WO2000005206A1 - Derives d'arylpiperazine utiles comme agents bloquants de recepteurs alpha 1-adrenergiques uroselectifs - Google Patents

Derives d'arylpiperazine utiles comme agents bloquants de recepteurs alpha 1-adrenergiques uroselectifs Download PDF

Info

Publication number
WO2000005206A1
WO2000005206A1 PCT/IB1999/000140 IB9900140W WO0005206A1 WO 2000005206 A1 WO2000005206 A1 WO 2000005206A1 IB 9900140 W IB9900140 W IB 9900140W WO 0005206 A1 WO0005206 A1 WO 0005206A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
propane
hydrochloride salt
methoxyphenyl
Prior art date
Application number
PCT/IB1999/000140
Other languages
English (en)
Other versions
WO2000005206A8 (fr
Inventor
Nitya Anand
Neelima Sinha
Sanjay Jain
Anita Mehta
Anil Kumar Saxena
Jang Bahadur Gupta
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/120,265 external-priority patent/US6083950A/en
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Priority to AU19797/99A priority Critical patent/AU1979799A/en
Priority to AU46410/99A priority patent/AU763541B2/en
Priority to IDW20010184A priority patent/ID28198A/id
Priority to BR9912318-5A priority patent/BR9912318A/pt
Priority to HU0102980A priority patent/HUP0102980A3/hu
Priority to PL99345562A priority patent/PL345562A1/xx
Priority to MXPA01000637A priority patent/MXPA01000637A/es
Priority to JP2000561162A priority patent/JP2002521362A/ja
Priority to CNB998108421A priority patent/CN1168714C/zh
Priority to CZ2001235A priority patent/CZ2001235A3/cs
Priority to SK93-2001A priority patent/SK932001A3/sk
Priority to EP99929633A priority patent/EP1097134A1/fr
Priority to NZ509388A priority patent/NZ509388A/en
Priority to CA002338317A priority patent/CA2338317A1/fr
Priority to PCT/IB1999/001296 priority patent/WO2000005205A1/fr
Priority to MYPI99003045A priority patent/MY120255A/en
Publication of WO2000005206A1 publication Critical patent/WO2000005206A1/fr
Publication of WO2000005206A8 publication Critical patent/WO2000005206A8/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D207/408—Radicals containing only hydrogen and carbon atoms attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • 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
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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

