CH675125A5 - - Google Patents
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- CH675125A5 CH675125A5 CH549/88A CH54988A CH675125A5 CH 675125 A5 CH675125 A5 CH 675125A5 CH 549/88 A CH549/88 A CH 549/88A CH 54988 A CH54988 A CH 54988A CH 675125 A5 CH675125 A5 CH 675125A5
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- CH
- Switzerland
- Prior art keywords
- compound
- formula
- salts
- monohydrate
- administered
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- YNAVUWVOSKDBBP-UHFFFAOYSA-O morpholinium Chemical compound [H+].C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-O 0.000 description 1
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- 230000003961 neuronal insult Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
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- 210000003101 oviduct Anatomy 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000007180 physiological regulation Effects 0.000 description 1
- JSSXHAMIXJGYCS-UHFFFAOYSA-N piperazin-4-ium-2-carboxylate Chemical group OC(=O)C1CNCCN1 JSSXHAMIXJGYCS-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
-
- 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
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- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- 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
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Description
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Beschreibung description
Aus der Britischen Patentanmeldung 2 157 685 sind in 4-Stellung substituierte Piperazin-2-carbon-säuren bekannt, die eine Wirkung auf das Zentralnervensystem haben. British patent application 2 157 685 discloses piperazine-2-carboxylic acids substituted in the 4-position, which have an effect on the central nervous system.
Es wurde nun gefunden, dass eine bisher nicht offenbarte Verbindung dieser Substanzklasse eine besonders starke Wirkung auf das Zentralnervensystem besitzt, gut verträglich und ihre Wirkung langanhaltend ist. It has now been found that a hitherto undisclosed compound of this class of substances has a particularly strong effect on the central nervous system, is well tolerated and its effect is long-lasting.
Die vorliegende Erfindung betrifft die [R-(E)]-4-(3-Phosphono-2-propenyl)-piperazin-2-carbonsäu-re der Formel I The present invention relates to the [R- (E)] - 4- (3-phosphono-2-propenyl) piperazine-2-carboxylic acid of the formula I.
/ Ci-. / Ci.
OH OH
P*0 P * 0
OH OH
COOK COOK
ihre Salze, ihre Herstellung und diese enthaltende pharmazeutische Präparate. their salts, their preparation and pharmaceutical preparations containing them.
Zu der Verbindung der Formel I und ihren Salzen kann man gelangen, indem man eine Verbindung der Formel II The compound of formula I and its salts can be obtained by using a compound of formula II
COOH COOH
II II
worin R für (Ci-4)Alkyl oder Aryl(Ci-4)alkyl steht, dealkyliert und gegebenenfalls die erhaltene Verbindung der Formel I in ein Salz überführt. wherein R is (Ci-4) alkyl or aryl (Ci-4) alkyl, dealkylated and optionally the compound of formula I obtained is converted into a salt.
Das Verfahren kann in an sich bekannter Weise durchgeführt werden. Die Dealkylierung kann beispielsweise durch Silylierung mit nachfolgender Hydrolyse des entstandenen Silylesters durchgeführt werden. Die Silylierung kann z.B. mit Bromtrimethylsilan in einem organischen Lösungsmittel wie Dichlor-methan oder Chloroform bei Raumtemperatur durchgeführt werden. Die nachfolgende Hydrolyse kann unter milden Bedingungen erfolgen. The process can be carried out in a manner known per se. The dealkylation can be carried out, for example, by silylation with subsequent hydrolysis of the silyl ester formed. The silylation can e.g. be carried out with bromotrimethylsilane in an organic solvent such as dichloromethane or chloroform at room temperature. The subsequent hydrolysis can take place under mild conditions.
Wenn R für Ary!(Ci-4)alky! steht, dann bedeutet Aryl zweckmässigerweise eine gegebenenfalls substituierte Phenylgruppe, worin geeignete Substituenten niedriges Alkyl oder niedriges Alkoxy umfassen. If R for Ary! (Ci-4) alky! then aryl expediently means an optionally substituted phenyl group, in which suitable substituents include lower alkyl or lower alkoxy.
Die Verbindung der Formel I sowie ihre Salze kann in Form von Hydraten, insbesondere des Monohydrates, erhalten werden. Die Hydrate, insbesondere das Monohydrat, sind ebenfalls Gegenstand der vorliegenden Erfindung. The compound of formula I and its salts can be obtained in the form of hydrates, in particular the monohydrate. The hydrates, in particular the monohydrate, are also the subject of the present invention.
Die Verbindung der Formel II kann gemäss folgendem Reaktionsschema hergestellt werden: The compound of formula II can be prepared according to the following reaction scheme:
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CH 675 125 A5 CH 675 125 A5
Die Verbindung der Formel I kann kationische Salze und Säureadditionssalze bilden. Solche Salze können nach bekannten Verfahren hergestellt werden. Als Beispiele für kationische Salze seien das Ammonium, Natrium, Kalium, Calcium, Piperidinium, Morpholinium oder Pyrrolidinium - Salz genannt. Als Beispiele für Säureadditionssalze seien Salze, die mit Chlorwasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure, Methansulfonsäure, Benzolsulfonsäure, p-Toluolsulfonsäure und Trifluoressigsäure gebildet werden, genannt. The compound of formula I can form cationic salts and acid addition salts. Such salts can be prepared by known methods. Examples of cationic salts are ammonium, sodium, potassium, calcium, piperidinium, morpholinium or pyrrolidinium salt. Examples of acid addition salts are salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid.
Die Hydrate, insbesondere das Monohydrat der Verbindung der Formel I haben besonders interessante physikalisch-chemische und andere Eigenschaften, z.B. bezüglich Löslichkeit, leichter Reinigung und Stabilität. Das Hydrat kann durch Kristallisation der Verbindung der Formel I aus einem wässerigen Medium, z.B. wie in Beispiel e) beschrieben, z.B. aus Wasser/Methanol, hergestellt werden. The hydrates, especially the monohydrate of the compound of formula I have particularly interesting physico-chemical and other properties, e.g. in terms of solubility, easy cleaning and stability. The hydrate can be obtained by crystallizing the compound of formula I from an aqueous medium, e.g. as described in example e), e.g. made of water / methanol.
