliaries.
  • Particularly suitable metals are transition metals, such as iron, cobalt, nickel, copper, zinc, manganese, chromium or silver; Alkaline earth metals, such as, for example, calcium or magnesium or else main group metals, such as, for example, aluminum.
  • the ions of other transition metals also show a reinforcing effect.
  • the salts of copper, chromium, manganese, cobalt, nickel, zinc, magnesium and calcium are particularly suitable.
  • the metal compound can be selected from the group of copper (II) salts, chromium (III) salts, manganese (II) salts, cobalt (II) salts, nickel (II) salts, zinc (II) salts, magnesium (II) salts, calcium (II) salts and iron (II) and iron (III) salts.
  • the metal compounds to be used according to the invention show an advantageous effect on the oxidation reaction even in small amounts.
  • the additive is used in an amount of at least 1 ⁇ M, at least 2 ⁇ M and more preferably in an amount of at least 3 ⁇ M and more preferably in an amount of at least 10 ⁇ M.
  • significantly higher amounts are used, but it has been shown that from a certain amount of metal-containing additive, the reaction can not be further accelerated by increasing the concentration.
  • the concentration optimum may vary depending on the metal-containing substance and the substance to be oxidized. It is therefore advisable to determine the optimum experimentally.
  • the metal-containing additive shows an accelerating effect even in small amounts and in the presence of high-affinity complexing agents is particularly advantageous in the treatment of keratin-containing structures. This, since it is known from cosmetic treatments that, for example, copper and iron in larger quantities can cause discoloration of keratin-containing structures (in particular of the hair), which should be avoided.
  • the compound according to alternative (a) has the following basic structure:
  • heterocycle is saturated or unsaturated depending on the choice of the substituents R1 to R6 and may accordingly have one or more double bonds;
  • V, W, X, Y and Z are either carbon atoms or nitrogen atoms, the heterocycle having a total of not more than three, preferably two, nitrogen atoms;
  • R6 represents hydrogen or an optionally substituted alkyl or aryl radical, or R6 together with R5 represents a five- or six-membered ring, which may also have heteroatoms and optionally carries further substituents, or R6 is missing.
  • substituents R 2 to R 6 may be absent if a nitrogen atom having a double bond is present at the linking position in the ring (see, for example, the compounds 2,6-dihydroxypyridine hydrochloride; uracil-6-carboxylic acid, 4,6 -Dihydroxypyrimidin).
  • Oxo group in the context of the invention means that the respective substituent forms an oxo group with the ring atom and, correspondingly, an oxygen atom is bonded to the ring via a double bond:
  • the heterocycle is unsaturated in the case of the presence of hydroxy groups.
  • Tautomers are structural isomers that differ only in the position of a group (eg, hydrogen) and in the position of a double bond.
  • a group eg, hydrogen
  • oxo group 0
  • the aromatically present compounds such as the 2,6-dihydroxy-pyridine hydrochloride can tautomerize. This is especially true for the enol forms, which may preferentially tautomerize toward the keto form.
  • Tautomeric (isomeric) forms of the substances shown are therefore included according to the invention.
  • the six-membered heterocycle has two nitrogen atoms which may be positioned differently.
  • active compounds of this structure are uracil-6-carboxylic acid, 2,4-dihydroxy-6-methylpyrimidine, 2,4-dimethyl-6-hydroxypyrimidine, 2-isopropyl-6-methyl-4-pyrimidinol, 4,6-dihydroxy 2-methylpyrimidine, 4,6-dihydroxypyrimidine, 1, 2-dihydro-3,6-pyridazinedione:
  • the compound has the following substructure:
  • heterocycle is saturated or unsaturated depending on the choice of the substituents R2, R3, R4 and R6 and may accordingly have one or more double bonds; in which
  • R2 and R3 each independently of one another represent hydrogen, an optionally substituted alkyl or aryl radical, an optionally substituted radical - (CH 2 ) n COOX where n is 0 to 10 and X is hydrogen or alkyl, an electron-withdrawing substituent, a functional group in particular a hydroxy group, an oxo group (OO) according to the invention, -CONH 2 or an oxime (NN-OH) or R 2 together with R 3 represents a five- or six-membered ring which may likewise have heteroatoms and optionally carries further substituents, or R2 and / or R3 are missing; - R4 is hydrogen or an optionally substituted alkyl or aryl radical or R4 is absent;
  • R6 is hydrogen or an optionally substituted alkyl or aryl radical or R6 is missing.
  • Active examples of this embodiment are, for example, barbituric acid, alloxan monohydrate and violuric acid
  • R4 and R6 are independently hydrogen or an optionally substituted alkyl or aryl radical, preferably hydrogen or a branched or unbranched C1 to C10 alkyl radical, particularly preferably a C1 to C4 alkyl radical or hydrogen.
  • the compound which promotes the formation of disulfide bonds is purine derivatives whose skeleton corresponds to the following general formula
  • R4 and R6, are hydrogen, an optionally substituted alkyl group or an optionally substituted aryl group; preferably hydrogen, an optionally substituted C 1 - to C 10 -alkyl radical or an optionally substituted C 6 - or C O-aryl radical; particularly preferably hydrogen, an optionally substituted C 1 - to C 6 -alkyl radical or an optionally substituted C 6 -aryl radical; in particular hydrogen or an optionally substituted C 1 to C 3 alkyl radical;
  • the cyclic compound can thus be based on a purestan skeleton.
  • the purine skeleton can be regarded as a condensed ring system composed of the two heterocycles pyrimidine and imidazole. Its systematic IUPAC name is 7H-imidazole [4,5-d] pyrimidine.