Definitions

  • the present invention relates to certain novel piperazine derivatives having protracted uro-selective ⁇ ,-adrenoceptor antagonistic activity exceeding those of previously described compounds.
  • the compounds of the present invention hold promise for treating benign prostatic hype ⁇ lasia (BPH).
  • This invention also relates to methods for m.aking the novel compounds, pharmaceutical compositions containing the compounds, and methods of treating benign prostatic hype ⁇ lasia using the compounds.
  • ⁇ ,-adrenoceptor antagonists are of particular importance as they were originally developed as antihypertensive agents and are likely also to have a beneficial effect on lipid dysfunction and insulin resistance, which are commonly associated with essential hypertension.
  • the present invention is directed to the development of novel ⁇ , -antagonists, namely, a new class of piperazine compounds, with greater selectivity of action against ⁇ 1A -adrenoceptors and which would thus offer selective relief for prostate hypertrophy as well as essential hypertension.
  • An object of the present invention is to provide novel arylpiperazine derivatives that exhibit significantly greater ⁇ 1A - adrenergic blocking potency than available with the known compounds in order to provide specific treatment for benign prostatic hype ⁇ lasia.
  • compositions containing the novel compounds which are useful in the treatment of benign prostatic hype ⁇ lasia are useful in the treatment of benign prostatic hype ⁇ lasia.
  • R 2 are independently selected from: H, F, CI, Br, OCH 3 , OC 2 H 5 , OCH 2 CF 3 , SCF 3 , CH 3 , C 2 H 5 , CF 3 , isopropyloxy, and cyclopropyl;
  • R 3 is H, Rj, OH or OR ⁇ ;
  • R ⁇ is a substituted or unsubstituted alkyl chain containing 1-6 carbon atoms; and
  • R 4 , R ⁇ e H, C U3 alkyl, substituted or unsubstituted phenyl, or a 5-membered spiro ring.
  • R is H
  • R, is H, R 2 is OCH 3 , R 3 , R ⁇ and R 5 H
  • R is H
  • R 2 is H, CI or CF 3
  • compositions for the treatment of benign prostatic hype ⁇ lasia comprise an effective amount of at least one of the above compounds of Formula I, or preferably of Formula II, and/or an effective amount of at least one physiologically acceptable acid addition salt thereof, with a pharmaceutically acceptable carrier.
  • the compounds of the present invention may be prepared by one of the reaction sequences (Schemes I, II & III) shown below to yield compounds of Formula II with the R,,
  • Scheme-I shows the synthesis of compounds of the Formula II in which Ri , R2, R3, R , R5, Rg m', n, Z, Z', Q, X, and Y are as defined earlier.
  • the preparation comprises condensing ⁇ , ⁇ -dicarboximides of Formula III with l-(4-arylpiperazin-l-yl)- ⁇ -chloroalkanes of Formula IV, in the presence of a base and.
  • Phase transfer catalysts preferably tetrabutylammonium bromide, are particularly useful in catalysing the reaction.
  • the compounds of Formula II can also be prepared by condensation of the piperazines of the Formula V with the anhydrides of Formula VI wherein Ri , R2, R3, Y, Z, Z ⁇ X, and m' are as defined above.
  • the compounds of Formula II can also be prepared by alkylation of the ⁇ , ⁇ - dicarboximide moiety with ⁇ , ⁇ -dihaloalkanes followed by condensation of l-( ⁇ - haloalkyl)dicarboximide thus obtained (Formula VII) with 1 -arylpiperazines (Formula VIII) as shown below, wherein Ri , R2, R3, Y, Z, Z', X, m' and n are as defined above.
  • the reaction is preferably carried out in the presence of a base and an organic solvent at a temperature ranging from 60-100 C for a period varying between 10-24 hours to produce the corresponding l-(4- arylpiperazin-l-yl)- ⁇ -[N-( ⁇ , ⁇ -dicarboximido)]alkanes of Formula II.
  • Phase transfer catalysts more preferably tetrabutylammonium bromide and potassium iodide, are useful in catalysing the reaction.
  • RBA's receptor binding assays
  • the present invention also provides a method to demonstrate the selective affinity of the compounds for prostatic tissues over vascular tissues Further, the examples presented below describe a method to treat BPH in mammals wherein the test compounds alleviated pressure at dosages which did not result in significant change in blood pressure.
  • the compounds of present invention demonstrated manifest selectivity for prostatic tissues in comparison to known compounds, such as terazosin, doxazosin, etc.
  • the compounds of the present invention also lowered the blood pressure with prolonged duration of action.