Die erfindungsgemässe Verbindung zeichnet sich durch pharmakologische Wirkungen aus und ist daher als Heilmittel verwendbar. Insbesondere hemmt die Verbindung die Sekretion des luteinisierenden Hormons (LH) und des Testosterons im folgenden Test: Adulten männlichen Ratten (SIV, Kissleg, BRD, 200-300g) wird die Testsubstanz intraperitoneal verabreicht. 2 Stunden später werden die Ratten deka-pitiert und Blutproben entnommen. Das LH-Serum wird unter Verwendung eines Bioassay's bestimmt. Dieses Bioassay basiert auf der Produktion von Testosteron durch dispergierte, Collagenase-behan-delte interstitielle Leydig'sche Zellen von Ratten, die einem LH-haltigen Serum oder einem Ratten-LH- The compound according to the invention is characterized by pharmacological effects and can therefore be used as a remedy. In particular, the compound inhibits the secretion of the luteinizing hormone (LH) and testosterone in the following test: Adult male rats (SIV, Kissleg, FRG, 200-300g) are administered the test substance intraperitoneally. 2 hours later, the rats are decapitated and blood samples are taken. LH serum is determined using a bioassay. This bioassay is based on the production of testosterone by dispersed, collagenase-treated interstitial Leydig cells from rats that contain an LH-containing serum or a rat LH-
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Standard ausgesetzt sind. Das Testosteron-Serum wird mit Hilfe eines Radioimmunoassay's (125-J-T-Cis, Medipro Teufen, Schweiz) bestimmt. [Vgl. E. del Pozo, A. Podestà, A. Solano, J. Calaf, M. Marko, in: Biorhythms and Stress in the Physiopathoiogy of Reproduction, P. Pancheri and L. Zichella (Eds), He-misphere Publishing Co. Washington, 389-398 (1988)]. Standard are exposed. The testosterone serum is determined using a radioimmunoassay (125-J-T-Cis, Medipro Teufen, Switzerland). [See. E. del Pozo, A. Podestà, A. Solano, J. Calaf, M. Marko, in: Biorhythms and Stress in the Physiopathoiogy of Reproduction, P. Pancheri and L. Zichella (Eds), He-misphere Publishing Co. Washington , 389-398 (1988)].
Die Verbindung der Formel I hemmt die LH- und Testosteron-Sekretion signifikant in einer Dosis von 3.2 mg/kg i.p. (±)-4-(3-Phosphono-2-propenyl)-piperazin-2-carbonsäure (im folgenden CPP-en genannt), das Racemat der Verbindung der Formel I, hat mit 3.2 mg/kg i.p. keine Wirkung auf die LH-Sekre-tion und hemmt die Testosteron-Sekretion nur schwach. The compound of formula I significantly inhibits LH and testosterone secretion at a dose of 3.2 mg / kg i.p. (±) -4- (3-Phosphono-2-propenyl) -piperazin-2-carboxylic acid (hereinafter called CPP-en), the racemate of the compound of formula I, has 3.2 mg / kg i.p. has no effect on LH secretion and only weakly inhibits testosterone secretion.
In weiblichen Ratten hemmt die Verbindung der Formel I LH-abhängige spontane Ovulation im folgenden Test [vgl. M. Marko, E. Flückiger, Neuroendocrinology 30, 228-231 (1980)]: Weibliche Ratten der Wistar Abstammung (SIV, Kissleg, BRD, 200-300g) mit regelmässigem 4-tägigem Zyklus erhalten die zu prüfende Substanz im ProÖstrus um 13.00 und 16.00 Uhr intraperitoneal appliziert. Am nächsten Morgen, wenn die Ratten im Oestrus sind, werden sie getötet, die Ovidukte mikroskopisch untersucht und die Eier ausgezählt. Die Ovulation wird nur als gehemmt bewertet, wenn keine Eier gefunden werden. Die Verbindung der Formel I (als Monohydrat getestet) hemmt die spontane Ovulation signifikant nach Verabreichung von 2 x 3.2 mg/kg i.p. (um 13.00 h 3.2 mg/kg i.p. und um 15.00 h 3.2 mg/kg i.p.). CPP-en hemmt unter denselben experimentellen Bedingungen die spontane Ovulation nach Verabreichung von 2 x 3.2 mg/kg i.p. sehr schwach. In female rats, the compound of the formula I inhibits LH-dependent spontaneous ovulation in the following test [cf. M. Marko, E. Flückiger, Neuroendocrinology 30, 228-231 (1980)]: Female rats of the Wistar lineage (SIV, Kissleg, FRG, 200-300g) with a regular 4-day cycle receive the substance to be tested in the Proestrus at 13.00 and 4:00 p.m. applied intraperitoneally. The next morning, when the rats are in oestrus, they are killed, the oviducts are examined microscopically and the eggs are counted. Ovulation is only assessed as inhibited if no eggs are found. The compound of formula I (tested as monohydrate) significantly inhibits spontaneous ovulation after administration of 2 x 3.2 mg / kg i.p. (at 13.00 h 3.2 mg / kg i.p. and at 15.00 h 3.2 mg / kg i.p.). CPP-en inhibits spontaneous ovulation after administration of 2 x 3.2 mg / kg i.p. under the same experimental conditions. very weak.
Die Verbindung der Formel I ist daher zur Behandlung von Erkrankungen, die mit der LH-Sekretion zusammenhängen oder worin die physiologische Regulierung der LH-Sekretion involviert ist, z.B. zur Behandlung von Prostata-Hypertrophie, des Menopause-Syndroms, des Mammakarzinoms und Prostatakarzinoms, geeignet. Die für diese Anwendung geeigneten Tagesdosen betragen etwa 1 bis etwa 800 mg, zweckmässigerweise verabreicht in Teilmengen zwischen etwa 0.25 und etwa 400 mg 2 bis 4 mal täglich oder in Retardform. The compound of formula I is therefore for the treatment of diseases associated with LH secretion or in which the physiological regulation of LH secretion is involved, e.g. suitable for the treatment of prostate hypertrophy, menopause syndrome, breast cancer and prostate cancer. The daily doses suitable for this application are about 1 to about 800 mg, expediently administered in portions between about 0.25 and about 400 mg 2 to 4 times a day or in prolonged-release form.
Die Verbindung der Formel I besitzt ferner eine muskelrelaxierende Wirkung am wachen Kaninchen in Dosen von 0.01 bis 0.05 mg/kg i.v. [H.J. Teschendorf et al., Arch.Exp.Pharmacol. 266. 467-468 (1970)]. In diesem Test hemmt das Monohydrat der Verbindung der Formel I den Muskeltonus um 50% mit 0.02 mg/kg i.V., während CPP-en den Muskeltonus um 47% hemmt mit 0.5 mg/kg i.V.; die Verbindung der Formel I somit etwa 25mal stärker als das entsprechende Racemat ist. The compound of formula I also has a muscle-relaxing effect on the awake rabbit in doses of 0.01 to 0.05 mg / kg IV. [H.J. Teschendorf et al., Arch.Exp.Pharmacol. 266, 467-468 (1970)]. In this test, the monohydrate of the compound of the formula I inhibits muscle tone by 50% with 0.02 mg / kg IV, while CPP-en inhibits muscle tone by 47% with 0.5 mg / kg IV; the compound of formula I is thus about 25 times stronger than the corresponding racemate.
Aufgrund der muskelrelaxierenden Wirkung ist die Verbindung der Formel I zur Behandlung von erhöhtem Muskeltonus, z.B. zur Behandlung von schmerzhaften Muskelspasmen bei statischen und funktionellen Störungen der Lenden- und Halswirbelsäure oder nach chirurgischen Eingriffen oder zur Behandlung von Spastizität, z.B. bei Multipler Sklerose, Rückenmarkserkrankungen, zerebrovaskulären Unfällen, Hirntrauma oder Zerebrallähmung angezeigt. Die für diese Anwendung geeigneten Tagesdosen betragen etwa 1 bis etwa 800 mg, zweckmässigerweise verabreicht in Teilmengen zwischen etwa 0.25 und etwa 400 mg 2 bis 4 mal täglich oder in Retardform. Due to the muscle relaxant effect, the compound of formula I is for the treatment of increased muscle tone, e.g. for the treatment of painful muscle spasms with static and functional disorders of the lumbar and cervical spine or after surgery or for the treatment of spasticity, e.g. indicated for multiple sclerosis, spinal cord diseases, cerebrovascular accidents, brain trauma or cerebral palsy. The daily doses suitable for this application are about 1 to about 800 mg, expediently administered in portions between about 0.25 and about 400 mg 2 to 4 times a day or in prolonged-release form.
