SK932001A3 - ARYLPIPERAZINE DERIVATIVES USEFUL AS UROSELECTIVEì (54) ALPHA1-ADRENOCEPTOR BLOCKERS - Google Patents
ARYLPIPERAZINE DERIVATIVES USEFUL AS UROSELECTIVEì (54) ALPHA1-ADRENOCEPTOR BLOCKERS Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
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- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
Description
Vynález sa týka piperazínových derivátov majúcich predĺženú uroselektívnu αρ -adrenoceptorovú antagonistickú aktivitu prevyšujúcu aktivitu vyššie opísaných zlúčenín. Zlúčeniny podľa vynálezu sú sľubné pre liečbu benígnej prostatickej hyperplázie (BPH). Vynález sa tiež týka spôsobov prípravy týchto zlúčenín, farmaceutických kompozícií obsahujúcich tieto zlúčeniny a spôsobov liečby benígnej prostatickej hyperplázie pomocou týchto zlúčenín.The invention relates to piperazine derivatives having an extended uroselective α-α-adrenoceptor antagonist activity in excess of that of the compounds described above. The compounds of the invention are promising for the treatment of benign prostatic hyperplasia (BPH). The invention also relates to methods for the preparation of these compounds, pharmaceutical compositions comprising the compounds, and methods for the treatment of benign prostatic hyperplasia with these compounds.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Review v J.Med.Chem., 1997, roč.40, č. 9, str. 1292-1315, opisuje najdôležitejšie súčasné farmakologické možnosti liečby benígnej prostatickej hyperplázie. Dve najúspešnejšie terapie sú založené na antagonizme k α-adrenergným receptorom a modulácii hladiny androgénov pomocou inhibítorov 5a-reduktázy. Inhibítory 5a-reduktázy majú obmedzenú účinnosť čo sa týka doby okamžitej symptomatickej a urodynamickej úľavy, αι-antagonisti sa javia ako omnoho účinnejšie, poskytujú okamžité subjektívne symptomatické zlepšenie a sú teda výhodným variantom liečby pri kontrole benígnej prostatickej hypertrofie, aiadrenoceptory sú prítomné tiež v krvných cievach a hrajú významnú úlohu pri regulácii krvného tlaku.Review in J. Med. Chem., 1997, 40, no. 9, p. 1292-1315, describes the most important current pharmacological options for the treatment of benign prostatic hyperplasia. The two most successful therapies are based on antagonism to α-adrenergic receptors and modulation of androgen levels by 5α-reductase inhibitors. 5α-reductase inhibitors have limited efficacy in terms of immediate symptomatic and urodynamic relief, α 1 -antagonists appear to be more effective, provide immediate subjective symptomatic improvement and are therefore a preferred treatment option for the control of benign prostatic hypertrophy, and the adrenoceptors are also present in blood vessels and play an important role in regulating blood pressure.
Antagonisti αι-adrenoceptorov sú teda látky obzvlášť dôležité, aj keď boli pôvodne vyvinuté ako antihypertenzné činidlá a majú tiež pravdepodobne prospešné účinky pri dysfunkcii metabolizmu lipidov a rezistencii k inzulínu, ktoré sú obvykle so základnou hypertenziou asociované.Thus, α-adrenoceptor antagonists are particularly important, although they were originally developed as antihypertensive agents and are also likely to have beneficial effects in lipid metabolism dysfunction and insulin resistance, which are usually associated with underlying hypertension.
Dôležitejší antagonisti αι-adrenoceptorov, ktorí sa v súčasnosti používajú pri kontrole BPH, sú:More important α-adrenoceptor antagonists currently used in BPH control are:
PRAZOSIHPRAZOSIH
TERAZOSINterazosin
OABOUT
(R)-(-)-TAMSUI-OSIM(R) - (-) - Tamsui-OSIM
Väčšina z týchto známych látok má však vedľajšie účinky na cievy (napríklad posturálnu hypertenziu, mdloby, závraty, bolesť hlavy, atd’.), čo je zapríčinené neselektivitou účinku na prostatické a vaskuláme αι-adrenoceptory. Je teda zrejmé, že antagonisti aj-adrenoceptorov, ktorí vykazujú väčšiu selektivitu pre prostatické αι-adrenoceptory, ponúkajú potenciál väčšieho urodynamického zlepšenia. To teda podtrhuje dôležitosť nájdenia pre prostatu selektívnych antagonistov aj-adrenoceptorov, ktoré poskytnú urodynamícké zlepšenie bez vedľajších účinkov spojených so súčasnými liekmi.However, most of these known substances have vascular side effects (e.g. postural hypertension, fainting, dizziness, headache, etc.), which is due to the non-selectivity of the effect on the prostate and vascular α-adrenoceptors. Thus, it is clear that α-adrenoceptor antagonists, which show greater selectivity for prostate α-adrenoceptors, offer the potential for greater urodynamic improvement. This underlines the importance of finding selective α-adrenoceptor antagonists for the prostate that will provide urodynamic improvement without the side effects associated with current drugs.
Nedávno sa ukázalo, že prostatické tkanivo vyšších živočíchov ako je človek, alebo pes, je obsadené cti a subtypom nízko afinitných adrenoceptorov. To dáva možnosť vyvinúť látky so selektívnym účinkom pri týchto patologických urodynamických stavoch. Vynález je zameraný na vývoj nových α i-antagonistov, osobitne novej triedy piperazínových zlúčenín s ·· ···· väčšou selektivitou účinku na αι-adrenoceptory, a ktoré by teda ponúkali úľavu od prostatickej hypertrofie rovnako ako základnú hypertenziu.It has recently been shown that prostate tissue of higher animals, such as man or dog, is occupied by the honor and subtype of low affinity adrenoceptors. This gives the possibility to develop substances with selective effect in these pathological urodynamic conditions. The invention is directed to the development of novel α 1 -antagonists, in particular a new class of piperazine compounds with greater selectivity of action on α-adrenoceptors, and which would therefore offer relief from prostatic hypertrophy as well as underlying hypertension.
V literatúre môžeme nájsť mnoho opisov farmakologických aktivít fenylpiperazínov. Eur. J. Med. Chem.-Chimica Therapeutica, 1977, roč. 12. č. 2, str. 173 až 176, opisuje substituované trifluórmetylfenylpiperaziny majúce cyklo-imidoalkylové postranné reťazce, pozri obr. nižšie, ako anorektické látky bez nežiadúcich vplyvov na CNS.Many descriptions of the pharmacological activities of phenylpiperazines can be found in the literature. Eur. J. Med. Chem.-Chimica Therapeutica, 1977, vol. 12. č. 2, p. 173-176, discloses substituted trifluoromethylphenylpiperazines having cyclo-imidoalkyl side chains, see Figs. lower than anorectic agents without adverse effects on the CNS.
Bola opísaná tiež syntéza a farmakológia niektorých 2-[3-(4-aryl-l-piperazinyl)propyl]lH-benz[de]izochinolín-l,3-(2H)-diónov/2,5-pyrolidíndiónov (J. Indián. Chem. Soc., 1986, V. LXIII, str. 529 až 530), N-(N4-aryl-N1-piperozinylmetyl)-4-(4'-metoxyfenyl)piperidín-2,6diónov (J. Indián Chem Soc., 1978, roč. LV, str. 819 až 821) a N-(N4-arylpiperazinylalkyl)ftalimidov (J Indián Chem Soc, 1979, roč. LVI, str. 1002 až 1005), uvedených nižšie. Tieto látky vykazovali antihypertenzívne a CNS tlmiace aktivity u experimentálnych zvierat.The synthesis and pharmacology of some 2- [3- (4-aryl-1-piperazinyl) propyl] -1H-benz [de] isoquinoline-1,3- (2H) -dione / 2,5-pyrrolidinediones has also been described (J. Indian) Soc., 1986, V. LXIII, pp. 529-530, N- (N 4 -aryl-N 1 -piperosinylmethyl) -4- (4'-methoxyphenyl) piperidine-2,6-dione (J. Indian) Chem Soc., 1978, Vol. LV, pp. 819-821) and N- (N 4 -arylpiperazinylalkyl) phthalimides (J Indian Chem Soc, 1979, Vol. LVI, pp. 1002-1005), listed below. These compounds exhibited antihypertensive and CNS depressant activities in experimental animals.
V týchto publikáciách však nie je žiadna zmienka o adrenoreceptorovej blokátorovej aktivite týchto zlúčenín a teda ich vhodnosť pre liečbu benígnej prostatickej hyperplázie z nich neplynie.However, there is no mention in these publications of the adrenoreceptor blocker activity of these compounds, and therefore their suitability for the treatment of benign prostatic hyperplasia does not arise from them.
Skoršie syntézy rôznych l-(4-aryl-piperazin-l-yl)-3-(2-oxo-pyrolidin-l-yl/piperidín-lyl)-alkánov a ich vhodnosť ako hypotenzívnych a antiischemických látok bola uvedená v nepublikovaných indických patentových prihláškach DEL 496/95 (3. brezna 1995), DEL/500/95 (21. marec 1995) a DEL/96/96 (29. marca 1996). Tieto zlúčeniny majú nízku ap adrenergnú blokátorovú aktivitu (pKi ~ 6 v porovnaní s aktivitou > 8 pri známych αρ antagonistoch, ako je prazozín) a prakticky nemajú selektivitu k a]A podskupine adrenoceptorov v porovnaní s cxib alebo ocid adrenoceptormi. Nedávno bolo zistené, že štrukturálna modifikácia týchto zlúčenín, zmena laktámu na dioxo zlúčeniny, to je 2oxopyrolidín na 2,5-dioxopyrolidín a 2,6-dioxopiperidín, zvyšujú adrenoceptorovú blokátorovú aktivitu a tiež veľmi zvyšujú selektivitu pre ajA oproti aiB-adrenoceptorovej blokátorovej aktivite, čo jasne ukazuje, že tieto zlúčeniny sú dobrými kandidátmi liekov BPH.Earlier syntheses of various 1- (4-aryl-piperazin-1-yl) -3- (2-oxo-pyrrolidin-1-yl / piperidin-lyl) -alkanes and their suitability as hypotensive and anti-ischemic agents have been reported in unpublished Indian patent applications. applications DEL 496/95 (3 March 1995), DEL / 500/95 (21 March 1995) and DEL / 96/96 (29 March 1996). These compounds have a low and p adrenergic blocking activity (pKi ~ 6 as compared to that of> 8 in the known αρ antagonists such as prazosin), and practically no selectivity ms] A subset adrenoceptors compared to CXIB or ocid adrenoceptors. Recently, it has been found that structural modification of these compounds, the conversion of lactam to dioxo compounds, i.e., 2-oxopyrrolidine to 2,5-dioxopyrrolidine and 2,6-dioxopiperidine, increase the adrenoceptor blocker activity and also greatly increase selectivity for both A and Aβ-adrenoceptor blocker activity. , which clearly shows that these compounds are good candidates for BPH.
