DE4307883A1 - Use of anti-retroviral substances - to treat motor-neuronal diseases - Google Patents

Use of anti-retroviral substances - to treat motor-neuronal diseases

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DE4307883A1
DE4307883A1 DE19934307883 DE4307883A DE4307883A1 DE 4307883 A1 DE4307883 A1 DE 4307883A1 DE 19934307883 DE19934307883 DE 19934307883 DE 4307883 A DE4307883 A DE 4307883A DE 4307883 A1 DE4307883 A1 DE 4307883A1
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test number
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acid
ethyl
deoxy
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Martin-Egon Dr Med Westarp
Hans-Helmut Prof Dr Kornhuber
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WESTARP MARTIN-EGON DR MED 7900 ULM DE
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WESTARP MARTIN-EGON DR MED 7900 ULM DE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • 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
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
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    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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Abstract

Use of the named antiretroviral substances in the prepn. of medicaments for therapy of motorneuronal disorders is new. The antiretroviral substances are e.g. (a) azidothymidine, didesoxydidehydrothymidine, didesoxycytidine, didesoxyinosine, 3-deaza-adonosine, (+)- or (-) 2'-deoxy-3'-thiacytidine(3TC), 3TC-5'-triphoshate, racemic 2'-deoxy-3'-thiacytidine, fluorothymidine, trifluorothymidine, ribavirin, nevirapin-dipuridodiazepinone, TIBO cpds. with no. L697, L661 or R18893 and/or tetrahydro-, imidazo or benzodiazepinethione cpds. with no. R82913. USE/ADVANTAGE - The substances are useful in treatment of e.g. lateral sclerosis, or spinal muscle atrophy, which are almost always fatal.

Description

Die Erfindung bezieht sich auf die Verwendung anti­ retroviraler Substanzen gemäß dem Oberbegriff des Anspruches 1 zur Herstellung eines Arzneimittels.The invention relates to the use anti retroviral substances according to the generic term of Claim 1 for the manufacture of a medicament.

Zunächst zur Erläuterung der im Oberbegriff angege­ benen Verbindungen. Durch den Begriff "Azidothymidin" wird in chemischer Hinsicht eine Substanz bezeichnet, die sich als 3′-Azido-2′3′-Di­ desoxythymidin darstellt. Es handelt sich um ein Analogon des Thymidins, welches eines der vier in die DNS eingebauten Nukleoside darstellt. Dabei un­ terscheidet sich das Azidothymidin von Thymidin durch die Substitution der OH-Gruppe an der 3′- Stellung des Desoxyzuckers durch eine Azido-Gruppe. Diese Substanz trägt die INN-Bezeichnung Zidovudin. Sie ist bekannt und wird eingesetzt zur Bekämpfung des Aids-Virus (humanes Immundefekt-Virus = HIV) im Sinne einer Wachstums- und Vermehrungshemmung.First, to explain the specified in the preamble connections. By the term "Azidothymidine" becomes a chemically Substance referred to as 3'-azido-2'3'-di represents deoxythymidine. It's about a Analogue of thymidine, which is one of the four in represents the DNA incorporated nucleosides. Thereby un the azidothymidine differs from thymidine by the substitution of the OH group at the 3′- Position of the deoxy sugar by an azido group. This substance carries the INN name zidovudine. It is known and used to combat of the AIDS virus (human immunodeficiency virus = HIV) in Meaning of an inhibition of growth and propagation.

Die Wirkungsweise ist wie folgt: In der menschli­ chen Zelle wird das AZT (=Azidothymidin) mittels der zellulären Thymidin-Kinase durch Übertragung eines Phosphorsäurerestes in das AZT-Monophosphat überführt. Durch anschließende Thymidilat-Kinase erfolgt die Umwandlung in das Diphosphat und durch weitere Zellenzyme in das eigentlich wirksame Viro­ statikum, das AZT-Triphosphat.The mode of action is as follows: In human Chen cell is the AZT (= azidothymidine) by means of cellular thymidine kinase by transfer of a phosphoric acid residue in the AZT monophosphate transferred. By subsequent thymidilate kinase  it is converted into the diphosphate and by more cell enzymes in the actually effective Viro static, the AZT triphosphate.

