DK168441B1 - [R- (E)] - 4- (3-phosphono-2-propenyl) -2-piperazine carboxylic acid, process for its preparation, pharmaceutical composition containing the compound and use thereof - Google Patents
[R- (E)] - 4- (3-phosphono-2-propenyl) -2-piperazine carboxylic acid, process for its preparation, pharmaceutical composition containing the compound and use thereof Download PDFInfo
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- DK168441B1 DK168441B1 DK079688A DK79688A DK168441B1 DK 168441 B1 DK168441 B1 DK 168441B1 DK 079688 A DK079688 A DK 079688A DK 79688 A DK79688 A DK 79688A DK 168441 B1 DK168441 B1 DK 168441B1
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- compound
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- pharmaceutically acceptable
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- pharmaceutical composition
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Classifications
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- 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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- 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
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Description
i DK 168441 B1 GB offentliggørelsesskrift nr. 2 157 685 omhandler 4-substi-tuerede 2-piperazincarboxylsyrer, som har virkning på centralnervesystemet .in DK 168441 B1 GB Publication No. 2 157 685 discloses 4-substituted 2-piperazine carboxylic acids which have an effect on the central nervous system.
Det har nu vist sig, at en af disse 4-substituerede 2-pipe-5 razincarboxylsyrer, som ikke tidligere har været specifikt beskrevet, har særlig kraftig virkning på centralnervesystemet , tol.ereres godt og har en langvarig, virkning.It has now been found that one of these 4-substituted 2-piperazinecarboxylic acids, which has not been specifically described previously, has a particularly strong effect on the central nervous system, is well tolerated and has a long-lasting effect.
Den foreliggende opfindelse angår [R-(E)]-4-(3-phosphono-2-propenyl)-2-piperazincarboxylsyre med formlen I,The present invention relates to [R- (E)] - 4- (3-phosphono-2-propenyl) -2-piperazine carboxylic acid of formula I,
OHOH
>0> 0
Il OHIl OH
ίο Γ iίο Γ i
Of·.Of ·.
H 'C00HH 'C00H
farmaceutisk acceptable salte og hydrater deraf, en fremgangsmåde til fremstilling deraf, farmaceutiske præparater indeholdende forbindelsen og anvendelse deraf til fremstilling af et farmaceutisk præparat.pharmaceutically acceptable salts and hydrates thereof, a process for the preparation thereof, pharmaceutical compositions containing the compound and their use in the preparation of a pharmaceutical composition.
15 Opfindelsen angår endvidere en fremgangsmåde til fremstilling af forbindelsen med formlen I eller salte eller hydrater deraf, hvilken fremgangsmåde er ejendommelig ved, at en forbindelse med den almene formel II, I ii a.The invention further relates to a process for the preparation of the compound of formula I or salts or hydrates thereof, characterized in that a compound of the general formula II, II ii a.
H \ C00H.H \ C00H.
DK 168441 B1 2 hvor R betegner (0Χ_4) alkyl eller aryl (^_4)alkyl, dealky-leres, hvorefter den vundne forbindelse om ønsket omdannes til et salt eller hydrat deraf.Wherein R represents (OΧ-4) alkyl or aryl (_-4) alkyl is dealkylated and then the desired compound is converted into a salt or hydrate thereof if desired.
Fremgangsmåden kan udføres på kendt måde. Fx kan dealkyler-5 ingen foretages ved silylering efterfulgt af hydrolyse af den resulterende silylester. Silylering kan udføres ved stuetemperatur med fx bromtrimethylsilan i et organisk opløsningsmiddel såsom dichlormethan eller chloroform. Den efterfølgende hydrolyse kan foretages under milde betingelser.The process can be carried out in known manner. For example, the dealkylation may be carried out by silylation followed by hydrolysis of the resulting silyl ester. Silylation can be carried out at room temperature with, for example, bromotrimethylsilane in an organic solvent such as dichloromethane or chloroform. Subsequent hydrolysis can be carried out under mild conditions.
10 Når R betegner aryl (C^) alkyl, er aryl hensigtsmæssigt en eventuelt substitueret phenylgruppe, hvor hensigtsmæssige substituenter omfatter lavere alkyl- og lavere alkoxygrupper.When R represents aryl (C 1-4) alkyl, aryl is suitably an optionally substituted phenyl group, where appropriate substituents include lower alkyl and lower alkoxy groups.
Forbindelsen med formlen I samt salte deraf kan også fås i form af hydraterne deraf, især monohydratet. Hydraterne, især 15 monohydratet, udgør ligeledes et aspekt af den foreliggende opfindelse.The compound of formula I and its salts can also be obtained in the form of their hydrates, especially the monohydrate. The hydrates, especially the monohydrate, are also an aspect of the present invention.
Forbindelsen med den almene formel II kan fremstilles som vist i nedenstående reaktionsskema: 3 DK Ί6344Ί Bl CH-C,Hc iH2C6H5 * CH3 CH3 .-'"ί r ί v I 1) (-)-menthol I jLM ! ^ N^COOCjHj _^'χοόγ'^ CHgCgHg 2) adskillelse af O^CgHj diastereoisomerer [H] CH, { X0R H CH, CHj r ♦ jrThe compound of the general formula II can be prepared as shown in the following reaction scheme: 3 CH 3 -C, H c 1 H 2 C 6 H 5 * CH 3 CH 3 .- "R ί v I 1) (-) - menthol I jLM! ^ N ^ COOCjHj 2) separation of O ^ CgHj diastereoisomers [H] CH, {X0R H CH, CHj r ♦ jr
8r Η v Ύ J8r Η v Ύ J
tC^JgMtC ^ JGM
ΨΨ
/V/ V
/ I CM, CH,/ I CM, CH,
8Ct3 Η V8Ct3 Η V
n *— LJUh :n * - LJUh:
H ’“‘QH "" Q
CHj 5 Forbindelsen med formlen I kan danne kationiske salte og syreadditionssalte. Sådanne salte fremstilles let ved standardmetoder. Kationiske salte omfatter ammonium-, natrium-, kalium-, calcium-, piperidin-, morpholin- og pyrrolidinsalte. Syreadditionssalte omfatter salte dannet med salt-, brom-10 brinte-, svovl-, methansulfon-, benzensulfon-, p-toluensul-fon- og trifluoreddikesyre.The compound of formula I can form cationic salts and acid addition salts. Such salts are readily prepared by standard methods. Cationic salts include the ammonium, sodium, potassium, calcium, piperidine, morpholine and pyrrolidine salts. Acid addition salts include salts formed with hydrochloric, hydrobromic, sulfuric, methanesulfonic, benzenesulfonic, p-toluenesulfonic and trifluoroacetic acids.
DK 168441 B1 4DK 168441 B1 4
Hydratet, især monohydratet, af forbindelsen med formlen I har særlig interessante fysisk-kemiske og øvrige egenskaber, fx hvad angår opløselighed, enkel oprensning og stabilitet. Hydratet kan fås ved krystallisation af forbindelsen med 5 formlen I fra et vandigt medium, fx som beskrevet i eksempel e), fx fra vand/methanol.The hydrate, especially the monohydrate, of the compound of formula I has particularly interesting physicochemical and other properties, for example in terms of solubility, ease of purification and stability. The hydrate can be obtained by crystallizing the compound of formula I from an aqueous medium, for example as described in Example e), for example from water / methanol.
I nedenstående eksempler er alle temperaturer angivet i °C og de er ukorrigerede. [a]D20-værdi erne er også ukorrigerede.In the examples below, all temperatures are given in ° C and are uncorrected. [a] The D20 values are also uncorrected.