Podstata vynálezuSUMMARY OF THE INVENTION
Vynález teda poskytuje arylpiperazínové deriváty, ktoré vykazujú významne vyšší ajA adrenergný blokátorový potenciál v porovnaní s doteraz dostupnými známymi zlúčeninami a dávajú tak možnosť špecifickej liečby benígnej prostatickej hyperplázie.Thus, the invention provides arylpiperazine derivatives that exhibit both significantly higher A adrenergic blocking potential compared to known compounds available hitherto and thus give the possibility of specifically treating benign prostatic hyperplasia.
Úlohou vynálezu je rovnako poskytnúť spôsoby syntézy zlúčenín podľa vynálezu.It is also an object of the invention to provide methods for the synthesis of compounds of the invention.
Ďalšou úlohou vynálezu je poskytnúť kompozície obsahujúce zlúčeniny, ktoré sú vhodné na liečbu benígnej prostatickej hyperplázie.It is a further object of the invention to provide compositions comprising compounds that are useful in the treatment of benign prostatic hyperplasia.
Vyššie uvedené úlohy sú dosiahnuté pomocou triedy piperazínových derivátov všeobecného vzorca I (CH^m (CHJn—CHThe above tasks are achieved by the class of piperazine derivatives of formula I (CH 2 m (CH 3 n-CH)
R3 (D kde Y je O alebo S; Q, X, Z a Z' sú nezávisle na sebe CH alebo N; m = 0 až 3; n = 0 až 4; Ri, R2 sú nezávisle na sebe vybrané zo skupiny: H, F, Cl, Br, OCHj, OC2H5, OCH2CF3, SCF3,R 3 (D wherein Y is O or S; Q, X, Z and Z 'are independently CH or N; m = 0 to 3; n = 0 to 4; R 1, R 2 are independently selected from: H, F, Cl, Br, OCH 3, OC 2 H 5, OCH 2 CF 3, SCF 3,
CH3, C2H5, CF3, izopropyloxy, a cyklopropyl; R3 je H, R$, OH, alebo OR^; R$ je ·· ···· ·· ·· • · · · · • · · · · · · ··· ·CH 3, C 2 H 5, CF 3 , isopropyloxy, and cyclopropyl; R 3 is H, R 8, OH, or OR 4; R $ is ··················
- ········ -5- ···· ·· ·· ·· ·· φ substituovaný alebo nesubstituovaný alkylový reťazec obsahujúci 1 až 6 uhlíkových atómov;- ········ 5- ··· ·· ·· ·· ·· φ substituted or unsubstituted alkyl chain of 1 to 6 carbon atoms;
a R4, R5 sú H, C1..C3 alkyl, substituovaný alebo nesubstituovaný fenyl. alebo 5-členný spiro kruh. S výhodou R] je H, R2 je H, Cl alebo CF3, R3, R4 a R5 je H, Y je O a Q je CH, a keď m = 0 a n = 1; alebo Ri je H, R2 je OCH3, R3, R4 a R5 je H, Y je O a Q je CH, a keď m = 0 a n =and R 4, R 5 are H, C 1 -C 3 alkyl, substituted or unsubstituted phenyl. or a 5-membered spiro ring. Preferably, R] is H, R2 is H, Cl or CF 3, R 3, R 4 and R 5 is H, Y is O and Q is CH, and when m = 0 and n = 1; or R 1 is H, R 2 is OCH 3, R 3, R 4 and R 5 is H, Y is O and Q is CH, and when m = 0 and n =
2.Second
Zlúčeniny spadajúce do rozsahu všeobecného vzorca I, ale majúce štruktúru všeobecného vzorca IICompounds falling within formula I but having the structure of formula II
kde n. X, Z, Z', R'i, R2 a R3 sú rovnaké ako je definované pre všeobecný vzorec I, a kde m'= 1 až 4, ktoré sú výhodné pre svoju selektívnu a účinnú aiA-adrenoceptorovú antagonistickú aktivitu. Vo všeobecnom vzorci II s výhodou Ri je H, R2 je H, Cl alebo CF3, a R3 je H, a keď m - 1 a n = 1; alebo R| je H, R2 je OCH3 a R3 je H, a kde m'= 1 a n = 2.where n. X, Z, Z ', R' 1, R 2 and R 3 are as defined for formula I, and wherein m '= 1 to 4, which are preferred for their selective and potent α 1A -adrenoceptor antagonist activity. In formula II, preferably R 1 is H, R 2 is H, Cl or CF 3, and R 3 is H, and when m-1 and n = 1; or R 1 is H, R 2 is OCH 3 and R 3 is H, and wherein m '= 1 and n = 2.
Vynález rovnako poskytuje farmaceutické kompozície na liečbu benígnej prostatickej hyperplázie. Tieto kompozície obsahujú účinné množstvo aspoň jednej z vyššie uvedených zlúčenín všeobecného vzorca I, alebo s výhodou všeobecného vzorca II, a/alebo účinné množstvo aspoň jednej ich fyziologicky prijateľnej soli, spolu s farmaceutický prijateľným nosičom.The invention also provides pharmaceutical compositions for the treatment of benign prostatic hyperplasia. These compositions comprise an effective amount of at least one of the aforementioned compounds of formula I, or preferably of formula II, and / or an effective amount of at least one physiologically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
Ilustratívny zoznam niektorých zlúčenín podľa vynálezu je nasledujúci:An illustrative list of some of the compounds of the invention is as follows:
Zlúčenina číslo Chemický názovCompound number Chemical name
1. l-[4-(4-fluórfenyl)piperazin-l-yl]-3-(2,5-dioxopyrolidin-l-yl)propán1. 1- [4- (4-Fluorophenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane
2. 1 -[4-(2-metoxyfenyl) piperazin-1 -yl]-3-(2,5-dioxopyrolidin-1 -yl)propán1- [4- (2-Methoxyphenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane
3. l-[4-(3-trifluórmetylfenyl)piperazin-l-yl]-3-(2,5-dioxopyrolidin-l-yl)propán1- [4- (3-Trifluoromethylphenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane
4. 1 -[4-(2-pyridyl)piperazin-l -yl]-3-(2,5-dioxopyrolidin-1 -yl)propán4. 1- [4- (2-Pyridyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane
5. l-[4-(3-chlórfenyl)piperazin-l-yl]-3-(2,5-dioxopyrolidin-l-yl)propán5. 1- [4- (3-Chloro-phenyl) -piperazin-1-yl] -3- (2,5-dioxo-pyrrolidin-1-yl) -propane
6. l-[4-(2-pyrimidyl)piperazin-l-yl]-3-(2,5-dioxopyrolidin-l-yl)propán6. 1- [4- (2-Pyrimidyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane
7. l-[4-(3,4-dimetylfenyl)piperazin-l-yl]-3-(2,5-dioxopyrolidin-l-yl)propán7. 1- [4- (3,4-Dimethyl-phenyl) -piperazin-1-yl] -3- (2,5-dioxo-pyrrolidin-1-yl) -propane
8. 1 -[4-(fenylpiperazin)-l-yl]-3-(2,5-dioxopyrolidin-l-yl)propán ·· ····8. 1- [4- (phenylpiperazin) -1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane ·· ····
9. 1 -(4-(2-metoxyfenyl)piperazin-1 -yl]-4-(2,5-dioxopyrolidin-1 -yl)bután9. 1- (4- (2-Methoxyphenyl) piperazin-1-yl) -4- (2,5-dioxopyrrolidin-1-yl) butane
10. 1 -[4-(2-metoxyfenyl)piperazin-1 -yl]-2-(2,5-dioxopyrolidin-1 -yl)etán10. 1- [4- (2-Methoxyphenyl) piperazin-1-yl] -2- (2,5-dioxopyrrolidin-1-yl) ethane
11. l-[4-(3-metoxyfenyl)piperazin-l-yl]-3-(2,5-dioxopyrolidin-l-yl)propán11. 1- [4- (3-Methoxyphenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane
12. 1 -[4-(4-metoxyfenyl)piperazin-1 -yl]-3-(2,5-dioxopyrolidin-1 -yl)propán12. 1- [4- (4-Methoxyphenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane
13. 1 -[4-(2-metoxyfenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidín-l -yl)propán13. 1- [4- (2-Methoxyphenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane
14. 1 -[4-(4-fluórfenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidín-l -yl)propán14. 1- [4- (4-Fluorophenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane
15. 1 -[4-(4-chlórfenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidíri-1 -yl)propán15. 1- [4- (4-Chloro-phenyl) -piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) -propane
16. 1 -[4-(3-trifluórmetylfenyl) piperazin-1 -yl]-3-(2,6-dioxopiperidín-l -yl)propán16. 1- [4- (3-Trifluoromethylphenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane
17. 1 -(4-(2-fluórfenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidín-1 -yl)propán17. 1- (4- (2-Fluorophenyl) piperazin-1-yl) -3- (2,6-dioxopiperidin-1-yl) propane
18. 1 -[4-(2-metylfenyl) piperazin-1 -yl]-3-(2,6-dioxopiperidín-1 -yl)propán18. 1- [4- (2-Methylphenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane
19. 1 -(4-(2-pyridy l)piperazin-1 -y l)-3 -(2,6-dioxopiperidín-1 -yl)propán19. 1- (4- (2-Pyridyl) piperazin-1-yl) -3- (2,6-dioxopiperidin-1-yl) propane
20. 1 -[4-(3-chlórfenyl)piperazin-l -yl]-3-(2,6-dioxopiperidín-l -yl)propán20. 1- [4- (3-Chloro-phenyl) -piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) -propane
21. 1 - [4-(3,4-dimetylfenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidín-1 -yl)propán21. 1- [4- (3,4-Dimethyl-phenyl) -piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) -propane
22. 1 -[4-(2-pyrimidyl)piperazin-l -yl]-3-(2,6-dioxopiperidín-l -yl)propán22. 1- [4- (2-Pyrimidyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane
23. 1 -[4-(3-metoxyfenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidín-1 -yl)propán23. 1- [4- (3-Methoxyphenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane
24. 1 -[4-(4-metoxyfenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidín-l -yl)propán24. 1- [4- (4-Methoxyphenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane
25. 1 -[4-(2-metoxyfenyl)piperazin-1 -yl]-4-(2,6-dioxopiperidín-1 -yl)bután25. 1- [4- (2-Methoxyphenyl) piperazin-1-yl] -4- (2,6-dioxopiperidin-1-yl) butane
26. l-[4-(2-metoxyfenyl)piperazin-l-yl]-3-[2,5-dioxo-3-fenyl-pyrolidin-l-yl]propán26. 1- [4- (2-Methoxy-phenyl) -piperazin-1-yl] -3- [2,5-dioxo-3-phenyl-pyrrolidin-1-yl] -propane
27. 1 -[4-(fenyl)piperidin-1 -yl]-3-[2,5-dioxopyrolidin-1 -yl] propán27. 1- [4- (phenyl) piperidin-1-yl] -3- [2,5-dioxopyrrolidin-1-yl] propane
Syntéza zlúčenín podľa vynálezuSynthesis of compounds of the invention
Zlúčeniny podľa vynálezu môžu byť pripravené jednou z reakčných sekvencií (schémy 1, 2 a 3) uvedených nižšie za získania zlúčenín všeobecného vzorca H, kde Ri, R2, R3, R4, Rs, R6, m, n, Z, Z', Q a Y sú skupiny definované vyššie. Vychodiaci materiál v schémach I, II a III môže byť vhodne adaptovaný a tak môže byť pripravených viac zlúčenín všeobecného vzorca I.The compounds of the invention can be prepared by one of the reaction sequences (Schemes 1, 2 and 3) below to give compounds of formula H wherein R 1, R 2, R 3, R 4, R 5, R 6 , m, n, Z, Z ', Q and Y are the groups defined above. The starting material in Schemes I, II and III may be suitably adapted, and thus multiple compounds of formula I may be prepared.
