WO2001032196A1 - Secretin fragments for treating autism - Google Patents

Secretin fragments for treating autism Download PDF

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Publication number
WO2001032196A1
WO2001032196A1 PCT/EP2000/010847 EP0010847W WO0132196A1 WO 2001032196 A1 WO2001032196 A1 WO 2001032196A1 EP 0010847 W EP0010847 W EP 0010847W WO 0132196 A1 WO0132196 A1 WO 0132196A1
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Prior art keywords
leu
gly
ser
gln
thr
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PCT/EP2000/010847
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German (de)
French (fr)
Inventor
Artur Frank
Karl Jordan
Wilfried Hiebl
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Goldham Pharma Gmbh
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Priority to AU10280/01A priority Critical patent/AU1028001A/en
Publication of WO2001032196A1 publication Critical patent/WO2001032196A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/645—Secretins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the use of certain secret fragments in the diagnosis and treatment or prevention of autism and autism-like symptoms.
  • Secretin is a hormone that is secreted by the mucosa of the duodenum and jejunum.
  • the amino acid sequence of the secretin is known and corresponds to the following in the three-letter code:
  • the stereochemical configuration of the native version is L. for each of the optically active amino acid residues.
  • Secretm stimulates the pancreatic secretion of water and bicarbonate. Secretm stimulates peptic secretion in the stomach and in particular inhibits gastric release stimulated by food.
  • Autism is a relatively profound developmental disorder, which is based on complex disorders of the central nervous system - especially in the area of perceptual processing - and which begins in childhood. At its center is a serious relationship and communication disorder. The effects of the disorder hinder relationships with the environment, participation in community life and the ability to integrate into society in a variety of ways, since cognitive as well as linguistic, motor, emotional and interactional functions are affected.
  • autistic disorder differs in their degree of expression. People with autism often have problems eating and sleeping from the age of suckling and develop self-stimulating behaviors. Such behavior can even lead to personal injury. In particular, it is observed that autistic people compulsively insist on very specific orders. Many autistic people also have no awareness of the dangers.
  • fragments of a larger peptide with pharmacological effects do not necessarily have the same or even similar pharmacological properties.
  • DE 27 35 712 AI reports that a specific secret fragment with at least 14 amino acids should have valuable pharmacological properties, which is why this fragment is said to be suitable, for example, as a gastric antisecretory agent.
  • this special activity was surprising, since one could not generally expect any biological activity for fragments of the secretin.
  • fragments of secretin regardless of their origin (human, pig, chicken, monkey), which have 4-15 ammosaur structures of the native secretin consisting of 27 amino acids, are particularly suitable in a preparation for the treatment or prevention of autism to have.
  • This observation is surprising in several respects, since on the one hand no fragile acological effectiveness was to be expected from the fragments and on the other hand a special effectiveness in the treatment of autism is surprising.
  • Certain fragments of secretin are very particularly preferred, which otherwise do not match the fragment described in DE 27 35 712 A1. These fragments are described in more detail below under their abbreviations (A), (B), (C), (D), (E), (F), (G), (H), (I) and (J).
  • each of the optically active amino acid residues can be D, L or DL independently of one another, it being preferred that this is L in each case.
  • ammosaic sequence is given from left to right from the N-termmus to the C-term ushm.
  • the invention thus relates to a pharmaceutical composition which comprises at least one peptide fragment selected from the group (A), (B), (C), (D), (E), (F), (G), (H) , (I) and (J).
  • a pharmaceutical composition which comprises at least one peptide fragment selected from the group (A), (B), (C), (D), (E), (F), (G), (H) , (I) and (J).
  • mixtures of the abovementioned peptides can also be present, for example mixtures of the peptides (A), (B), (C), (D), (E), (F), (G), (H), (I) and (J), in particular the mixtures (A), (B) or (A), (C) or (C), (D) or (C), (D), (E), (F) or (E ), (F), (G), (H) or (F), (G), (H), (I) etc.