Die reverse Transkriptase des HIV wird durch das AZT-Triphosphat kompetitiv gehemmt, so daß das ei­ gentliche Substrat, das Thymidin-Triphosphat von der reversen Transkriptase verdrängt wird. Einer­ seits wird hierdurch die Syntheseleistung dieses Enzyms reduziert, andererseits wird das AZT-Tri­ phosphat selbst in die DNS eingebaut. Aufgrund der Tatsache, daß an die Azidogruppe des AZT′s kein weiterer DNS-Baustein angehängt werden kann, führt dies zum Kettenabbruch. Auf diese Weise wird die Umschreibung der Retrovirus-RNS in Retrovirus-DNS verhindert, so daß kein komplettes Virus-Genom ent­ steht, das in das Erbgut der Zelle integriert wer­ den könnte. Damit wird die Zelle vor einer latenten Infektion geschützt und die Virusvermehrung ge­ stoppt.The reverse transcriptase of HIV is caused by the AZT triphosphate competitively inhibited, so that the egg generic substrate, the thymidine triphosphate of the reverse transcriptase is displaced. One on the one hand, the synthesis performance of this Enzyme is reduced, on the other hand the AZT-Tri phosphate itself built into the DNA. Due to the The fact that to the azido group of AZT's none additional DNS module can be added leads this to break the chain. In this way the Rewriting the retrovirus RNA into retrovirus DNA prevented so that no complete virus genome ent that is integrated into the cell's genetic makeup that could. This turns the cell into a latent one Protection against infection and the virus multiplication stops.

Die im Oberbegriff angegebene Stoffbezeichnung "Nevirapin-Dipyridodiazepinon" ist die Kurzbezeich­ nung der exakten, den Stoff beschreibenden chemi­ schen Formel:
6,11-dihydro-11-cyclopropyl-4-methyldipyrido(2,3- b:2′,3′-e) (1,4)diazepin-6-one.The substance name "Nevirapine Dipyridodiazepinon" given in the generic term is the short name of the exact chemical formula describing the substance:
6,11-dihydro-11-cyclopropyl-4-methyldipyrido (2,3-b: 2 ′, 3′-e) (1,4) diazepin-6-one.

Die angegebene Tetrahydro. Imidazo. Benzodiazepin (TIBO)-Verbindungen sind von komplexer chemischer Struktur und wurden deshalb nur mit ihren amtlichen Prüfnummern bezeichnet. Lediglich vertreten läßt sich bei der letzten angegebenen Struktur der Te­ trahydro. Imidazo. Benzodiazepinthion-Verbindung R82913 die chemische Formel anzugeben: (+)-(55) 4, 5, 6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2- butenyl)imidazo(4,5,1-jk) (1,4)benzodiazepin-2(1H)­ thione.The specified tetrahydro. Imidazo. Benzodiazepine (TIBO) compounds are of complex chemical Structure and were therefore only with their official Test numbers designated. Only represented the last structure of the Te trahydro. Imidazo. Benzodiazepinthion compound  R82913 state the chemical formula: (+) - (55) 4, 5, 6,7-tetrahydro-9-chloro-5-methyl-6- (3-methyl-2- butenyl) imidazo (4,5,1-jk) (1,4) benzodiazepin-2 (1H) thione.

Die verschiedenen Bisheteroarylpiperazine sind in ihrem chemischen Aufbau durch die nachfolgend ange­ gebenen Strukturformeln wiedergegeben. Zur Erläute­ rung ist anzumerken, daß der Buchstabe E die Abkür­ zung für den Ester der entsprechenden Verbindung bedeutet.The different bisheteroarylpiperazines are in their chemical structure by the following given structural formulas. To explain It should be noted that the letter E is the abbreviation for the ester of the corresponding compound means.

In Worten ist die Verbindung mit der Prüfnummer U- 88204 wie folgt zu charakterisieren:
(1-(3-(1-isopropylamino)-2-pyridinyl)-4-(1-H-indol- 2-yl)carbonyl)piperazin).In words, the connection with the test number U- 88204 can be characterized as follows:
(1- (3- (1-isopropylamino) -2-pyridinyl) -4- (1-H-indol-2-yl) carbonyl) piperazine).

Die Substanz mit der Prüfnummer U-80493-E charakte­ risiert sich als N-ethyl-2-(4-((4-methoxy-3,5-dime­ thylphenyl)methyl)-1-piperazinyl)-3-pyridinamin.The substance with the test number U-80493-E character It turns out to be N-ethyl-2- (4 - ((4-methoxy-3,5-dime thylphenyl) methyl) -1-piperazinyl) -3-pyridinamine.

Die Prüfsubstanz mit der Nummer U-75875 meint im Sinne der Erfindung eine chemische Substanz mit der Formel:
N-(N-(N-(N-(1-naphthoxyacethyl)-5-amino-3,4,-dihy­ droxy-2-isobuthyl-7-methyloctanoyl)isoleucyl)-2-py­ ridylmethylamin. Die Strukturformel der Substanz mit der Prüfnummer U-75875 ist wie folgt:For the purposes of the invention, the test substance with the number U-75875 means a chemical substance with the formula:
N- (N- (N- (N- (1-naphthoxyacethyl) -5-amino-3,4, -dihydroxy-2-isobuthyl-7-methyloctanoyl) isoleucyl) -2-pyridylmethylamine. The structural formula of the substance with the test number U-75875 is as follows:

Die identische Struktur läßt sich ebenfalls be­ schreiben durch die chemische Zusammensetzung:
N-naphthoxyacethyl-His-(55)-amino-6-cyclohexyl- (3R,4R)-dihydroxy-(2R)-isopropylhexanoyl-Ile-Amp. The identical structure can also be described by the chemical composition:
N-naphthoxyacethyl-His- (55) -amino-6-cyclohexyl- (3R, 4R) -dihydroxy- (2R) -isopropylhexanoyl-Ile amp.