  • the 7H-purine is in a tautomeric equilibrium with its isomer, the 9H-purine, and compounds which are based on both tautomeric forms are also included in the context of the present invention:
  • At least one radical R4, R6, R7 and R9 is an alkyl group and at least one, preferably two of the radicals R4, R6, R7 and R9 represent hydrogen or a C 1 to C 3 alkyl group, preferably methyl.
  • heterocyclic compounds based on purine are 3-methylxanthine, theobromine, theophylline, caffeine, isocaffeine, xanthine, theophylline-7-acetic acid, theophylline-8-butyric acid and 3-isobutyl-1-methylxanthine:
  • R2 and R3 together form an optionally substituted six-membered ring optionally having at least one heteroatom.
  • This embodiment is preferably compounds in which an aromatic has been fused to the basic heterocycle. This prefers a bridge of two carbon atoms. Examples in which a 5-membered ring has been condensed (for example imidazole) have already been explained above (compounds based on the purine skeleton). Further examples of fused ring structures are pyrazine and quinoxaline.
  • the compound has the following basic structure:
  • rings may be unsaturated depending on the choice of the substituents and may carry one or more double bonds, and accordingly
  • R4 and R6, each independently of the other, are or are absent for hydrogen, an optionally substituted alkyl radical or an optionally substituted aryl radical; preferably hydrogen, an optionally substituted branched or unbranched C 1 - to do-alkyl radical or an optionally substituted C 6 - or C 10 -
  • Aryl radical particularly preferably represents hydrogen, an optionally substituted C 1 - to C 6 -alkyl radical or a given if substituted C 6 aryl radical; in particular hydrogen or an optionally substituted C 1 to C 3 alkyl radical;
  • R10 and R13 are hydrogen, an optionally substituted alkyl radical or an optionally substituted aryl radical, or R10 and / or R13 are absent; are preferably hydrogen, an optionally substituted branched or unbranched C r to Cio-alkyl radical or an optionally substituted C 6 - or Ci O -aryl radical; particularly preferably represents hydrogen, an optionally substituted C 1 - to C 6 -alkyl radical or an optionally substituted C 6 aryl group; in particular hydrogen or a Ci to C 6 alkyl radical substituted by at least one hydroxyl group;
  • R 2, R 3, R 4 and R 5 may furthermore be, independently of one another, hydrogen, an optionally substituted branched or unbranched C 1 - to C 10 -alkyl radical or an optionally substituted C 6 - or C 10 -
  • aryl preferably hydrogen, an optionally substituted branched or unbranched C 1 - to C 6 -alkyl radical or an optionally substituted C 6 -aryl radical; in particular hydrogen or an optionally substituted C 1 to C 3 -alkyl radical, in particular methyl radical.
  • R 6 is preferably hydrogen or an alkyl radical, C 1 to C 8 , preferably C 1 to C 4 , particularly preferably hydrogen or a methyl group.
  • Electron-withdrawing groups or atoms which may also be used herein as substituents on the heterocycle (see above), are, for example, electron-withdrawing groups or atoms which as substituents lower the electron density on a corresponding aromatic heterocyclic ring (also referred to as deactivating groups). Electron-withdrawing groups have an (-) - M and / or a (-) - I effect.
  • the resonance effect (M effect, mesomeric effect) generally only works when the group is directly attached to the unsaturated heterocyclic system. It acts via ⁇ -electrons, in contrast to the field effect (I-effect, inductive effect), which acts through space, through solvation molecules or preferably via ⁇ bonds of a system.
  • An electron-withdrawing effect can be either inductive (i.e., by the so-called (-) I effect) and / or mesomerically (i.e., by the so-called (-) - M effect).
  • the classification of aromatic substituents in substituents with (+) - l and (-) - l effect and with (+) - M effect and (-) - M effect is known in the art per se. For further details, reference is made to Beyer / Walter, "Lehrbuch der Organischen Chemie", 1998, 23rd revised and updated edition, pages 515 to 518, the disclosure of which is included in the present invention.
  • the terms" electron-withdrawing group "and” functional group can be used.
  • Corresponding groups are examples of useful substituents.
  • the compound according to alternative (b) has a substituent A which
  • heterocyclyl is hydrogen, an optionally substituted C 1 - to do-alkyl radical, an optionally substituted C 6 - or Cio-aryl radical or a saturated or unsaturated heterocyclyl having 3 to 10 ring members and 1 heteroatom, such as nitrogen, oxygen and / or sulfur, wherein the heterocyclyl is unsubstituted or mono- or polysubstituted by halogen, alkyl having 1 to 4 carbon atoms, cyano, nitro, cycloalkyl having 3 to 6 carbon atoms, hydroxy, alkoxy having 1 to 4
  • Carbon atoms and / or mercapto preferably represents hydrogen, an optionally substituted C 1 - to C 6 -alkyl radical, an optionally substituted C 6 -aryl radical or saturated heterocyclyl having 5 or 6 ring members and 1 heteroatom, such as nitrogen, oxygen and / or sulfur, wherein the heterocyclyl is unsubstituted or monosubstituted or polysubstituted by halogen, alkyl having 1 to 4 carbon atoms, cyano, nitro, cycloalkyl having 3 to 6 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms and / or mercapto; in particular hydrogen, an optionally substituted C 1 to C 3
  • heterocyclic compounds described above can be used both in pure form and as mixtures of various possible isomeric forms, in particular of stereoisomers, such as E and Z, threo and erythro, and optical isomers, such as R and S isomers or atropisomers and of tautomers.
  • the invention includes both the pure isomers and their mixtures.
  • the heterocyclic compounds have acidic or basic properties and can form salts, optionally also internal salts. If the compounds of the formula (I) bear hydroxy, carboxy or other groups which induce acidic properties, these compounds can be reacted with bases to form salts.