  • the compounds of the present invention have been demonstrated to be useful for treating warm blooded animals and mammals. These compounds can be administered orally or parenterally in suitable pharmaceutical compositions.
  • Preferred compounds of the invention are l-[4-(2-methoxyphenyl)piperazin-l-yl]-3-(2,5- dioxopyrrolidin-l-yl)propane (Compound No. 2), l-[4-(2-methoxyphenyl)piperazin-l-yl]-4-(2,5- dioxopyrrolidin-l-yl)butane (Compound No. 9), and l-[4-(2-methoxyphenyl)piperazin-l-yl]-3- (2,6-dioxopiperidin-l-yl)propane (Compound No. 13).
  • Pharmaceutically acceptable, non-toxic, acid addition salts of the compounds of the present invention having the utility of the free bases of Formulas I and II may be formed with inorganic or organic acids, by methods well known in the art and may be used in place of the free bases.
  • suitable acids for formation of such acid addition salts are malic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene salicylic, methanesulfonic, ethane disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfamic, phosphoric, hydrobromic, sulfuric, cyclohexylsulfamic, hydrochloric and nitric acids.
  • the present invention also includes within its scope prodrugs of the compounds of Formulas 1 and II.
  • prodrugs will be functional derivatives of these compounds which are readily converted in vivo into the defined compounds.
  • Conventional procedures for the selection and preparation of suitable prodrugs are known.
  • the invention also includes the enantiomers, diastereomers, N-oxides and pharmaceutically acceptable salts of these compounds, as well as metabolites having the same type of activity
  • the invention further includes pharmaceutical compositions comprising the molecules of Formula I and II, or prodrugs, metabolites, enantiomers, diastereomers, N-oxides, or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable carrier and optionally included excipients.
  • the invention is directed to methods for selectively blocking ⁇ , A receptors by delivering in the environment of said receptors, e.g., to the extracellular medium (or by administering to a mammal possessing said receptors), an effective amount of the compounds of the invention.
  • the hydrochloride salt of l-[4-(4-fluorophenyl)piperazin-I -yl]-3-(2,5-dioxopyrrolidin- l - yl)-propane (Compound No. 1) was formed in quantitative yield by the addition of ethereal hydrogen chloride solution to a methanolic solution of the free base and the resultant precipitate was collected by filtration; m.p 246-247°C.
  • the aqueous solution was extracted with chloroform (3 x 50 ml) and the organic layers combined, washed with water 2 x 50 ml), dried over Na 2 S0 4 and evaporated in vacuo to give the title compound.
  • the product was purified by column chromatography over flash silica gel using chloroform-methanol (99: 1) as eluent; yield 8.00 g (65%) in oil.
  • the hydrochloride salt was prepared by the method described above; mp 199-202°C.
  • Residue was suspended in ethyl acetate (600 ml), washed with water (5 x 100 ml.) and dried over Na2S04 and concentrated to give an oil which was purified by column chromatography over silica gel (100-200 mesh) using chloroform-methanol (99:2) as eluent; yield 55.1 g, (80%), oil.
  • the hydrochloride salt of this product was formed in the manner described above; mp 199-202°C.
  • l-Chloro-3-(2,5-dioxopyrrolidin-l-yl)propane can be prepared by the reaction of 2,5- dioxopyrrolidine and l-bromo-3-chloropropane in the presence of potassium carbonate and tetrabutylammonium bromide in acetone.
  • l-Chloro-4-(2,5-d ⁇ oxopyrrolidin-l-yl)butane can be prepared by the reaction of 2,5- dioxopyrrolidine and 1 -bromo-4-chlorobutane in the presence of potassium carbonate and tetrabutylammonium bromide in acetone.
  • the hydrochloride salt was prepared in the quantitative yield by the method described above; m.p. 206-210°C.
  • Residue was dissolved in ethyl acetate (400 ml), washed with water (5 x 100 ml) and dried over Na 2 S0 4 and concentrated to given an oil which was purified by column chromatography over silica gel ( 100-200 mesh) using chloroform-methanol (99: 1 ) as eluent; yield
  • hydrochloride salt was prepared in the quantitative yield by the addition of excess ethereal hydrogen chloride solution to a methanolic solution of the free base and collected by filtration of the resultant precipitate; m.p. 206-210°C.