Die Verbindung der Formel I reduziert ferner die durch Ischaemie induzierten neuronalen Schädigungen und nachfolgenden Symptomen in der middle cerebral artery (MCA) Okklusions-Modell an Ratten in Dosen von 1-30 mg/kg s.c. und insbesondere mit 3x10 mg/kg i.p. [vgl. A. Tamura et al., J.Cereb.Blood Flow Metabol. 1, 53-60 (1981); A. Sauter, N. Rudin, Stroke 17, 1228-1234 (1986)]. Die Infarktgrösse wird unter Verwendung von MCID image analysis software (entwickelt von Imaging Research Inc.) an 5 horizontalen 20 firn dicken Schnitten von verschiedenen Schnittebenen stammend, die mit Cresylviolett gefärbt sind, bestimmt. Die Infarktgrösse wird durch Summation der 5 Gebiete von den 5 Schnitten gemessen. Die 5 Tage nach MCA-Okklusion histologisch bestimmte Infarktgrösse wird durch das Monohydrat der Verbindung der Formel I mit 3 x 10 mg/kg i.p. (1. Injektion unmittelbar nach MCA-Okklusion, 2. und 3. nach 8 bzw. 16 Stunden) um mehr als 20% reduziert. The compound of formula I further reduces ischemia-induced neuronal damage and subsequent symptoms in the middle cerebral artery (MCA) occlusion model in rats in doses of 1-30 mg / kg s.c. and especially with 3x10 mg / kg i.p. [see. A. Tamura et al., J. Cereb. Blood Flow Metabol. 1, 53-60 (1981); A. Sauter, N. Rudin, Stroke 17, 1228-1234 (1986)]. The infarct size is determined using MCID image analysis software (developed by Imaging Research Inc.) on 5 horizontal 20 firn thick sections from different section planes stained with cresyl violet. The infarct size is measured by summing the 5 areas from the 5 sections. The infarct size determined histologically 5 days after MCA occlusion is determined by the monohydrate of the compound of the formula I with 3 × 10 mg / kg i.p. (1st injection immediately after MCA occlusion, 2nd and 3rd after 8 or 16 hours) reduced by more than 20%.
Die Verbindung ist daher zur Prophylaxe und Behandlung von Zuständen, die mit zerebraler Ischaemie assoziert sind, z.B. Schlaganfall, geeignet. Die für diese Anwendung geeigneten Tagesdosen betragen etwa 25 bis etwa 800 mg, zweckmässigerweise verabreicht in Teilmengen zwischen etwa 6 und etwa 400 mg 2 bis 4 mal täglich oder in Retardform. The compound is therefore for the prophylaxis and treatment of conditions associated with cerebral ischemia, e.g. Stroke, suitable. The daily doses suitable for this application are about 25 to about 800 mg, expediently administered in portions between about 6 and about 400 mg 2 to 4 times a day or in sustained release form.
Die Verbindung der Formel I ist ferner ein starker, selektiver und kompetitiver Antagonist von NMDA (N-Methyl-D-asparaginsäure)-Rezeptoren. So hemmt das Monohydrat der Verbindung der Formel i NMDA-induzierte Depolarisationen am isolierten Amphibien-Rückenmark-Test [P.L. Herrling, Neuroscience 14, 417-426 (1985)] mit einem pA2 Wert von 6.8, CPP-en mit einem pA2 von 6.2. Die Verbindung der Formel I ist also etwa 4 mal so wirksam wie das entsprechende Racemat. CPP [(±)-3-(2-Car-boxypiperazin-4-yl)propyl-1-phosphonsäure, die in der Britischen Patentanmeldung 2 157 685 hervorgehobene Verbindung, hat einen pA2-Wert von 5.8. The compound of formula I is also a strong, selective and competitive antagonist of NMDA (N-methyl-D-aspartic acid) receptors. The monohydrate of the compound of the formula i inhibits NMDA-induced depolarizations on the isolated amphibian spinal cord test [P.L. Herrling, Neuroscience 14, 417-426 (1985)] with a pA2 of 6.8, CPP-en with a pA2 of 6.2. The compound of the formula I is therefore about 4 times as active as the corresponding racemate. CPP [(±) -3- (2-car-boxypiperazin-4-yl) propyl-1-phosphonic acid, the compound highlighted in British patent application 2 157 685, has a pA2 of 5.8.
In dem NMDA-induzierten Natrium-efflux Test an Rattenhirnschnitten [A.Luini et al., Proc. Nati. Acad. Sei. USA 78, 3250-3254 (1981)] hat das Monohydrat der Verbindung der Formel I einen pA2 Wert von 6.5, CPP-en einen pA2 Wert von 6.2; die Verbindung der Formel I ist etwa 2 mal so wirksam wie das entsprechende Racemat. CPP hat einen pA2 Wert von 6.0. In the NMDA-induced sodium efflux test on rat brain sections [A. Luini et al., Proc. Nati. Acad. Be. USA 78, 3250-3254 (1981)] the monohydrate of the compound of the formula I has a pA2 value of 6.5, CPP-en a pA2 value of 6.2; the compound of formula I is about 2 times as active as the corresponding racemate. CPP has a pA2 value of 6.0.
Die Selektivität der NMDA-antagonistischen Wirkung ist dadurch angezeigt, dass die Verbindung wie auch das CPP und CPP-en im Quisqualat- und Kainat-induzierten Natrium-efflux Test bis zu einer Konzentration von 1 mM inaktiv ist. The selectivity of the NMDA-antagonistic effect is indicated by the fact that the compound, like the CPP and CPP-ene, is inactive in the quisqualate and kainate-induced sodium efflux test up to a concentration of 1 mM.
Aufgrund ihres NMDA-Rezeptor Antagonismus ist die Verbindung der Formel I zur Behandlung von Because of its NMDA receptor antagonism, the compound of formula I is used to treat
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Angstzuständen, Schizophrenie, Depression oder von ZNS-degenerativen Krankheiten, wie Huntington-, Alzheimer- oder Parkinson-Krankheit, angezeigt. Die für diese Anwendungen geeigneten Tagesdosen betragen etwa 25 bis etwa 800 mg, zweckmässigerweise verabreicht in Teilmengen zwischen etwa 6 und etwa 400 mg 2 bis 4 mal täglich oder in Retardform. Anxiety, schizophrenia, depression, or CNS degenerative diseases such as Huntington's, Alzheimer's, or Parkinson's disease. The daily doses suitable for these applications are about 25 to about 800 mg, expediently administered in portions between about 6 and about 400 mg 2 to 4 times a day or in sustained release form.