  • the invention also relates to peptide fragments which result from the ammosaic sequence of the secretion in pigs. This sequence corresponds to the following in the three-letter code:
  • Schwemesekretm differs from human secretin in that 15 and 16 other amino acids are present in the amino acid positions (Asp and Ser).
  • Peptide fragments according to the invention are therefore also those peptides which have the amino acid positions 1 to 4, 1 to 5, 1 to 6, 1 to 7 and 1 to 8 or 20 to 27, 21 to 27, 22 to 27, 23 to 27 and 24 to 27 correspond to the above sequence.
  • the fragments according to the invention can be obtained in a simple manner from the naturally occurring secret of human or animal origin.
  • the structure of the peptide chain from the individual building blocks also lends itself. Methods for the construction of peptides are generally known, for example by means of an automatic peptide synthesizer " . Methods for the production of such peptides are disclosed, inter alia, in DE 27 35 712 A1.
  • acid addition salts can be derived from a large number of inorganic and organic acids, such as, for example, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfamic acid, citric acid, lactic acid, pyruvic acid, oxalic acid, maleic acid, succinic acid, acetic acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tarta
  • preparations according to the invention can be administered in a wide variety of ways, for example intravenously, but also orally, intramuscularly, intra-articularly, intradermally, subcutaneously, rectally and by inhalation or nasal administration.
  • Usual dosages of the compounds according to the invention are 1 to 1000 ⁇ g / kg (body weight) per day.

Abstract

The invention relates to pharmaceutical compositions containing certain secretin fragments that are particularly suitable for diagnosing and treating autism. Said pharmaceutical compositions preferably contain at least one of the peptides of formulae: His-Ser-Asp-Gly-Thr-Phe-Thr-Ser (A), His-Ser-Asp-Gly-Thr-Phe-Thr (B), His-Ser-Asp-Gly-Thr-Phe (C), His-Ser-Asp-Gly-Thr (D), His-Ser-Asp-Gly-(E), Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val (F), Arg-Leu-Leu-Gln-Gly-Leu-Val (G), Leu-Leu-Gln-Gly-Leu-Val (H), Leu-Gln-Gly-Leu-Val (I) and Gln-Gly-Leu-Val (J).

Description

SECRETINFRAGMENTE ZUR BEHANDLUNG VON AUTI SMUS SECRET FRAGMENTS FOR TREATING AUTI SMUS
Die vorliegende Erfindung betrifft die Verwendung bestimmter Secretmfragmente bei der Diagnostik und Behandlung bzw. Prävention von Autismus und autismusahnlichen Erscheinungen.The present invention relates to the use of certain secret fragments in the diagnosis and treatment or prevention of autism and autism-like symptoms.
Sekretin ist ein Hormon, das durch die Mucosa des Duodenums und Jejunums abgeschieden wird. Die Aminosauresequenz des Secretins ist bekannt und entspricht im Dreibuchstabencode dem Folgenden:Secretin is a hormone that is secreted by the mucosa of the duodenum and jejunum. The amino acid sequence of the secretin is known and corresponds to the following in the three-letter code:
H-His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-H-His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu
1 2 3 4 5 6 7 8 9 Leu-Ser-Arg-Leu-Arg-Glu-Gly-Ala-Arg-1 2 3 4 5 6 7 8 9 Leu-Ser-Arg-Leu-Arg-Glu-Gly-Ala-Arg-
10 11 12 13 14 15 16 17 18 Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH2 10 11 12 13 14 15 16 17 18 Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH 2
19 20 21 22 23 24 25 26 2719 20 21 22 23 24 25 26 27
Die stereochemische Konfiguration der nativen Version ist bei jedem der optisch aktiven Ammosaurereste L.The stereochemical configuration of the native version is L. for each of the optically active amino acid residues.
Secretm stimuliert die pankreatische Sekretion von Wasser und Bicarbonat. Im Magen stimuliert Secretm die Pepsmsekre- tion und inhibiert insbesondere die durch Nahrungsmittel stimulierte Gastnnfreisetzung.Secretm stimulates the pancreatic secretion of water and bicarbonate. Secretm stimulates peptic secretion in the stomach and in particular inhibits gastric release stimulated by food.