  • Receptor binding assays were performed for native ⁇ j -adrenoceptors. Rat submaxillary and rat liver membrane preparations were used to assess the affinity for ⁇ , A and ⁇ , B subtypes, respectively. Aliquots of membrane protein (100 - 200 mg) were incubated in a final volume of 250 ml assay buffer (50 mM Tris. 0.5 mM EDTA at pH 7.4) with 0.5 nM [ 3 H] prazosin for 60 mins at 28 C. Reaction was stopped by rapid filtration on Millipore filters. Filters were dried and bound radioactivity counted. Non-specific binding was determined in the presence of 0.3 mM prazosin. Protein was assayed according to the method of protein estimation by Lowry, O.H. et al., J. Biol. Chem., V. 193, pp. 265-275 (1951 ) Results are listed in Table 1
  • Isolated tissues were mounted in organ bath containing Krebs Henseleit buffer of the following composition (mM): NaCl 118; KC1 4.7; CaCl 2 2.5; MgS0 4 « H 2 0 1.2; NaHC0 3 25; KH 2 P0 4 1.2; glucose 11.5. Buffer was maintained at 37°C and aerated with a mixture of 95% O2 and 5% CO2. A resting tension of 2g (aorta) or 1 g (spleen and prostate) was applied to tissues. Contractile response was monitored using a force displacement transducer and recorded on chart recorders. Tissues were allowed to equilibrate for 2 hours.
  • mM mM
  • concentration response curves to norepinephrine (aorta) and phenylephrine (spleen and prostate) were obtained in the absence and presence of the tested compound (at concentrations of 0.1, 1 and 10 ⁇ M).
  • Antagonist affinity was calculated and expressed as pKg values in Table 1.
  • Angiotensin II receptor antagonistic activity was studied in rabbit aorta Musca ⁇ nic chohnergic receptor and ETg receptor antagonistic activity was studied in rat trachea, while guinea pig trachea was used to study U ⁇ receptor antagonistic activity. Electrically stimulated rat vas deferens was used to investigate the effect of ⁇ 2 -adrenoceptors, while ⁇ ,- adrenoceptor antagonistic activity was studied using electrically stimulated rat ventricular strips. Results of this selectivity study is shown in (Table 2).
  • Antihypertensive effect of selected compounds according to the invention were studied for their ability to lower blood pressure in anaesthetized and conscious normotensive and spontaneously hypertensive rats via intravenous, oral and intraduodenal routes. Results are shown in Tables 1 and 3.
  • Anaesthetized Normotensive Rats Intravenous Route Male wistar rats were anaesthetized with urethane (2.5 g/kg). Femoral vein and carotid artery were cannulated. Blood pressure and heart rate were recorded using Statham pressure transducer. Data was recorded on Grass polygraph as well as using online data acquisition system (Buxco AT). Intravenously administered compounds of the invention were initially tested at 0.3 mg/kg over a period of 3 hours for their effect on blood pressure and the results are shown in Table 1. For a select few of the compounds, the blood pressure lowering effect upon intravenous administration was also studied at dosages of 0.03, 0.1, 0.3, and 1 mg/kg.
  • Rats Male wistar rats were fasted for 18 hours. Rats were anaesthetized with urethane. Femoral vein and carotid artery were cannulated. A catheter was placed in the duodenum following lapratomy. The compounds of the present invention (at dosages of 0.3, 1, 3 and 10 mg/kg) were administered in the duodenum and blood pressure was monitored for 3 hours. Results are recorded in Table 3. O 00/05206
  • Spontaneously hypertensive rats weighing between 250 - 300 g were used in this study. Rats were fasted overnight. Blood pressure was monitored from tail artery using semi-automatic noninvasive blood pressure monitoring apparatus. Compounds of the present invention (at dosages of 1, 3, 10, and 30 mg/kg) were administered orally. Blood pressure was monitored prior to and 1.5, 4, 6 and 24 hours after drug administration. Results are shown in Table 5. Table 5 Effect on mean arterial blood pressure in conscious freely moving normotensive rats.
  • Intraurethral pressure was recorded on the polygraph through a pressure transducer.
  • Graded dose response relationship of phenylephrine (1 - 16 ⁇ g/kg, iv) was obtained on prostatic pressure and blood pressure, prior to administration of the compounds of the present invention.
  • Compounds 2, 9, and 13 (at dosages of 0.01 , 0.03, 0.1 , and 0.3 mg/kg) were administered intravenously 10 min before obtaining phenylephrine dose response curves. Results were analyzed and pseudo pKg values were calculated as described in Kenny et al (1996). Results are shown in Table 6.