Aufgrund ihres NMDA-Rezeptor Antagonismus ist die Verbindung zur Behandlung von Tinnitus geeignet. Die für diese Anwendung geeignete Tagesdosis beträgt etwa 25 bis etwa 800 mg, zweckmässigerweise verabreicht in Teilmengen zwischen etwa 6 und etwa 400 mg 2 bis 4 mal täglich oder in Retardform. Due to its NMDA receptor antagonism, the compound is suitable for the treatment of tinnitus. The daily dose suitable for this application is about 25 to about 800 mg, expediently administered in portions between about 6 and about 400 mg 2 to 4 times a day or in sustained release form.
Ferner besitzt die Verbindung der Formel I eine antikonvulsive Wirkung in durch Elektroschock-indu-zierten Krämpfen in der Maus [vgl. E. Swinyard, J.Am.Pharm.Assoc.Scient.Ed. 38, 201 (1949) und J.Pharmacol.Exptl.Therap. 106, 319 (1952)]. In diesem Test wird Gruppen zu je 6 Mäusen (18-26 g OF-1, Sandoz Basel) Versuchssubstanz i.p. verabreicht. 1, 2 und 4 Stunden nach der Verabreichung der Testsubstanz wird ein 50 mA, 200 ms langer Schock mittels Cornealelektroden, die mit Elektrolytgel bestrichen sind, angewandt. Dieser supramaximale Schock erzeugt tonische Krämpfe an allen Extremitäten. Die Hemmung der Krämpfe der Hinterextremitäten wird als Schutzwirkung angenommen. Nach Verabreichung von verschiedenen Dosen wird die Schwellendosis bestimmt. Die Schwellendosis nach 1 Stunde, d.i. die Dosis, die zur Hemmung der Krämpfe der Hinterextremitäten erforderlich ist, beträgt für das Monohydrat der Verbindung der Formel I < 1 mg/kg i.p. und zwischen 3 bis 10 mg/kg. i.p. für CPP-en. Die aus der Literatur bekannte Schwellendosis von CPP beträgt 10 mg/kg i.p. Furthermore, the compound of formula I has an anticonvulsant effect in cramps induced by electroshock in the mouse [cf. E. Swinyard, J.Am.Pharm.Assoc.Scient.Ed. 38, 201 (1949) and J.Pharmacol.Exptl.Therap. 106, 319 (1952)]. In this test, groups of 6 mice (18-26 g OF-1, Sandoz Basel) test substance i.p. administered. 1, 2 and 4 hours after the administration of the test substance, a 50 mA, 200 ms long shock is applied by means of corneal electrodes which are coated with electrolyte gel. This supramaximal shock creates tonic spasms on all extremities. The inhibition of the cramps of the hind limbs is assumed to be a protective effect. The threshold dose is determined after administration of various doses. The threshold dose after 1 hour, i.e. the dose required to inhibit the cramps of the hind limbs is <1 mg / kg i.p. for the monohydrate of the compound of the formula I. and between 3 to 10 mg / kg. i.p. for CPP-en. The threshold dose of CPP known from the literature is 10 mg / kg i.p.
In der folgenden Tabelle ist die Hemmung der Krämpfe der Hinterextremitäten in % für die Verbindung der Formel I im Vergleich zu dem entsprechenden Racemat angegeben: The following table shows the% inhibition of the hind limbs for the compound of the formula I in comparison to the corresponding racemate:
Dosis Hemmung der durch E-Schock induzierten mg/kg i.p. Krämpfe der Hinterextremitäten in % 1h 2h 4h Dose inhibition of the mg / kg i.p. Cramps of the hind limbs in% 1h 2h 4h
Verbindung der Formel I Compound of formula I.
1 1
67* 67 *
67* 67 *
33 33
(Monohydrat) (Monohydrate)
2,5 2.5
83* 83 *
83* 83 *
67* 67 *
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100* 100 *
100* 100 *
83* 83 *
CPP-en CPP-en
1 1
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3 3rd
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67* 67 *
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67* 67 *
80* 80 *
80* 80 *
Fisher-Test, Kontrollgruppe gegenüber der Substanzgruppe, * p < = 0,05. Fisher test, control group versus substance group, * p <= 0.05.
Aus der Tabelle ist zu entnehmen, dass die antikonvulsive Wirkung der Verbindung der Formel I im durch E-Schock induzierten Krampf-Test an der Maus stärker als die des entsprechenden Racemats ist. It can be seen from the table that the anticonvulsant activity of the compound of the formula I in the cramp test induced by E-shock on the mouse is stronger than that of the corresponding racemate.
Die Verbindung der Formel I hemmt ferner die durch N-Methyl-D-asparaginsäure (NMDA) induzierten Krämpfe in der Maus. In diesem Test wird die Testsubstanz Gruppen von 6 weiblichen Mäusen (18— 6 g, OF-1, Sandoz Basel) i.p. verabreicht. 30 Minuten später erhalten die Mäuse 400 mg/kg NMDA s.c. in den Nacken verabreicht und werden 30 Minuten lang beobachtet. Die Latenzen bis zum Auftreten von ersten Zeichen von Krämpfen, der ersten tonischen Krämpfe und des Eintritts des Todes werden aufgezeichnet. Die Bedeutung von Unterschieden wird mit Hilfe des Mann-Whitney U-Tests (S. Siegel, Non-parametric Statistics, McGraw-Hill, New York 1956) bewertet. Die Schwellendosis ist die kleinste Dosis, bei der eine signifikante Hemmung der konvulsiven Symptome stattfindet. Die Schwellendosis für das Monohydrat der Verbindung der Formel I beträgt etwa 5 mg/kg i.p., die Schwellendosis für CPP 10 mg/kg i.p. The compound of formula I also inhibits mouse cramps induced by N-methyl-D-aspartic acid (NMDA). In this test, the test substance is administered to groups of 6 female mice (18-6 g, OF-1, Sandoz Basel) i.p. administered. 30 minutes later, the mice receive 400 mg / kg NMDA s.c. administered to the neck and are observed for 30 minutes. The latencies until the first signs of convulsions, the first tonic convulsions and the onset of death are recorded. The significance of differences is assessed using the Mann-Whitney U test (S. Siegel, Non-parametric Statistics, McGraw-Hill, New York 1956). The threshold dose is the smallest dose at which there is a significant inhibition of convulsive symptoms. The threshold dose for the monohydrate of the compound of the formula I is approximately 5 mg / kg i.p., the threshold dose for CPP 10 mg / kg i.p.
Aufgrund ihrer antikonvulsiven Wirkung ist die Verbindung der Formel I zur Behandlung von Epilepsie angezeigt. Die für diese Anwendung geeignete Tagesdosis beträgt etwa 25 bis etwa 800 mg, zweckmässigerweise verabreicht in Teilmengen zwischen etwa 6 und etwa 400 mg 2 bis 4 mal täglich oder in Retardform. Because of its anticonvulsant effect, the compound of formula I is indicated for the treatment of epilepsy. The daily dose suitable for this application is about 25 to about 800 mg, expediently administered in portions between about 6 and about 400 mg 2 to 4 times a day or in sustained release form.