Als Nachbarverbindungen sollen ausdrücklich jene Substanzen, bei welchen der 1-naphthoxyacetyl-Rest durch einen Phenoxyacetyl-Rest ersetzt ist, so daß die chemische Formel nunmehr lautet
Phenoxyacetyl-His-(5S)-amino-6-cyclohexyl-(3R,4R)­ dihydroxy-(2R)-isopropylhexanoyl-Ile-Amp.Those compounds in which the 1-naphthoxyacetyl radical is replaced by a phenoxyacetyl radical are expressly to be considered as neighboring compounds, so that the chemical formula is now
Phenoxyacetyl-His- (5S) -amino-6-cyclohexyl- (3R, 4R) dihydroxy- (2R) -isopropylhexanoyl-Ile amp.

Zur Klarstellung ist anzumerken, daß die mit der Bezeichnung 3-Mercapto-D-valin bezeichnete Substanz mitunter als (D-)Penicillamin ebenso wie die Sub­ stanz Ammonium-5-tungsto-2-antimoniat als Hetero- Poly-Anion 23 bezeichnet wird.For clarification, it should be noted that those with the Name 3-Mercapto-D-valine designated substance sometimes as (D-) penicillamine as well as the sub punch ammonium-5-tungsto-2-antimoniate as hetero- Poly-anion 23 is called.

Die ausführliche Formel der mit Isoquinolin-Pro­ teaseinhibitor Ro-31-8959 bezeichneten Substanz ist Quinolin-2-carbonyl-Asn-Phehydroxyethylamin (CHOH in R-Konfiguration)-(4aS,8aS)-decahydro-3(S)-isoquino­ lincarbonyl.NH-tert-butyl, deren Kurzschreibweise Qc.Asn-Phe.ψ-(CH(OH)CH2N)DIQ.NHtBu lautet. Die Strukturformel ist:The detailed formula of the substance designated with isoquinoline protease inhibitor Ro-31-8959 is Quinolin-2-carbonyl-Asn-Phehydroxyethylamin (CHOH in R configuration) - (4aS, 8aS) -decahydro-3 (S) -isoquino lincarbonyl. NH-tert-butyl, whose shorthand is Qc.Asn-Phe.ψ- (CH (OH) CH 2 N) DIQ.NH t Bu. The structural formula is:

Die Nachbarverbindung, bei der das Dekahydroisoqui­ nolincarbonyl durch Piperidin-2(S)-carbonyl ersetzt ist, trägt demnach die Kurzbezeichnung QC.Asn.Phe.ψ (CH(OH)CH2N)PIC.NHtBu. Bei jenem Derivat bei dem die Übergangshydroxylgruppe in S-Konformation ange­ ordnet ist, ist die Kurzbezeichnung der Substanz Ac-Ser-Leu-Asn-Phe.ψ(CH(OH) CH2N)Pro-Ile-Val-OMe.The neighboring compound in which the decahydroisoquinoline carbonyl is replaced by piperidine-2 (S) -carbonyl therefore has the short name QC.Asn.Phe.ψ (CH (OH) CH 2 N) PIC.NH t Bu. In the case of the derivative in which the transition hydroxyl group is arranged in the S conformation, the short name of the substance is Ac-Ser-Leu-Asn-Phe.ψ (CH (OH) CH 2 N) Pro-Ile-Val-OMe.

Schließlich wird mitunter die Verbindung N-Ace­ tylcystein (NAC) auch als (R)-2-Acetamido-3-mercap­ topropionsäure und Pentoxifyllin als 1-(5-Oxo­ hexyl)theobromin bezeichnet. Das Trichosanthin ist ein Compound-Q aus chinesischen Kürbispflanzen Tri­ chosanthes kirilowii, mit der Prüfnummer GLQ-223. Die Substanz 2-(Benzoxazol-2-yl)ethyl-5-ethyl-6-me­ thylpyridin-2(1H)-one ist die Prüfsubstanz L- 696229. Das Semi-naphthoquinon mit der Prüfnummer A-80915A ist aus Streptomyces aculeolatus gewonnen.Eventually the connection becomes N-Ace tylcysteine (NAC) also as (R) -2-acetamido-3-mercap topropionic acid and pentoxifylline as 1- (5-oxo hexyl) theobromine. The trichosanthin is a compound Q from Chinese pumpkin plants Tri chosanthes kirilowii, with the test number GLQ-223. The substance 2- (benzoxazol-2-yl) ethyl-5-ethyl-6-me thylpyridin-2 (1H) -one is the test substance L- 696229. The semi-naphthoquinone with the test number A-80915A is derived from Streptomyces aculeolatus.