Abstract

L'invention concerne des composés représentés par la formule (I), qui possèdent une activité sélective à l'égard du récepteur alpha 1-adrénergique. Les composés sont utiles dans le traitement d'états pathologiques tels que l'acrosyndrome vasculaire, l'insuffisance cardiaque congestive, l'hypertension et en particulier l'hypertrophie bénigne de la prostate.
PCT/IB1999/000140 1998-07-21 1999-01-26 Derives d'arylpiperazine utiles comme agents bloquants de recepteurs alpha 1-adrenergiques uroselectifs WO2000005206A1 (fr)

Priority Applications (16)

Application Number Priority Date Filing Date Title
AU19797/99A AU1979799A (en) 1998-07-21 1999-01-26 Arylpiperazine derivatives useful as uro-selective alpha-1-adrenoceptor blockers
PCT/IB1999/001296 WO2000005205A1 (fr) 1998-07-21 1999-07-16 Derives d'arylpiperazine utilises comme agents bloquants les recepteurs alpha1-adrenergiques uroselectifs
CNB998108421A CN1168714C (zh) 1998-07-21 1999-07-16 可用于尿选择性α1-肾上腺素能受体阻滞剂的芳基哌嗪衍生物
SK93-2001A SK932001A3 (en) 1998-07-21 1999-07-16 ARYLPIPERAZINE DERIVATIVES USEFUL AS UROSELECTIVEì (54) ALPHA1-ADRENOCEPTOR BLOCKERS
BR9912318-5A BR9912318A (pt) 1998-07-21 1999-07-16 Compostos de 1- (4-arilpiperazin-1-il) -w- [n- (ol, w -dicarboximido) ] alcanos de utilidade como bloqueadores uro-seletivos de 1 - adrenoceptor.
HU0102980A HUP0102980A3 (en) 1998-07-21 1999-07-16 Arylpiperazine derivatives useful as uroselective alpha1-adrenoceptor blockers, pharmaceutical compositions containing them and their use
PL99345562A PL345562A1 (en) 1998-07-21 1999-07-16 Arylpiperazine derivatives useful as uroselective alpha1-adrenoceptor blockers
MXPA01000637A MXPA01000637A (es) 1998-07-21 1999-07-16 Derivados de arilpiperazina utiles como bloqueadores uroselectivos de alfa 1-adrenoceptor.
JP2000561162A JP2002521362A (ja) 1999-01-26 1999-07-16 ウロ選択性α１−アドレノセプターブロッカーとして有用なアリルピペラジン誘導体
AU46410/99A AU763541B2 (en) 1998-07-21 1999-07-16 Arylpiperazine derivatives useful as uroselective alpha1-adrenoceptor blockers
CZ2001235A CZ2001235A3 (cs) 1998-07-21 1999-07-16 Arylpiperazinové deriváty vhodné jako uroselektivní alfa 1-adrenoceptorové blokátory
IDW20010184A ID28198A (id) 1998-07-21 1999-07-16 Derivatip-derivatip arilpiperazin yang berguna sebagai penghalang uroselektif alfa-1 adrenoseptor
EP99929633A EP1097134A1 (fr) 1998-07-21 1999-07-16 Derives d'arylpiperazine utilises comme agents bloquants les recepteurs alpha1-adrenergiques uroselectifs
NZ509388A NZ509388A (en) 1998-07-21 1999-07-16 Arylpiperazine derivatives useful as uroselective alpha1-adrenoceptor blockers
CA002338317A CA2338317A1 (fr) 1998-07-21 1999-07-16 Derives d'arylpiperazine utilises comme agents bloquants les recepteurs alpha1-adrenergiques uroselectifs
MYPI99003045A MY120255A (en) 1998-07-21 1999-07-20 1-(4-arylpiperazin-1-yl)-hertz-[n-(alpha, hertz-dicarboximido)]-alkanes useful as uro-selective (alpha1)-adrenoceptor blockers

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
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
US09/120,265 1998-07-21

Publications (2)

Publication Number Publication Date
WO2000005206A1 true WO2000005206A1 (fr) 2000-02-03
WO2000005206A8 WO2000005206A8 (fr) 2000-03-16

Family

ID=22389214

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB1999/000140 WO2000005206A1 (fr) 1998-07-21 1999-01-26 Derives d'arylpiperazine utiles comme agents bloquants de recepteurs alpha 1-adrenergiques uroselectifs

Country Status (10)

Country Link
CN (1) CN1168714C (fr)
AR (1) AR019438A1 (fr)
AU (1) AU1979799A (fr)
CO (1) CO5241280A1 (fr)
CZ (1) CZ2001235A3 (fr)
ID (1) ID28198A (fr)
MY (1) MY120255A (fr)
RU (1) RU2221794C2 (fr)
WO (1) WO2000005206A1 (fr)
ZA (1) ZA200100440B (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003084928A1 (fr) * 2002-04-08 2003-10-16 Ranbaxy Laboratories Limited Derives d'alpha, omega-dicarboximide utiles en tant qu'inhibiteurs uroselectifs de l'adreno-recepteur ?1?
WO2005037282A1 (fr) * 2003-10-15 2005-04-28 Ranbaxy Laboratories Limited Derives de 1-alkylpiperazinyl-pyrrolidin-2,5-dione utiles comme antagonistes du recepteur adrenergique
WO2005113498A1 (fr) * 2004-05-19 2005-12-01 Ranbaxy Laboratories Limited Antagonistes du recepteur adrenergique
WO2005118591A1 (fr) * 2004-05-31 2005-12-15 Ranbaxy Laboratories Limited Composes a base de piperidines condenses agissant comme antagonistes des recepteurs adrenergiques, utilises dans le traitement des symptomes lies a l'hyperplasie benigne de la prostate et aux voies urinaires inferieures
WO2006018815A1 (fr) * 2004-08-16 2006-02-23 Ranbaxy Laboratories Limited Derives de piperazine utilises comme antagonistes de recepteurs adrenergiques
WO2006051374A2 (fr) * 2004-11-11 2006-05-18 Ranbaxy Laboratories Limited Antagonistes des recepteurs adrenergiques
US7053355B2 (en) 2003-03-18 2006-05-30 Brion Technologies, Inc. System and method for lithography process monitoring and control
CN103864761A (zh) * 2014-03-12 2014-06-18 天津药物研究院 一种含吡啶的哌嗪类衍生物及其制备方法和用途