Die Verbindung der Formel I besitzt ferner eine analgetische Wirkung im isolierten Rückenmark-Schwanz der Ratte in vitro unter Verwendung von Capsaicin (0.8-1 nM) als chemische Stimulation, das depolarisierende Vorderwurzel-Reflexe auslöst [M. Yanagisawa et al., European J.Pharmacol. 106. 231-239 (1984)]. Das Monohydrat der Verbindung der Formel I reduziert die chemische Stimulation bei einer Konzentration von 10 nM um 75-80%. The compound of formula I also has an analgesic effect in the isolated spinal tail of the rat in vitro using capsaicin (0.8-1 nM) as a chemical stimulation which triggers depolarizing front root reflexes [M. Yanagisawa et al., European J. Pharmacol. 106, 231-239 (1984)]. The monohydrate of the compound of formula I reduces the chemical stimulation at a concentration of 10 nM by 75-80%.
Die Verbindung ist daher zur Bekämpfung von Schmerzen geeignet. Geeignete Tagesdosen betragen etwa 25 bis etwa 800 mg, zweckmässigerweise verabreicht in Teilmengen zwischen etwa 6 und etwa 400 mg 2 bis 4 mal täglich oder in Retardform. The compound is therefore suitable for combating pain. Suitable daily doses are about 25 to about 800 mg, conveniently administered in portions between about 6 and about 400 mg 2 to 4 times a day or in sustained release form.
Die Verbindung der Formel I als auch das entsprechende Racemat hat keine Wirkungen auf den Blutdruck und die Herzfrequenz an der narkotisierten Katze bis zu einer Dosis von 10 mg/kg i.v. In der Pilot-Toxizitätsstudie am Hund werden 3 mg/kg/Tag i.v. der Verbindung der Formel I gut vertragen. The compound of the formula I and the corresponding racemate have no effects on the blood pressure and the heart rate in the anesthetized cat up to a dose of 10 mg / kg IV. In the pilot toxicity study on dogs, 3 mg / kg / day i.v. well tolerated the compound of formula I.
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Aus den genannten Versuchen ergibt sich, dass die starke LH-sekretionshemmende Wirkung, die bedeutende Steigerung (25-fache) der muskelrelaxierenden Wirkung sowie die 2- bis 4-fache NMDA-Re-zeptor antagonistische Wirkung der Verbindung der Formel I im Vergleich zu dem entsprechenden Racemat keineswegs von einer ähnlichen Steigerung der Nebenwirkungen, z.B. der kardiovaskulären Wirkungen, begleitet ist. From the experiments mentioned it follows that the strong LH secretion-inhibiting effect, the significant increase (25-fold) in the muscle-relaxing effect and the 2 to 4-fold NMDA receptor antagonistic effect of the compound of the formula I compared to that corresponding racemate in no way from a similar increase in side effects, e.g. of cardiovascular effects.
Die Verbindung der Formel I kann als solche oder in Form ihrer pharmazeutisch verträglichen Salze verabreicht werden, die den gleichen Grad an Aktivität besitzen wie die Verbindung der Formel I. The compound of formula I can be administered as such or in the form of its pharmaceutically acceptable salts which have the same level of activity as the compound of formula I.
Gegenstand der Erfindung ist ferner ein pharmazeutisches Präparat enthaltend die Verbindung der Formel I oder ein pharmazeutisch verträgliches Salz derselben zusammen mit einem pharmazeutischen Träger- oder Verdünnungsmittel. The invention further relates to a pharmaceutical preparation containing the compound of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier or diluent.
Die Verbindung der Formel I kann in üblicher Weise, insbesondere enterai, vorzugsweise oral oder parenteral verabreicht werden. Die Verbindung der Formel I kann als solche oder zusammen mit üblichen pharmazeutischen Trägermitteln verabreicht werden. Beispielsweise zur oralen Verabreichung z.B. in Form von Tabletten oder Kapseln, kann die Verbindung der Formel I mit üblichen pharmazeutisch verträglichen Exzipienzen vermischt werden, z.B. inerten Verdünnungsmitteln, wie Lactose, Mannit, Calciumsulfat, mikrokristalline Cellulose; Zerfallhilfsmitteln, z.B. Stärke, Natriumcarboxymethylcellulo-se, Natriumcarboxymethyistärke, Algininsäure, Crospovidon; Bindemitteln, wie Ceiluiosederivate (Methyl-, Hydroxymethyl-, Hydroxypropylmethyl-), Povidon, Gelatine; Schmiermittel, z.B. Siliciumdioxid, Stearinsäure, Magnesium- oder Calciumstearat; hydrierte Oele, wie Rizinusöl, Glycerolester, z.B. Pal-mitostearat und/oder Geschmacksstoffe, Farbstoffe und Süsstoffe, Die Tabletten können nicht überzogen oder in bekannter Weise überzogen sein, um hierdurch Zerfall und Absorption im Gastrointestinal-trakt zu verzögern und so eine verzögerte Wirkung über einen längeren Zeitraum zu erhalten. Parenterale Präparate liegen vorzugsweise in Form von sterilen injizierbaren wässerigen Lösungen vor. Solche wässerigen Lösungen sollten, wenn erforderlich, gepuffert sein und isotonisch durch Zugabe von Salz vorliegen. Wahlweise kann auch ein Konservierungsmittel, z.B. Benzylalkohol, zugegeben werden. The compound of the formula I can be administered in a conventional manner, in particular enterally, preferably orally or parenterally. The compound of the formula I can be administered as such or together with customary pharmaceutical carriers. For example, for oral administration e.g. in the form of tablets or capsules, the compound of formula I can be mixed with conventional pharmaceutically acceptable excipients, e.g. inert diluents, such as lactose, mannitol, calcium sulfate, microcrystalline cellulose; Disintegrants, e.g. Starch, sodium carboxymethyl cellulose, sodium carboxymethyl starch, alginic acid, crospovidone; Binders, such as ceiliosis derivatives (methyl, hydroxymethyl, hydroxypropylmethyl), povidone, gelatin; Lubricants, e.g. Silicon dioxide, stearic acid, magnesium or calcium stearate; hydrogenated oils such as castor oil, glycerol esters, e.g. Pal-mitostearate and / or flavors, colorings and sweeteners, The tablets may not be coated or coated in a known manner in order to delay decay and absorption in the gastrointestinal tract and thus to have a delayed effect over a longer period of time. Parenteral preparations are preferably in the form of sterile injectable aqueous solutions. Such aqueous solutions should, if necessary, be buffered and isotonic by adding salt. A preservative, e.g. Benzyl alcohol can be added.
Eine Einheitsdosis kann zwischen etwa 0.25 bis etwa 400 mg der Verbindung der Formel I oder ihres pharmazeutisch verträglichen Salzes enthalten. A unit dose can contain between about 0.25 to about 400 mg of the compound of formula I or its pharmaceutically acceptable salt.
Die pharmazeutischen Präparate können nach hierfür üblichen Verfahren hergestellt werden. The pharmaceutical preparations can be produced by methods customary for this.