  • bases are, for example, hydroxides, carbonates, bicarbonates of the alkali and alkaline earth metals, in particular those of sodium, potassium, magnesium and calcium, furthermore ammonia, primary, secondary and tertiary amines with (C 1 -C 4 ) -alkyl radicals and also mono-, Di- and trialkanolamines of (CrC 4 ) -alkanols.
  • acids are, for example, mineral acids, such as hydrochloric, sulfuric and phosphoric acids, organic acids, such as acetic acid or oxalic acid, and acidic salts, such as NaHSO 4 and KHSO 4 .
  • mineral acids such as hydrochloric, sulfuric and phosphoric acids
  • organic acids such as acetic acid or oxalic acid
  • acidic salts such as NaHSO 4 and KHSO 4 .
  • heterocyclic compounds which can be used according to the invention for promoting the formation of the disulfide bridges can also be described as follows:
  • radicals R 1 ', R 2 ' and R 3 ' are either the same or different; However, at least one of the radicals represents an alkyl group. It is understood that tautomers, in which Among other things, the double bond migrates, also be captured by the above formula. Corresponding structural isomers are therefore also encompassed by this formula. As has been stated, these compounds are particularly suitable for promoting the formation of disulfide bridges in amino acid-containing substances, in particular in peptides and proteins.
  • At least one, preferably two of the radicals R 1 ', R 2 ' and R 3 ' which are either identical or different, preferably represents either hydrogen or a C 1 to C 5 alkyl group.
  • the radicals may include a functional group.
  • residues R 4 '(on the nitrogen) and R 5 ' are present at the remaining positions on the heterocyclic 5-membered ring (especially in the tautomeric forms).
  • These are customizable, preferably organic radicals. According to one embodiment, they are functional groups which allow the attachment of the substance to, for example, a carrier. This variant will be described in detail below.
  • heterocyclic compounds to be used according to the invention are N-methyl-2-pyridone, 2,6-dihydroxypyridine
  • peptides and proteins in particular peptides having an amino acid length between 5 and 100, preferably 10 and 50, more preferably between 15 to 40 amino acids in water even at higher peptide concentration at room temperature according to the invention according to the process can be cyclized by formation of intramolecular disulfide bridges.
  • the method is therefore particularly suitable for the formation of intramolecular disulfide bridges and therefore in particular for the cyclization of peptides.
  • polypeptides and proteins can be cyclized with the appropriate method.
  • disulfide bridges with differently structured substances carrying SH groups.
  • disulfide bridges for example, in a cyclization, takes place due to the addition of the heterocyclic compound of the invention such as caffeine or a caffeine-like substance (see above formulas) in some peptides almost quantitatively. However, this is not mandatory. Surprisingly, it is not necessary (but possible) to add an oxidizing agent to accelerate the reaction, since the atmospheric oxygen is sufficient in the presence of the above-characterized substance to form disulfide bridges.
  • the reaction rate may increase in the course of the reaction.
  • the positive influence of the inventive addition of the above-characterized substance is surprising in that it is mostly - in contrast to the substances used in the prior art DMSO or iodine - not oxidizing agent.
  • the atmospheric oxygen is sufficient for the oxidation, wherein the reaction rate increases in an advantageous manner due to the addition of the heterocyclic compound according to the invention.
  • Increasing the reaction rate might also suggest an autocatalytic mechanism, possibly through the cyclized product.
  • the process according to the invention can advantageously be carried out at room temperature.
  • the apparently autocatalytic course of the reaction occurs both in unbuffered and in buffered solutions (for example phosphate buffer, pH 6 - 9).
  • buffered solutions for example phosphate buffer, pH 6 - 9
  • the amount of substance added to the reaction mixture to promote the formation of the particular intramolecular disulfide bridges will vary depending on the compound and the substance to which disulfide bridges are to be formed. As a rule, small catalytic amounts are sufficient.
  • the amount to be employed is preferably at least about 0.0001 mg / ml, more preferably in a range of about 0.0001, 0.001 or 0.01 to 20 mg / ml, 0.001 or 0.01 to 15 mg / ml, 0.001 or 0.01 to 10 mg / ml, 0.001 or 0.01 to 5 mg / ml, preferably 0.001 or 0.01 to 1 mg / ml, and more preferably in a range of 0.03 to 0.5 mg / ml.
  • the amounts vary depending on the selected substance (eg caffeine or caffeine-like substance) and the peptide or protein to be treated and should therefore be individually optimized in each case.
  • a particularly suitable concentration range for peptides with a length of about 15 to 25 amino acids is 0.05 to 0.3 mg / ml, more preferably 0.075 to 0.15 mg / ml.
  • the amounts vary depending on the peptide and can also be significantly higher; the amounts should therefore preferably be optimized for the particular peptide.
  • the reaction rate can be further accelerated if an additional oxidizing agent is added to the reaction mixture.
  • an additional oxidizing agent for example, glutathione in oxidized form (GSSG) may be mentioned.
  • a disulfide bridge is formed in a peptide or protein between two cysteines.
  • the disulfide bridge can also be formed between other natural and non-natural amino acids, provided that they have corresponding groups which are suitable for forming a disulfide bridge (-SS-).
  • Thiolysin, homocysteine and other cysteine derivatives are to be mentioned as examples of suitable amino acids in addition to cysteine.
  • the term disulfide bridge however, is not to be equated with the term cysteine bridge, but includes the formation of corresponding -SS bonds between any natural or non-natural SH-containing amino acids or other SH-containing compounds.
  • the method according to the invention can therefore also disulfide bridges in other SH-containing compounds, in particular polymers, train.