Schéma IScheme I
Schéma I ukazuje syntézu zlúčenín všeobecného vzorca II, kde R|, R2, R3, R4, R5, Ró, m',Scheme I shows the synthesis of compounds of formula II wherein R 1, R 2, R 3, R 4, R 5, R 6, m ',
n. Z, Z', Q a Y sú definované vyššie. Príprava zahŕňa kondenzáciu α,ω-dikarboximidov všeobecného vzorca III s l-(4-aryIpiperazin-l-yl)-o-chIóraIkány všeobecného vzorca IV, v prítomnosti bázy a organického rozpúšťadla pri teplotách od 80 až 150°C v dobe pohybujúcej v rozmedzí 8 až 24 hodín za vzniku odpovedajúcich l-(4-arylpiperazil-l-yl)-(n-[a,codikarboximido]alkánov všeobecného vzorca II, kde R| a R2 má význam uvedený vyššie. Pre katalýzu reakcie je zvlášť vhodný fázovo prenosový katalyzátor, s výhodou tetrabutylamóniumbromid.n. Z, Z ', Q and Y are as defined above. The preparation comprises the condensation of the α, ω-dicarboximides of formula III with 1- (4-arylpiperazin-1-yl) -o-chloroalkanes of formula IV, in the presence of a base and an organic solvent at temperatures ranging from 80 to 150 ° C for a period of time 8 to 24 hours to give the corresponding 1- (4-arylpiperazil-1-yl) - (n- [α, codicarboximido] alkanes of formula II wherein R 1 and R 2 are as defined above. a catalyst, preferably tetrabutylammonium bromide.
Schéma 1Scheme 1
(Π)(Π)
Schéma 2Scheme 2
Zlúčeniny všeobecného vzorca II môžu byť tiež pripravené kondenzáciou piperazínov všeobecného vzorca V s anhydridmi všeobecného vzorca VI, kde Rb R2, R3, Y, Z, Z', X a m sú definované vyššie.Compounds of formula II may also be prepared by condensation of piperazines of formula V with anhydrides of formula VI wherein R b R 2, R 3, Y, Z, Z ', X and m are as defined above.
(VI) (V)(VI)
Schéma 3Scheme 3
Zlúčeniny všeobecného vzorca II môžu byť rovnako pripravené alkyláciou α,ωdikarboximidovej skupiny α,ω-dihalogénalkány následnou kondenzáciou získaného 1-(ωhalogénalkyl)dikarboximidu (všeobecný vzorec VII) s 1-arylpiperaziny (všeobecný vzorec VIII) uvedenými nižšie, kde Ri, R2, R3, Y, Z, Z', X a m sú definované vyššie. Reakcia je s výhodou uskutočnená v prítomnosti bázy a organického rozpúšťadla pri teplotách od 60 až 100 °C v dobe pohybujúcej v rozmedzí 10 až 24 hodín za vzniku odpovedajúcich l-(4arylpiperazin-l-yl)-o-[N-(a,o-dikarboximido)]alkánov všeobecného vzorca II. Pre katalýzu reakcie je zvlášť vhodný fázovo prenosový katalyzátor, s výhodou tetrabutylamónium bromid a jodid draselný.Compounds of formula II may also be prepared by alkylation of the α, ω-dicarboximide group α, ω-dihaloalkanes by subsequent condensation of the obtained 1- (ω-haloalkyl) dicarboximide (VII) with 1-arylpiperazines (VIII) below, wherein R 1, R 2, R 3 , Y, Z, Z ', X and m are as defined above. The reaction is preferably carried out in the presence of a base and an organic solvent at temperatures of from 60 to 100 ° C for a time ranging from 10 to 24 hours to give the corresponding 1- (4-arylpiperazin-1-yl) -o- [N- (a, o) -dicarboximido)] alkanes of formula II. Particularly suitable for the catalysis of the reaction is a phase transfer catalyst, preferably tetrabutylammonium bromide and potassium iodide.
·· ···· (CHJnľ—i <ΑγΑ>·· ···· (CHJnľ — i <ΑγΑ>
(CHilír—CH-CH2—Cl(CHilír-CH-CH 2 -Cl
R3 R 3
(VID(VID
II
(Π)(Π)
Ak sú vo vyššie uvedených schémach uvádzané konkrétne bázy, kyseliny, fázovo prenosové katalyzátory, atd’., je odborníkovi zrejmé, že môžu byť tiež použité iné bázy, kyseliny, fázovo prenosové katalyzátory atd’.. Podobne môžu byť upravené podľa potreby i teploty pri reakcii a doby trvania reakcií.When specific bases, acids, phase transfer catalysts, etc. are mentioned in the above schemes, it will be apparent to those skilled in the art that other bases, acids, phase transfer catalysts, etc. may also be used. reaction and duration of reactions.
Východiskové piperazíny všeobecných vzorcov IV, V a VIII sú z literatúry známe a môžu byť syntetizované postupy opísanými v Kiritzy, J.A., a kol., J. Med. Chem., 1978, roč. 21, str. 1301; USA patent č. 3,637,705 (Abbott, 1972); FR 2,179,491 (1973); Aggarwal S.K., a kol., Ind. J. Chem., 1982, roč.21B; str. 435-439; a USA patent č. 2,922,788 (Parcell, 1960).The starting piperazines of formulas IV, V and VIII are known in the literature and can be synthesized according to the methods described in Kiritzy, J.A., et al., J. Med. Chem., 1978, vol. 21, p. 1301 U.S. Pat. 3,637,705 (Abbott, 1972); FR 2,179,491 (1973); Aggarwal S.K., et al., Ind. J. Chem., 1982, 21B; p. 435-439; and U.S. Pat. 2,922,788 (Parcell, 1960).
Výsledky farmakologických testovResults of pharmacological tests
Afinita zlúčenín podľa vynálezu pre každý subtyp α-adrenoceptorov môže byť stanovená pomocou rôznych stanovení väzby na receptor (RBA) opísaných v príkladoch ďalej. Je treba poznamenať, že identifikácia a charakterizácia receptorov je stále vo vývoji, a že ich typy a subtypy sú predmetom skúmania a upresňovania.The affinity of the compounds of the invention for each α-adrenoceptor subtype can be determined using the various receptor binding assays (RBAs) described in the Examples below. It should be noted that the identification and characterization of receptors is still under development and that their types and subtypes are subject to investigation and refinement.
Stanovenie väzby na receptor a in vitro štúdie ich funkcie opísané ďalej ukazujú, že zlúčeniny podľa vynálezu predstavujú selektívne a účinné antagonisty ociA adrenoceptorov v ·· ····Determination of receptor binding and in vitro study of their functions described below show that the compounds of the invention are selective and potent antagonists of the eyes and of ·· ···· adrenoceptors
-10porovnaní s ich aktivitou voči am a am adrenoceptorom. Vynález tiež poskytuje spôsob pre demonštráciu selektívne afinity zlúčenín pre tkanivo prostaty na rozdiel od cievneho tkaniva. Príklady uvedené ďalej rovnako opisujú spôsob liečby BPH, cievnych chorôb, hromadného srdcového zlyhania, alebo hypertenziu u cicavcov, kde testované zlúčeniny ovplyvňujú krvný tlak, používajú sa v dávkach, ktoré nespôsobujú významné zmeny v krvnom tlaku. Niektoré zo zlúčenín podľa vynálezu ukázali jasnú selektivitu pre prostatické tkanivo v porovnaní so známymi zlúčeninami, ako je terazozín, doxazozín atď.. Zlúčeniny podľa vynálezu rovnako znižujú krvný tlak, pričom ich účinok je pomerne dlhodobý. Zlúčeniny podľa vynálezu sa ukázali, že sú vhodné pre liečbu teplokrvných živočíchov a cicavcov. Tieto zlúčeniny môžu byť podávané orálne alebo parenterálne vo vhodných farmaceutických kompozíciách.-Compared to their activity against am and am adrenoceptors. The invention also provides a method for demonstrating the selective affinity of compounds for prostate tissue as opposed to vascular tissue. The examples below also describe a method of treating BPH, vascular disease, multiple heart failure, or hypertension in a mammal where the test compounds affect blood pressure are used at doses that do not cause significant changes in blood pressure. Some of the compounds of the invention have shown a clear selectivity for prostate tissue over known compounds such as terazosin, doxazosin, etc. The compounds of the invention also lower blood pressure, and their effect is relatively long lasting. The compounds of the invention have been shown to be useful in the treatment of warm-blooded animals and mammals. These compounds may be administered orally or parenterally in suitable pharmaceutical compositions.