EKSEMPELEXAMPLE
10 fR- (E) 1 -4- (3-Phosphono-2-nronenvl) -2-piperazincarboxylsyre a) (R) -1,4-Bis (phenylmethyl) -2-piperazincarboxylsyre-(1R,2S,5R) -methyl-2- (1-methylethyl)cyclohexylester(R) (E) 1- -4- (3-Phosphono-2-nronenyl) -2-piperazinecarboxylic acid a) (R) -1,4-Bis (phenylmethyl) -2-piperazinecarboxylic acid (1R, 2S, 5R) - methyl 2- (1-methylethyl) cyclohexyl ester
Til en opløsning af 761 g 1,4-dibenzyl-2-piperazincarboxylsyre -ethylester (fremstillet ifølge E. Jucker og E. Rissi, 15 Helv. Chim. Acta 45. s. 2383, (1962)) og 458 g (-)-menthol sættes ved 45°C 15 g NaH (55-60% dispersion) og 1 1 toluen.To a solution of 761 g of 1,4-dibenzyl-2-piperazine carboxylic acid ethyl ester (prepared according to E. Jucker and E. Rissi, 15 Helv. Chim. Acta 45. p. 2383, (1962)) and 458 g (-) menthol is added at 45 ° C 15 g NaH (55-60% dispersion) and 1 l toluene.
Ca. 700 ml af opløsningsmidlet fjernes derefter langsomt ved destillering og erstattes kontinuert af nye mængder toluen (reaktionen overvåges af TLC, ethylacetat/hexan 1:3). Bland-20 ingen afkøles til stuetemperatur, behandles med 1,25 1 2N vandig HC1 og 6 liter diethylether og omrøres kraftigt i 1 time. Det krystallinske bundfald frafiltreres og vaskes med diethylether og 0,1N vandig HC1. Råproduktet omkrystalliseres fra ethanol/0,2N vandig HC1, hvorved der fås hydrochlorid-25 hydratet af titelforbindelsen, [a]D20 = +18,5° (c = 1,2 i CHC13), som uden yderligere oprensning anvendes i det næste trin.Ca. 700 ml of the solvent is then slowly removed by distillation and continuously replaced by new amounts of toluene (the reaction is monitored by TLC, ethyl acetate / hexane 1: 3). The mixture is cooled to room temperature, treated with 1.25 L of 2N aqueous HCl and 6 liters of diethyl ether and stirred vigorously for 1 hour. The crystalline precipitate is filtered off and washed with diethyl ether and 0.1 N aqueous HCl. The crude product is recrystallized from ethanol / 0.2N aqueous HCl to give the hydrochloride hydrate of the title compound, [α] D20 = + 18.5 ° (c = 1.2 in CHCl13), which is used in the next step without further purification. .
b) Piperazincarboxylsyre(IR,2S,5R)-5-methyl-2-(1-methylethyl) cyclohexylesterb) Piperazine carboxylic acid (IR, 2S, 5R) -5-methyl-2- (1-methylethyl) cyclohexyl ester
30 210 g af produktet fra trin a) i 2 1 ethanol og 10,5 g Pd/C30 210 g of the product of step a) in 2 L of ethanol and 10.5 g of Pd / C
(10%) hydrogeneres 7 timer ved stuetemperatur og normalt 5 DK 168441 B1 tryk, filtreres derefter og inddampes i vakuum. Remanensen behandles med ethanolisk HC1, og bundfaldet filtreres og vaskes med ethanol/diethylether (1:1). Produktet omkrystalliseres fra vand/methanol/ethylacetat til dannelse af dihydro-5 chloridformen af den omhandlede forbindelse, smeltepunkt 225-226°C, [a]D20 = -52,0° (c = 1,34 i vand). Dihydrochloridet behandles med diethylether/vandig ammoniak, og den organiske fase inddampes til tørhed, hvorved fås titel forbindelsen med smeltepunkt 50-52°C, [a]D20 - -56,7° (c = 1,05 i CHC13) .(10%) is hydrogenated for 7 hours at room temperature and usually under pressure, then filtered and evaporated in vacuo. The residue is treated with ethanolic HCl and the precipitate is filtered and washed with ethanol / diethyl ether (1: 1). The product is recrystallized from water / methanol / ethyl acetate to give the dihydrochloride form of the subject compound, mp 225-226 ° C, [α] D 20 = -52.0 ° (c = 1.34 in water). The dihydrochloride is treated with diethyl ether / aqueous ammonia and the organic phase is evaporated to dryness to give the title compound, mp 50-52 ° C, [α] D20-56.7 ° (c = 1.05 in CHCl3).
10 c) [R-(E)]-4-(3-Diethoxyphosphinyl-2-propenyl)-2-piperazin-carboxylsyre(IR,2S,5R)- 5-methyl-2-(1-methylethyl)cyclohexyl-esterC) [R- (E)] - 4- (3-Diethoxyphosphinyl-2-propenyl) -2-piperazine carboxylic acid (IR, 2S, 5R) - 5-methyl-2- (1-methylethyl) cyclohexyl ester
Til en omrørt opløsning af 11,3 g af den frie base fra trin b) og 5,9 ml triethylamin i 90 ml tetrahydrofuran sættes 15 under omrøring ved -30°C i løbet af 30 minutter 10,7 g 3-brompropen-2-yl-phosphonsyre-diethylester (fremstillet i henhold til K. Hemmi, H. Takeno, M. Hashimoto og T. Kamiya, Chem. Pharm. Bull 30, s. 111, 1982) i 45 ml tetrahydrofuran. Omrøringen fortsættes ved -25°C i 20 timer. Efter frafil-20 trering af bundfaldet koncentreres opløsningen ved reduceret tryk, og den resulterende "sirup" chromatograferes på silica-gel under anvendelse af dichlormethan med tilsætning af en stigende koncentration af en 1:19 koncentreret vandig ammo-niak/ethanol-blanding, som når 10% efter 2 timer. Den frak-25 tion, som elueres med dichlormethan/koncentreret vandig ammoniak/ethanol, 200:1:19 (rf = 0,35) isoleres og koncentreres i vakuum, hvorved titelforbindelsen fås i form af en olie, [a]D20 = -56,0° (c = 1,3 i 2N vandig HC1) . Ved at behandle produktet med ethanolisk HCl/ether fås dihydrochlo-30 ridet med smeltepunkt 157-163°C, [æ]D20 = -48,2° (c = 1,4 i 2N HC1).To a stirred solution of 11.3 g of the free base from step b) and 5.9 ml of triethylamine in 90 ml of tetrahydrofuran is added with stirring at -30 ° C over 30 minutes 10.7 g of 3-bromopropene-2 -yl-phosphonic acid diethyl ester (prepared by K. Hemmi, H. Takeno, M. Hashimoto and T. Kamiya, Chem. Pharm. Bull. 30, p. 111, 1982) in 45 ml of tetrahydrofuran. Stirring is continued at -25 ° C for 20 hours. After filtration of the precipitate, the solution is concentrated at reduced pressure and the resulting "syrup" is chromatographed on silica gel using dichloromethane with the addition of a rising concentration of a 1:19 concentrated aqueous ammonia / ethanol mixture which reaches 10% after 2 hours. The fraction eluted with dichloromethane / concentrated aqueous ammonia / ethanol, 200: 1: 19 (rf = 0.35) is isolated and concentrated in vacuo to give the title compound as an oil, [α] D20 = - 56.0 ° (c = 1.3 in 2N aqueous HCl). By treating the product with ethanolic HCl / ether, the dihydrochloride is obtained, mp 157-163 ° C, [α] D20 = -48.2 ° (c = 1.4 in 2N HCl).