  • a plurality of disulfide bridges can also be formed with the method according to the invention.
  • the present process can be used particularly advantageously for the cyclization of EPO-mimetic peptides (see, for example, WO 96/40479).
  • Novel EPO mimetic peptides are described in PCT / EP2005 / 012075 (WO 2006/050959), the disclosure content of which with respect to the peptides is hereby made the subject of this application in its entirety.
  • these novel EPO mimetic peptides have no proline in position 10 of the EPO mimetic consensus motif (for numbering, see Johnson et al., 1997). Rather, the proline is replaced by a non-conservative amino acid, in particular a basic amino acid, in particular lysine.
  • EPO mimetic peptides show a particularly good activity in cyclized form.
  • two peptide monomers (the monomers correspond to binding domains) are each cyclized with an EPO mimetic consensus and linked to a dimer, since binding to the EPO receptor is most effective in this form.
  • the EPO mimetic monomers have an average of 10 to 25 amino acids.
  • they are synthesized as continuous dimers (bivalent peptides) to avoid separate dimerization steps.
  • Cyclization by the process according to the invention has some decisive advantages over the processes known in the prior art. Thus, better yields and greater purity of the product are achieved than with the method known in the art.
  • Another decisive advantage of the method according to the invention is the simple separability of the cyclization reagent according to the invention from the reaction product by a simple HPLC.
  • the heterocyclic compound eg caffeine
  • caffeine can be separated off by liquid-liquid extraction.
  • caffeine can be separated from an aqueous peptide solution by repeated extraction with dichloromethane.
  • SEC size exclusion chromatography
  • the reaction time can be reduced to less than eight hours (for example by lowering the pH, choosing an additional oxidizing agent).
  • H-CYIQNCPLG-OH which is also cyclized by formation of an intramolecular cysteine bridge.
  • the intramolecular disulfide bridge is preferably formed between two amino acids. These may be natural or non-natural, the only requirement is the ability to form a disulfide bridge by reacting the SH group. Cysteine is probably the best known disulfide bridge-forming amino acid, which is also used in nature predominantly for the formation of disulfide bridges. Disulfide bridges occur in nature especially in the formation of intra- and intermolecular disulfide bridges. Thus, for example, they effect the cohesion between the individual polypeptide chains of proteins (for example insulin) in the form of intermolecular disulfide bridges and regularly stabilize the conformation within a protein by forming intramolecular disulfide bridges. The proteins are to be seen here only as a special case of SH-functionalized polymers. Synthetic fibers having SH functions can also be treated with the substances of the invention and e.g. be stabilized.
  • the keratin of wool and hair contains, for example, more than 10% cysteine, which is why there are also many disulfide bridges. If these disulfide bridges are broken up (for example, by lyes, light, heating, etc.), the tensile strength of the fibers decreases sharply.
  • the method according to the invention can therefore also be used to form disulfide bridges in fibers (natural and synthetic fibers). The same applies to the Treatment of hair, in which disulfide bridges are also of great importance for structural strength.
  • the method according to the invention can therefore also be used to form disulfide bridges in hair, which also opens up a field of cosmetic application (for example shampoos, reagents for forming perms, etc.).
  • the method according to the invention can be used, for example, as means for closing the disulfide bridges in the context of a permanent wave treatment.
  • a particularly suitable oxidizing agent is oxidized glutathione (GSSG). The resulting improvement in the closure of disulfide bridges in both quantitative and temporal terms is clearly described in the experimental examples.
  • the present invention also relates to the use of the previously described heterocyclic compounds in cosmetic compositions.
  • these cosmetic compositions can be promoted according to the formation of disulfide bridges, for example, hair or nails.
  • the cosmetic preparations may contain, in addition to the previously described heterocyclic compound, suitable solvents and in such
  • Formulations contain usual additives. Emulsifiers and co-emulsifiers, surfactants, oil bodies, preservatives, perfume oils, and cosmetic substances are examples.
  • Care and active ingredients such as AHA acids, fruit acids, ceramides, phytantriol, collagen,
  • Vitamins and pro-vitamins for example vitamins A, E and C, retinol, bisabolol, panthenol, natural and synthetic sunscreens, natural products, opacifiers,
  • Micropigments such as titanium oxide or zinc oxide, superfatting agents, pearlescent waxes,
  • Bodying agents thickeners, solubilizers, complexing agents, fats, waxes,
  • Silicone compounds hydrotropes, dyes, stabilizers, pH regulators,
  • Reflectors proteins and protein hydrolysates, protein hydrolysates, salts, gelling agents, bodying agents, silicones, humectants, moisturizers and other common additives.
  • polymers can be contained to adjust the respective desired properties.
  • UV light stabilizers may also be present in the cosmetic preparations.
  • Hair cosmetic preparations comprise, in particular, styling agents and / or conditioners in hair cosmetic preparations, such as hair treatments, hair mousses, hair gels, hair sprays, hair lotions, hair conditioners, hair shampoos, hair emulsions, perms, permanent waving preparations, hair dyeing and bleaching agents, setting lotions or similar products.
  • the hair cosmetic preparations can be applied as (Erosol) spray, (Erosol) foam, gel, gel spray, cream, lotion, milk or wax.
  • the agent is a product for the hair selected from shampoos and hair products which are rinsed or not rinsed and applied before, during or after shampooing, coloring, decoloring, perming or wrinkling ,
  • a method for the treatment of hair is provided, which is characterized in that the hair with the cosmetic agent, containing at least one of the previously explained in more detail heterocyclic compound are brought into contact and optionally rinsed with water.
  • the heterocyclic compound is preferably selected from the compounds and classes of compounds detailed above.