In jüngster Zeit ist verschiedentlich berichtet worden, dass Secretm als Therapeutikum bei der Behandlung von Autismus eingesetzt werden kann, wobei vorzugsweise an die intravenöse Verabreichung von hohen Secret dosen gedacht wird (vgl. sb. WO 98/52593) .There have been various reports recently that Secretm can be used as a therapeutic in the treatment of autism, preferably intravenously Administration of high secret doses is thought (see sb. WO 98/52593).
Autismus ist eine relativ tiefgreifende Entwicklungsstorung, der komplexe Störungen des zentralen Nervensystems zugrunde- liegen - insbesondere im Bereich der Wahrnehmungsverarbeitung - und die bereits im Kindesalter beginnt. In ihrem Zentrum steht eine schwere Beziehungs- und Kommunikationsstorung. Die Auswirkungen der Störung behindern auf vielfaltige Weise die Beziehungen zur Umwelt, die Teilnahme am Leben in der Gemeinschaft und die Fähigkeit zur Eingliederung m die Gesellschaft, da sowohl kognitive als auch sprachliche, motorische, emotionale und teraktionale Funktionen betroffen sind.Autism is a relatively profound developmental disorder, which is based on complex disorders of the central nervous system - especially in the area of perceptual processing - and which begins in childhood. At its center is a serious relationship and communication disorder. The effects of the disorder hinder relationships with the environment, participation in community life and the ability to integrate into society in a variety of ways, since cognitive as well as linguistic, motor, emotional and interactional functions are affected.
Dazu kommen zahlreiche Verhaltensauffalligkeiten, die besonders für die Bezugsperson im alltäglichen Umgang mit den au- tistischen Menschen sehr belastend sein können. Autistische Menschen sind in der Regel mehrfach behindert.There are also numerous behavioral problems, which can be particularly stressful for the caregiver in everyday dealings with autistic people. Autistic people are usually disabled several times.
Nach der internationalen Klassifikation der Erkrankungen der Weltgesundheitsorganisation werden, neben dem frühen Beginn, folgende Kennzeichen als Def tionsmerkmale für insbesondere fruhk dlichen Autismus genannt:According to the international classification of diseases of the World Health Organization, in addition to the early onset, the following characteristics are mentioned as defining characteristics for particularly early autism:
1. Qualitative Beeinträchtigungen der zwischenmenschlichen Beziehungen;1. Qualitative impairments in interpersonal relationships;
2. Beeinträchtigungen der Kommunikation und der Fantasie;2. impaired communication and imagination;
3. Ein deutlich eingeschränktes Repertoire von Aktivitäten und Interessen.3. A clearly limited repertoire of activities and interests.
Beispielsweise beobachtet man bei Kindern mit Autismus, dass diese zunächst keine Geste, kein Lachein, kein Wort verstehen. Diese Kinder können zu anderen Personen, selbst zu den eigenen Eltern, kein normales Verhältnis herstellen. Anders ausgedruckt, diese Kinder ziehen sich m sich zurück und kapseln sich "autistisch" ab. Andererseits kann aber jede Veränderung der Umwelt der Kinder zu starken Erregungen fuhren. Kinder mit Autismus können insbesondere nicht "normal" spielen und sie benutzen ihr Spielzeug oft m immer gleicher zweckentfremdeter Art und Weise, wobei sie Stereotypien entwickeln: z . B. Drehen und Kreiseln von Radern, Rieseln mit Sand, Wedeln mit Faden oder Papier usw.For example, in children with autism, one observes that they initially do not understand a gesture, a smile or a word. These children cannot establish a normal relationship with other people, even with their own parents. In other words, these children withdraw and isolate themselves "autistically". On the other hand, any change in the environment of the children can lead to strong excitement. Children with autism, in particular, cannot play "normally" and they often use their toys in the same misused way, developing stereotypes: e.g. B. turning and spinning wheels, trickling with sand, wagging with thread or paper, etc.