Motorneuron-Erkrankungen sowie ihre Unterformen als amyotrophe Lateralsklerose (ALS), spinale Muskel­ atrophie und progressive Bulbärparalyse stellen eine Erkrankungsgruppe dar, die nicht wirksam be­ handelbar oder schon gar nicht heilbar ist und des­ halb immer mit dem Tod enden.Motor neuron diseases and their sub-forms as amyotrophic lateral sclerosis (ALS), spinal muscle atrophy and progressive bulbar paralysis is a group of diseases that are not effective is tradable or not curable at all and des half always end with death.

Hiervon ausgehend hat sich die Erfindung die Her­ stellung eines Arzneimittel zur Bekämpfung motor­ neuronaler Erkrankungen zur Aufgabe gemacht. Es fanden sich im Blut von Motorneuronalpatienten er­ höhte Reaktivitäten gegen retrovirale Elemente wie Humane Spuma Retroviren.Proceeding from this, the invention has the Her provision of a drug to combat motor neuronal diseases. It were found in the blood of motor neuronal patients increased reactivities against retroviral elements such as Human spuma retroviruses.

Gelöst wird diese Aufgabe durch die im Anspruch l angegebenen Merkmale. This problem is solved by the in claim l specified characteristics.  

Der Begriff "Antiretrovirale Substanz" umfaßt gemäß üblicher Terminologie die reversen Transkriptase- Hemmer als auch, als Teilmenge hiervon, die nukleo­ sidanalogen Substanzen. Die Wirkung der nukleo­ sianalogen Retrovirostatika besteht damit in der Hemmung der reversen Transkriptase. Andere der Sub­ stanzen sind hinsichtlich ihres Wirkprinzipes Inhi­ bitoren des tat-(transcriptional activator trans­ acting), bei der eine Hemmung der reversen Tran­ skriptase nicht zwingend vorliegen muß. Eine wei­ tere Gruppe antiretroviralen Substanzen stellen die Protease-Inhibitoren dar, die nicht über die re­ verse Transkriptase wirken. Andere der im Oberbe­ griff genannten antiretroviralen Substanzen haben in klinischen Untersuchungen Wirkungen gegen HIV gezeigt.The term "antiretroviral substance" accordingly includes common terminology the reverse transcriptase Inhibitors as well, as a subset thereof, the nucleo side-analog substances. The effect of the nucleo sianalogue retrovirostatics therefore exists in the Inhibition of reverse transcriptase. Others of the sub punching are Inhi based on their active principle tat- (transcriptional activator trans acting), in which an inhibition of the reverse Tran scriptase does not have to be present. A white The third group of antiretroviral substances represent the Protease inhibitors that do not have the right verse transcriptase act. Others in the Oberbe handle called antiretroviral substances effects against HIV in clinical studies shown.

Ausgangspunkt vorliegender Überlegungen war die auf den Erfinder zurückgehende Erkenntnis, daß Antikör­ per gegen humane Retroviren bei amyotropher Late­ ralsklerose (ALS) -Patienten vermehrt auftreten, hierbei insbesondere der humane Spuma-Retrovirus (HSRV) und Visna-Virus, das ebenfalls humaninfek­ tiös ist, des weiteren sind die zirkulierenden Im­ munkomplexe bei amyotropher Lateralsklerose (ALS)- Patienten oft und stark erhöht. Diese Erkenntnisse gehen unmittelbar auf den Erfinder zurück und sind in sich in der Vorbereitungsphase zur Veröffentli­ chung befindenden wissenschaftlichen Artikeln nie­ dergelegt. Als Fundstellen werden angegeben:
Westarp ME et al.: Human spuma retrovirus antibo­ dies in patients with amyotrophic lateral sclero­ sis, Neurol Psychiatr Brain Res 1992
Westarp ME et al.: Retroviral interference with neuronotrophic signalling in human motor neuron di­ sease?, Arch Ital Biol 1992
Westarp ME et al.: Dermal, serological and CSF changes in amyotrophic lateral sclerosis with and without intrathecal interferon beta treatment, Int J Clin Pharmacol Ther Toxicol 1992.The starting point of the present considerations was the knowledge attributed to the inventor that antibodies to human retroviruses occur increasingly in amyotrophic late ralsclerosis (ALS) patients, in particular the human spuma retrovirus (HSRV) and Visna virus, which is also human-infectious. furthermore, the circulating im complexes in amyotrophic lateral sclerosis (ALS) patients are often and greatly increased. These findings go back directly to the inventor and are never stated in the preparatory phase for the publication of scientific articles. The following sources are given:
Westarp ME et al .: Human spuma retrovirus antibo dies in patients with amyotrophic lateral sclero sis, Neurol Psychiatr Brain Res 1992
Westarp ME et al .: Retroviral interference with neuronotrophic signaling in human motor neuron di sease ?, Arch Ital Biol 1992
Westarp ME et al .: Dermal, serological and CSF changes in amyotrophic lateral sclerosis with and without intrathecal interferon beta treatment, Int J Clin Pharmacol Ther Toxicol 1992.