DK 168441 B1 6 d) [R-(E)]-4-(3-Diethoxyphosphinyl-2-propenyl)-2-piperazin-carboxylsyreD) [R- (E)] - 4- (3-Diethoxyphosphinyl-2-propenyl) -2-piperazine carboxylic acid
Til en omrørt opløsning af 5,79 g af det ifølge trin c) vundne produkt i 58 ml absolut CH2C12 sættes ved -30°C i 5 løbet af 30 minutter 22,8 ml af en opløsning af bortrichlorid i 1,2-dichlorethan (ca. 2,2M). Reaktionsblandingen omrøres i 1 time ved -25°C og i 3 1/2 time ved 0°C. Ved 0°C tilsættes 50 ml vand, og blandingen neutraliseres ved tilsætning af 2N vandig NaOH og fordeles mellem H20 og CH2C12. Den vandige 10 fase inddampes til tørhed i vakuum, remanensen optages i CHC13, filtreres, tørres (NaS04) og inddampes til tørhed i vakuum, hvorved der fås titelforbindelsen, som uden yderligere oprensning anvendes i det næste trin.To a stirred solution of 5.79 g of the product obtained in step c) in 58 ml of absolute CH 2 Cl 2 is added at -30 ° C for 5 minutes over 22.8 ml of a solution of boron trichloride in 1,2-dichloroethane ( about 2.2M). The reaction mixture is stirred for 1 hour at -25 ° C and for 3 1/2 hours at 0 ° C. At 0 ° C, 50 ml of water is added and the mixture is neutralized by the addition of 2N aqueous NaOH and partitioned between H2 O and CH2 Cl2. The aqueous phase is evaporated to dryness in vacuo, the residue is taken up in CHCl3, filtered, dried (NaSO4) and evaporated to dryness in vacuo to give the title compound which is used in the next step without further purification.
En analytisk prøve renses ved HPLC (Nucleosil RP-8, H20/CH30H 15 3:2), hvilket giver et skum, [a]D20 = -18,0° (c = 1,1 i 0,5NAn analytical sample is purified by HPLC (Nucleosil RP-8, H 2 O / CH 3 OH 3 3: 2) to give a foam, [α] D20 = -18.0 ° (c = 1.1 in 0.5N
HC1) .HCl).
360 MHz 'H-NMR (DMSO, 150°C) : 1,24 (6H, t, J = 7,0 Hz), 2,26 (IH, dxdxd, J = 11,3 x 9,0 x 3,3 Hz), 2,35 (IH, dxd, J = 11,3 x 8,6 Hz), 2,52 - 2,58 (IH, m), 2,77 (IH, dxdxd, J = 12,1 x 20 9,0 x 3,3 Hz), 2,83 (IH, dxdxd, J = 11,3 x 3,3 x 1,7 Hz), 2,99 (IH, dxt, J = 12,1 x 3,9 Hz), 3,10-3,15 (2H, m), 3,33 (IH, dxd, J - 8,6 x 3,3 Hz), 3,97 (4H, dxq, J = 8,6 x 7,0 Hz), 5,50 (2H, bred), 5,88 (IH, dxdxt, J = 21,5 x 17,1 x 2,1 Hz), 6,52 (IH, dxdxt, J = 22,0 x 17,1 x 5,6 Hz).360 MHz 1 H NMR (DMSO, 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 20 9.0 x 3.3 Hz), 2.83 (1H, dxdxd, J = 11.3 x 3.3 x 1.7 Hz), 2.99 (1H, 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, wide), 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).
25 e) [R-(E)]-4-(3-Phosphono-2-propenyl)-2-piperazincarboxylsyre 3,9 af den rå forbindelse fra trin d) opløses i 300 ml absolut CH2C12, behandles ved stuetemperatur med 9,6 ml bromtri-methylsilan og omrøres i 16 timer. Reaktionsblandingen inddampes, og remanensen optages i vand, omrøres i 1 time og 30 filtreres. Opløsningens pH justeres til 6 ved tilsætning af "Dowex" 1x4 (OH-form), og blandingen placeres på toppen af en søjle indeholdende "Dowex" 1x4 (acetatform) . Eluering med en gradient af vandig eddikesyre (0,05-0,25N) giver efter DK 168441 B1 7 koncentrering til tørhed i vakuum et skum. Skummet krystalliseres fra H20/CH30H og omkrystalliseres fra H20/C2H50Hf hvilket giver titelforbindelsen som sit monohydrat, smeltepunkt 206°C (sønderdeling). [cn]D20 - -21,6° (c 1,1 i 2N HC1). Den 5 absolutte konfiguration er afgjort ud fra kemisk korrelation med D-asparagin og bekræftet ved røntgenstrukturanalyse.E) [R- (E)] - 4- (3-Phosphono-2-propenyl) -2-piperazine carboxylic acid 3.9 of the crude compound of step d) is dissolved in 300 ml of absolute CH 2 Cl 2, treated at room temperature with 9, 6 ml of bromotrimethylsilane and stir for 16 hours. The reaction mixture is evaporated and the residue is taken up in water, stirred for 1 hour and filtered. The pH of the solution is adjusted to 6 by adding "Dowex" 1x4 (OH form) and the mixture is placed on top of a column containing "Dowex" 1x4 (acetate form). Elution with a gradient of aqueous acetic acid (0.05-0.25N) gives, according to DK 168441 B1 7, concentration to dryness in vacuum. The foam is crystallized from H 2 O / CH 3 OH and recrystallized from H 2 O / C 2 H 50 Hf to give the title compound as its monohydrate, mp 206 ° C (dec.). [cn] D20 - -21.6 ° (c 1.1 in 2N HCl). The 5 absolute configuration is determined from chemical correlation with D-asparagine and confirmed by X-ray structure analysis.
Forbindelsen med formlen I udviser værdifuld farmakologisk aktivitet, hvilket indikerer en anvendelse som farmaceutikum, fx til terapi. Især besidder forbindelsen luteiniserende 10 hormon- (LH) og testosteronsekretioninhiberende aktivitet i følgende test:The compound of formula I exhibits valuable pharmacological activity, indicating a use as a pharmaceutical, eg for therapy. In particular, the compound possesses luteinizing hormone (LH) and testosterone secretion inhibitory activity in the following tests:
Voksne hanrotter af Wistar-stammen (SIV, Kissleg, Vesttyskland, 200-300 g) fik testforbindelsen administreret intra-peritonealt. 2 timer senere blev rotterne aflivet ved dekapi-15 tering, og der blev taget blodprøver. Serum-LH blev målt ved hjælp af bioassay baseret på fremstilling af testosteron ved hjælp af disperse, kollagenasebehandlede interstitielle Leydig-celler fra rotter påvirket af serum indeholdende LH eller af rotte-LH-standard; serumtestosteron måltes ved hjælp 20 af radioimmunoassay (125-J-T, cis, Medipro Teufen, Schweiz) [jfr. E. del Pozo, A. Podesta, A. Solano, J. Calaf, M. Marko, i "Biorhytms and Stress in the Physiopathology of Reproduction, P. Pancheri and L. Zichella (red.), Hemisphere Publishing Co., Washington, 2. 389-389, 1988].Adult male rats of the Wistar strain (SIV, Kissleg, West Germany, 200-300 g) received the test compound administered intraperitoneally. Two hours later, the rats were sacrificed by decapitation and blood samples were taken. Serum LH was measured by bioassay based on testosterone production using dispersed, collagenase-treated interstitial Leydig cells from rats affected by serum containing LH or by rat LH standard; Serum testosterone was measured by radioimmunoassay (125-J-T, cis, Medipro Teufen, Switzerland) [cf. E. del Pozo, A. Podesta, A. Solano, J. Calaf, M. Marko, in "Biorhythms and Stress in the Physiopathology of Reproduction, P. Pancheri and L. Zichella (ed.), Hemisphere Publishing Co., Washington , 2. 389-389, 1988].
25 Forbindelsen med formlen I inhiberer LH- og testosteronsekretion signifikant ved en dosis på 3,2 mg/kg intraperitonealt.The compound of formula I significantly inhibits LH and testosterone secretion at a dose of 3.2 mg / kg intraperitoneally.
(±)-4-(3-phosphono-2-propenyl)-2-piperazincarboxylsyre (herefter kaldt CPP-en), som er det til forbindelsen med formlen I svarende racemat, har ingen effekt på LH-sekretionen og in-30 hiberer kun svagt testosteronsekretionen.(±) -4- (3-phosphono-2-propenyl) -2-piperazine carboxylic acid (hereinafter called the CPP), which is the racemate corresponding to the compound of formula I, has no effect on LH secretion and inhibits only weak testosterone secretion.