  • the present invention also provides a process for forming disulfide bridges in keratin-containing structures, in which the keratin-containing structure is treated with at least one compound which promotes the formation of disulfide bridges, this compound being selected from the group consisting of:
  • Oxo group ( 0), wherein in the case of the presence of a hydroxy group, the heterocycle is unsaturated;
  • - is hydrogen, an optionally substituted alkyl radical, an optionally substituted aryl radical or a saturated or unsaturated heterocyclyl having 3 to 10 ring members and 1 to 3 heteroatoms, such as nitrogen, oxygen and / or sulfur, wherein the heterocyclyl unsubstituted or mono- or polysubstituted is halogen, alkyl of 1 to 4 carbon atoms, cyano, nitro, cycloalkyl of 3 to 6
  • Suitable heterocyclic compounds are described above and are also useful with the method of treating keratin-containing structures. We therefore refer to our comments in this regard. In addition, already low enough
  • the keratin-containing structures may be, for example, fibers, such as, for example, hair, or the skin or nails. Furthermore, one of those described above
  • Metal compounds are used to further accelerate the reaction.
  • the method for the deformation of keratin-containing structures, in particular hair is used, it is advantageous if, in a first step, first the existing disulfide bridges are at least partially opened and the hair is then brought into the desired shape.
  • Suitable substances for opening the disulfide bridges are known to the person skilled in the art and are also described above in connection with the prior art.
  • keratin-reducing mercapto compounds such as, for example, salts or esters of mercaptocarboxylic acids can be used.
  • new disulfide bridges are then knotted by the process of the invention.
  • heterocyclic compounds to be used according to the invention are gentler than the conventionally used oxidizing agents, such as, for example, hydrogen peroxide.
  • oxidizing agents such as, for example, hydrogen peroxide.
  • one Embodiment has the following basic structure of the heterocyclic compound which promotes formation of disulfide bridges:
  • heterocycle is saturated or unsaturated depending on the choice of the substituents R1 to R6 and may accordingly have one or more double bonds;
  • V, W, X, Y and Z are either carbon atoms or nitrogen atoms, the heterocycle having a total of not more than three, preferably two, nitrogen atoms;
  • R6 is hydrogen or an optionally substituted alkyl or aryl radical, or R6 is absent.
  • the heterocyclic compound preferably has the following substructure:
  • heterocycle is saturated or unsaturated depending on the choice of the substituents R2, R3, R4 and R6 and may accordingly have one or more double bonds; in which
  • - R4 is hydrogen or an optionally substituted alkyl or
  • Aryl radical or R4 is absent
  • R6 is hydrogen or an optionally substituted alkyl or aryl radical or R6 is missing.
  • the method can also be used to form disulfide bridges of synthetic substances which have only functional groups bearing SH groups, but are not constructed from amino acids, for example (but for example from an organic polymer).
  • the separation of the substance promoting the formation of disulfide bridges is considerably facilitated.
  • a carrier is loaded with the disulfide bridge promoting substance.
  • the carrier may, for example, be a (hydrophilic) resin.
  • the binding of the substance to the carrier has the consequence that the separation of the supported substance, for example.
  • Both derivatives promote the formation of disulfide bridges and thus the cyclization of peptides in solution.
  • an immobilized reagent capable of accelerating the closure of disulfide bridges is obtained.
  • the reagent can be removed by simple filtration from the reaction solution.
  • R 1 'to R 3 ' radicals as here in the case of 8- (3-Carbo xypropyl) -1
  • 3-dimethylxanthine for example, a functional group as R 5 'for coupling to the carrier, attach.
  • heterocyclic substances to be used according to the invention are particularly suitable for the cyclization of peptides, in particular EPO mimetic peptides, by forming intramolecular disulfide bridges.
  • Such disulfide bridges are formed between SH-containing groups.
  • natural and non-natural amino acids which have free SH groups are suitable disulfide bridge formers.
  • the compounds of the above formula can be used, for example, to treat SH group-containing substances and materials to promote the formation of disulfide bridges.
  • the substances can be used, for example, for the treatment of hair or fibers (natural and synthetic fibers). This applies in particular to cysteine-containing fibers.
  • the heterocyclic compounds to be used according to the invention can also be used, for example, in liquid formulations (for example in the form of rinses or shampoos or other agents for the treatment of hair such as, for example, perming agents).
  • Corresponding compositions comprising at least one heterocyclic compound according to the invention are therefore also encompassed by the invention.
  • the heterocyclic disulfide bond promoting compound has the following basic structure:
  • heterocycle is saturated or unsaturated depending on the choice of the substituents R1 to R6 and may accordingly have one or more double bonds;
  • V, W, X, Y and Z are either carbon atoms or nitrogen atoms, the heterocycle having a total of not more than three, preferably two, nitrogen atoms;
  • R6 is hydrogen or an optionally substituted alkyl or aryl radical, or R6 is absent.
  • the heterocyclic compound has the following substructure:
  • heterocycle is saturated or unsaturated depending on the choice of the substituents R2, R3, R4 and R6 and may accordingly have one or more double bonds; in which
  • R 2 and R 3 each independently of one another represent hydrogen, an optionally substituted alkyl or aryl radical, an optionally substituted radical - (CH 2 J n COOX with n being 0-10 and X is hydrogen or alkyl, an electron-withdrawing substituent, a functional group in particular a hydroxy group, an oxo group (OO) according to the invention, -CONH 2 or an oxime (NN-OH), or R 2 and / or R 3 are absent;
  • - R4 is hydrogen or an optionally substituted alkyl or aryl radical or R4 is absent; - R6 is hydrogen or an optionally substituted alkyl or aryl radical or R6 is missing.