Weiter konnte der Erfinder feststellen, daß amyo­ trophe Lateralsklerose (ALS)-Patienten um so länger leben, je jünger sie sind, so daß in soweit eine Parallele zu HIV-Infizierten besteht:
Westarp ME et al.: Amyotrophic lateral sclerosis:
dermal and body fluid alterations with and without intrathecal interferon beta treatment, Neurol Psychiatr Brain Res 1992 (1:1-4 und 1:65-75).The inventor was also able to determine that amyotrophic lateral sclerosis (ALS) patients live longer, the younger they are, so that there is a parallel to HIV-infected people:
Westarp ME et al .: Amyotrophic lateral sclerosis:
dermal and body fluid alterations with and without intrathecal interferon beta treatment, Neurol Psychiatr Brain Res 1992 (1: 1-4 and 1: 65-75).

Weiter ist bekannt, daß Spuma-Viren das Immunsystem verändern können, was den letztlich erfolglosen Kampf des Immunsystems des Motorneuron-Patienten erklären könnte.It is also known that spuma viruses are the immune system can change what the ultimately unsuccessful Fight of the motor neuron's immune system could explain.

Auch gegen Visna-Retrovirales Antigen zeigten die Seren von ALS-Kranken erhöhte Reaktionen in einem indirekten ELiSA-Test (Abb. 1). Die auffällige Häu­ fung positiver spumaretroviraler Tests bei Motor­ neuronpatienten zeigt Abb. 2 im Vergleich zu ande­ ren Ulmer Patienten. Abb. 3 zeigt Besonderheiten des Immunstatus von ALS-Patienten, insbesondere bei Nachweis von Spuma-retroviralen Antikörpern.The sera of ALS patients also showed increased reactions in an indirect ELiSA test against Visna retroviral antigen ( Fig. 1). Fig. 2 shows the striking frequency of positive spumaretroviral tests in motor neuron patients compared to other Ulm patients. Fig. 3 shows peculiarities of the immune status of ALS patients, especially when detecting spuma-retroviral antibodies.

Ausgehend von diesen weitgehend durch den Erfinder erkannten Zusammenhänge hat sich zunächst die Ver­ mutung ergeben, daß ein Retrovirus, d. h. ein infek­ tiöses oder anders übertragenes oder endogenes aber auch retrovirusähnliche Elemente (wie z. B. HERV=human endogenous retrovirus-like element) Ver­ ursacher der Motorneuron-Erkrankung und auch der Unterformen amyotrophe Lateralsklerose (ALS), spi­ nale Muskelstrophie und progressive Bulbärparalyse sei.Based on these largely by the inventor recognized relationships, the Ver suggests that a retrovirus, i. H. an infectious tious or otherwise transferred or endogenous also elements similar to retrovirus (such as HERV = human endogenous retrovirus-like element) Ver cause of the motor neuron disease and also the Subforms of amyotrophic lateral sclerosis (ALS), spi nale muscle strophy and progressive bulbar paralysis be.

Um welche Art Retrovirus es sich hierbei handelt, ob es sich also im speziellen um ein humanes Spuma- Retrovirus (HSRV), ein verwandtes Retrovirus oder ein anderes Retrovirus wie Maedi-Visna-verwandte Lentiviren handelt, kann dahinstehen.What kind of retrovirus is this whether it is specifically a human spuma Retrovirus (HSRV), a related retrovirus or another retrovirus like Maedi-Visna-related Lentiviruses can stand still.

Auf dieser Grundlage wurde die Durchführung eines individuellen Therapieversuches an zehn amyotrophen Lateralsklerose (ALS) -Patienten vorgenommen, die zum Teil hohe und zum Teil keine Antikörper gegen HSRV aufwiesen. Verabreicht wurden 500 mg Zidovudin p.o./d für 2 bis 10 Monate. Nachdem sich bei AIDS- Patienten die Virustiter, positive Mikrophagenkul­ turen und die T-Helfer-Lymphozyten in den Behand­ lungsgruppen mit 300, 600 und 1500 mg/d Zidovudin nicht unterscheiden, wurde für das vermutlich für die amyotrophe Lateralsklerose (ALS) wesentlich mitverantwortliche humane Retrovirus angenommen, daß es auf 500 mg/d Zidovudin empfindlich sei, zumal bei dieser niedrigen Dosierung wesentlich we­ niger Nebenwirkungen der sogenannten Nukleosida­ nalog-Substanzen zu befürchten waren.On this basis, the implementation of a individual therapy attempt on ten amyotrophic Lateral sclerosis (ALS) patients made the some high and some no antibodies against HSRV had. 500 mg of zidovudine were administered p.o./d for 2 to 10 months. After AIDS Patients the virus titer, positive microphage turen and the T-helper lymphocytes in the treatment groups with 300, 600 and 1500 mg / d zidovudine not differentiate, was probably for that for amyotrophic lateral sclerosis (ALS) essential responsible human retrovirus accepted, that it is sensitive to 500 mg / d zidovudine, especially at this low dosage we  side effects of the so-called nucleosida nalog substances were to be feared.