Zur Herstellung von Tabletten kann die Verbindung der Formel I mit Lactose vermischt werden und mit Wasser, 0.5% Natriumalginat oder 5% Hydroxypropylmethylcellulose-Lösung granuliert werden. Das getrocknete Granulat wird in Gegenwart von etwa 20% Maisstärke und 1% Magnesiumstearat zu Tabletten verpresst. Auf diese Weise erhält man z.B. Tabletten, die die im folgenden genannten Bestandteile enthalten: To prepare tablets, the compound of the formula I can be mixed with lactose and granulated with water, 0.5% sodium alginate or 5% hydroxypropylmethyl cellulose solution. The dried granules are pressed into tablets in the presence of about 20% corn starch and 1% magnesium stearate. In this way you get e.g. Tablets that contain the following ingredients:
Bestandteile Components
Tablette tablet
Gewicht (mg) Weight (mg)
Verbindung der Formel I Monohydrat Compound of formula I monohydrate
50 50
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97 97
Maisstärke Cornstarch
40 40
Hydroxypropylmethylcellulose Hydroxypropylmethyl cellulose
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2 2nd
Siliciumdioxid Silicon dioxide
1 1
200 200
Die Tabletten, die mit einer Bruchlinie versehen sind, können oral in einer Dosis von einer halben oder einer ganzen Tablette 1 bis 4 mal täglich verabreicht werden. The tablets with a break line can be administered orally in a dose of half or a whole tablet 1 to 4 times a day.
Kapsein können den aktiven Wirkstoff allein oder im Gemisch mit einem inerten festen Excipienzen, wie z.B. oben genannt, enthalten. Capsules can be the active ingredient alone or in admixture with an inert solid excipient, e.g. mentioned above.
Kapseln, die die im folgenden genannten Bestandteile enthalten, können nach hierfür üblichen Verfahren hergestellt und in einer Dosis von 1 Kapsel 1 bis 4 mal täglich verabreicht werden. Capsules containing the components mentioned below can be produced according to the usual methods and administered in a dose of 1 capsule 1 to 4 times a day.
Bestandteile Components
Kapsei Capsule
Gewicht (mg) Weight (mg)
Verbindung der Formel I - Monohydrat Compound of formula I - monohydrate
50 50
festes inertes Exzipienz solid inert excipience
250 250
(Maisstärke, Lactose, Aerosil, Magnesiumstearat) (Corn starch, lactose, aerosil, magnesium stearate)
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Aehnlich können Tabletten und Kapseln, die 25 mg und 100 mg der Verbindung der Formel I enthalten, hergestellt werden. Similarly, tablets and capsules containing 25 mg and 100 mg of the compound of formula I can be prepared.
Die folgende injizierbare Lösung wird mit der angegebenen Menge an Wirkstoff nach üblichen Verfahren formuliert. Die injizierbare Lösung kann einmal täglich verabreicht werden. The following injectable solution is formulated with the specified amount of active ingredient by conventional methods. The injectable solution can be administered once a day.
Bestandteile Sterile injizierbare Lösung Gewicht (mg/ml) Ingredients Sterile Injectable Solution Weight (mg / ml)
Verbindung der Formel I - Monohydrat 25 Compound of the formula I - monohydrate 25
Natriumchlorid 7.0 Sodium chloride 7.0
Kaliumdihydrogenphosphat 3.63 Potassium dihydrogen phosphate 3.63
Dinatriumhydrogenphosphat 5.68 Disodium hydrogen phosphate 5.68
Benzylalkohol 9.0 Benzyl alcohol 9.0
Wasser zur Injektion q.s. auf 1 ml Water for injection q.s. to 1 ml
Die Lösungen können durch ein 0.2 um steriles Filter filtriert und aseptisch in Ampullen abgefüllt werden. Die Ampullen können mit Kohlendioxid begast werden. The solutions can be filtered through a 0.2 µm sterile filter and filled aseptically into ampoules. The ampoules can be gassed with carbon dioxide.
Die Erfindung betrifft ferner die Verwendung der Verbindung der Formel I oder ihrer pharmazeutisch verträglichen Salze zur Herstellung eines pharmazeutischen Präparates zur Behandlung von Erkrankungen, die mit der LH-Sekretion zusammenhängen; erhöhtem Muskeltonus, zerebraler Ischaemie, Angstzuständen, Schizophrenie, Depression, ZNS-degenerativen Krankheiten, Tinnitus, Epilepsie oder zur Bekämpfung von Schmerzen. The invention further relates to the use of the compound of formula I or its pharmaceutically acceptable salts for the manufacture of a pharmaceutical preparation for the treatment of diseases which are associated with LH secretion; increased muscle tone, cerebral ischemia, anxiety, schizophrenia, depression, CNS degenerative diseases, tinnitus, epilepsy or to combat pain.
In den nachfolgenden Beispielen sind die Temperaturen in Grad-Celsius angegeben und sind unkorri-giert. Die [a]D20- Werte sind ebenfalls unkorrigiert. In the following examples, the temperatures are given in degrees Celsius and are uncorrected. The [a] D20 values are also uncorrected.
Beispiel: rR-(EVl-4-(3-Phosphono-2-propenvh-piperazin-2-carbon- säure a) (RÌ-1.4-Bis(phenvlmethvli-piperazin-2-carbonsäure (1 R.2S.5RÌ-5-methvl-2-d -methvIethvDcvclohexvlester Example: rR- (EVl-4- (3-phosphono-2-propenvh-piperazin-2-carboxylic acid a) (RÌ-1.4-bis (phenvlmethvli-piperazin-2-carboxylic acid (1 R.2S.5RÌ-5 -methvl-2-d -methvIethvDcvclohexvlester
Zu einer Lösung von 761 g 1,4-Dibenzyl-piperazin-2-carbonsäureethylester [hergestellt gemäss E. Jucker und E. Rissi, Helv.Chim. Acta 45, 2383 (1962)] und 458 g (-)-Menthol werden bei 45° 15g NaH (55-60% Dispersion) und 1 I Toluol gegeben. Sodann werden etwa 700 ml des Lösungsmittels langsam durch Destillation entfernt und kontinuierlich durch neue Toluolportionen ersetzt (die Reaktion wird durch TLC, Ethylacetat/Hexan 1:3 verfolgt). Das Gemisch wird auf Raumtemperatur abgekühlt, mit 1.25 I 2N HCl und 6 I Diethylether versetzt und während 1 Stunde energisch gerührt. Der kristalline Niederschlag wird abfiltriert und mit Diethylether und 0.1 N HCl gewaschen. Das Rohprodukt wird aus Ethanol/0.2 N HCl umkristallisiert, wobei man das Hydrochlorid-Hydrat der Titelverbindung, [oc]^° = +18.5° (c = 1.2 in CHCI3) erhält, das ohne weitere Reinigung in der nächsten Stufe eingesetzt wird. To a solution of 761 g of 1,4-dibenzyl-piperazine-2-carboxylic acid ethyl ester [prepared according to E. Jucker and E. Rissi, Helv.Chim. Acta 45, 2383 (1962)] and 458 g of (-) menthol are added at 45 ° to 15 g of NaH (55-60% dispersion) and 1 l of toluene. Then about 700 ml of the solvent are slowly removed by distillation and continuously replaced by new toluene portions (the reaction is monitored by TLC, ethyl acetate / hexane 1: 3). The mixture is cooled to room temperature, mixed with 1.25 I 2N HCl and 6 I diethyl ether and stirred vigorously for 1 hour. The crystalline precipitate is filtered off and washed with diethyl ether and 0.1 N HCl. The crude product is recrystallized from ethanol / 0.2 N HCl, giving the hydrochloride hydrate of the title compound, [oc] ^ ° = + 18.5 ° (c = 1.2 in CHCI3), which is used in the next step without further purification.