  • the invention further relates to the use of the above-described heterocyclic compounds or compositions containing these heterogeneous compounds for the formation of disulfide bridges, in particular of intra- or intermolecular disulfide bridges in peptides and proteins as well as keratin-containing structures. These compounds are preferably used in combination with a metal compound according to the invention.
  • a corresponding composition comprising at least one heterocyclic compound according to the invention, which promotes the formation of disulfide bridges, and preferably a metal compound according to the invention.
  • composition according to the invention is used according to one embodiment as a cosmetic and / or therapeutic composition for the treatment of keratin-containing structures such as skin, hair or nails.
  • this composition can be used in the case of hair, for example, for hair deformation or fixation.
  • the composition is preferably applied to the nail to promote the formation of disulfide bridges and thus to harden the nail.
  • heterocyclic compounds according to the present invention have a hair growth-promoting and stabilizing effect. Without being limited to this explanation, it is assumed that this hair growth-promoting or stabilizing effect of the substances according to the invention is also traceable to promoting the formation of the disulfide bridges.
  • the cross-linking of the disulfide bridges occurs during the intradermal phase of the hair shaft formation.
  • the extent of hardening of the keratin mass determines the
  • the basal keratin mass Keratinocytes As part of the overall mechano-sensitivity of the skin, the basal keratinocytes react to backpressure with greater proliferation, resulting in more stable hair growth. If the back pressure is weaker, the supply of keratin mass weakens, which can set a negative cycle in motion. In extreme cases, this can contribute to the development of thinning hair or hair loss (alopecia).
  • the disulfide bridge-closing properties of the substances according to the invention presumably intervene in this growth-regulating interplay, by promoting the early hardening of the hair shaft and thus enabling better back pressure, which promotes hair growth. Therefore, the treatment of the hair and the easily accessible from the outside intradermal sections of the hair with the substances according to the invention - even without the intention of deformation as described above - is suitable to prevent premature hair loss or minimize it.
  • the substances according to the invention also have a hair growth-promoting and stabilizing effect by way of stable disulfide cross-linking.
  • the compounds according to the invention can therefore be used in suitable external cosmetic or therapeutic preparations in order to prevent hair loss, e.g. the so-called androgenetic alopecia, or to promote and stabilize hair growth.
  • composition according to the invention can also be applied to the skin in order to promote the formation of disulfide bridges in the keratin-containing skin layers. This is particularly advantageous for the treatment of skin diseases or symptoms of skin diseases that are associated with a weakening of the keratin structure, such as, for example, hypokeratosis or epidermolysis.
  • heterocyclic compounds characterized according to the invention Due to the catalytic effect of heterocyclic compounds characterized according to the invention on the formation of disulfide bridges, they can also be used, for example, for catalysis in the formation of intermolecular or intramolecular disulfide bridges for the preparation of dynamic combinatorial libraries. They can therefore serve to form disulfide bridges between synthetic or natural or modified natural molecules. Therefore, they can find application in the production of dynamic combinatorial libraries for drug discovery. In dynamic combinatorial libraries, the individual units are often linked to macromolecules via disulfide bridges (see Fig. 15). Details of the libraries are described, for example, in "Dynamic combinatorial libraries of macrocyclic disulfides in water" by S. Otto, RLE Furlan and JKM Sanders, J.
  • EPO mimetic peptides and oxytocin were chosen as examples of the peptides that can be cyclized by the method according to the invention.
  • Fig. 2 shows the cyclization of the same peptide as in Fig. 1 (0.7 mg / ml) to its cyclized form in the absence of caffeine. As can be clearly seen, the reaction rate is considerably reduced.
  • EMP1 Ac-GGTYSCHFGPLTWVCKPQGG-Am
  • APG1 Ac-GGTYSCHFGKLTWVCKKQGG-Am
  • APG2 Ac-GGTYSCHFGKLT-NaI-VCKKQRG-Am
  • FIG. 8 Shown is the cyclization of dimeric EPO mimetic peptides.
  • the cyclization of di- or multimeric peptides is preferably carried out in several steps.
  • FIG. 8 shows the synthesis scheme based on a bivalent (dimeric) EPO-mimetic peptide, which is cyclized in 2 steps by formation of two intramolecular disulfide bridges.
  • the first disulfide bridge is formed by the method according to the invention.
  • the second intramolecular disulfide bridge was performed using optimized iodine oxidation.
  • the first cyclization using caffeine according to the invention is preferably carried out at pH 6, while the second cyclization was carried out in 80% acetic acid according to the example shown.
  • the yield of the synthesis was typically between 60 and 90%.
  • EPO mimetic peptides are very difficult to cyclize.
  • An example of this is the following peptide:
  • Aad 2-aminoadipic acid, "homoglutamic acid” NaI: naphthylalanine
  • oxytocin, reduced (OyxR), crude product was dissolved in water (or H 2 O / ACN / TFA) and allowed to stand in air with various concentrations of caffeine (and possibly GSSG).
  • the reaction batch was measured by HPLC at regular intervals to determine the levels of OxyR and the product oxytocin (oxy).
  • the reaction time until complete conversion of OxyR correlates with the concentration of caffeine in the reaction solution. Up to a concentration of 0.5 mg / ml caffeine, the more caffeine the faster the oxidation proceeds. The peptide concentration has only a minor influence on the duration of the reaction.
  • Minoxidil as a further representative of the heterocyclic compounds according to the invention, therefore likewise has a positive effect on the formation of disulfide bridges.
  • the yield in solution of the minoxidil-catalyzed reaction is over 95%.
  • the fact that the reaction is a catalytically proceeding reaction is shown by the fact that the concentration of minoxidil in the reaction does not decrease practically (decrease ⁇ 2% at 4.4 eq minoxidil based on BB57, see FIG. 14).