Výhodnými zlúčeninami podľa vynálezu sú l-[4-(2-metoxyfenyl)piperazin-l-yl]-3-(2,5-dioxopyrolidin-l-yl)propán (zlúčenina č. 2) l-(4-(2-metoxyfenvl)piperazin-l-yl]-4-(2,5-dioxopyrolidin-l-yl)bután (zlúčenina č. 9) l-[4-(2-metoxyfenyl)piperazin-l-yl]-3-(2,6-dioxopiperidín-l-yl)propán (zlúčenina č. 13).Preferred compounds of the invention are 1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane (Compound No. 2) 1- (4- (2- methoxyphenyl) piperazin-1-yl] -4- (2,5-dioxopyrrolidin-1-yl) butane (Compound No. 9) 1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (2 6-dioxopiperidin-1-yl) propane (Compound No. 13).
Farmaceutický prijateľné netoxické soli zlúčenín podľa vynálezu, majúce rovnaké účinky ako samotné bázy všeobecných vzorcov I a II, môžu byť pripravené reakciou s anorganickými alebo organickými kyselinami pomocou metód dobre známych a môžu byť použité na miesto samotných báz. Príklady vhodných kyselín pre prípravu takýchto solí sú kyseliny jablčná, fumarová, benzoová, askorbová, embonová, jantárová, bismetylén salicylová, metánsulfónová, etándisulfónová, octová, propiónová, vínna, sylicylová, citrónová, glukónová, asparágová, stearová, palmitová, itakonová, glykolová, p-aminobenzoová, glutamová, benzénsulfónová, fosforová, bromovodíková, sírová, cyklohexylsulfónová, chlorovodíková a dusičná.The pharmaceutically acceptable non-toxic salts of the compounds of the invention, having the same effects as the bases of formulas I and II themselves, can be prepared by reaction with inorganic or organic acids by methods well known and can be used in place of the bases themselves. Examples of suitable acids for the preparation of such salts are malic, fumaric, benzoic, ascorbic, embonic, succinic, bismethylene salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, sylicylic, citric, gluconic, aspartic, aspartic, itparagic, aspartic, p-aminobenzoic, glutamic, benzenesulfonic, phosphorus, hydrobromic, sulfuric, cyclohexylsulfonic, hydrochloric and nitric.
Vynález rovnako vo svojom rozsahu zahŕňa zlúčeniny, ktoré sa môžu premeniť na zlúčeniny všeobecných vzorcov I a II to je proléčiva. Všeobecne ide o íunkčné deriváty zlúčenín podľa vynálezu, ktoré sa in vivo ľahko premieňajú na zlúčeniny podľa vynálezu. Konvenčné postupy pre výber a prípravu takýchto zlúčenín sú známe.The invention also includes within its scope compounds which can be converted to compounds of formulas I and II, i.e. prodrugs. In general, they are functional derivatives of the compounds of the invention that are readily converted in vivo to the compounds of the invention. Conventional procedures for the selection and preparation of such compounds are known.
Vynález rovnako zahŕňa enantioméry, diastereoizoméiy, N-oxidy a farmaceutický prijateľné soli týchto zlúčenín, rovnako ako metabolity majúce rovnaký typ aktivity. Vynález ďalej zahŕňa farmaceutické kompozície obsahujúce molekuly všeobecných vzorcov I a II, alebo ich preliečivá, metabolity, enantioméry, diastereoizoinéry, N-oxidy, alebo farmaceutický prijateľné soli v kombinácii s farmaceutický prijateľným nosičom a prípadne ďalšími excipientmi.The invention also includes enantiomers, diastereoisomers, N-oxides and pharmaceutically acceptable salts of these compounds, as well as metabolites having the same type of activity. The invention further encompasses pharmaceutical compositions comprising molecules of formulas I and II, or prodrugs, metabolites, enantiomers, diastereoisomers, N-oxides, or pharmaceutically acceptable salts thereof in combination with a pharmaceutically acceptable carrier and optionally other excipients.
Ďalší aspekt vynálezu je zameraný na spôsoby pre selektívne blokovanie aiA receptorov ·· ····Another aspect of the invention is directed to methods for selectively blocking α 1 A receptors.
- 11 tak, že je do ich blízkosti, alebo do extracelulámeho média (alebo podaním cicavcom majúcim tieto receptory) dopravené účinné množstvo zlúčenín podľa vynálezu.By administering an effective amount of the compounds of the invention to their vicinity or to the extracellular medium (or administration to a mammal having these receptors).
Vynález bude teraz opísaný nasledujúcimi príkladmi, ktoré nie sú obmedzujúce.The invention will now be described by the following non-limiting examples.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1Example 1
Príprava l-[4-(4-fluórfenyl)piperazin-l-yl]-3-(2,5-dioxopyrolidin-l-yl)propánu (zlúčen. č. 1)Preparation of 1- [4- (4-fluorophenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane (Compound No. 1)
Schéma 1: Zmes 2,5-dioxopyrolidínu (0,500 g, 5 mmol), l-[4-(4-fluórfenyl) piperazin-1yl]-3-chlórpropánu (1,28 g, 5 mmol), uhličitanu draselného (0,502 g, 3,75 mmol) a tetrabutylamónium bromidu (0,322 g, 1 mmol) v acetóne (25 ml) sa 16 hodín za miešania zahrievala na 80 °C pod spätným chladičom. Rozpúšťadlo bolo odparené vo vákuu a zvyšok sa rozsuspendoval vo vode (80 ml). Vodný roztok bol extrahovaný chloroformom (3x50 ml), organické podiely sa spojili, premyli vodou (2x50 ml), vysušili nad Na2SO4 a odparili vo vákuu za získania titulnej zlúčeniny. Produkt bol purifíkovaný kolonovou chromatografiou na silikagéli pomocou zmesi chloroform-metanol (98:2) ako eluentu; výťažok 1,00 g (65%), olej.Scheme 1: A mixture of 2,5-dioxopyrrolidine (0.500 g, 5 mmol), 1- [4- (4-fluorophenyl) piperazin-1-yl] -3-chloropropane (1.28 g, 5 mmol), potassium carbonate (0.502 g) , 3.75 mmol) and tetrabutylammonium bromide (0.322 g, 1 mmol) in acetone (25 mL) was heated at 80 ° C under reflux for 16 h with stirring. The solvent was evaporated in vacuo and the residue was suspended in water (80 mL). The aqueous solution was extracted with chloroform (3x50 mL), the organics were combined, washed with water (2x50 mL), dried over Na 2 SO 4 and evaporated in vacuo to afford the title compound. The product was purified by column chromatography on silica gel using chloroform-methanol (98: 2) as eluent; yield 1.00 g (65%), oil.
Schéma 2: l-Amino-3-[4-(4-fluórfenyl)piperazin-l-yl]propánu (0,700 g, 2,95 mmol) a anhydridu kyseliny jantárovej (0,295 g, 2,95 mmol) v pyridíne (10 ml) sa 10 hodín varili pod spätným chladičom. Ďalej sa pridal anhydrid kyseliny octovej (2 ml, prebytok) a zmes sa ďalej zahrievala pod spätným chladičom 5 hodín. Rozpúšťadlo sa odparilo vo vákuu a zvyšok sa rozsuspendoval vo vode a extrahoval chloroformom (2x25 ml). Organické podiely sa spojili, premyli vodou (2x25 ml), vysušili nad Na2SO4 a zahustili. Produkt sa purifikoval kolonovou chromatografiou na silikagéli pomocou zmesi chloroform-metanol (98:2) ako eluentu; výťažok 0,436 g (46%), olej.Scheme 2: 1-Amino-3- [4- (4-fluorophenyl) piperazin-1-yl] propane (0.700 g, 2.95 mmol) and succinic anhydride (0.295 g, 2.95 mmol) in pyridine (10 ml) were refluxed for 10 hours. Acetic anhydride (2 ml, excess) was further added and the mixture was further heated under reflux for 5 hours. The solvent was evaporated in vacuo and the residue was suspended in water and extracted with chloroform (2 x 25 mL). The organics were combined, washed with water (2 x 25 mL), dried over Na 2 SO 4 and concentrated. The product was purified by column chromatography on silica gel using chloroform-methanol (98: 2) as eluent; yield 0.436 g (46%), oil.
Schéma 3: Zmes l-chIór-3-(2,5-dioxopyrolidin-l-yl)propánu (1.54 g, 8,80 mmol), l-(4-fluórfenyl)piperazín (1,58 g, 8,80 mmol), uhličitanu draselného (1,21 g, 8,80 mmol) a jodidu draselného (0,322 g, 1 mmol) v N,N-dimetylformamidu (25 ml) sa zahrievala na 100 °C po dobu 18 hodín. Rozpúšťadlo sa odparilo za zníženého tlaku. Zvyšok sa rozsuspendoval vo vode (25 ml), extrahoval chloroformom (2x25 ml) a organické podiely sa spojili, premyli vodou (2x20 ml), vysušili nad Na2SC>4 a zahustili za získania oleja, ktorý sa purifikoval kolonovou chromatografiou na silikagéli pomocou zmesi chloroform-metanol (98:2) ako eluente; výťažok 2,00 g (71%), olej.Scheme 3: A mixture of 1-chloro-3- (2,5-dioxopyrrolidin-1-yl) propane (1.54 g, 8.80 mmol), 1- (4-fluorophenyl) piperazine (1.58 g, 8.80 mmol) of potassium carbonate (1.21 g, 8.80 mmol) and potassium iodide (0.322 g, 1 mmol) in N, N-dimethylformamide (25 mL) was heated at 100 ° C for 18 hours. The solvent was evaporated under reduced pressure. The residue was suspended in water (25 mL), extracted with chloroform (2 x 25 mL) and the organics were combined, washed with water (2 x 20 mL), dried over Na 2 SO 4 and concentrated to give an oil which was purified by silica gel column chromatography using chloroform. -methanol (98: 2) as eluent; yield 2.00 g (71%), oil.