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2242382A1 (de) * 1971-09-04 1973-03-15 Pfizer Neue piperazinverbindungen
EP0000220A1 (fr) * 1977-06-18 1979-01-10 Hoechst Aktiengesellschaft Dihydrouraciles, procédé pour leur préparation et médicaments les contenant
EP0103357A2 (fr) * 1982-06-22 1984-03-21 Warner-Lambert Company Composés de phénylpipérazine substitués, appropriés comme agents antihypertensifs, et les procédés de leur préparation
US4479954A (en) * 1981-05-29 1984-10-30 Eisai Co., Ltd. Piperazine substituted carboxamide derivatives, compositions and method of use
US4675403A (en) * 1985-10-16 1987-06-23 American Home Products Corporation 3-Aminoalkyl derivatives of 5,5-disubstituted hydantoins with psychotropic activity
EP0748800A2 (fr) * 1995-06-09 1996-12-18 F. Hoffmann-La Roche Ag Dérivés de pyrimidine dione, pyrimidine trione, triazine dione, tetrahydroquinazoline dione comme antagonistes des récepteurs alpha-1-adrénergiques
ES2094690A1 (es) * 1994-11-22 1997-01-16 Univ Madrid Complutense Nuevos derivados de imida-piperazinas.

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2242382A1 (de) * 1971-09-04 1973-03-15 Pfizer Neue piperazinverbindungen
EP0000220A1 (fr) * 1977-06-18 1979-01-10 Hoechst Aktiengesellschaft Dihydrouraciles, procédé pour leur préparation et médicaments les contenant
US4479954A (en) * 1981-05-29 1984-10-30 Eisai Co., Ltd. Piperazine substituted carboxamide derivatives, compositions and method of use
EP0103357A2 (fr) * 1982-06-22 1984-03-21 Warner-Lambert Company Composés de phénylpipérazine substitués, appropriés comme agents antihypertensifs, et les procédés de leur préparation
US4675403A (en) * 1985-10-16 1987-06-23 American Home Products Corporation 3-Aminoalkyl derivatives of 5,5-disubstituted hydantoins with psychotropic activity
ES2094690A1 (es) * 1994-11-22 1997-01-16 Univ Madrid Complutense Nuevos derivados de imida-piperazinas.
EP0748800A2 (fr) * 1995-06-09 1996-12-18 F. Hoffmann-La Roche Ag Dérivés de pyrimidine dione, pyrimidine trione, triazine dione, tetrahydroquinazoline dione comme antagonistes des récepteurs alpha-1-adrénergiques

Non-Patent Citations (23)