Die wichtigsten Symptome der autistischen Störung sind in ihrem Auspragungsgrad jeweils unterschiedlich. Menschen mit Autismus haben häufig vom Saugl gsalter an Probleme beim Essen und Schlafen und entwickeln selbststimulierende Verhaltensweisen. Solche Verhaltensweisen können sogar zu Eigen- verletzungen fuhren. Insbesondere wird beobachtet, dass Autisten zwanghaft auf ganz bestimmte Ordnungen bestehen. Viele Autisten haben auch kein Gefahrenbewusstsem.The most important symptoms of autistic disorder differ in their degree of expression. People with autism often have problems eating and sleeping from the age of suckling and develop self-stimulating behaviors. Such behavior can even lead to personal injury. In particular, it is observed that autistic people compulsively insist on very specific orders. Many autistic people also have no awareness of the dangers.
Die intellektuelle Begabung von Menschen mit Autismus ist sehr unterschiedlich. Sie reicht von geistiger Behinderung bis zu normaler Intelligenz, wobei einige Autisten erstaunliche Teilleistungen im Rechnen, technischen Disziplinen, der Musik und auf anderen Gebieten erbringen können.The intellectual talent of people with autism is very different. It ranges from intellectual disabilities to normal intelligence, with some autistic people performing astonishingly well in arithmetic, technical disciplines, music and other areas.
Trotz umfangreicher Forschungen gibt es bislang noch kein schlussiges Erklarungsmodell, das vollständig und überzeugend die Entstehungsursache der autistischen Störung belegen kann. Nach dem heutigen Stand ist Autismus nicht wirklich heilbar.Despite extensive research, there is still no conclusive explanation model that can fully and convincingly prove the cause of the autistic disorder. As of today, autism is not really curable.
Allerdings wird m der zuvor erwähnten WO 98/52593 berichtet, dass die Behandlung autistischer Kinder mit Secretm vielversprechend ist. Dieses Dokument behauptet insbesondere einen Zusammenhang zwischen bestimmten gastromtenstmalen Fehlfunktionen bei autistischen Kindern und dem Emfluss von Secretm auf Hirnzellen. So wird beispielsweise festgehalten, dass Secretm sowohl bei der Behandlung gastrointenstmaler Fehlfunktion bestimmter Autismusformen bei Kindern erfolgreich ist. Insbesondere zeigt sich bei der Behandlung autistischer Kinder mit chronischer Diarrho, dass es nach einer Injektion von Secretm zu einer beträchtlichen Steigerung der Flussigkeitsproduktion durch den Pankreas kam. Bei weitergehenden klinischen Untersuchungen wurden dann auffällige Verhaltensverbesserungen festgestellt. Die Verabreichung des Secretins führte aber nicht zu einer Steigerung der Eigenproduktion, sondern es wurde eine vermehrte Serotoninproduktion festgestellt.However, it is reported in the previously mentioned WO 98/52593 that the treatment of autistic children with Secretm is promising. In particular, this document asserts a relationship between certain gastric malfunctions in autistic children and the flow of Secretm to brain cells. For example, it is noted that Secretm is successful in treating gastrointestinal malfunction of certain forms of autism in children. In particular, treatment of autistic children with chronic diarrhea shows that there was a significant increase in pancreatic fluid production after Secretm injection. In further clinical examinations, noticeable improvements in behavior were found. However, administration of the secretin did not lead to an increase in in-house production, but an increased serotonin production was found.
Neben diesen Befunden ist aber nicht bekannt, was die Wirksamkeit des Secretins tatsächlich ausmacht, d.h. welche Mechanismen mvolviert sind bzw. welche Wechselwirkungen oder Sekundarwirkungen (beispielsweise Serotonmausschuttung) für die beobachteten Wirkungen verantwortlich sind.In addition to these findings, it is not known what actually makes Secretins effective, i.e. which mechanisms are involved or which interactions or secondary effects (e.g. serotonin secretion) are responsible for the observed effects.