Zu den Wirkungen des Versuches ist zunächst folgen­ des zu erläutern:
Infolge des Muskelfaserunterganges bei amyotropher Lateralsklerose (ALS) steigt die Serum-Kreatinki­ nase, ein in der Muskelzelle beheimatetes Enzym, an. Allerdings fällt dieser Wert auch wieder ab, wenn nur noch wenig Muskelmasse übrig ist. Dennoch eignet sie sich in kurzfristigen Zeitspannen von Tagen und Wochen und einigen Monaten ohne weiteres bei amyotropher Lateralsklerose (ALS) als Maß für den motorneuro-axonalen Schaden, der zum Muskelun­ tergang führt.Regarding the effects of the experiment, the following must first be explained:
As a result of muscle fiber death in amyotrophic lateral sclerosis (ALS), the serum creatine nose, an enzyme native to the muscle cell, rises. However, this value drops again when there is only little muscle left. Nevertheless, in short-term periods of days, weeks and a few months, it is easily used for amyotrophic lateral sclerosis (ALS) as a measure of the motor neuro-axonal damage that leads to muscle failure.

Je höher der CK-Wert ist, um so aktiver ist, kurz­ fristig gesehen, der Krankheitsprozeß. Dieser Wert der Serum-Kreatinkinase sank bei allen Patienten der Therapiegruppe unmittelbar binnen weniger Tage (2-10 Tage). Diese Abnahme des CK-Wertes war bei allen Patienten gleichmäßig bei der nächsten Blut­ kontrolle meßbar, ohne daß die Patienten ihren Ta­ gesablauf verändert hatten.The higher the CK value, the more active is short seen in time, the disease process. This value serum creatine kinase decreased in all patients the therapy group immediately within a few days (2-10 days). This decrease in the CK value was at all patients evenly with the next blood control measurable without the patient had changed.

Die Ergebnisse dieses Versuches sind in einer Gra­ phik wiedergegeben, welche das Resultat, genauer den Wert der Kreatinkinase (gemessen in units per liter) nach der Gabe von Zidovudin (= Azidothymi­ din) über die Zeit graphisch aufzeigt.The results of this experiment are in a graph reproduced phik, which is the result, more precisely the value of creatine kinase (measured in units per liter) after the administration of zidovudine (= azidothymi din) shows graphically over time.

Die beigefügte Abbildung zeigt den Verlauf der Se­ rum-Kreatinkinase (CK) bei acht verschiedenen Pati­ enten, deren Namen mit den Buchstabenkombinationen LG, LP, HM, SH, HF, MK, UE und JR abgekürzt sind. Die jeweiligen Meßpunkte sind - soweit ein weiterer Graph aufgetragen ist - als Sterne eingezeichnet und der Tag des Beginns der Verabreichung von Zido­ vudin ist durch die Pfeilspitze angegeben. Nach ei­ nem in der Gruppe signifikanten Abfall am Beginn der Behandlung ist mit zunehmender Dauer der Be­ handlung ein erneuter Anstieg zu verzeichnen, der auf eine Resistenzentwicklung zurückzuführen sein könnte, wie er vom HIV-Erreger her allgemein geläu­ fig ist.The attached figure shows the course of the Se  rum creatine kinase (CK) in eight different pati ducks, their names with the letter combinations LG, LP, HM, SH, HF, MK, UE and JR are abbreviated. The respective measuring points are - as far as another Graph is plotted - shown as a star and the day of starting Zido administration vudin is indicated by the arrowhead. After egg significant drop in the group at the beginning the treatment is with increasing duration of the loading a renewed increase in activity be due to a development of resistance could, as he is generally known about the HIV pathogen fig is.

Im Falle der Patienten LP und UE wurde zusätzlich die zirkulierenden Immunkomplexe (circulating im­ mune complexes = CIC) gemessen und in den Kurven­ verlauf aufgetragen, da diese Werte bei amyotropher Lateralsklerose (ALS) oft und stark erhöht sind, eine weitere Parallele zur HIV-Infektion.In the case of patients LP and UE was additional the circulating immune complexes (circulating in mune complexes = CIC) measured and in the curves applied as this is the case with amyotrophic Lateral sclerosis (ALS) is often and greatly increased, another parallel to HIV infection.