b) (RVPioerazin-2-carbonsäure i 1 R.2S.5Ri-5-methvl-2-( 1 -methvIethvO-cvclohexvlester b) (RVPioerazin-2-carboxylic acid i 1 R.2S.5Ri-5-methvl-2- (1 -methvIethvO-cvclohexvlester
210 g der nach Stufe a) hergestellten Verbindung, 2 I Ethanol und 10.5 g Pd/C (10%) werden bei Raumtemperatur und Normaldruck 7 Stunden hydriert. Das Gemisch wird filtriert und im Vakuum eingedampft. Der Rückstand wird mit ethanolischer HCl behandelt, der Niederschlag filtriert und mit Etha-nol/Diethylether (1:1) gewaschen. Das Produkt wird aus Wasser/Methanol/Ethylacetat umkristallisiert, wobei man das Dihydrochlorid der Titelverbindung, Smp. 225-226°, [a]^0 = -52.0° (c = 1.34 in Wasser) 210 g of the compound prepared according to step a), 2 l of ethanol and 10.5 g of Pd / C (10%) are hydrogenated for 7 hours at room temperature and normal pressure. The mixture is filtered and evaporated in vacuo. The residue is treated with ethanolic HCl, the precipitate is filtered and washed with ethanol / diethyl ether (1: 1). The product is recrystallized from water / methanol / ethyl acetate, the dihydrochloride of the title compound, mp. 225-226 °, [a] ^ 0 = -52.0 ° (c = 1.34 in water)
erhält. Das Dihydrochlorid wird mit Diethylether/aq.Ammoniak behandelt, die organische Phase wird zur Trockne eingedampft, wobei man die Titelverbindung, Smp. 50-52°, [a]*0 = -56.7° (c = 1.05 in CHCI3) erhält. receives. The dihydrochloride is treated with diethyl ether / aq. Ammonia, the organic phase is evaporated to dryness, giving the title compound, mp 50-52 °, [a] * 0 = -56.7 ° (c = 1.05 in CHCl 3).
c) rR-(Eïl-4-(3-Diethoxvphosphinvl-2-propenvh-piperazin-2-carbon-sâure-(1R.2S.5RV5-methvl-2-11 -methvlethvhcvclohexvlester c) rR- (Eïl-4- (3-Diethoxvphosphinvl-2-propenvh-piperazin-2-carbon-acidic- (1R.2S.5RV5-methvl-2-11 -methvlethvhcvclohexvlester
11.3 g der nach Stufe b) hergestellten freien Base und 5.9 ml Triethylamin in 90 ml Tetrahydrofuran werden unter Rühren bei -30° innerhalb 30 Minuten mit 10.7 g 3-Brompropen-2-yl-phosphonsäurediethyl-ester [hergestellt gemäss K. Hemmi, H. Takeno, M. Hashimoto und T. Kamiya, Chem.Pharm.Bull 30. 111 (1982)] in 45 ml Tetrahydrofuran versetzt. Das Gemisch wird weiter bei -25° während 20 Stunden gerührt. Der Niederschlag wird abfiltriert und die Lösung unter vermindertem Druck konzentriert. Der erhaltene Syrup wird an Kieselgel mit Dichlormethan und Zugabe von einer steigenden Konzentration eines 11.3 g of the free base prepared according to stage b) and 5.9 ml of triethylamine in 90 ml of tetrahydrofuran are stirred with -30 ° within 30 minutes with 10.7 g of diethyl 3-bromopropen-2-ylphosphonate [prepared according to K. Hemmi, H Takeno, M. Hashimoto and T. Kamiya, Chem. Pharm.Bull 30, 111 (1982)] in 45 ml of tetrahydrofuran. The mixture is further stirred at -25 ° for 20 hours. The precipitate is filtered off and the solution is concentrated under reduced pressure. The syrup obtained is on silica gel with dichloromethane and the addition of an increasing concentration of one
7 7
5 5
10 10th
15 15
20 20th
25 25th
30 30th
35 35
40 40
45 45
50 50
55 55
CH 675 125 A5 CH 675 125 A5
Gemisches von konz. Ammoniak/Ethanol (1:19), das nach 2 Stunden 10% erreicht, chromatographiert. Die mit Dichlormethan/konz. Ammoniak/Ethanol 200:1:19 (rf = 0.35) eluierte Fraktion wird isoliert und im Vakuum konzentriert, wobei man die Titelverbindung als Oel, [a]p° = -56.0° (c = 1.3 in 2N HCl) erhält. Mixture of conc. Ammonia / ethanol (1:19), which reaches 10% after 2 hours, chromatographed. The with dichloromethane / conc. Ammonia / ethanol 200: 1:19 (rf = 0.35) eluted fraction is isolated and concentrated in vacuo to give the title compound as an oil, [a] p ° = -56.0 ° (c = 1.3 in 2N HCl).
Durch Behandlung mit ethanolischem HCI/Ether erhält man das Dihydrochlorid, Smp. 157-163°, [a]2D° = -48.2° (c = 1.4 in 2N HCl). Treatment with ethanolic HCl / ether gives the dihydrochloride, mp. 157-163 °, [a] 2D ° = -48.2 ° (c = 1.4 in 2N HCl).
d) fR-fE)1-4-f3-Diethoxvphosphinvl-2-propenvfl-piperazin-2-carbonsäure d) fR-fE) 1-4-f3-diethoxvphosphinvl-2-propenvfl-piperazin-2-carboxylic acid
Zu einer Lösung von 5.79 g der nach Stufe c) hergestellten Verbindung in 58 ml abs. CH2CI2 werden unter Rühren bei -30° innerhalb von 30 Minuten 22.8 ml einer Lösung von- Bortrichlorid in 1, 2-Dichloret-han (etwa 2.2 M) gegeben. Das Reaktionsgemisch wird 1 Stunde bei -25° und 3h Stunden bei 0° gerührt. Sodann werden bei 0° 50 ml Wasser dazugegeben, das Gemisch durch Zugabe von 2N NaOH neutralisiert und zwischen Wasser und CH2CI2 verteilt. Die wässrige Phase wird im Vakuum zur Trockne eingedampft, der Rückstand in CHCI3 aufgenommen, filtriert, getrocknet (Na2S04) und im Vakuum zur Trockne eingedampft, wobei man die Titelverbindung erhält, die ohne weitere Reinigung in der nächsten Stufe verwendet wird. To a solution of 5.79 g of the compound prepared according to step c) in 58 ml of abs. 22.8 ml of a solution of boron trichloride in 1,2-dichloroethane (about 2.2 M) are added to CH2Cl2 with stirring at -30 ° within 30 minutes. The reaction mixture is stirred at -25 ° for 1 hour and at 0 ° for 3 hours. Then 50 ml of water are added at 0 °, the mixture is neutralized by adding 2N NaOH and partitioned between water and CH2Cl2. The aqueous phase is evaporated to dryness in vacuo, the residue is taken up in CHCl 3, filtered, dried (Na2S04) and evaporated to dryness in vacuo to give the title compound which is used in the next step without further purification.