-[4-(4-Fluórfenyl)piperazin-1 -yl]-3-(2,5-dioxopyrolidin-1 -yl)propán hydrochlorid- [4- (4-Fluorophenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane hydrochloride
(zlúčenina č. 1) sa pripravil v kvantitatívnom výťažku pridaním éterického roztoku chlorovodíka do metanolického roztoku látky a vzniknutý precipitát sa oddelil filtráciou, teplota topenia 246 až 247 °C.(Compound No. 1) was prepared in quantitative yield by adding ethereal hydrogen chloride to a methanolic solution of the substance and the resulting precipitate was collected by filtration, mp 246-247 ° C.
Príklad 2Example 2
Príprava 1 -[4-(2-metoxyfenyl)piperazin-1 -yl]-3-(2,5-dioxopyrolidin-1 -yl)propánu (zlúčenina č. 2)Preparation of 1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane (Compound No. 2)
Schéma 1: Zmes 2,5-dioxopyrolidínu (3,68 g, 37,24 mmol), l-[4-(4-metoxyfenyl)-piperazin-l-yl]-3-chlórpropánu (10,0 g, 37,24 mmol), uhličitanu draselného (7,70 g, 55,8 mmol) a tetrabutylamóniumbromidu (2,38 g, 7,4 mmol) v acetóne (100 ml) sa 12 hodín za miešania zahrievala na 80 °C pod spätným chladičom. Rozpúšťadlo sa odparilo vo vákuu a zvyšok sa rozsuspendoval vo vode (80 ml). Vodný roztok sa extrahoval chloroformom (3x50 ml), organické podiely sa spojili, premyli vodou (2x50 ml), vysušili nad Na2SC>4 a odparili vo vákuu za získania žiadanej zlúčeniny. Produkt bol purifikovaný kolonovou chromatografiou na silikagéli pomocou zmesi chloroform-metánol (99:1) ako eluente; výťažok 8,00 g (65%), olej. Hydrochlorid sa pripravil spôsobom opísaným vyššie; teplota topenia 199 až 202°C.Scheme 1: A mixture of 2,5-dioxopyrrolidine (3.68 g, 37.24 mmol), 1- [4- (4-methoxyphenyl) -piperazin-1-yl] -3-chloropropane (10.0 g, 37, 24 mmol), potassium carbonate (7.70 g, 55.8 mmol) and tetrabutylammonium bromide (2.38 g, 7.4 mmol) in acetone (100 mL) were stirred and heated at 80 ° C under reflux for 12 h. The solvent was evaporated in vacuo and the residue was suspended in water (80 mL). The aqueous solution was extracted with chloroform (3 x 50 mL), the organics were combined, washed with water (2 x 50 mL), dried over Na 2 SO 4 and evaporated in vacuo to give the title compound. The product was purified by column chromatography on silica gel using chloroform-methanol (99: 1) as eluent; yield 8.00 g (65%), oil. The hydrochloride was prepared as described above; mp 199-202 ° C.
Schéma 3: Zmes l-chlor-3-(2,5-dioxopyrolidin-l-yl)propánu (28 g, 159,5 mmol), l-(2-metoxyfenyl)piperazín hydrochloridu (36,45 g, 159,5 mmol), uhličitanu draselného (44,03 g, 319,0 mmol) a jodidu draselného (1,58 g, 9,57 mmol) v N,N-dimetylformamide (115 ml) sa zahrievala na 80 °C po dobu 17 hodín a rozpúšťadlo sa odparilo za zníženého tlaku. Zvyšok sa rozsuspendoval v etylacetáte (600 ml), premyl vodou (5x100 ml) a vysušil nad NazSCh a zahustil za získania oleja, ktorý sa purifikoval kolonovou chromatografiou na silikagéli 39 až 78 ôk.cm’1 (100 až 200 mesh) pomocou zmesi chloroform-metanol (99:2) ako eluente; výťažok 55,1 g (80%), olej. Hydrochlorid sa pripravil spôsobom opísaným vyššie; teplota topenia 199 až 202°C.Scheme 3: A mixture of 1-chloro-3- (2,5-dioxopyrrolidin-1-yl) propane (28 g, 159.5 mmol), 1- (2-methoxyphenyl) piperazine hydrochloride (36.45 g, 159.5 mmol), potassium carbonate (44.03 g, 319.0 mmol) and potassium iodide (1.58 g, 9.57 mmol) in N, N-dimethylformamide (115 mL) were heated at 80 ° C for 17 hours and the solvent was evaporated under reduced pressure. The residue was suspended in ethyl acetate (600 mL), washed with water (5x100 mL) and dried over NazSCh and concentrated to give an oil which was purified by column chromatography on silica gel 39-78 ôk.cm '1 (100-200 mesh) using chloroform -methanol (99: 2) as eluent; yield 55.1 g (80%), oil. The hydrochloride was prepared as described above; mp 199-202 ° C.
l-Chlór-3-(2,5-dioxopyrolidin-l-yl)propán môže byť pripravený reakciou 2,5dioxopyrolidínu a l-bróm-3-chlórpropánu v prítomnosti uhličitanu draselného a tetrabutylamónium bromidu v acetóne.1-Chloro-3- (2,5-dioxopyrrolidin-1-yl) propane can be prepared by reacting 2,5-dioxopyrrolidine and 1-bromo-3-chloropropane in the presence of potassium carbonate and tetrabutylammonium bromide in acetone.
Príklad 3Example 3
Príprava l-(4-(2-metoxyfenyl)piperazin-l-yl]-4-(2,5-dioxopyrolidin-l-yl)butánu (zlúč. č. 9) ·· ···· ·· ·· • · · • · · ··· ··· • ··· ··· ···· · • ········ -13- ···· ·· ·· ·· ·· ···Preparation of 1- (4- (2-methoxyphenyl) piperazin-1-yl) -4- (2,5-dioxopyrrolidin-1-yl) butane (Compound No. 9) ·· ········ · · · · · 13 · ·---13 13 13 13 13 13 13 13 13 13 13 13 13 13 13
Schéma 3: Zmes l-chlór-4-(2,5-dioxopyrolidin-l-yl)butánu (11,0 g, 58,04 mmol), l-(2-metoxyfenyl)piperazín hydrochloridu (12,99 g, 56,85 mmol), uhličitanu draselného (16,02 g, 116,09 mmol) a jodidu draselného (0,577 g, 3,48 mmol) v N,N-dimetylformamide (45 ml) sa miešala pri 100 °C po dobu 18 hodín. Ν,Ν-Dimetylformamid sa odparil za zníženého tlaku a zvyšok sa rozsuspendoval vo vode (100 ml) a extrahoval chloroformom (2x100 ml). Extrakt sa vysušil nad Na2SO4 a zahustil za zníženého tlaku za získania 1-(4-(2metoxyfenyl)piperazin-l-yl]-4-(2,5-dioxopyrolidin-l-yl)butánu ako oleja, ktorý sa purifikoval kolonovou chromatografiou na silikagéli 90 až 156 ôk.cm'1 (230 až 400 mesh) pomocou zmesi chloroform-metanol (98:2) ako eluente; výťažok 18,00 g (92%), olej. Hydrochlorid sa pripravil spôsobom opísaným vyššie; teplota topenia 218 až 220 °C.Scheme 3: A mixture of 1-chloro-4- (2,5-dioxopyrrolidin-1-yl) butane (11.0 g, 58.04 mmol), 1- (2-methoxyphenyl) piperazine hydrochloride (12.99 g, 56 , 85 mmol), potassium carbonate (16.02 g, 116.09 mmol) and potassium iodide (0.577 g, 3.48 mmol) in N, N-dimethylformamide (45 mL) were stirred at 100 ° C for 18 hours . Ν, Ν-Dimethylformamide was evaporated under reduced pressure and the residue was suspended in water (100 mL) and extracted with chloroform (2 x 100 mL). The extract was dried over Na 2 SO 4 and concentrated under reduced pressure to give 1- (4- (2-methoxyphenyl) piperazin-1-yl) -4- (2,5-dioxopyrrolidin-1-yl) butane as an oil which was purified by column chromatography silica gel 90-156 ôk.cm '1 (230-400 mesh) using chloroform-methanol (98: 2) as eluent; yield: 18.00 g (92%), oil. the hydrochloride was prepared as described above, m.p. Mp 218-220 ° C.
l-Chlor-3-(2,5-dioxopyrolidin-l-yl) propán môže byť pripravený reakciou 2,5dioxopyrolidinu a l-brom-3-chlorpropánu v prítomnosti uhličitanu draselného a tetrabutylamónium bromidu v acetóne.1-Chloro-3- (2,5-dioxopyrrolidin-1-yl) propane can be prepared by reacting 2,5-dioxopyrrolidine and 1-bromo-3-chloropropane in the presence of potassium carbonate and tetrabutylammonium bromide in acetone.