Herauszustellen ist m diesem Zusammenhang, daß im Stand der Technik bei der Autismusbehandlung lediglich das Peptid mit mindestens 27 Ammosaurebaustemen eingesetzt wurde. Die Verwendung von Fragmenten gleich welcher Große wird nicht erwogen.In this connection it should be emphasized that in the prior art only the peptide with at least 27 ammosaur building blocks was used in the treatment of autism. The use of fragments of any size is not considered.
Es ist allgemein anerkannt, dass Fragmente eines größeren Peptids mit pharmakologischen Wirkungen nicht zwangsläufig wieder gleiche oder auch nur ähnliche pharmakologische Eigenschaften haben. So wird in der DE 27 35 712 AI berichtet, dass ein bestimmtes Secretmfragment mit mindestens 14 Aminosäuren wertvolle pharmakologische Eigenschaften haben soll, weshalb sich dieses Fragment beispielsweise als gastrisches antisekretorisches Mittel eignen soll. Im Zusammenhang mit der Darstellung dieses Fragments wurde aber auch festgehalten, dass diese spezielle Wirksamkeit überraschend sei, da man keinerlei biologische Wirksamkeit für Fragmente des Secretins allgemein erwarten konnte. Es wurde nun überraschend festgestellt, daß Fragmente des Secretins, gleich welcher Herkunft (Mensch, Schwein, Huhn, Affe), die 4 - 15 Ammosaurebausteme des aus 27 Aminosäuren bestehenden nativen Secretins aufweisen, eine besondere Eignung m einer Praparation zur Behandlung oder Prävention des Autismus haben. Diese Beobachtung ist in mehrfacher Hinsicht überraschend, da einerseits von den Fragmenten generell keine phar akologiscne Wirksamkeit zu erwarten war und andererseits eine spezielle Wirksamkeit bei der Behandlung des Autismus überraschend ist.It is generally accepted that fragments of a larger peptide with pharmacological effects do not necessarily have the same or even similar pharmacological properties. For example, DE 27 35 712 AI reports that a specific secret fragment with at least 14 amino acids should have valuable pharmacological properties, which is why this fragment is said to be suitable, for example, as a gastric antisecretory agent. In connection with the representation of this fragment, however, it was also stated that this special activity was surprising, since one could not generally expect any biological activity for fragments of the secretin. It has now surprisingly been found that fragments of secretin, regardless of their origin (human, pig, chicken, monkey), which have 4-15 ammosaur structures of the native secretin consisting of 27 amino acids, are particularly suitable in a preparation for the treatment or prevention of autism to have. This observation is surprising in several respects, since on the one hand no fragile acological effectiveness was to be expected from the fragments and on the other hand a special effectiveness in the treatment of autism is surprising.
Bevorzugt werden insbesondere solche Fragmente des Secretins, die 4 - 8 Ammosaurebausteme der nativen Ammosauresequenz aufweisen.Those fragments of secretin which have 4-8 ammosaur building blocks of the native ammosaur sequence are particularly preferred.
Ganz besonders bevorzugt werden bestimmte Fragmente des Secretins, die im übrigen nicht mit den m der DE 27 35 712 AI beschriebenen Fragment übereinstimmen. Diese Fragmente werden im Folgenden unter deren Abkürzungen (A) , (B), (C) , (D), (E), (F), (G) , (H), (I) und (J) naher beschrieben.Certain fragments of secretin are very particularly preferred, which otherwise do not match the fragment described in DE 27 35 712 A1. These fragments are described in more detail below under their abbreviations (A), (B), (C), (D), (E), (F), (G), (H), (I) and (J).