I hunrotter inhiberer forbindelsen med formlen I LH-afhængig, spontan ægløsning i den følgende test (jfr. M. Marko og E. Fluckiger, Neuroendocrinolocrv. 30. s. 228-231, 1980) : DK 168441 B1 8In female rats, the compound of formula I inhibits LH-dependent, spontaneous ovulation in the following test (cf. M. Marko and E. Fluckiger, Neuroendocrinolocrv. 30. pp. 228-231, 1980): DK 168441 B1 8
Hunrotter af Wistar-stammen (SIV, Kissleg, Vesttyskland, 200-300 g) med regelmæssig 4-dages cyklus fik testforbindel-sen administreret intraperitonealt under proøstrus kl. 13.00 og kl. 15.00. Den følgende dag kl. 9.00, da rotterne var i 5 østrus, blev de aflivet, æggelederne blev undersøgt mikroskopisk, og antallet af æg blev talt. Ægløsningen blev kun bedømt som værende blevet inhiberet, hvis antallet af talte æg var 0. Forbindelsen med formlen I (testet som monohydratet) inhiberer signifikant spontan ægløsning ved administration i 10 doser på 2 x 3,2 mg/kg intraperitonealt (kl. 13.00 3,2 mg/kg intraperitonealt og kl. 15.00 3,2 mg/kg intraperitonealt). CPP-en udviser en meget svag inhibering af spontan ægløsning ved administration i doser på 2 x 3,2 mg/kg intraperitonealt under de samme eksperimentelle betingelser.Female rats of the Wistar strain (SIV, Kissleg, West Germany, 200-300 g) with a regular 4-day cycle were given the test compound administered intraperitoneally during the prostration at 1am. 1 pm and 2 pm 15.00. The following day at 1 p.m. 9am, when the rats were in 5 estrus, they were sacrificed, the fallopian tubes were examined microscopically, and the number of eggs was counted. The ovulation was judged to be inhibited only if the number of eggs talked was 0. The compound of formula I (tested as the monohydrate) significantly inhibits spontaneous ovulation by administration at 10 doses of 2 x 3.2 mg / kg intraperitoneally (at 1 pm 3 , 2 mg / kg intraperitoneally and at 3:00 pm 3.2 mg / kg intraperitoneally). The CPP exhibits a very weak inhibition of spontaneous ovulation when administered at doses of 2 x 3.2 mg / kg intraperitoneally under the same experimental conditions.
15 Dette indikerer derfor anvendelse af forbindelsen med formlen I i behandlingen af lidelser med en ætiologi knyttet til eller moduleret af LH-sekretion eller som har en ætiologi, i hvilken den fysiologiske regulering af LH-sekretionen er indblandet, fx i behandlingen af prostatahypertrofi, i be-20 handlingen af menopausalt syndrom samt i behandlingen af bryst- og prostatacarcinomer. Til denne anvendelse indikeres en daglig dosis i området fra ca. 1 til ca. 800 mg af forbindelsen, bekvemt indgivet i deldoser 2-4 gange pr. dag i en enhedsdosisform indeholdende fx fra ca. 0,25 til ca. 400 mg 25 af forbindelsen eller i "sustained release"-form (forsinket afgivelse).This therefore indicates the use of the compound of formula I in the treatment of disorders with an aetiology associated with or modulated by LH secretion or having an etiology in which the physiological regulation of LH secretion is implicated, e.g., in the treatment of prostate hypertrophy, in the treatment of menopausal syndrome as well as the treatment of breast and prostate carcinomas. For this use, a daily dose in the range of from 1 to approx. 800 mg of the compound conveniently administered in sub-doses 2-4 times per day. per day in a unit dosage form containing e.g. 0.25 to approx. 400 mg of the compound or in sustained release form (delayed release).
Forbindelsen med formlen I udviser muskelafslappende aktivitet hos vågne kaniner ved doser fra 0,01 til 0,05 mg/kg intravenøst (H.J. Teschendorf et al., Arch. Exp. Pharmacol., 266.The compound of formula I exhibits muscle relaxant activity in awake rabbits at doses of 0.01 to 0.05 mg / kg intravenously (H.J. Teschendorf et al., Arch. Exp. Pharmacol., 266.
30 s. 467-468, 1970). I denne test forårsager monohydratet af forbindelsen med formlen I en 50%'s inhibering af refleksmuskel tonus efter administration af 0,02 mg/kg intravenøst, hvorimod CPP-en inhiberer refleksmuskeltonus med 47% efter indgivelse af 0,5 mg/kg intravenøst; således er forbindelsen 35 med formlen I ca. 25 gange mere aktiv end det tilsvarende racemat.30, pp. 467-468, 1970). In this test, the monohydrate of the compound of formula I causes a 50% inhibition of reflex muscle tone after administration of 0.02 mg / kg intravenously, whereas the CPP inhibits reflex muscle tone by 47% after administration of 0.5 mg / kg intravenously; thus, the compound 35 of formula I is ca. 25 times more active than the corresponding breed food.
DK 168441 B1 9DK 168441 B1 9
Dette indikerer derfor anvendelse af forbindelsen med formlen I i behandlingen af forøget muskeltonus, fx i behandlingen af smertefulde muskelspasmer, som kan tilskrives statiske og funktionelle lidelser i rygsøjlen i lænde- eller halsregio-5 nen, eller efter kirurgi eller i behandlingen af spasticitet, fx som følge af multipel sclerose, sygdomme i rygmarven, cerebrovasculære ulykker, cerebralt trauma eller cerebrale lammelser. Til denne anvendelse indikeres en daglig dosis i området fra ca. 1 til ca. 800 mg af forbindelsen, bekvemt 10 administreret i deldoser 2-4 gange pr. dag i en enhedsdosis-fom indeholdende fx fra ca. 0,25 til ca. 400 mg af forbindelsen i "sustained release"-fom.This therefore indicates the use of the compound of formula I in the treatment of increased muscle tone, for example in the treatment of painful muscle spasms, which can be attributed to static and functional disorders of the spine in the lumbar or neck region, or after surgery or in the treatment of spasticity, e.g. as a result of multiple sclerosis, spinal cord diseases, cerebrovascular accidents, cerebral trauma or cerebral palsy. For this use, a daily dose in the range of from 1 to approx. 800 mg of the compound, conveniently administered in sub-doses 2-4 times per day. per day in a unit dose form containing, for example, from ca. 0.25 to approx. 400 mg of the compound in sustained release form.
Endvidere reducerer forbindelsen med formlen I iskæmiindu-ceret neuronal skade og påfølgende symptomer i den mellemste 15 cerebrale arterie (MCA)-okklusionsmodel i rotter ved en dosis på 1-30 mg/kg subcutant og især ved 3 x 10 mg/kg intraperito-nealt (jfr. A. Tamura et al., J. Cereb. Blood Flow Metabol.. i, S. 53-60, 1981, A. Sauter, M. Rudin, Stroke, 17. s. 1228-1234, 1986). Arealet af væv med infarkt måles ved hjælp af 20 MCID-imageanalyse-software (udviklet af Imaging Research Inc.) i 5 horisontale 20 jum tynde skiver sektioneret ved multiple niveauer og farvet med kresylviolet. Det totale hjernevolumen udvisende iskæmisk skade estimeres ved at addere de 5 arealer målt på de 5 skiver. Størrelsen af in-25 farkten, der bestemmes histologisk 5 dage efter okklusion af MCA, reduceres med mere end 20% efter behandling med 3 x 10 mg/kg intraperitonealt af monohydratet af forbindelsen med fomlen I (første injektion umiddelbart efter MCA okklusion, anden og tredje injektion efter 8 respektive 16 timer).Furthermore, the compound of formula I reduces ischemia-induced neuronal damage and subsequent symptoms in the middle 15 cerebral artery (MCA) occlusion model in rats at a dose of 1-30 mg / kg subcutaneously and especially at 3 x 10 mg / kg intraperitoneally. (cf. A. Tamura et al., J. Cereb. Blood Flow Metabol .. i, pp. 53-60, 1981, A. Sauter, M. Rudin, Stroke, 17. pp. 1228-1234, 1986). The area of infarcted tissue is measured by 20 MCID image analysis software (developed by Imaging Research Inc.) in 5 horizontal 20 µm thin slices sectioned at multiple levels and stained with cresyl violet. The total brain volume exhibiting ischemic damage is estimated by adding the 5 areas measured on the 5 slices. The size of the infarct, determined histologically 5 days after MCA occlusion, is reduced by more than 20% after treatment with 3 x 10 mg / kg intraperitoneally of the monohydrate of the compound with the follicle I (first injection immediately after MCA occlusion, second and third injection after 8 and 16 hours, respectively).