Príklad 4Example 4
Príprava l-[4-(2-metoxyfenyl)piperazin-l-yl]-3-(2,6-dioxopiperidín- l-yl)propánu (zlúčenina č. 13)Preparation of 1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane (Compound No. 13)
Schéma 1: Zmes 2,6-dioxopiperidínu (2,60 g, 23,02 mmol), l-[4-(2-metoxyfenyl)-piperazin-l-yl]-3-chlorpropánu (6,18 g, 23,02 mmol), uhličitanu draselného (2,38 g, 17,27 mmol) a tetrabutylamónium bromidu (1,48 g, 4,60 mmol) v acetóne (80 ml) sa varila 16 hodín za miešania pri 80 °C pod spätným chladičom. Rozpúšťadlo sa odparilo vo vákuu a zvyšok sa rozsuspendoval vo vode (60 ml), roztok sa extrahoval chloroformom (3x40 ml), organické podiely sa spojili, premyli vodou (2x40 ml), vysušili nad bezvodým Na2SO4 a odparili vo vákuu za získania žiadanej zlúčeniny. Produkt sa purifikoval kolonovou chromatografiou na silikagéli 90 až 156 ôk.cm'1 (230 - 400 mesh) pomocou zmesi chloroform-metanol (98:1) ako eluente; výťažok 3,58 g (45%), olej. Hydrochlorid sa pripravil spôsobom opísaným vyššie; teplota topenia 206 až 210°C.Scheme 1: A mixture of 2,6-dioxopiperidine (2.60 g, 23.02 mmol), 1- [4- (2-methoxyphenyl) -piperazin-1-yl] -3-chloropropane (6.18 g, 23, 02 mmol), potassium carbonate (2.38 g, 17.27 mmol) and tetrabutylammonium bromide (1.48 g, 4.60 mmol) in acetone (80 mL) were refluxed for 16 h at 80 ° C under reflux. . The solvent was evaporated in vacuo and the residue was suspended in water (60 mL), the solution was extracted with chloroform (3 x 40 mL), the organics were combined, washed with water (2 x 40 mL), dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give the title compound. . The product was purified by column chromatography on silica gel 90-156 ôk.cm '1 (230-400 mesh) using chloroform-methanol (98: 1) as eluent; yield 3.58 g (45%), oil. The hydrochloride was prepared as described above; mp 206-210 ° C.
Schéma 3: Zmes l-chlór-3-(2,6-dioxopiperidín-l-yl) propánu (22,06 g, 116,40 mmol), 1(2-metoxyfenyl)piperazínu (21,90 g, 114,06 mmol), uhličitanu draselného (16,06 g, 116,40 mmol) a jodidu draselného (1,16 g, 6,98 mmol) v N,N-dimetylformamide (90 ml) sa zahrievala na 80 °C po dobu 17 hodín a rozpúšťadlo sa odparilo za zníženého tlaku. ZvyšokScheme 3: A mixture of 1-chloro-3- (2,6-dioxopiperidin-1-yl) propane (22.06 g, 116.40 mmol), 1- (2-methoxyphenyl) piperazine (21.90 g, 114.06) mmol), potassium carbonate (16.06 g, 116.40 mmol) and potassium iodide (1.16 g, 6.98 mmol) in N, N-dimethylformamide (90 mL) were heated at 80 ° C for 17 hours and the solvent was evaporated under reduced pressure. Rest
sa rozsuspendoval v etylacetáte (400 ml), premyl vodou (5x100 ml) a vysušil nad Na2SO4 a zahustil za získania oleja, ktorý sa purifikoval kolonovou chromatografiou na silikagele 39 až 78 ôk.cm'1 (100 až 200 mesh) pomocou zmesi chloroform-metanol (99:1) ako eluente; výťažok 33,8 g (86%), olej. Hydrochlorid sa pripravil v kvantitatívnom výťažku pridaním nadbytku éterického roztoku chlorovodíka do metanolickej zlúčeniny a získal odfiltrovaním vzniknutého precipitátu; teplota topenia 206 až 210 °C.was suspended in ethyl acetate (400 mL), washed with water (5x100 mL) and dried over Na2SO4 and concentrated to give an oil which was purified by column chromatography on silica gel 39-78 ôk.cm -1 (100 to 200 mesh) using a mixture of chloroform methanol (99: 1) as eluent; yield 33.8 g (86%), oil. The hydrochloride was prepared in quantitative yield by adding an excess of ethereal hydrogen chloride solution to the methanolic compound and recovering the precipitate formed by filtration; mp 206-210 ° C.
Ďalej je uvedený ilustratívny zoznam zlúčenín podľa vynálezu, ktoré boli syntetizované jedným, alebo viac z vyššie opísaných spôsobov.The following is an illustrative list of compounds of the invention that have been synthesized by one or more of the methods described above.
-[4-(4-fluórfenyl)piperazin-1 -yl]-3-(2,5-dioxopyrolidin-1 -yl)propán hydrochlorid;[4- (4-fluorophenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane hydrochloride;
teplota topenia 246 až 247 °C.mp 246-247 ° C.
-[4-(2-metoxyfenyl)piperazin-1 -yl]-3-(2,5-dioxopyrolidin-1 -yl)propán hydrochlorid;[4- (2-methoxyphenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane hydrochloride;
teplota topenia 199 až 202 °C.mp 199-202 ° C.
l-[4-(3-trifluórmetylfenyl)piperazin-l-yl]-3-(2,5-dioxopyrolidin-l-yl)propán hydrochlorid; teplota topenia 218 až 220 °C.1- [4- (3-Trifluoromethylphenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane hydrochloride; mp 218-220 ° C.
-[4-(2-pyridyl)piperazin-1 -yl]-3-(2,5-dioxopyrolidin-1 -yl)propán hydrochlorid; teplota topenia 261 až 262 °C.[4- (2-pyridyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane hydrochloride; mp 261-262 ° C.
l-[4-(3-chlórfenyl)piperazin-l-yl]-3-(2,5-dioxopyrolidin-l-yl)propán hydrochlorid;1- [4- (3-chlorophenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane hydrochloride;
teplota topenia 230 až 231 °C.mp 230-231 ° C.
l-[4-(2-pyrimidyl)piperazin-l-yI]-3-(2,5-dioxopyrolidin-l-yI)propán hydrochlorid;1- [4- (2-pyrimidyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane hydrochloride;
teplota topenia 196 až 198 °C.mp 196-198 ° C.
l-[4-(3,4-dimetylfenyl)piperazin-l-yl]-3-(2,5-dioxopyrolidin-l-yl)propán hydrochlorid; teplota topenia 244 až 246 °C.1- [4- (3,4-dimethylphenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane hydrochloride; mp 244-246 ° C.
-[4-(fenyl)piperazin-1 -yl]-3-(2,5-dioxopyrolidin-1 -yl)propán hydrochlorid; teplota topenia 258 až 259 °C.[4- (phenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane hydrochloride; mp 258-259 ° C.
-(4-(2-metoxyfenyl)piperazin-1 -yl]-4-(2,5-dioxopyrolidin-1 -yl)bután teplota topenia 218 až 220 °C.- (4- (2-methoxyphenyl) piperazin-1-yl) -4- (2,5-dioxopyrrolidin-1-yl) butane, m.p. 218-220 ° C.
-[4-(2-metoxyfenyl)piperazin-1 -y 1]-2-(2,5-dioxopyrolidin-1 -yl)etán- [4- (2-Methoxyphenyl) piperazin-1-yl] -2- (2,5-dioxopyrrolidin-1-yl) ethane
-[4-(3-metoxyfenyl)piperazin-1 -yl]-3-(2,5-dioxopyrolidin-1 -yl)propán hydrochlorid;[4- (3-methoxyphenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane hydrochloride;
hydrochlorid;hydrochloride;
hydrochlorid;hydrochloride;
teplota topenia 232 až 234 °C.mp 232-234 ° C.
teplota topenia 199 až 201 °C.mp 199-201 ° C.
-[4-(4-metoxyfenyI)piperazin-1 -yl]-3-(2,5-dioxopyrolidin-1 -yl)propán hydrochlorid;[4- (4-methoxyphenyl) piperazin-1-yl] -3- (2,5-dioxopyrrolidin-1-yl) propane hydrochloride;
-15·· ·· ·· ···· ·· · • · · · ·· · ···· • ··· ··· · · 4 · · * · ······ · ···· ·· ·· ·· ·· teplota topenia 240 až 242 °C.-15 ································ · 4 Mp 240-242 ° C.
-[4-(2-metoxyfenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidín-1 -yl)propán hydrochlorid;[4- (2-methoxyphenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane hydrochloride;
teplota topenia 206 až 210 °C.mp 206-210 ° C.
-[4-(4-fluórfenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidín-1 -yl)propán teplota topenia 200 až 202 °C.[4- (4-Fluorophenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane, m.p. 200-202 ° C.
-[4-(4-chlórfenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidín-1 -yl)propán hydrochlorid;[4- (4-chlorophenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane hydrochloride;
hydrochlorid;hydrochloride;
teplota topenia 206 až 208 °C.mp 206-208 ° C.
-[4-(3-trifluórmetylfenyl)piperazin-1 -yI]-3-(2,6-dioxopiperidín-1 -yl)propán hydrochlorid; teplota topenia 228 až 229 °C.[4- (3-Trifluoromethylphenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane hydrochloride; mp 228-229 ° C.
-(4-(2-fluórfenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidín-1 -yl)propán hydrochlorid;- (4- (2-fluorophenyl) piperazin-1-yl) -3- (2,6-dioxopiperidin-1-yl) propane hydrochloride;
teplota topenia 215 až 216 °C.mp 215-216 ° C.
-[4-(2-metylfenyl) piperazin-1 -yl]-3-(2,6-dioxopiperidín-1 -y l)propán hydrochlorid;[4- (2-methylphenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane hydrochloride;
teplota topenia 206 až 207 °C.mp 206-207 ° C.
-(4-(2-pyridyl)piperazin-1 -yl)-3-(2,6-dioxopiperidín-1 -yl)propán hydrochlorid; teplota topenia 244 až 245 °C.- (4- (2-pyridyl) piperazin-1-yl) -3- (2,6-dioxopiperidin-1-yl) propane hydrochloride; mp 244-245 ° C.
-[4-(3-chlórfenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidín-l -yl) propán hydrochlorid;[4- (3-chlorophenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane hydrochloride;
teplota topenia 214 až 215 °C.mp 214-215 ° C.
-[4-(3,4-dimetylfenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidín-1 -yl)propán hydrochlorid; s nízku teplotou topenia hygroskopický.[4- (3,4-dimethylphenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane hydrochloride; low melting point hygroscopic.
-[4-(2-pyrimidyl)piperazin-1 -yl]-3-(2,6-dioxopiperidín-1 -yl)propán hydrochlorid;[4- (2-pyrimidyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane hydrochloride;
teplota topenia 195 až 196 °C.mp 195-196 ° C.
l-[4-(3-metoxyfenyl)piperazin-l-yl]-3-(2,6-dioxopiperidín-l-yl)propán hydrochlorid;1- [4- (3-methoxyphenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane hydrochloride;
teplota topenia 196 až 197°C.mp 196-197 ° C.