Eine analytische Probe wird mit Hilfe von HPLC (Nucleosil RP-8, H2O/CH3OH 3:2) gereinigt, wobei man einen Schaum [a]^° = -18.0° (c = 1.1 in 0.5N HCl) erhält. An analytical sample is purified using HPLC (Nucleosil RP-8, H2O / CH3OH 3: 2), giving a foam [a] ^ ° = -18.0 ° (c = 1.1 in 0.5N HCl).
360 MHz 1H-NMR (DNS0, 150°C): 1.24 (6H, t, J = 7.0 Hz), 2.26 (1H, dxdxd, J = 11.3 x 9.0 x 3.3 Hz), 2.35 (1H, dxd, J = 11.3 x 8.6 Hz), 2.52-2.58 (1H, m), 2.77 (1H, dxdxd, J = 12.1 x 9.0 x 3.3 Hz), 2.83 (1H, dxdxd, J = 11.3 x 3.3 x 1.7 Hz), 2.99 (1 H, dxt, J =, 12.1 x 3.9 Hz), 3.10 -3.15 (2H, m), 3.33 (1H, dxd, J = 8.6 x 3.3 Hz), 3.97 (4H, dxq, J = 8.6 x 7.0 Hz), 5.50 (2H, broad), 5.88 (1H, dxdxt, J = 21.5 x 17.1 x 2.1 Hz), 6.52 (1H, dxdxt, J = 22.0 x 17.1 x 5.6 Hz). 360 MHz 1H-NMR (DNS0, 150 ° C): 1.24 (6H, t, J = 7.0 Hz), 2.26 (1H, dxdxd, J = 11.3 x 9.0 x 3.3 Hz), 2.35 (1H, dxd, J = 11.3 x 8.6 Hz), 2.52-2.58 (1H, m), 2.77 (1H, dxdxd, J = 12.1 x 9.0 x 3.3 Hz), 2.83 (1H, dxdxd, J = 11.3 x 3.3 x 1.7 Hz), 2.99 (1 H , dxt, J =, 12.1 x 3.9 Hz), 3.10 -3.15 (2H, m), 3.33 (1H, dxd, J = 8.6 x 3.3 Hz), 3.97 (4H, dxq, J = 8.6 x 7.0 Hz), 5.50 (2H, broad), 5.88 (1H, dxdxt, J = 21.5 x 17.1 x 2.1 Hz), 6.52 (1H, dxdxt, J = 22.0 x 17.1 x 5.6 Hz).
e) fR-(E)1-4-(3-Phosphono-2-propenvl)-piperazin-2-cabonsäure e) fR- (E) 1-4- (3-phosphono-2-propenvl) piperazin-2-cabonic acid
3.9 g des nach Stufe d) erhaltenen Rohproduktes werden in 300 ml abs. CH2CI2 gelöst, bei Raumtemperatur mit 9.6 ml Bromtrimethylsilan versetzt und 16 Stunden gerührt. Das Reaktionsgemisch wird eingedampft, der Rückstand in Wasser aufgenommen, 1 Stunde gerührt und filtriert. Der pH-Wert der Lösung wird durch Zugabe von Dowex 1 x 4 (OH-Form) auf 6 gebracht und das Gemisch auf eine Säule mit Do-wex 1x4 (Acetat-Form) aufgeschichtet. Durch Eluierung mit einem Gradienten von wässeriger Essigsäure (0.05 bis 0.25 N) und Eindampfen im Vakuum zur Trockne erhält man einen Schaum. Der Schaum wird aus H2O/CH3OH kristallisiert und aus H2O/C2H5OH umkristallisiert, wobei man die Titelverbindung als Monohydrat, Smp. 206° (Zers.), [et]20 = -21.6° (c = 1.1 in 2N HCl) erhält. Die absolute Konfiguration ist durch eine chemische Korrelation mit D-Asparagin abgeleitet und durch Röntgenstrukturanalyse bestätigt. 3.9 g of the crude product obtained after stage d) are abs in 300 ml. CH2CI2 dissolved, mixed with 9.6 ml of bromotrimethylsilane at room temperature and stirred for 16 hours. The reaction mixture is evaporated, the residue is taken up in water, stirred for 1 hour and filtered. The pH of the solution is brought to 6 by adding Dowex 1 x 4 (OH form) and the mixture is layered on a column with Do-wex 1x4 (acetate form). A foam is obtained by elution with a gradient of aqueous acetic acid (0.05 to 0.25 N) and evaporation in vacuo to dryness. The foam is crystallized from H2O / CH3OH and recrystallized from H2O / C2H5OH, whereby the title compound is obtained as a monohydrate, mp. 206 ° (dec.), [Et] 20 = -21.6 ° (c = 1.1 in 2N HCl). The absolute configuration is derived from a chemical correlation with D-asparagine and confirmed by X-ray structure analysis.
Claims (6)
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| Application Number | Priority Date | Filing Date | Title |
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| GB878703749A GB8703749D0 (en) | 1987-02-18 | 1987-02-18 | Piperazinecarboxylic acid |
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| HU202111B (en) * | 1988-03-11 | 1991-02-28 | Sandoz Ag | Process for producing pharmaceutical compositions containing (r)-(e)-4--(3-phosphono-2-propenyl)-2-piperazine-carboxylic acid as active component |
| US5086072A (en) * | 1990-06-18 | 1992-02-04 | The United States Of America As Represented By The Department Of Health And Human Services | Treatment of mood disorders with functional antagonists of the glycine/nmda receptor complex |
| EP0488959A3 (en) * | 1990-11-28 | 1992-08-05 | Sandoz Ltd. | New uses of competitive nmda receptor antagonists |
| US5260286A (en) * | 1992-10-16 | 1993-11-09 | Japan Tobacco, Inc. | 2-piperidinecarboxylic acid derivatives useful as NMDA receptor antagonists |
| US6214604B1 (en) * | 1995-05-08 | 2001-04-10 | Lonza Ag | Biotechnical production process of piperazine R-α-carboxylic acids and piperazine S-α-carboxylic acid amide |
| TR199902971T2 (en) | 1997-05-12 | 2001-03-21 | Ortho-Mcneil Pharmaceutical, Inc. | Aryl substituted piperazines useful in the treatment of benign prostatic hyperplasia. |
| GB9821179D0 (en) * | 1998-09-30 | 1998-11-25 | Merck Sharp & Dohme | Therapeutic use |
| JP2008124531A (en) | 2006-11-08 | 2008-05-29 | Nec Electronics Corp | Semiconductor device and audio processor chip |
| EP3427729A1 (en) | 2017-07-13 | 2019-01-16 | Paris Sciences et Lettres - Quartier Latin | Probenecid for use in treating epileptic diseases, disorders or conditions |
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| CA1248531A (en) * | 1984-04-17 | 1989-01-10 | Jeffrey C. Watkins | 4-substituted piperazine-2-carboxylic acids |
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