30 Der er således indikation for anvendelse af forbindelsen i profylaksen og terapien af tilstande associeret med cerebral iskæmi, fx slagtilfælde. Til denne anvendelse indikeres en daglig dosis i området fra ca. 25 til ca. 800 mg af forbindelsen, bekvemt administreret i deldoser 2-4 gange daglig i en 35 enhedsdosisf om indeholdende fx ca. 6 til ca. 400 mg af forbindelsen eller i "sustained release"-fom.Thus, there is indication for use of the compound in the prophylaxis and therapy of conditions associated with cerebral ischemia, e.g., stroke. For this use, a daily dose in the range of from 25 to approx. 800 mg of the compound conveniently administered in sub-doses 2-4 times daily in a 35 unit dose containing, e.g. 6 to approx. 400 mg of the compound or in sustained release form.
DK 168441 B1 10DK 168441 B1 10
Endvidere har forbindelsen med formlen I en potent, selektiv og kompetitiv antagonistisk virkning på NMDA- (N-methyl-D-asparaginsyre)receptorer. Således inhiberer monohydratet af forbindelsen med formlen I NMDA-inducerede depolarisationer i 5 det isolerede rygmarvs-assay fra en frø (P.L. Herrling,Furthermore, the compound of formula I has a potent, selective and competitive antagonistic effect on NMDA (N-methyl-D-aspartic acid) receptors. Thus, the monohydrate of the compound of formula I inhibits NMDA-induced depolarizations in the isolated spinal cord assay from a seed (P.L. Herrling,
Neuroscience. 14. s. 417-426, 1985) med en pA2-værdi på 6,8, CPP-en med pA2-værdi på 6,2, hvorved forbindelsen med formlen I er ca. 4 gange så aktiv som det tilsvarende racemat. CPP [(+)-3-(2-carboxypiperazin-4-yl)propyl- 1-phosphonsyre], som 10 er den i GB offentliggørelsesskrift nr. 2.157.685 især omhandlede forbindelse, har en pA2 værdi på 5,8.Neuroscience. 14. pp. 417-426, 1985) having a pA2 value of 6.8, the CPP having a pA2 value of 6.2, whereby the compound of formula I is ca. 4 times as active as the corresponding racemate. CPP [(+) - 3- (2-carboxypiperazin-4-yl) propyl-1-phosphonic acid], which is the compound of GB-A-2,157,685 in particular, has a pA2 value of 5.8.
I det NMDA-inducerede natriumudstrømningsassay på udsnit af rottehjerner (A. Luini, O. Goldberg og V.I. Teichberg, Proc. Natl. Acad. Sci.. USA. 78. s. 3250-3254, 1981) har monohy-15 dratet af forbindelsen med formlen I en pA2-værdi på 6,5 og CPP-en en pA2-værdi på 6,2, hvorved forbindelsen med formlen I er ca. dobbelt så aktiv som det tilsvarende racemat. CPP-en har en pA2-værdi på 6,0.In the NMDA-induced sodium efflux assay on rat brain sections (A. Luini, O. Goldberg, and VI Teichberg, Proc. Natl. Acad. Sci. USA. 78. pp. 3250-3254, 1981), the monohydrate of the compound the formula I has a pA2 value of 6.5 and the CPP a pA2 value of 6.2, wherein the compound of formula I is approx. twice as active as the corresponding breed food. The CPP has a pA2 value of 6.0.
Selektiviteten af den NMDA-antagonistiske virkning indikeres 20 ved, at den er inaktiv, ligesom CPP-en og CPP er det, i den guisgualat- og kainat-inducerede natriumudstrømningstest op til en koncentration på 1 iriM.The selectivity of the NMDA antagonistic action is indicated by being inactive, as is the CPP and CPP, in the guisgualate and kainate-induced sodium efflux test up to a concentration of 1 µM.
Som et resultat af dens NMDA-receptorantagonisme er der indikation for anvendelse af forbindelsen med formlen I i 25 behandlingen af angst, skizofreni og depression eller af degenerative lidelser i centralnervesystemet (CNS) som fx Huntington's, Alzheimer's eller Parkinson's sygdomme. Til disse anvendelser er en indikeret daglig dosis i området fra ca. 25 til ca. 800 mg af forbindelsen, bekvemt administreret 30 i deldoser 2-4 gange daglig i en enhedsdosisform fx fra ca. 6 til ca. 400 mg af forbindelsen eller i "sustained release"-form.As a result of its NMDA receptor antagonism, there is indication for use of the compound of Formula I in the treatment of anxiety, schizophrenia and depression or of central nervous system (CNS) degenerative disorders such as Huntington's, Alzheimer's or Parkinson's diseases. For these applications, an indicated daily dose is in the range of approx. 25 to approx. 800 mg of the compound, conveniently administered in sub-doses 2-4 times daily in a unit dosage form e.g. 6 to approx. 400 mg of the compound or in "sustained release" form.
Som et resultat af dens NMDA-receptorantagonisme er der yderligere indikation for anvendelse af forbindelsen med formlen DK 168441 B1 11 I i behandling af tinnitus. Til denne anvendelse indikeres en daglig dosis i området fra ca. 25 til ca. 800 mg af forbindelsen, bekvemt administreret i deldoser 2-4 gange daglig i en enhedsdosisform indeholdende fx fra ca. 6 til ca. 400 mg 5 af forbindelsen eller i "sustained release"-form.As a result of its NMDA receptor antagonism, there is further indication for use of the compound of formula DK 168441 B1 11 I in the treatment of tinnitus. For this use, a daily dose in the range of from 25 to approx. 800 mg of the compound conveniently administered in sub-doses 2-4 times daily in a unit dosage form containing e.g. 6 to approx. 400 mg of the compound or in sustained release form.
Yderligere udviser forbindelsen med formlen I antikonvulsi-visk virkning på elektroshock-inducerede konvulsioner hos mus (E.A. Swinyard, J. Am. Pharm. Assoc. Scient. Ed.. 38. s. 201, 1949 og J. Pharmacol. Exptl. Therao. 106. s. 319, 1952). I 10 denne test fik grupper på 6 hanmus (18-26 g, OF-1, Sandoz,Furthermore, the compound of formula I exhibits anticonvulsant effect on electroshock-induced convulsions in mice (EA Swinyard, J. Am. Pharm. Assoc. Scient. Ed. 38. p. 201, 1949 and J. Pharmacol. Exptl. Therao. 106. pp. 319, 1952). In this test, groups of 6 male mice (18-26 g, OF-1, Sandoz,
Basel) testforbindelsen administreret intraperitonealt. Efter 1, 2 og 4 timer tilførtes et 50 mA, 200 ms langt shock via hornhindeelektroder, indsmurt i elektrolytisk salve. Dette supra-maksimale shock medfører toniske ekstensorkonvulsioner 15 i alle ekstremiteter. Inhibering af ekstension af baglemmerne tages som beskyttende virkning. Efter undersøgelse af adskillige dosisniveauer blev tærskeldosis estimeret. Ved 1 time er tærskeldosis, hvilken er den nødvendige dosis for inhibering af ekstensionen af baglemmerne, mindre end 1 mg/kg intraperi-20 tonealt for forbindelsen med formlen I (monohydrat) og mellem 3-10 mg/kg intraperitonealt for CPP-en. I litteraturen er tærskeldosis for CPP 10 mg/kg intraperitonealt.Basel) test compound administered intraperitoneally. After 1, 2 and 4 hours, a 50 mA, 200 ms long shock was applied via corneal electrodes, lubricated in electrolytic ointment. This supra-maximal shock causes tonic extensor convulsions 15 in all extremities. Inhibition of extension of the hind limbs is taken as a protective effect. After examining several dose levels, the threshold dose was estimated. At 1 hour, the threshold dose, which is the dose required to inhibit the extension of the hind limbs, is less than 1 mg / kg intraperitoneally for the compound of formula I (monohydrate) and between 3-10 mg / kg intraperitoneally for the CPP. In the literature, the threshold dose for CPP is 10 mg / kg intraperitoneally.
DK 168441 B1 12 I nedenstående tabel er anført inhiberingen af ekstensionen af baglemmeme, udtrykt i %, henholdsvis for forbindelsen med formlen I og det tilsvarende racemat: 5 % Inhibering af elektro-DK 168441 B1 12 The following table lists the inhibition of the extension of the hind limbs, expressed in%, respectively, for the compound of formula I and the corresponding racemate: 5%
Dosis shockinduceret baglems- mg/kg ekstension i.p. 1 t 2 t 4 t 10 Forbindelsen med formlen I, monohydrat 1 67* 67* 33 2,5 83* 83* 67* 3 100* 100* 83* 15 CPP-en 1 20 50 25 3 33 67* 17 4· 4· 10 67 80 80Dose of shock-induced hind limb mg / kg extension i.p. 1 t 2 t 4 t 10 The compound of formula I, monohydrate 1 67 * 67 * 33 2.5 83 * 83 * 67 * 3 100 * 100 * 83 * 15 CPP 1 20 50 25 3 33 67 * 17 4 · 4 · 10 67 80 80
Fisher-test, kontrol-vs. stofgruppe, * p< = 0,05.Fisher test, control vs. substance group, * p <= 0.05.
20 i.p. = intraperitonealt20 i.p. = intraperitoneally
Som det ses af tabellen har forbindelsen med formlen I højere antikonvulsivisk virkning end det tilsvarende racemat, når de testes på elektroshock-inducerede konvulsioner hos mus.As seen from the table, the compound of formula I has higher anticonvulsant effect than the corresponding racemate when tested on electroshock-induced convulsions in mice.
Endvidere inhiberer forbindelsen med formlen I N-methyl-D-25 asparaginsyre (NMDA) -inducerede konvulsioner hos mus. I denne test blev en gruppe på 6 hunmus (18-26 g, OF-1, Sandoz,Furthermore, the compound of formula I inhibits N-methyl-D-25 aspartic acid (NMDA) -induced convulsions in mice. In this test, a group of 6 female mice (18-26 g, OF-1, Sandoz,
Basel) forbehandlet med teststoffet intraperitonealt. 30 minutter senere fik de tilført 400 mg/kg NMDA subcutant i nakkeregionen, hvorefter de blev observeret i 30 minutter.Basel) pretreated with the test substance intraperitoneally. Thirty minutes later, they were administered 400 mg / kg NMDA subcutaneously in the neck region, after which they were observed for 30 minutes.
30 Latenstiden for fremkomst af det første tegn på konvulsioner, på de første toniske konvulsioner og på dødens indtræden blev noteret. Signifikansen for forskellene blev fastsat ved hjælp af Mann-Whitney's U-test (S. Siegel, Non-parametric Statistics, McGraw-Hill, New York, 1956). Tærskeldosis er den 35 mindste dosis, ved hvilken der er en signifikant inhibering af konvulsiviske symptomer. Tærskeldosis for forbindelsen med DK 168441 B1 13 formlen I (testet som monohydrat) er ca. 5 mg/kg intraperito-nealt, medens den er 10 mg/kg intraperitonealt for CPP.30 The latency for the appearance of the first sign of convulsions, of the first tonic convulsions and of the onset of death was noted. The significance of the differences was determined using Mann-Whitney's U-test (S. Siegel, Non-parametric Statistics, McGraw-Hill, New York, 1956). The threshold dose is the 35 lowest dose at which there is a significant inhibition of convulsive symptoms. The threshold dose for the compound of DK 168441 B1 13 of formula I (tested as monohydrate) is approx. 5 mg / kg intraperitoneally while being 10 mg / kg intraperitoneally for CPP.
Som et resultat af dens antikonvulsiviske virkning er der indikation for anvendelse af forbindelsen med formlen I i 5 behandling af epilepsi. Til denne anvendelse indikeres en daglig dosis i området fra ca. 25 til ca. 800 mg af forbindelsen, bekvemt administreret i deldoser 2-4 gange daglig i enhedsdosisform indeholdende fx fra ca. 6 til ca. 400 mg af forbindelsen eller i "sustained release"-form.As a result of its anticonvulsant effect, there is indication for use of the compound of formula I in the treatment of epilepsy. For this use, a daily dose in the range of from 25 to approx. 800 mg of the compound conveniently administered in sub-doses 2-4 times daily in unit dosage form containing e.g. 6 to approx. 400 mg of the compound or in "sustained release" form.
10 Endvidere udviser forbindelsen med formlen I analgetisk virkning i isolerede rotterygmarvshaler in vitro med capsaicin (0,8-1 μΜ) som en kemisk skadelig stimulans, der udløser depolariseringsrespons fra ventral rod (M. Yanagisawa et al., European J. Pharmacol.. 106. s. 231-239, 1984) . Monohydratet 15 af forbindelsen med formlen I reducerer den kemiske stimulans med 75-80% ved en koncentration på 10 μΜ.Furthermore, the compound of Formula I exhibits analgesic action in isolated rat spinal cord tails in vitro with capsaicin (0.8-1 μΜ) as a chemically harmful stimulant that triggers the ventral root depolarization response (M. Yanagisawa et al., European J. Pharmacol. 106. pp. 231-239, 1984). The monohydrate 15 of the compound of formula I reduces the chemical stimulus by 75-80% at a concentration of 10 μΜ.
Der er derfor indikation for anvendelsen af forbindelsen med formlen I som smertestillende middel. Til denne anvendelse indikeres en daglig dosis i området fra c. 25 til ca. 800 mg 20 af forbindelsen, bekvemt administreret i deldoser 2-4 gange daglig i enhedsdosisform indeholdende fx fra ca. 6 til ca.Therefore, there is indication for the use of the compound of formula I as a pain reliever. For this use, a daily dose in the range of about 25 to about 25 is indicated. 800 mg 20 of the compound conveniently administered in sub-doses 2-4 times daily in unit dosage form containing e.g. 6 to approx.
400 mg af forbindelsen eller i "sustained release"-form.400 mg of the compound or in "sustained release" form.
Ydermere har forbindelsen med formlen I såvel som det tilsvarende racemat ingen virkning på blodtryk og hjerterytme i 25 en anæstetiseret kat i en dosis op til 10 mg/kg intravenøst.Furthermore, the compound of formula I as well as the corresponding racemate has no effect on blood pressure and heart rate in an anesthetized cat at a dose up to 10 mg / kg intravenously.
I 4 uger lange pilottoxicitetsforsøg med hunde tolereres 3 mg/kg/dag intravenøst af forbindelsen med formlen I godt.In 4-week pilot toxicity studies with dogs, 3 mg / kg / day is intravenously tolerated by the compound of formula I well.
Som det ses af de ovenstående forsøgsresultater, er den kraftige LH-sekretionsinhiberende virkning, den markante (25 30 gange) forøgelse af den muskelafslappende virkning samt den 2-4 gange store NMDA-receptorantagonistiske virkning af forbindelsen med formlen I i sammenligning med det tilsvarende DK 168441 B1 14 racemat ikke ledsaget af en tilsvarende forøgelse i bivirkningerne, fx cardiovasculære virkninger.As can be seen from the above test results, the potent LH secretion inhibitory effect, the marked (25-fold) increase of the muscle relaxant effect, and the 2-4-fold NMDA receptor antagonistic effect of the compound of formula I in comparison with the corresponding DK Racemate not accompanied by a corresponding increase in side effects, eg cardiovascular effects.
Forbindelsen med den almene formel I kan administreres som sådan eller som farmaceutisk acceptable salte eller hydrater 5 deraf. Sådanne salte eller hydrater udviser den samme grad af virkning som forbindelsen med formlen I.The compound of general formula I may be administered as such or as pharmaceutically acceptable salts or hydrates thereof. Such salts or hydrates exhibit the same degree of action as the compound of formula I.
Den foreliggende opfindelsen angår endvidere farmaceutiske præparater indeholdende forbindelsen med formlen I eller et farmaceutisk acceptabelt salt eller hydrat deraf i kombina-10 tion med et farmaceutisk acceptabelt bærestof eller fortyndingsmiddel .The present invention further relates to pharmaceutical compositions containing the compound of formula I or a pharmaceutically acceptable salt or hydrate thereof in combination with a pharmaceutically acceptable carrier or diluent.
Forbindelsen med formlen I kan administreres på enhver konventionel måde, især enteralt, fortrinsvis oralt eller paren-teralt. Forbindelsen med formlen I kan administreres per se 15 eller iblandet konventionelle farmaceutiske bærestoffer. Til oral administration, fx i form af tabletter eller kapsler, kan forbindelsen med formlen I fx iblandes konventionelle farmaceutisk acceptable excipienser, fx inerte fortyndings-midler såsom lactose, mannitol, calciumsulfat, mikrokrystal-20 linsk cellulose; desintegrerende midler, fx stivelse, natri-umcarboxymethylcellulose, natriumcarboxymethylstivelse, algi-ninsyre, crospovidon; bindemidler såsom cellulosederivater (methyl-, hydroxymethyl-, hydroxypropylmethyl-), povidon, gelatine; smøremidler såsom siliciumdioxid, stearinsyre, 25 magnesium- eller calciumstearat; hydrogenerede olier såsom ricinusolie, glycerolestere, fx palmitostearat og/eller smagsstoffer, farvestoffer og sødemidler. Tabletterne kan være ucoatede eller coatede i henhold til kendte teknikker for at forsinke desintegration og absorption i mave- og 30 tarmkanalen og derved sørge for en "sustained" virkning over en længere periode. Parenterale præparater er fortrinsvis i form af sterile injicerbare vandige opløsninger. Sådanne vandige opløsninger bør om nødvendigt være passende pufferopløsninger og gjort isotoniske med tilstrækkeligt saltvand.The compound of formula I may be administered in any conventional manner, especially enterally, preferably orally or parenterally. The compound of Formula I may be administered per se or in admixture with conventional pharmaceutical carriers. For oral administration, for example, in the form of tablets or capsules, the compound of formula I may, for example, be mixed with conventional pharmaceutically acceptable excipients, e.g., inert diluents such as lactose, mannitol, calcium sulfate, microcrystalline cellulose; disintegrants, eg starch, sodium carboxymethyl cellulose, sodium carboxymethyl starch, alginic acid, crospovidone; binders such as cellulose derivatives (methyl, hydroxymethyl, hydroxypropylmethyl), povidone, gelatin; lubricants such as silica, stearic acid, magnesium or calcium stearate; hydrogenated oils such as castor oil, glycerol esters, e.g., palmitostearate and / or flavors, dyes and sweeteners. The tablets may be uncoated or coated according to known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a prolonged period. Preferably, parenteral preparations are in the form of sterile injectable aqueous solutions. Such aqueous solutions should, if necessary, be appropriate buffer solutions and made isotonic with sufficient saline.
DK 168441 B1 15DK 168441 B1 15
Eventuelt kan der tilsættes et konserveringsmiddel såsom benzylalkohol.Optionally, a preservative such as benzyl alcohol may be added.
En enhedsdosis kan indeholde fra ca. 0,25 til ca. 400 mg af forbindelsen med formlen I eller et farmaceutisk acceptabelt 5 salt deraf.A unit dose may contain from ca. 0.25 to approx. 400 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.
De farmaceutiske præparater kan fremstilles i henhold til konventionelle teknikker.The pharmaceutical compositions can be prepared according to conventional techniques.
Til fremstilling af tabletter kan forbindelsen med formlen I blandes med lactose og granuleres med vand, 0,5% natriumalgi-10 nat- eller 5% hydroxypropylmethylcelluloseopløsning. Det tørrede granulat presses til tabletter sammen med ca. 20% majs-stivelse og 1% magnesiumstearat. På denne måde fås der eksempelvis tabletter med nedenstående sammensætning: 15 Bestanddele Tabletvægt (mg)For the preparation of tablets, the compound of formula I can be mixed with lactose and granulated with water, 0.5% sodium alginate or 5% hydroxypropyl methylcellulose solution. The dried granules are pressed into tablets together with approx. 20% corn starch and 1% magnesium stearate. In this way, for example, tablets of the following composition are obtained: 15 Ingredients Tablet weight (mg)
Monohydratet af forbindelsen med formlen I 50The monohydrate of the compound of formula I 50
Lactose 97 20 Majsstivelse 40Lactose 97 20 Corn starch 40
Hydroxypropylmethylcellulose 10Hydroxypropylmethylcellulose 10
Magnesiumstearat 2Magnesium stearate 2
Siliciumdioxid 1 25 200Silica 1 25 200
Disse tabletter, som er forsynet med delekærv, kan administreres oralt i en dosis på 1/2 til 1 tablet 1-4 gange pr. dag.These slab-sized tablets can be administered orally at a dose of 1/2 to 1 tablet 1-4 times per day. day.
Kapsler kan indeholde det aktive middel alene eller iblandet 30 en inert fast excipiens, fx som nævnt ovenfor.Capsules may contain the active agent alone or in admixture with an inert solid excipient, e.g., as mentioned above.
DK 168441 B1 16DK 168441 B1 16
Kapsler indeholdende de nedenfor anførte bestanddele kan fremstilles ved kendte teknikker og kan administreres i en dosis på én kapsel 1-4 gange daglig.Capsules containing the ingredients listed below can be prepared by known techniques and can be administered at a dose of one capsule 1-4 times daily.
5 Bestanddele Kapselvægt (mg)5 Ingredients Capsule weight (mg)
Monohydratet af forbindelsen med formlen I 50The monohydrate of the compound of formula I 50
Inert fast excipiens (majssti-10 velse, lactose, aerosil, mag- nesiumstearat) 250Inert solid excipient (corn starch, lactose, aerosil, magnesium stearate) 250
Tilsvarende kan der fremstilles tabletter og kapsler indeholdende 25 mg og 100 mg af forbindelsen med formlen I.Similarly, tablets and capsules containing 25 mg and 100 mg of the compound of formula I can be prepared.
15 Den følgende, injicerbare opløsning er formuleret med den indikerede mængde aktivt middel ved hjælp af kendte teknik ker. Den injicerbare opløsning er egnet til administration én gang daglig.The following injectable solution is formulated with the indicated amount of active agent by known techniques. The injectable solution is suitable for once-daily administration.
Steril, inj icerbar opløsning 20 _Sterile injectable solution 20
Bestanddele Kapselvægt (mg)Ingredients Capsule Weight (mg)
Monohydratet af forbindelsen med formlen I 25 25 Natriumchlorid 7,0The monohydrate of the compound of formula I 25 Sodium chloride 7.0
Kai iumdihydrogenphosphat 3,63Kaai dihydrogen phosphate 3.63
Dinatriumhydrogenphosphat 5,68Disodium hydrogen phosphate 5.68
Benzylalkohol 9,0Benzyl alcohol 9.0
Vand til injektion, q.s. ad 1 ml 30 _Water for injection, q.s. ad 1 ml 30
Opløsningerne kan filtreres gennem et 0,2 μπι sterilt filter og derefter aseptisk fyldes i ampuller. Ampullerne gasses med carbondioxid.The solutions can be filtered through a 0.2 μπι sterile filter and then aseptically filled into vials. The vials are gassed with carbon dioxide.
DK 168441 B1 17DK 168441 B1 17
Den foreliggende opfindelse angår også forbindelsen med formlen I til brug i behandlingen af lidelser associeret med LH-sekretion, forøget muskeltonus, tilstande associeret med cerebral iskæmi, angst, skizofreni, depression eller degene-5 rative lidelser i centralnervesystemet, tinnitus, epilepsi eller til lindring af smerter.The present invention also relates to the compound of formula I for use in the treatment of disorders associated with LH secretion, increased muscle tone, conditions associated with cerebral ischemia, anxiety, schizophrenia, depression or degenerative disorders of the central nervous system, tinnitus, epilepsy or for relief. of pain.
Forbindelsen med formlen I kan således anvendes ved en metode til behandling af lidelser associeret med LH-sekretion, forøget muskeltonus, tilstande associeret med cerebral iskæmi, 10 angst, skizofreni, depression eller degenerative lidelser i centralnervesystemet, tinnitus, epilepsi og til lindring af smerter, hvilken metode består i administration af en terapeutisk virksom mængde af forbindelsen eller et farmaceutisk acceptabelt salt eller hydrat deraf til et individ med behov 15 for sådan behandling.Thus, the compound of formula I can be used in a method of treating disorders associated with LH secretion, increased muscle tone, conditions associated with cerebral ischemia, anxiety, schizophrenia, depression or degenerative disorders of the central nervous system, tinnitus, epilepsy and for the relief of pain, which method consists in administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt or hydrate thereof to a subject in need of such treatment.
Endelig angår den foreliggende opfindelse anvendelsen af forbindelsen med formlen I eller et farmaceutisk acceptabelt salt eller hydrat deraf til fremstilling af et farmaceutisk præparat til brug i behandling af lidelser associeret med LH-20 sekretion, forøget muskeltonus, tilstande associeret med cerebral iskæmi, angst, skizofreni, depression, degenerative lidelser i centralnervesystemet, tinnitus, epilepsi eller til lindring af smerter.Finally, the present invention relates to the use of the compound of formula I or a pharmaceutically acceptable salt or hydrate thereof for the preparation of a pharmaceutical composition for use in the treatment of disorders associated with LH-20 secretion, increased muscle tone, conditions associated with cerebral ischemia, anxiety, schizophrenia. , depression, central nervous system degenerative disorders, tinnitus, epilepsy, or pain relief.
Claims (7)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB878703749A GB8703749D0 (en) | 1987-02-18 | 1987-02-18 | Piperazinecarboxylic acid |
| GB8703749 | 1987-02-18 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK79688D0 DK79688D0 (en) | 1988-02-16 |
| DK79688A DK79688A (en) | 1988-08-19 |
| DK168441B1 true DK168441B1 (en) | 1994-03-28 |
Family
ID=10612501
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK079688A DK168441B1 (en) | 1987-02-18 | 1988-02-16 | [R- (E)] - 4- (3-phosphono-2-propenyl) -2-piperazine carboxylic acid, process for its preparation, pharmaceutical composition containing the compound and use thereof |
Country Status (28)
| Country | Link |
|---|---|
| JP (1) | JPH0723387B2 (en) |
| KR (1) | KR960015190B1 (en) |
| AT (1) | AT391320B (en) |
| AU (1) | AU613009B2 (en) |
| BE (1) | BE1002427A3 (en) |
| CA (1) | CA1327799C (en) |
| CH (1) | CH675125A5 (en) |
| CY (1) | CY1739A (en) |
| DE (1) | DE3804936C2 (en) |
| DK (1) | DK168441B1 (en) |
| ES (2) | ES2011319A6 (en) |
| FI (1) | FI86733C (en) |
| FR (1) | FR2610932B1 (en) |
| GB (2) | GB8703749D0 (en) |
| GR (1) | GR1002471B (en) |
| HK (1) | HK142093A (en) |
| HU (2) | HU199858B (en) |
| IE (1) | IE59098B1 (en) |
| IL (1) | IL85436A0 (en) |
| IT (1) | IT1219447B (en) |
| LU (1) | LU87129A1 (en) |
| MY (1) | MY103206A (en) |
| NL (1) | NL8800412A (en) |
| NZ (1) | NZ223529A (en) |
| PH (1) | PH25512A (en) |
| PT (1) | PT86776B (en) |
| SE (1) | SE467256B (en) |
| ZA (1) | ZA881146B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1248531A (en) * | 1984-04-17 | 1989-01-10 | Jeffrey C. Watkins | 4-substituted piperazine-2-carboxylic acids |
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1987
- 1987-02-18 GB GB878703749A patent/GB8703749D0/en active Pending
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1988
- 1988-02-11 LU LU87129A patent/LU87129A1/en unknown
- 1988-02-12 IT IT47631/88A patent/IT1219447B/en active
- 1988-02-12 BE BE8800177A patent/BE1002427A3/en active
- 1988-02-12 FR FR888801782A patent/FR2610932B1/en not_active Expired - Lifetime
- 1988-02-15 GB GB8803438A patent/GB2201676B/en not_active Expired - Lifetime
- 1988-02-15 MY MYPI88000155A patent/MY103206A/en unknown
- 1988-02-16 IL IL85436A patent/IL85436A0/en not_active IP Right Cessation
- 1988-02-16 DK DK079688A patent/DK168441B1/en not_active IP Right Cessation
- 1988-02-16 NZ NZ223529A patent/NZ223529A/en unknown
- 1988-02-16 HU HU88746A patent/HU199858B/en not_active IP Right Cessation
- 1988-02-16 GR GR880100084A patent/GR1002471B/en not_active IP Right Cessation
- 1988-02-16 IE IE41388A patent/IE59098B1/en not_active IP Right Cessation
- 1988-02-16 CA CA000559170A patent/CA1327799C/en not_active Expired - Fee Related
- 1988-02-16 PH PH36514A patent/PH25512A/en unknown
- 1988-02-16 AU AU11758/88A patent/AU613009B2/en not_active Ceased
- 1988-02-16 CH CH549/88A patent/CH675125A5/de not_active IP Right Cessation
- 1988-02-17 KR KR1019880001680A patent/KR960015190B1/en not_active IP Right Cessation
- 1988-02-17 AT AT0036788A patent/AT391320B/en not_active IP Right Cessation
- 1988-02-17 FI FI880744A patent/FI86733C/en not_active IP Right Cessation
- 1988-02-17 PT PT86776A patent/PT86776B/en not_active IP Right Cessation
- 1988-02-17 JP JP63036458A patent/JPH0723387B2/en not_active Expired - Lifetime
- 1988-02-17 SE SE8800541A patent/SE467256B/en not_active IP Right Cessation
- 1988-02-17 DE DE3804936A patent/DE3804936C2/en not_active Expired - Fee Related
- 1988-02-18 ZA ZA881146A patent/ZA881146B/en unknown
- 1988-02-18 NL NL8800412A patent/NL8800412A/en not_active Application Discontinuation
- 1988-02-18 ES ES888800466A patent/ES2011319A6/en not_active Expired - Lifetime
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1989
- 1989-10-16 ES ES8903482A patent/ES2021904A6/en not_active Expired - Lifetime
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1993
- 1993-12-30 HK HK1420/93A patent/HK142093A/en not_active IP Right Cessation
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