Aus humanen HIV-Zellkulturversuchen ist bekannt, daß auch die anderen Nukleosidanaloge gemäß An­ spruch 1 die retrovirale reverse Transkriptase hem­ men, zu einem Kettenabbruch führen und damit Wachs­ tum und Proliferation des Erregers eindämmen. In ersten Tierversuchen, unterschiedlich je nach Test­ system, zeigen mehr oder weniger alle genannten Nu­ kleosidanaloge eine antiretrovirale oder retroviro­ statische Wirkung.It is known from human HIV cell culture experiments that the other nucleoside analogues according to An saying 1 the retroviral reverse transcriptase hem lead to a chain break and thus wax curb the pathogen and proliferation of the pathogen. In first animal experiments, different depending on the test system, show more or less all the nu an antiretroviral or retroviro static effect.

Da Zidovudin das einzige bisher auf dem deutschen Markt zur Anwendung beim Menschen zugelassene Nu­ kleosidanalog ist, mußte zum jetzigen Zeitpunkt von einem Therapieversuch mit anderen Nukleosidanalogen abgesehen werden.Since Zidovudin is the only one so far on the German Nuclear use approved market  is analogous to kleoside at the current time of a therapy attempt with other nucleoside analogues be disregarded.

Nach Zulassung des ddI (DidanosinINN, VidexR) bekam Patient LP nach Wiederansteigen der CIC 300mg/Tag ddI verordnet, worauf die Immunkomplexe erneut auf niedrignormale Werte absanken.After approval of the ddI (didanosine INN , Videx R ), patient LP was prescribed 300 mg / day ddI after the CIC increased again, whereupon the immune complexes dropped again to low-normal values.

Claims (4)