* Cited by examiner, † Cited by third party
Title
ARCH. PHARM. (WEINHEIM, GER.) (1997), 330(5), 146-160 ;ISSN: 0365-6233, 1997 *
ARCH. PHARM. (WEINHEIM, GER.) (1997), 330(6), 177-180 ;ISSN: 0365-6233 *
B. KENNY ET AL: "Pharmacological Options in the Treatment of Benign Prostatic Hyperplasia", JOURNAL OF MEDICINAL CHEMISTRY., vol. 40, no. 9, 1997, WASHINGTON US, pages 1292 - 1315, XP002103453 *
CHEMICAL ABSTRACTS, vol. 105, no. 19, 10 November 1986, Columbus, Ohio, US; abstract no. 164679, RYAN, M. J. ET AL: "CI-926 (3-[4-[4-(3-methylphenyl)-1-piperazinyl]butyl]-2,4- imidazolinedione): antihypertensive profile and pharmacology" XP002103459 *
CHEMICAL ABSTRACTS, vol. 107, no. 21, 23 November 1987, Columbus, Ohio, US; abstract no. 198046, KHADILKAR, B. M. ET AL: "Synthesis and pharmacology of some 2-[3-(4-aryl-1-piperazinyl)propyl]-1H- benz[de]isoquinolin-1,3(2H)-diones and -2,5-pyrrolidinediones" XP002103457 *
CHEMICAL ABSTRACTS, vol. 108, no. 3, 18 January 1988, Columbus, Ohio, US; abstract no. 21844, HAYS, SHERYL J.: "Synthesis of carbon-14 labeled CI-926 and CI-927, new antihypertensives" XP002103461 *
CHEMICAL ABSTRACTS, vol. 119, no. 3, 19 July 1993, Columbus, Ohio, US; abstract no. 27951, KHADILKAR, B. M. ET AL: "Synthesis and hypotensive activity of some succinimide derivatives" XP002103456 *
CHEMICAL ABSTRACTS, vol. 127, no. 17, 27 October 1997, Columbus, Ohio, US; abstract no. 234308, CHILMONCZYK, ZDZISLAW ET AL: "Conformational flexibility of serotonin1A receptor ligands from crystallographic data. Updated model of the receptor pharmacophore" XP002103460 *
CHEMICAL ABSTRACTS, vol. 128, no. 1, 5 January 1998, Columbus, Ohio, US; abstract no. 128, MOKROSZ, MARIA J. ET AL: "Structure-activity relationship studies of CNS agents. Part 32. Effect o structural modifications in 1-arylpiperazine derivatives on.alpha.1-adrenoreceptor affinity" XP002103455 *
CHEMICAL ABSTRACTS, vol. 129, no. 3, 20 July 1998, Columbus, Ohio, US; abstract no. 22916, DIMOGLO, A. S. ET AL: "Study of structure-activity relations in a series of buspirone analogs using an electron-topological approach" XP002103458 *
DATABASE CHEMICAL ABSTRACTS Chemical Abstracts Service; XP002103462 *
DATABASE CHEMICAL ABSTRACTS Chemical Abstracts Service; XP002103463 *
DATABASE CHEMICAL ABSTRACTS Chemical Abstracts Service; XP002103464 *
DATABASE CHEMICAL ABSTRACTS Chemical Abstracts Service; XP002103465 *
INDIAN J. CHEM., SECT. B (1993), 32B(3), 338-42 ;ISSN: 0376-4699 *
ISHIZUMI, KIKUO ET AL: "Synthesis and anxiolytic activity of N-substituted cyclic imides (1R*,2S*,3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3- bicyclo[2.2.1]heptanedicarboximide (tandospirone) and related compounds", CHEM. PHARM. BULL. (1991), 39(9), 2288-300 ;ISSN: 0009-2363, 1991, XP002103452 *
J. INDIAN CHEM. SOC. (1986), 63(5), 529-30 CODEN: JICSAH;ISSN: 0019-4522, 1986 *
J. LABELLED COMPD. RADIOPHARM. (1987), 24(4), 351-60 ;ISSN: 0362-4803, 1987 *
J. PHARMACOL. EXP. THER. (1986), 238(2), 473-9 ;ISSN: 0022-3565, 1986 *
JERZY L MOKROSZ ET AL: "8-[4-[2-(1,2,3,4-tetrahydroisoquinolyl)butyl]-8-azaspiro[4,5]decane-7,9-dione: A new 5-HT1a receptor ligand with the same activity profile as buspirone", JOURNAL OF MEDICINAL CHEMISTRY, vol. 5, no. 39, 1 January 1996 (1996-01-01), pages 1125 1129, XP002074949 *
KHIM.-FARM. ZH. (1998), 32(1), 36-40 ;ISSN: 0023-1134 *
P.E. CROSS ET AL: "Substituted trifluoromethyl phenyl piperazines as anorectic agents", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY.CHIMICA THERAPEUTICA., vol. 12, no. 2, 1977, PARIS FR, pages 173 - 176, XP002103454 *
WU, YAO-HUA ET AL: "Psychosedative agents. N-(4-phenyl-1-piperazinylalkyl)-substituted cycli imides", J. MED. CHEM. (1969), 12, 876-81, 1969, XP002103451 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003084928A1 (fr) * 2002-04-08 2003-10-16 Ranbaxy Laboratories Limited Derives d'alpha, omega-dicarboximide utiles en tant qu'inhibiteurs uroselectifs de l'adreno-recepteur ?1?
US7053355B2 (en) 2003-03-18 2006-05-30 Brion Technologies, Inc. System and method for lithography process monitoring and control
WO2005037282A1 (fr) * 2003-10-15 2005-04-28 Ranbaxy Laboratories Limited Derives de 1-alkylpiperazinyl-pyrrolidin-2,5-dione utiles comme antagonistes du recepteur adrenergique
WO2005037281A1 (fr) * 2003-10-15 2005-04-28 Ranbaxy Laboratories Limited Derives de 1-alkylpiperazinyl-pyrrolidin-2,5-dione utiles comme antagonistes du recepteur adrenergique
WO2005113498A1 (fr) * 2004-05-19 2005-12-01 Ranbaxy Laboratories Limited Antagonistes du recepteur adrenergique
WO2005118591A1 (fr) * 2004-05-31 2005-12-15 Ranbaxy Laboratories Limited Composes a base de piperidines condenses agissant comme antagonistes des recepteurs adrenergiques, utilises dans le traitement des symptomes lies a l'hyperplasie benigne de la prostate et aux voies urinaires inferieures
WO2006018815A1 (fr) * 2004-08-16 2006-02-23 Ranbaxy Laboratories Limited Derives de piperazine utilises comme antagonistes de recepteurs adrenergiques
WO2006051374A2 (fr) * 2004-11-11 2006-05-18 Ranbaxy Laboratories Limited Antagonistes des recepteurs adrenergiques
WO2006051374A3 (fr) * 2004-11-11 2006-07-06 Ranbaxy Lab Ltd Antagonistes des recepteurs adrenergiques
CN103864761A (zh) * 2014-03-12 2014-06-18 天津药物研究院 一种含吡啶的哌嗪类衍生物及其制备方法和用途
CN103864761B (zh) * 2014-03-12 2016-01-20 天津药物研究院有限公司 一种含吡啶的哌嗪类衍生物及其制备方法和用途