Diese Peptidfragmente des Secretins haben jeweils die folgende Ammosauresequenz:These secretin peptide fragments each have the following ammosaur sequence:
His-Ser-Asp-Gly-Thr-Phe-Thr-Ser (A) His-Ser-Asp-Gly-Thr-Phe-Thr (B) His-Ser-Asp-Gly-Thr-Phe (C) His-Ser-Asp-Gly-Thr (D) His-Ser-Asp-Gly (E)His-Ser-Asp-Gly-Thr-Phe-Thr-Ser (A) His-Ser-Asp-Gly-Thr-Phe-Thr (B) His-Ser-Asp-Gly-Thr-Phe (C) His- Ser-Asp-Gly-Thr (D) His-Ser-Asp-Gly (E)
Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val (F) Arg-Leu-Leu-Gln-Gly-Leu-Val (G) Leu-Leu-Gln-Gly-Leu-Val (H) Leu-Gln-Gly-Leu-Val (I) und Gln-Gly-Leu-Val (J) Die stereochemische Konfiguration von jedem der optisch aktiven Ammosaurereste kann unabhängig voneinander D, L oder DL sein, wobei bevorzugt wird, dass diese jeweils L ist.Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val (F) Arg-Leu-Leu-Gln-Gly-Leu-Val (G) Leu-Leu-Gln-Gly-Leu-Val (H) Leu- Gln-Gly-Leu-Val (I) and Gln-Gly-Leu-Val (J) The stereochemical configuration of each of the optically active amino acid residues can be D, L or DL independently of one another, it being preferred that this is L in each case.
Die Ammosauresequenz ist von links nach rechts vom N- Termmus zum C-Term us hm angegeben.The ammosaic sequence is given from left to right from the N-termmus to the C-term ushm.
Gegenstand der Erfindung ist somit eine pharmazeutische Zusammensetzung, die mindestens ein Peptidf ragment, ausgewählt aus der Gruppe (A) , (B) , (C) , (D) , (E) , (F), (G) , (H) , (I) und (J) umfasst. Selbstverständlich können aber auch Mischungen der vorstehend genannten Peptide vorliegen, oeispielsweise Mischungen der Peptide (A) , (B) , (C) , (D) , (E) , (F) , (G) , (H) , (I) und (J), insbesondere die Mischungen (A) , (B) oder (A) , (C) oder (C) , (D) oder (C) , (D) , (E) , (F) oder (E), (F), (G) , (H) oder (F), (G) , (H) , (I) usw.The invention thus relates to a pharmaceutical composition which comprises at least one peptide fragment selected from the group (A), (B), (C), (D), (E), (F), (G), (H) , (I) and (J). Of course, mixtures of the abovementioned peptides can also be present, for example mixtures of the peptides (A), (B), (C), (D), (E), (F), (G), (H), (I) and (J), in particular the mixtures (A), (B) or (A), (C) or (C), (D) or (C), (D), (E), (F) or (E ), (F), (G), (H) or (F), (G), (H), (I) etc.
Gegenstand der Erfindung sind auch Peptidf ragmente, die sich aus der Ammosauresequenz des Sekretms beim Schwein ergeben. Diese Sequenz entspricht im Dreibuchstabencode dem Folgenden:The invention also relates to peptide fragments which result from the ammosaic sequence of the secretion in pigs. This sequence corresponds to the following in the three-letter code:
H-His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-H-His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu
1 2 3 4 5 6 7 8 9 Leu-Ser-Arg-Leu-Arg-Asp-Ser-Ala-Arg-1 2 3 4 5 6 7 8 9 Leu-Ser-Arg-Leu-Arg-Asp-Ser-Ala-Arg-
10 11 12 13 14 15 16 17 18 Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH2 10 11 12 13 14 15 16 17 18 Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH 2
19 20 21 22 23 24 25 26 2719 20 21 22 23 24 25 26 27
Das Schwemesekretm unterscheidet sich vom menschlichen Sekretin dadurch, daß in den Ammosaurepositionen 15 und 16 andere Aminosäuren vorliegen (Asp und Ser) . Erfmdungsgemäße Peptidfragmente sind somit auch solche Peptide, die den Ammosaurepositionen 1 bis 4, 1 bis 5, 1 bis 6, 1 bis 7 und 1 bis 8 bzw. 20 bis 27, 21 bis 27, 22 bis 27, 23 bis 27 und 24 bis 27 der vorstehenden Sequenz entsprechen. Die erfmdungsgemaßen Fragmente können m einfacher Weise aus dem naturlich vorkommenden Secretm menschlicher oder tierischer Herkunft gewonnen werden. Daneben bietet sich aber auch der Aufbau der Peptidkette aus den einzelnen Bausteinen an. Verfahren zum Aufbau von Peptiden sind allgemein geläufig, beispielsweise mittels eines automatischen Peptidsynthetisators". Verfahren zur Herstellung solcher Peptide werden unter anderem m der DE 27 35 712 AI offenbart .Schwemesekretm differs from human secretin in that 15 and 16 other amino acids are present in the amino acid positions (Asp and Ser). Peptide fragments according to the invention are therefore also those peptides which have the amino acid positions 1 to 4, 1 to 5, 1 to 6, 1 to 7 and 1 to 8 or 20 to 27, 21 to 27, 22 to 27, 23 to 27 and 24 to 27 correspond to the above sequence. The fragments according to the invention can be obtained in a simple manner from the naturally occurring secret of human or animal origin. In addition, the structure of the peptide chain from the individual building blocks also lends itself. Methods for the construction of peptides are generally known, for example by means of an automatic peptide synthesizer " . Methods for the production of such peptides are disclosed, inter alia, in DE 27 35 712 A1.
Neben den Peptiden der vorstehend gezeigten Sequenzen (A) bis (J) eignen sich für die erfmdungsgemaßen pharmazeutischen Zwecke selbstverständlich allgemein vertragliche Saureadditionssalze . Diese Saureadditionssalze können sich von einer Vielzahl von anorganischen und organischen Sauren ableiten wie beispielsweise Schwefelsaure, Phosphorsaure, Salzsaure, Bromwasserstoffsaure, Jodwasserstoffsaure, Salpetersaure, Sulfammsaure, Zitronensaure, Milchsäure, Brenztraubensaure, Oxalsäure, Maleinsäure, Bernsteinsaure, Weinsäure, Zimtsaure, Essigsaure, Tπfluoressigsaure, Benzoesaure, Salicylsaure, Gluconsaure, Ascorbmsaure und verwandte Sauren, die zum Zwecke der Bildung pharmazeutisch vertraglicher Saureadditionssalze allgemein bekannt sind.In addition to the peptides of the sequences (A) to (J) shown above, it is of course generally suitable to use acid addition salts in the form of a contract for the pharmaceutical purposes according to the invention. These acid addition salts can be derived from a large number of inorganic and organic acids, such as, for example, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfamic acid, citric acid, lactic acid, pyruvic acid, oxalic acid, maleic acid, succinic acid, acetic acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, acid; , Salicylic acid, gluconic acid, ascorbic acid and related acids, which are generally known for the purpose of forming pharmaceutically acceptable acid addition salts.
Die erfmdungsgemaßen Praparationen können auf verschiedenstem Weg verabreicht werden, beispielsweise intravenös aber auch oral, intramuskulär, intraartikular, intradermal, subkutan, rektal sowie durch Inhalation oder nasale Verabreichung.The preparations according to the invention can be administered in a wide variety of ways, for example intravenously, but also orally, intramuscularly, intra-articularly, intradermally, subcutaneously, rectally and by inhalation or nasal administration.
Übliche Dosierungen der erf dungsgemaßen Verbindungen sind 1 bis 1000 μg/kg (Korpergewicht) pro Tag.Usual dosages of the compounds according to the invention are 1 to 1000 μg / kg (body weight) per day.
Es bietet sich auch an, d e erfmdungsgemaßen Verbindungen mit anderen pharmazeutischen Tragerstoffen zu kombinieren, beispielsweise mit solche Stoffen, die zu einer verzögerten Freisetzung im Korper fuhren. It also makes sense to combine the compounds according to the invention with other pharmaceutical carriers, for example with those which lead to a delayed release in the body.

Claims

P a t e n t a n s p r ü c h e Patent claims
1. Pharmazeutische Zusammensetzung enthaltend mindestens em 4 - 15 Aminosäuren umfassendes Peptidfragment des Secretins .1. Pharmaceutical composition containing at least one peptide fragment of secretin comprising 4 to 15 amino acids.
2. Pharmazeutische Zusammensetzung nach Anspruch 1, dadurch gekennzeichnet, daß das Peptid 4 - 8 Aminosäuren umfaßt.2. Pharmaceutical composition according to claim 1, characterized in that the peptide comprises 4-8 amino acids.
3. Pharmazeutische Zusammensetzung nach einem der vorstehenden Ansprüche enthaltend mindestens em Peptid der folgenden Formel:3. Pharmaceutical composition according to one of the preceding claims containing at least one peptide of the following formula:
His-Ser-Asp-Gly-Thr-Phe-Thr-Ser (A) His-Ser-Asp-Gly-Thr-Phe-Thr (B) His-Ser-Asp-Gly-Thr-Phe (C) His-Ser-Asp-Gly-Thr (D) His-Ser-Asp-Gly (E)His-Ser-Asp-Gly-Thr-Phe-Thr-Ser (A) His-Ser-Asp-Gly-Thr-Phe-Thr (B) His-Ser-Asp-Gly-Thr-Phe (C) His- Ser-Asp-Gly-Thr (D) His-Ser-Asp-Gly (E)
Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val ( F) Arg-Leu-Leu-Gln-Gly-Leu-Val (G) Leu-Leu-Gln-GIy-Leu-Val (H) Leu-Gln-Gly-Leu-Val (I) und Gln-Gly-Leu-Val (J)Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val (F) Arg-Leu-Leu-Gln-Gly-Leu-Val (G) Leu-Leu-Gln-GIy-Leu-Val (H) Leu- Gln-Gly-Leu-Val (I) and Gln-Gly-Leu-Val (J)
4. Pharmazeutiscne Zusammensetzung nach Anspruch 3, dadurch gekennzeichnet, daß sie zummdestens em Peptid der Peptide (A) , (B) , (C), (D) und (E) enthalt.4. Pharmaceutical composition according to claim 3, characterized in that it contains at least one peptide of peptides (A), (B), (C), (D) and (E).
5. Zusammensetzung nach Anspruch 3, dadurch gekennzeichnet, dass sie zumindest em Peptid der Peptide (F), (G) , (H) , (I) und (J) enthalt.5. Composition according to claim 3, characterized in that it contains at least one peptide of peptides (F), (G), (H), (I) and (J).
6. Zusammensetzung nach einem der vorstehenden Ansprüche, dadurch gekennzeichnet, dass die stereochemische Konfiguration der Ammosaurereste der Peptide jeweils L ist. 6. Composition according to one of the preceding claims, characterized in that the stereochemical configuration of the amino acid residues of the peptides is in each case L.
7. Zusammensetzung nach einem der vorstehenden Ansprüche, dadurch gekennzeichnet, daß die oder das Peptid/e als Saureadditionssalz vorliegen.7. Composition according to one of the preceding claims, characterized in that the or the peptide (s) are present as an acid addition salt.
8. Verwendung zumindest eines Peptids wie m einem der vorstehenden Ansprüche definiert zur Behandlung von Autismus 8. Use of at least one peptide as defined in any one of the preceding claims for the treatment of autism
PCT/EP2000/010847 1999-11-05 2000-11-03 Secretin fragments for treating autism WO2001032196A1 (en)

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US7820617B2 (en) 1998-05-20 2010-10-26 Biotempt B.V. Methods of selecting immunoregulator peptides obtained from gonadotropins
US8680059B2 (en) 1998-05-20 2014-03-25 Biotempt B.V. Oligopeptide acetate and formulations thereof
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US7786084B2 (en) 2001-12-21 2010-08-31 Biotempt B.V. Treatment of burns
US8216998B2 (en) 2001-12-21 2012-07-10 Biotempt B.V. Treatment of ischemic events
US8524665B2 (en) 2003-05-13 2013-09-03 The Mclean Hospital Corporation Use of secretin in treatments of disorders associated with the amygdala
US7662776B2 (en) 2005-07-05 2010-02-16 Biotempt B.V. Treatment of tumors using short peptides from human chorionic gonadotropin (HCG)
US7795226B2 (en) 2006-03-07 2010-09-14 Biotempt B.V. Control of radiation injury
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