  • Oxidizing agent here oxidized glutathione-GSSG
  • the method according to the invention can be used advantageously also in the cosmetic field and in particular in the hairdressing sector for the treatment of hair.
  • Hair samples are a) in H 2 O, or an aqueous solution of b) 10 mg / ml caffeine, c)
  • the hair after removal of the reaction solution with Ellman's reagent (5,5'-dithiobis (2-nitrobenzoic acid), DTNB) is reacted.
  • Ellman's reagent (5,5'-dithiobis (2-nitrobenzoic acid), DTNB) is reacted.
  • additional reference samples are untreated hair and reduced hair, which was otherwise subjected to no further treatment.
  • the hair samples are each with 200 ⁇ l one Add 10 mM phosphate buffer, pH 8.0 and 1 mM EDTA, and 300 ⁇ l of a 1 mM DTNB solution in the same EDTA-containing buffer. The solution is measured after a few minutes in a UV-Vis spectrometer.
  • FIGS. 40 to 59 demonstrate the reinforcing effect of the metal-containing additive.
  • the activities of the additives were again determined by the cyclization of the following example substance BB57, an epo-mimetic peptide containing 2 free cysteines
  • Fig. 40 shows the oxidation of BB57 to BB57C by caffeine. A complete turnover took place after approx. 15h. This reaction can surprisingly be further accelerated by the combination with iron (II) salts. With slight addition of iron (II) sulfate (3 .mu.M), the reaction time to complete conversion to about 10h shortened. The results are shown in FIG. 41. Intermediates appeared directly at the beginning in the HPLC chromatogram, but these converted into the product as the reaction progressed.
  • Fig. 42 shows the oxidation of BB57 to BB57C by caffeine and the addition of ferrous ions (30 ⁇ M).
  • the monitoring was carried out by means of the Ellmans test. Caffeine cyclization time is reduced to about one hour with iron (II).
  • Figure 43 shows the oxidation of BB57 to BB57C by caffeine and the addition of various ferric ions (30 ⁇ M). The monitoring took place again by means of the Ellmans test. The caffeine cyclization time is also shortened to about one hour with iron (III) salts.
  • Figure 44 shows oxidation of BB57 to BB57C by caffeine and the addition of copper (II) ions (30 ⁇ M). The monitoring took place again by means of the Ellmans test. The cyclization time is also shortened by the addition of copper salts.
  • Figure 45 shows the oxidation of BB57 with and without Fe (II) salt, ferrous sulfate (3 ⁇ M), followed by the Ellmans test.
  • the increase potential is further clarified by the example with the substance alloxan monohydrate. With alloxan (5 ⁇ g / ml) 0.66 mg / ml BB57 are almost completely cyclized within about 2 hours.
  • Figure 47 shows the acceleration of the oxidation of BB57 with alloxan and the addition of iron (III) ions (30 ⁇ M). Monitoring was carried out by Ellmans test. As previously shown for caffeine, iron (III) ions also measure an acceleration effect in combination with alloxan.
  • the ions of other transition metals also show a reinforcing effect.
  • the effects of the salts copper (II) sulfate, chromium (III) chloride, manganese (II) sulfate, cobalt (II) chloride, nickel (II) chloride, zinc (II) sulfate, magnesium (II) sulfate and calcium (II) chloride are tracked for accelerating the oxidation of BB57 by alloxan or caffeine, respectively.
  • a particularly strong effect can be observed with the iron (II) and iron (III) salts.
  • Figure 49 shows the oxidation of BB57 by alloxan and the metal ion of cobalt (II) chloride. The monitoring was carried out using the Ellman's reagent.
  • Fig. 50 shows the oxidation of BB57 by alloxan and the metal ions of nickel (II) chloride. The monitoring was carried out using the Ellman's reagent.
  • Fig. 51 shows the oxidation of BB57 by alloxan and the metal ion of zinc (II) sulfate.
  • the monitoring was carried out using the Ellman's reagent.
  • Figure 52 shows the oxidation of BB57 by alloxan and the metal ions of manganese (II) sulfate. The monitoring was carried out using the Ellman's reagent.
  • Fig. 53 shows the oxidation of BB57 by alloxan and the metal ions of chromium (III) chloride. The monitoring was carried out using the Ellman's reagent.
  • Figure 54 shows the oxidation of BB57 by alloxan and the metal ion of calcium (II) chloride. The monitoring was carried out using the Ellman's reagent.
  • Figure 55 shows the oxidation of BB57 by alloxan and the metal ion of magnesium (II) chloride. Monitoring over Ellman's reagent.
  • Figure 56 shows the oxidation of BB57 by alloxan and the metal ions of silver (I) nitrate. Monitoring over Ellman's reagent.
  • Stable metal ion complexes also have an accelerating effect, as shown by the example of potassium hexacyanoferrate in the following two examples.
  • Figures 57 and 58 show the cyclization of BB57 with alloxan and alloxan in combination with potassium hexacyanoferrate (II) or potassium hexacyanoferrate (III) (30 ⁇ M). The monitoring was carried out using the Ellman's reagent.
  • FIG. 59 shows the cyclization of BB57 with alloxan in combination with iron ions (3 ⁇ M) with and without 2 equivalents of EDTA. The monitoring was carried out using the Ellman's reagent.
  • Ammonium thiolactate (commercial permwave formulation) reduced to open. Subsequently, the reduction solution is removed and the hair was washed several times with water. Subsequently, the hairs were the different
  • the specific effectiveness of the heterocyclic reaction accelerator in combination with the metal-containing compound according to the invention was demonstrated on the basis of the following examples. In some experiments, combinations of different metal additives are used instead of larger amounts of a single salt component.