-[4-(4-metoxyfenyl)piperazin-1 -yl]-3-(2,6-dioxopiperidín-1 -yl)propán hydrochlorid;[4- (4-methoxyphenyl) piperazin-1-yl] -3- (2,6-dioxopiperidin-1-yl) propane hydrochloride;
teplota topenia 218 až 220 °C.mp 218-220 ° C.
-[4-(2-metoxyfenyl)piperazin-1 -yl]-4-(2,6-dioxo piperidín-1 -yl)bután hydrochlorid;[4- (2-methoxyphenyl) piperazin-1-yl] -4- (2,6-dioxo piperidin-1-yl) butane hydrochloride;
teplota topenia 190 až 192 °C.mp 190-192 ° C.
l-[4-(2-metoxyfenyl)piperazin-l-yl]-3-[2,5-dioxo-3-fenyl-pyrolidin-l-yl]propán hydrochlorid; teplota topenia 171 až 172 °C.1- [4- (2-methoxyphenyl) piperazin-1-yl] -3- [2,5-dioxo-3-phenyl-pyrrolidin-1-yl] propane hydrochloride; mp 171-172 ° C.
-[4-(fenyl)piperidín-1 -yl]-3-[2,5-dioxopyrolidin-1 -yljpropán hydrochlorid; teplota topenia 208 až 209 °C.- [4- (phenyl) piperidin-1-yl] -3- [2,5-dioxopyrrolidin-1-yl] propane hydrochloride; mp 208-209 ° C.
Všetky vyššie uvedené teploty topenia sú nekorigované a stanovené metódou otvorenej kapiláry pomocou aparátu Buchi 535.All of the above melting points are uncorrected and determined by the open capillary method using a Buchi 535 apparatus.
·· ···· • ··· ···· · ·
-16Stanovenie väzby na receptory In vitro väzba na receptory-16 Determination of Receptor Binding In vitro binding to receptors
Stanovenie väzby na receptory (RBA) sa vykonávalo pre natívne αι-adrenoceptory. Na stanovenie afinity k ocia alebo ais subtypom boli použité membrány pripravené z krysieho tkaniva pod spodnou čeľusťou, respektíve pečene. Alikvóty membránových proteínov (100 200 mg) boli inkubované v konečnom objeme 250 ml pufŕa (50 mM Tris, 0,5 mM EDTA, pH 7,4) s 0,5 nM [3H] prazozínom 60 minút pri 28 °C. Reakcia sa zastavila rýchlou filtráciou cez filtre Millipore. Filtre boli vysušené a naviazaná rádioaktivita bola zmeraná. Nešpecifická väzba bola stanovená v prítomnosti 0,3 mM prazozínu. Obsah proteínov sa stanovil metódou podľa Lowryho, O.H. et al., J.Biol.Chem., roč. 193, strany 265-275 (1951). Výsledky sú uvedené v tabuľke 1.Receptor Binding Assay (RBA) was performed for native α-adrenoceptors. Membranes prepared from rat tissue under the lower jaw and liver, respectively, were used to determine the affinity for the eyes or ais subtypes. Aliquots of membrane proteins (100-200 mg) were incubated in a final volume of 250 ml buffer (50 mM Tris, 0.5 mM EDTA, pH 7.4) with 0.5 nM [ 3 H] prazosin for 60 minutes at 28 ° C. The reaction was stopped by rapid filtration through Millipore filters. The filters were dried and the bound radioactivity was measured. Non-specific binding was determined in the presence of 0.3 mM prazosin. Protein content was determined by the method of Lowry, OH et al., J. Biol. Chem. 193, pages 265-275 (1951). The results are shown in Table 1.
Tabuľka 1Table 1
·· ···· ·· • ··· ··· ···· · * ········ ···· ·· ·· «· ·· ·····················································································
In vitro funkčné štúdieIn vitro functional studies
Selektivita cq-adrenoceptorov in vitroSelectivity of cq-adrenoceptors in vitro
Na zistenie selektivity účinku zlúčenín podľa vynálezu pre rôzne subtypy aadrenoceptorov bola študovaná schopnosť týchto zlúčenín pôsobiť proti kontraktívnej odozve spôsobenej agonistami αι-adrenoceptorov pri aorte(aip), prostaty(aiA) a sleziny(aie). Tkanivá aorty, prostaty a sleziny boli izolované z cicavcov wistar krýs znecitlivených uretánom (1,5 mg/kg). Izolované tkanivá boli prenesené do organového kúpeľa obsahujúce Krebsov-Henseleitov pufer nasledujúceho zloženia (mM): NaCl 118; KC1 4,7; CaCl2 2,5; MgSO.|.7H2O 1,2; NaHCCh 25; KH2PO4 1,2; glukóza 11,5. Pufer bol udržiavaný pri 37 °C a prevzdušňovaný zmesou 95% O2 a 5% CO2. Na tkanivo bolo aplikované kľudové napätie 2 g (aorta), alebo 1 g (slezina a prostata). Kontraktívna odpoveď bola sledovaná pomocou prevodníka síl a zaznamenávaná na zapisovači. Tkanivá boli 2 hodiny ekvilibrované. Po ekvilibrácii boli zaznamenané krivky odpovedí a ich závislosť na koncentrácii noradrenalínu (aorta) a fenylefrínu (slezina a prostata) v prítomnosti a neprítomnosti testovanej zlúčeniny (v koncentráciách 0,1, 1 a 10 μΜ). Afinita antagonistov bola vypočítaná a vyjadrená ako hodnoty pKe v tabuľke 1.To determine the selectivity of the effect of the compounds of the invention for various subtypes of aadrenoceptors, the ability of these compounds to counteract the contractile responses caused by α-adrenoceptor agonists in the aorta (aip), prostate (aiA) and spleen (aie) was studied. Aortic, prostate and spleen tissues were isolated from urethane-desensitized mammalian wistar rats (1.5 mg / kg). Isolated tissues were transferred to an organic bath containing Krebs-Henseleit buffer of the following composition (mM): NaCl 118; KCl 4.7; CaCl 2 2.5; MgSO4.7H2O 1.2; NaHCCh 25; KH2PO4 1.2; glucose 11.5. The buffer was maintained at 37 ° C and aerated with 95% O 2 and 5% CO 2. A resting tension of 2 g (aorta) or 1 g (spleen and prostate) was applied to the tissue. The contractive response was monitored using a force transducer and recorded on a recorder. The tissues were equilibrated for 2 hours. After equilibration, response curves and their dependence on the concentrations of noradrenaline (aorta) and phenylephrine (spleen and prostate) were recorded in the presence and absence of test compound (at concentrations of 0.1, 1, and 10 μΜ). The antagonist affinity was calculated and expressed as pKe values in Table 1.
·· ···· • ··· ···· · ·
-18Selektivita receptorov in vitro-18 Receptor selectivity in vitro
Selektivita účinku zlúčenín podľa vynálezu sa testovala na rozličných receptoroch, napríklad βι- a a2-adrenergných, muskarínových cholínergných, sérotoninergných (5-ΗΪ2α), histamínergných (Hi), angiotenzínových II, endotelínových (ETa a b), rovnako ako na vápnikových a draslíkových kanáloch. Krysia aorta sa použila na štúdium účinku zlúčenín na receptoroch 5-ΗΪ2Α, -ETa, vápnikových a draslíkových kanáloch. Antagonistická aktivita voči angiotenzinovým II receptorom sa študovala na králičej aorte. Antagonistická aktivita voči muskarinovým cholinergným receptorom sa študovala na krysej priedušnici a antagonistická aktivita voči Hi receptorom bola študovaná na priedušnici morčiat. Na štúdium účinku na a2-adrenoceptory sa použili elektricky stimulované krysie chámovody, zatiaľ čo βiadrenoceptorová aktivita sa študovala pomocou elektricky stimulovaných prúžkov z krysieho ventrikulámeho (srdcová komora) tkaniva.The selectivity of the compounds of the invention has been tested at various receptors, for example, beta- and α2-adrenergic, muscarinic cholinergic, serotoninergic (5--2α), histaminergic (Hi), angiotensin II, endothelin (ETa and b), as well as calcium and potassium channels. . Rat aorta was used to study the effect of compounds on the 5-Α2Α, -ET α , calcium and potassium channels receptors. Antagonist activity against angiotensin II receptors was studied in rabbit aorta. Antagonist activity against muscarinic cholinergic receptors was studied in rat trachea and H 1 receptor antagonist activity was studied in guinea pig trachea. Electrically stimulated rat ducts were used to study the effect on α 2 -adrenoceptors, while β-adrenoceptor activity was studied using electrically stimulated strips from rat ventricular (heart chamber) tissue.
Výsledky tejto štúdie selektivity sú ukázané v tabuľke (tabuľka 2).The results of this selectivity study are shown in the table (Table 2).
Tabuľka 2Table 2
Štúdie selektivity ρΚβ pre daný typ receptoraΡΚβ selectivity studies for a given receptor type
NIE: žiadny efekt (-): bolo tetované • · · · · · ·· ·· ···· ··· · ······ ·· • ····· ···· ·NO: no effect (-): tattooed ··· ·································
Λ · ·······Λ · ·······
- 17“ ···· ·· ·· ····- 17 “··············
In vivo antihypertenzny účinokIn vivo antihypertensive effect
Antihypertenzný účinok vybraných zlúčenín podľa vynálezu bol študovaný sledovaním ich schopnosti znižovať krvný tlak u znecitlivenej živej spontánne hypertenznej krysy pri vedomí po intravenóznom, orálnom, alebo intraduodenálnom podaní. Výsledky sú uvedené v tabuľkách 1 a 3.The antihypertensive effect of selected compounds of the invention was studied by monitoring their ability to lower blood pressure in an anesthetized live spontaneously hypertensive conscious rat after intravenous, oral, or intraduodenal administration. The results are shown in Tables 1 and 3.