1. Verwendung von antiretroviralen Substanzen, näm­ lich Azidothymidin und/oder Didesoxydidehydrothymi­ din und/oder Didesoxycytidin und/oder Didesoxyino­ sin und/oder 3-Deaza-Adenosin und/oder (+) und (-) enantiomeries 2′-deoxy-3′-ThiaCytidine (3TC) und/oder 3TC-5′-triphosphat (3TCTP) und/oder Race­ misches 2′-deoxy-3′-thiacytidine und/oder Fluoro­ thymidin (FLT) und/oder Trifluorothymidin (TFT) und/oder Hydroxy. ethoxymethyl. phenylthio. thymin- (HEPT-) Reverse-Transkriptase-Hemmer und/oder Riba­ virin und/oder Nevirapin-Dipyridodiazepinon und/oder TIBO-Verbindungen mit den Prüfnummern L697, L661 und R18893 und/oder Tetrahydro, Imidazo, Benzodiazepinthion-Verbindung mit der Prüfnummer R82913
und/oder 5-ethyl-1-ethoxy-methyl- 6(phenylthio) uracil und/oder 5-ethyl-1-benzyloxyme­ thyl-6(phenylthio)uracil und/oder Bisheteroarylpi­ perazine mit den Prüfnummern U-87201-Ester, Prüf­ nummer U-88204, Prüfnummer U-30493-Ester sowie die Derivate mit den Prüfnummern U-85961, U-87201, U- 88352 und U-88353
und/oder Liponsäure und/oder Alpha-Liponsäure (1,2- Dithiacyclopentan-3-valeriansäure und ±alpha-1,2- Dithiacyclopentan-3-valeriansäure) und/oder Ami­ triptylin und/oder Amitriptylinoxid und/oder Sub­ stanzen mit der Prüfnummer U-75875 sowie Nachbar­ verbindungen hierzu, in denen der 1-naphthoxyace­ thyl-Rest durch einen Phenoxyacetyl-Rest ersetzt ist
und/oder 7-chloro-5-(2-pyrryl)-3H-1,4-benzodia­ zepin-2(H)-on und/oder 3-Mercapto-D-valin und/oder Ammonium-5-tungsto-2 und/oder Isoquinolin-Pro­ teaseinhibitor mit der Prüfnummer Ro-31-8959 sowie dessen Nachbarverbindung in der das Dekahydroiso­ quinolincarbonyl durch Piperidin-2(S)-carbonyl er­ setzt ist oder bei der sich die Übergangshydroxyl­ gruppe in S-Konformation befindet und/oder
Foscarnet-Phosphonoameisensäure und/oder Phospho­ noazetessigsäure-Analoge und/oder Desoxynojirimycin (DNJ) oder Butyl-Desoxynojirimycin und/oder Dex­ transulfate (DexSO4) und/oder Dehydroepiandroste­ ron-EL-10 und/oder Oxothiazolidin-4-Carboxylat und/oder N-Acetylcystein (NAC) und/oder Trichosan­ thin und/oder Hypericin und/oder Pentoxifyllin und/oder 12-desoxy-Phorbolester 12-Desoxyphorbol- 13-azetat "Prostratin" und/oder 12-Desoxyphorbol- 13-phenylazetat "dPP" und/oder Tetradecanoylphor­ bol-Azetat und/oder 5-Aminoimidazol-4-Carboxamid und/oder 2-(Benzoxazol-2-yl)ethyl-5-ethyl-6-methyl­ pyridin-2(1H)-one und/oder Semi-naphthoquinon mit der Prüfnummer A-80915A und/oder analoge oder spie­ gelbildliche retrovirale Antisense-Ribonukleinsäure (RNA) analog oder spiegelbildlich zu Sequenzen mit Homologie zu Spumaviren oder Visnaviren oder Spuma/Visna-verwandten endogenen retrovirusähnli­ chen Sequenzen und/oder Kombinationen hiervon sowie deren Derivate zur Herstellung eines Arzneimittels, dadurch gekennzeichnet, daß es als Therapeutikum bei motorneuronalen Erkrankungen dient. 1. Use of antiretroviral substances, namely azidothymidine and / or dideoxydidehydrothymi din and / or dideoxycytidine and / or dideoxyino sin and / or 3-deaza-adenosine and / or (+) and (-) enantiomeries 2'-deoxy-3 ' -ThiaCytidine (3TC) and / or 3TC-5′-triphosphate (3TCTP) and / or race mix 2′-deoxy-3′-thiacytidine and / or fluoro thymidine (FLT) and / or trifluorothymidine (TFT) and / or hydroxy . ethoxymethyl. phenylthio. thymine (HEPT) reverse transcriptase inhibitor and / or ribavirin and / or nevirapine dipyridodiazepinone and / or TIBO compounds with the test numbers L697, L661 and R18893 and / or tetrahydro, imidazo, benzodiazepinthion compound with the test number R82913
and / or 5-ethyl-1-ethoxy-methyl-6 (phenylthio) uracil and / or 5-ethyl-1-benzyloxyme thyl-6 (phenylthio) uracil and / or bisheteroarylpi perazine with the test numbers U-87201-ester, test number U-88204, test number U-30493-ester and the derivatives with test numbers U-85961, U-87201, U-88352 and U-88353
and / or lipoic acid and / or alpha-lipoic acid (1,2-dithiacyclopentan-3-valeric acid and ± alpha-1,2-dithiacyclopentan-3-valeric acid) and / or ami triptylin and / or amitriptyline oxide and / or substances with the Test number U-75875 as well as neighboring compounds in which the 1-naphthoxyace thyl radical is replaced by a phenoxyacetyl radical
and / or 7-chloro-5- (2-pyrryl) -3H-1,4-benzodia zepin-2 (H) -one and / or 3-mercapto-D-valine and / or ammonium-5-tungto-2 and / or isoquinoline protease inhibitor with the test number Ro-31-8959 and its neighboring compound in which the decahydroiso quinoline carbonyl is replaced by piperidine-2 (S) carbonyl or in which the transition hydroxyl group is in the S conformation and / or
Foscarnet phosphonoformic acid and / or phospho noacetoacetic acid analogs and / or deoxynojirimycin (DNJ) or butyl deoxynojirimycin and / or dex transulfate (DexSO4) and / or dehydroepiandroste ron-EL-10 and / or oxothiazolidine / 4-carboxylate -Acetylcysteine (NAC) and / or trichosan thin and / or hypericin and / or pentoxifylline and / or 12-deoxy-phorbol ester 12-deoxyphorbol-13-acetate "prostatin" and / or 12-deoxyphorbol-13-phenyl acetate "dPP" and / or Tetradecanoylphor bol acetate and / or 5-aminoimidazole-4-carboxamide and / or 2- (benzoxazol-2-yl) ethyl-5-ethyl-6-methyl pyridin-2 (1H) -one and / or semi- naphthoquinone with the test number A-80915A and / or analog or mirror-image retroviral antisense ribonucleic acid (RNA) analog or mirror image to sequences with homology to spumaviruses or visna viruses or spuma / visna-related endogenous retrovirus-like sequences and / or combinations thereof and their derivatives for the manufacture of a drug because characterized in that it serves as a therapeutic agent in motor neuronal diseases. 2. Verwendung nach Anspruch 1, dadurch gekennzeich­ net, daß die motorneuronale Erkrankung die amyotro­ phe Lateralsklerose (ALS) ist.2. Use according to claim 1, characterized net that the motor neuronal disease the amyotro phe lateral sclerosis (ALS). 3. Verwendung nach Anspruch 1, dadurch gekennzeich­ net, daß die motorneuronalen Erkrankung die spinale Muskelatrophie ist.3. Use according to claim 1, characterized net that the motor neuronal disease the spinal Muscle atrophy is. 4. Verwendung nach Anspruch 1 und 2, dadurch ge­ kennzeichnet, daß die motorneuronale Erkrankung die progressive Bulbärparalyse ist.4. Use according to claim 1 and 2, characterized ge indicates that the motor neuronal disease progressive bulb paralysis is.
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