  • the contents of the "artificial drinking water" mixture described below are based on the maximum values given in the Drinking Water Ordinance of the Federal Republic of Germany using the following combination of metal ions: 0.2 mg / L iron (Fe 3+ ), 5 mg / L zinc (Zn 2+ ), 2mg / L copper (Cu 2+ ) and some hardness components 100mg / L calcium (Ca 2+ ) and 50mg / L magnesium (Mg 2+ ).
  • Fig. 61 shows the oxidation of hair with alloxan, alloxan with ferric chloride and alloxan with the above-described mixture "artificial drinking water.”
  • iron (III) chloride and artificial drinking water is under control After 10 minutes a lesser advantage to see through the salt additions, which proves the extraordinary properties of alloxan on keratinveni structures.
  • Fig. 62 shows the oxidation of reduced hair with caffeine and alloxan, respectively in combination with a mixture of salts corresponding to the maximum content in drinking water.
  • the monitoring comparison of caffeine and alloxan on hair shows that both reagents in combination with artificial drinking water completely oxidize the hair, but the reaction with caffeine takes longer.
  • Fig. 63 shows the oxidation of reduced hair with various amounts of alloxan in combination with varying amounts of iron (III) ions.
  • the monitoring was carried out by means of Ellmans reagent.
  • This example with different amounts of alloxan and ferric chloride shows that small amounts of alloxan, a 0.1% solution in combination with small amounts of iron ions, is sufficient to achieve almost complete reoxidation of the thiols in the hair after 10 minutes. These small amounts are particularly advantageous, since this little burden on the structure of the hair.
  • the process according to the invention is therefore gentler than conventional processes which, for example, operate on the basis of hydrogen peroxide.

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Abstract

Procédé amélioré de formation de ponts disulfure dans des substances portant des groupes SH, en particulier des peptides, par exemple par formation de ponts disulfure intramoléculaires. Selon ledit procédé, un composé hétérocyclique contenant au moins un atome d'azote (par ex. de la caféine ou une substance de type caféine) est utilisé pour la catalyse de la réaction. Il a été étonnamment découvert que l'ajout de la substance hétérocyclique augmente tant le rendement que la pureté du produit portant les ponts disulfure.
EP07857071A 2006-12-23 2007-12-21 Procédé de formation de ponts disulfure Withdrawn EP2125863A1 (fr)

Priority Applications (1)

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EP07857071A EP2125863A1 (fr) 2006-12-23 2007-12-21 Procédé de formation de ponts disulfure

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Application Number Priority Date Filing Date Title
PCT/EP2006/012526 WO2007076993A1 (fr) 2005-12-23 2006-12-23 Procede de formation de ponts disulfure
US94908207P 2007-07-11 2007-07-11
EP07013584 2007-07-11
EP07857071A EP2125863A1 (fr) 2006-12-23 2007-12-21 Procédé de formation de ponts disulfure
PCT/EP2007/011362 WO2008077621A1 (fr) 2006-12-23 2007-12-21 Procédé de formation de ponts disulfure

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EP2212020B1 (fr) * 2007-11-12 2018-07-04 Sellergren, Börje Polymères imprimés présentant une affinité pour les protéines et les peptides phosphorylés

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US3929758A (en) * 1974-09-12 1975-12-30 Armour Pharma Cyclization of cysteine-containing peptides
US4871535A (en) * 1986-10-24 1989-10-03 Gaf Corporation Compositions used in permanent structure altering of hair
JPH04193821A (ja) * 1990-11-27 1992-07-13 Takeo Kaneko 養毛化粧料
US5663304A (en) * 1993-08-20 1997-09-02 Genentech, Inc. Refolding of misfolded insulin-like growth factor-I
EP0725797B1 (fr) * 1993-10-25 2001-01-10 National Research Council Of Canada Inhibiteurs bivalents de thrombine
USH1480H (en) * 1993-12-09 1995-09-05 The Procter & Gamble Company Methods of using dyphylline for the promotion of hair growth
US5910435A (en) * 1996-07-25 1999-06-08 Wisconsin Alumni Research Foundation Method of folding proteins with synthetic dithiol catalysts
FR2769217B1 (fr) * 1997-10-03 2000-03-17 Oreal Composition oxydante et utilisations pour la teinture, pour la deformation permanente ou pour la decoloration des fibres keratiniques
US6703480B1 (en) * 1999-11-24 2004-03-09 Palani Balu Peptide dimers as agonists of the erythropoientin (EPO) receptor, and associated methods of synthesis and use
MXPA03003576A (es) * 2000-11-27 2003-10-14 Rmf Dictagene Sa Procedimiento para plegar polipeptidos sintetizados quimicamente.
ATE336226T1 (de) * 2002-07-05 2006-09-15 Unilever Nv Haarbehandlungszusammensetzungen mit xanthin und alpha-hydroxysäure
JP2004269430A (ja) * 2003-03-10 2004-09-30 Ichimaru Pharcos Co Ltd 毛髪処理用組成物及び損傷毛用毛髪化粧料
JP4343953B2 (ja) * 2003-05-29 2009-10-14 ユニリーバー・ナームローゼ・ベンノートシヤープ ヘアトリートメント組成物
FR2878435B1 (fr) * 2004-11-26 2009-04-03 Oreal Procede de defrisage des fibres keratiniques avec un moyen de chauffage et un agent denaturant
DE102005003949A1 (de) * 2005-01-27 2005-08-04 Alcina Cosmetic Dr. Kurt Wolff Gmbh & Co. Kg Coffeinhaltiges Mittel zur Aktivierung der Haarwurzeln

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