Znecitlivené krvsv s normálnym krvným tlakomHypersensitive blood with normal blood pressure
Intravenózne podanieIntravenous administration
Samce wistar krýs sa znecitliveli uretánom (2,5 g/kg). Do femorálnej žily a karotíny boli zavedené kanyly. Krvný tlak a srdcový tep sa zaznamenávali pomocou prevodníka tlaku Satham. Dáta boli zaznamenávané na polygrafe Grass a tiež pomocou on line systému (Buxco AT). Intravenózne podávané zlúčeniny podľa vynálezu boli najprv testované v dávke 0,3 mg/kg po dobu 3 hodín a ich vplyv na krvný tlak je uvedený v tabuľke 1. Pre niekoľko vybraných zlúčenín sa účinok na zníženie krvného tlaku po intravenóznom podaní študoval tiež v dávkach 0,03,0,1,0,3 a 1 mg/kg.Male wistar rats were anesthetized with urethane (2.5 g / kg). Cannulas were inserted into the femoral vein and carotin. Blood pressure and heart rate were recorded using a Satham pressure transducer. Data were recorded on a Grass Polygraph and also using an on-line system (Buxco AT). Intravenously administered compounds of the invention were first tested at a dose of 0.3 mg / kg for 3 hours and their effect on blood pressure is shown in Table 1. For several selected compounds, the blood pressure lowering effect after intravenous administration was also studied in doses of 0. , 03.0,1.0.3 and 1 mg / kg.
Intraduodenálne podanieIntraduodenal administration
Samce wistar krýs sa na 18 hodín priviazali. Krysy sa znecitliveli uretánom. Do femorálnej žily a karotídy sa zaviedli kanyly. Do duodéna sa po laparotómii umiestnil katéter. Zlúčeniny podľa vynálezu (v dávkach 0,3, 1,3, a 10 mg/kg) sa podávali do duodéna a krvný tlak sa monitoroval 3 hodín. Výsledky sú uvedené v tabuľke 3.Male wistar rats were tied for 18 hours. The rats were anesthetized with urethane. Cannulas were inserted into the femoral vein and carotid artery. A catheter was placed in the duodenum after laparotomy. Compounds of the invention (at doses of 0.3, 1.3, and 10 mg / kg) were administered to the duodenum and blood pressure was monitored for 3 hours. The results are shown in Table 3.
Tabuľka 3Table 3
Účinok na priemerný arteriálny tlak znecitlivených krýs s normálnym tlakomEffect on average arterial pressure of numbed normal pressure rats
-20Krvsv s normálnym krvným tlakom pri vedomí-20Kvvsv with normal conscious blood pressure
Femorálne artérie samcov živých wistar krýs, cez noc udržiavaných na ľahkej diéte, sa kateterizovali pri znecitlivení pentobarbitónom (35 mg/kg). Femorálny katéter sa vyviedol v oblasti krku a pomocou neho sa sledoval krvný tlak. Zlúčeniny podľa vynálezu (v dávkach 0,1, 0,3 a 1 mg/kg) sa podali 24 hodín po operácii, a to orálnou cestou pomocou sondy do žalúdka krysám, ktoré boli cez noc priviazané. Krvný tlak a srdcový rytmus sa zaznamenávali pomocou prevodníka tlaku Statham a polygrafii Grass a výsledky sú uvedené v tabuľke 4.Femoral arteries of male live wistar rats, kept on a light diet overnight, were catheterized under anesthesia with pentobarbitone (35 mg / kg). The femoral catheter was dislocated in the neck area and blood pressure was monitored. The compounds of the invention (at doses of 0.1, 0.3 and 1 mg / kg) were administered 24 hours post-operatively by oral gavage to rats that were bound overnight. Blood pressure and heart rhythm were recorded using a Statham pressure transducer and Grass polygraphy and the results are shown in Table 4.
Tabuľka 4Table 4
Účinok na systolický krvný tlak u spontánne hypertenzných krýs pri vedomíEffect on systolic blood pressure in conscious spontaneous hypertensive rats
Spontánne hypertenzné krysy pri vedomíSpontaneous hypertensive conscious rats
V tejto štúdii sa použili spontánne hypertenzné krysy vážiace medzi 250 až 300 g. Krysy sa cez noc pripútali. Krvný tlak sa monitoroval na chvostovej artérii pomocou poloautomatického neinvazívného prístroja na meranie krvného tlaku. Zlúčeniny podľa vynálezu (v dávkach 1,3, 10 a 30 mg/kg) sa podávali orálne. Krvný tlak bol pred a 1,5, 4, 6 a 24 hodín po podaní zlúčenín. Výsledky sú uvedené v tabuľke 5.Spontaneous hypertensive rats weighing between 250 and 300 g were used in this study. The rats were strapped overnight. Blood pressure was monitored on the tail artery using a semi-automatic non-invasive blood pressure measuring device. The compounds of the invention (at doses of 1.3, 10 and 30 mg / kg) were administered orally. Blood pressure was before and 1.5, 4, 6 and 24 hours after compound administration. The results are shown in Table 5.
• · · · · ·• · · · · ·
-21 Tabuľka 5-21 Table 5
Účinok na priemerný arteriálny krvný tlak u volne pohyblivých živých krýs pri vedomí.Effect on average arterial blood pressure in conscious free-living rats.
In vivo štúdie selektivityIn vivo selectivity studies
Samce psov zmiešanej rasy (12 až 20 kg) sa znecitliveli pentobarbitálom sodným (35 mg/kg, intravenózne) Priedušnica sa intubovala kvôli umelej pľúcnej ventilácii. Do femorálnej artérie a femorálnej žily sa zaviedli kanyly, aby bolo umožnené meranie krvného tlaku, respektíve podávanie roztokov zlúčenín. Krvný tlak sa zaznamenával pomocou prevodníka tlaku a polygrafii. Vykonal sa rez blízko stredu laterálne k penisu a tak sa odhalil močový mechúr. Moč sa odviedol pomocou kanyly zavedenej priamo do mechúra a potom sa viedol do močovej trubice a umiestnil vo vývode prostaty. Balónik sa nafúkol asi 2 cm3 vzduchu a overilo sa jeho umiestnenie. Intrauretrálny tlak sa zaznamenával na polygrafe pripojenom k prevodníku tlaku. Závislosť tlaku na zvyšujúcej sa dávke fenylefrínu (1 až 16 pg/kg, intravenózne) sa získala pre tlak prostatický a krvný pred podaním zlúčenín podľa vynálezu. Potom sa intravenózne podávali zlúčeniny 2, 9, a 13 (v dávkach 0,01, 0,03, 0,1 a 0,3 mg/kg), a to 10 minút pred meraním kriviek odpovedí na fenylefrín. Výsledky sa analyzovali a vypočítali sa hodnoty ρΚβ spôsobom opísaným v Kenny et al. (1996). Výsledky sú uvedené v tabuľke 6.Mixed race male dogs (12-20 kg) were anesthetized with sodium pentobarbital (35 mg / kg, intravenous). The trachea was intubated for artificial lung ventilation. Cannulas were inserted into the femoral artery and femoral vein to allow blood pressure or compound solutions to be administered, respectively. Blood pressure was recorded using a pressure transducer and polygraphy. An incision was made near the center laterally to the penis to expose the bladder. Urine was collected via a cannula inserted directly into the bladder and then passed into the urethra and placed in the prostate duct. The balloon was inflated with about 2 cm 3 of air and verified its location. Intraurethral pressure was recorded on a polygraph attached to a pressure transducer. The pressure dependence on the increasing dose of phenylephrine (1-16 pg / kg, intravenous) was obtained for prostatic and blood pressure prior to administration of the compounds of the invention. Compounds 2, 9, and 13 were then administered intravenously (at doses of 0.01, 0.03, 0.1 and 0.3 mg / kg) 10 minutes prior to the measurement of phenylephrine response curves. The results were analyzed and ρΚβ values calculated as described by Kenny et al. (1996). The results are shown in Table 6.
Tabuľka 6Table 6
Účinok na krvný tlak a intrauretrálny tlak u znecitlivených psovEffect on blood pressure and intraurethral pressure in desensitized dogs
-22Vynález je opísaný odkazom na špecifické uskutočnenie vynálezu. Je to však iba ilustratívne. Existuje veľký počet ďalších vyhotovení, zrejmých odborníkovi v obore, ktoré sú tiež zahrnuté do rozsahu vynálezu.The invention is described by reference to a specific embodiment of the invention. However, this is only illustrative. There are a number of other embodiments obvious to those skilled in the art and are also included within the scope of the invention.
-23« · ·· ♦ · ·*·· ·· • · · · · · · • ··· ··· · · · · · • ········ ··· ·· ·· ·· ·· ···-23 · * * * * 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 · ·· ···
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| US09/120,265 US6083950A (en) | 1997-11-13 | 1998-07-21 | 1-(4-arylpiperazin-1-yl)-ω-[n-(α,ω-dicarboximido)]-alka nes useful as uro-selective α1-adrenoceptor blockers |
| PCT/IB1999/000140 WO2000005206A1 (en) | 1998-07-21 | 1999-01-26 | Arylpiperazine derivatives useful as uro-selective alpha-1-adrenoceptor blockers |
| PCT/IB1999/001296 WO2000005205A1 (en) | 1998-07-21 | 1999-07-16 | Arylpiperazine derivatives useful as uroselective alpha1-adrenoceptor blockers |
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| DE2727469A1 (en) * | 1977-06-18 | 1978-12-21 | Hoechst Ag | NEW HEXAHYDROPYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
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| US4452798A (en) * | 1982-06-22 | 1984-06-05 | Warner-Lambert Company | 1-Substituted phenyl-4-alkyl hydantoin piperazine compounds as antihypertensive agents |
| US4675403A (en) * | 1985-10-16 | 1987-06-23 | American Home Products Corporation | 3-Aminoalkyl derivatives of 5,5-disubstituted hydantoins with psychotropic activity |
| ES2094690B1 (en) * | 1994-11-22 | 1997-08-01 | Univ Madrid Complutense | NEW DERIVATIVES OF IMIDA-PIPERAZINES. |
| ATE201016T1 (en) * | 1995-06-09 | 2001-05-15 | Hoffmann La Roche | PYRIMIDINDIONE, PYRIMIDINDRION, TRIAZINDIONE DERIVATIVES AS ALPHA-1 ADRENERGIC RECEPTOR ANTAGONISTS |
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