Also Published As

Publication number Publication date
MY120255A (en) 2005-09-30
CN1168714C (zh) 2004-09-29
CZ2001235A3 (cs) 2001-08-15
ZA200100440B (en) 2002-10-04
AU1979799A (en) 2000-02-14
AR019438A1 (es) 2002-02-20
CO5241280A1 (es) 2003-01-31
WO2000005206A8 (fr) 2000-03-16
RU2221794C2 (ru) 2004-01-20
ID28198A (id) 2001-05-10
CN1318052A (zh) 2001-10-17

Similar Documents

Publication Publication Date Title
US6090809A (en) 1-(4-arylpiperazin-1-yl)-ω-[n-(α..omega.-dicarboximido)]-alkanes useful as uro-selective α1 -adrenoceptor blockers
US6914064B2 (en) 1,4-Disubstituted piperazine derivatives useful as uro-selective α1-adrenoceptor blockers
EP0750614B1 (fr) Derives quinazolinyl-amino possedant une activite contre les adrenorecepteurs alpha
WO2000005206A1 (fr) Derives d'arylpiperazine utiles comme agents bloquants de recepteurs alpha 1-adrenergiques uroselectifs
AU2002222315A1 (en) 1,4-disubstituted piperazine derivatives useful as uro-selective alpha1-adrenoceptor blockers
US4652573A (en) Calcium antagonist N-hetero ester 1,4-dihydropyridines
AU763541B2 (en) Arylpiperazine derivatives useful as uroselective alpha1-adrenoceptor blockers
US6624314B2 (en) Pyrrolothiazine and pyrrolothiazepine compounds having serotonin-2 receptor antagonistic and alpha-1-blocking action
US6331623B1 (en) Pyrrolothiazine and pyrrolothiazepine compounds having serotonin-2 receptor antagonistic and alpha-1-blocking action
US4677108A (en) 4-oxo-pyrido[2,3-d]pyrimidinone derivatives
EP0915881B1 (fr) Composes de pyrroloazepine
EP0892790B1 (fr) Nouveaux derives quinazoline-4-amino-2-(piperidine-1-yl-4-substitues) presentant une activite contre l'hypertension, procede de preparation et utilisation pharmaceutique desdits derives
TW562798B (en) 1-(4-arylpiperazin-1-yl)-omega-[N-(alpha,omega-dicarboximido)]-alkanes useful as uroselective alpha1-adrenoceptor blockers and pharmaceutical compositions for treating benign prostatic hypertrophy in a mammal
JP2002521362A (ja) ウロ選択性α１−アドレノセプターブロッカーとして有用なアリルピペラジン誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

AK Designated states

Kind code of ref document: C1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: C1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

WR Later publication of a revised version of an international search report
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase