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WO1995004049A1 - DERIVES DE PIPERAZINE UTILISES COMME ANTAGONISTES DES RECEPTEURS α1A-ADRENERGIQUES - Google Patents

DERIVES DE PIPERAZINE UTILISES COMME ANTAGONISTES DES RECEPTEURS α1A-ADRENERGIQUES Download PDF

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Publication number
WO1995004049A1
WO1995004049A1 PCT/EP1994/002437 EP9402437W WO9504049A1 WO 1995004049 A1 WO1995004049 A1 WO 1995004049A1 EP 9402437 W EP9402437 W EP 9402437W WO 9504049 A1 WO9504049 A1 WO 9504049A1
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WIPO (PCT)
Prior art keywords
methoxyphenyl
propyl
piperazinyl
group
compound
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PCT/EP1994/002437
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English (en)
Inventor
Amedeo Leonardi
Gianni Motta
Carlo Riva
Rodolfo Testa
Original Assignee
Recordati S.A., Chemical And Pharmaceutical Company
Recordati Industria Chimica E Farmaceutica S.P.A.
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Application filed by Recordati S.A., Chemical And Pharmaceutical Company, Recordati Industria Chimica E Farmaceutica S.P.A. filed Critical Recordati S.A., Chemical And Pharmaceutical Company
Priority to AU75323/94A priority Critical patent/AU680037B2/en
Priority to EP94925382A priority patent/EP0711288A1/fr
Priority to JP7505546A priority patent/JPH09500883A/ja
Priority to KR1019960700460A priority patent/KR960703884A/ko
Publication of WO1995004049A1 publication Critical patent/WO1995004049A1/fr
Priority to NO960371A priority patent/NO960371L/no

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention relates to piperazine derivatives and to pharmaceutical compositions containing them.
  • R one or more of H, halogen, alkyl and alkoxy
  • R l H, halogen, methyl or methoxy
  • R ! and Y having the same meanings but R being a cyclic amino group
  • the compounds of the invention essentially include bulky substituents on the phenyl ring linked to Y and/or new values for Y, not yet described in the literature for this class of derivatives.
  • the invention provides compounds of the general formula I:
  • Y represents a valence bond or one of the following groups, each of which is depicted with its left hand end being the end which attaches to the phenyl group and its right hand end being the end which attaches to the group W:
  • R 2 represents a hydrogen atom, an alkyl group having up to 4 carbon atoms, a carbamoyl group, or an alkanoyl or alkylcarba oyl group each having from 2 to 5 carbon atoms;
  • W represents a linear or branched alkylene group having from 2 to 6 carbon atoms
  • A represents (i) a substituted phenyl group, the or each substituent being a halogen atom or an alkoxy, alkyl or hydroxy group, the substituent or one of the substituents being in the 2-position, or (ii) a group of the formula
  • R represents a group of the formula -X-(CH 2 )p-Z, wherein
  • X represents a valence bond or one of the following groups, each of which is depicted with its left hand end being the end which attaches to the phenyl group and its right hand end being the end which attaches to the group -(CH 2 )p-Z: -0-, -S(0) n -, -CO-, -N(R 2 )-, -N(R 2 )CO- and -N(R 2 )S0 2 -; wherein n and R are as above defined; p is 0 to 10, and
  • Z represents a hydrogen atom, a cycloalkyl group having from 4 to 8 carbon atoms, a 1-naphthyl group, a 2-naphthyl group, a diphenyl ethyl group or one of the groups having the following formulae
  • R 3 has the same values as R defined below; and R represents one or more hydrogen or halpgen atoms or cyano, hydroxy, alkoxy, alkyl, trifluoromethyl, alkanoyl, ⁇ -hydroxyalkyl, nitro, amino, alkylamino, dialkyla ino, alkanoylamino, alkylsulphonylamino, phenyl, phenoxy or benzoyl groups;
  • Z does not represent a hydrogen atom unless p is greater than 3;
  • Ri does not represent a hydrogen atom.
  • the invention further includes prodrugs of the formula I compounds, e.g., the derivatives of compounds of formula I bearing reactive groups such as NH, NH 2 and in particular OH (i.e., at positions Ri or R 3 ) prepared for various purposes, e.g., to improve the pharmacokinetic properties (adsorption, distribution, metabolism, plasmatic half-life, etc.) of said compounds of formula I, which can be administered in this "masked” or prodrug form and are liberated, exerting their pharmacological action, in mammals receiving them.
  • prodrug derivatives have the following structure:
  • J represents a valence bond, an oxygen or sulphur atom or an amino group
  • F represents an alkyl group (optionally containing hetero atoms such as O, S, N or substituted -nitrogen) , a carbocyclic group or heterocyclic group, optionally substituted with amino, alkyla ino, dialkyla ino, dialkylaminoalkyl, carboxy, alkoxycarbonyl, carboxamido.
  • J represents a valence bond and F represents a methyl, t-butyl, n-butyl, B-CH 2 -phenyl, B-alkyl, B-CO-alkyl, HOCO-alkyl, alkyl-OCO-alkyl, where B represents a dialkylamino group or a cyclic amino group, optionally containing other heteroatoms such as N, 0 or S.
  • B represents a dialkylamino group or a cyclic amino group, optionally containing other heteroatoms such as N, 0 or S.
  • derivatives having the formula (Compound I)-OP(O) (OAlkyl) 2 .
  • the invention also includes the enantiomers, diastereoisomers, crystalline forms, solvates, N-oxides and pharmaceutically acceptable salts of these compounds, as well as metabolites of these compounds having the same type of activity (hereafter sometimes referred to as "active metabolites") and prodrugs of said "active metabolites”.
  • The..invention further provides pharmaceutical compositions comprising a compound of Formula I or a prodrug, a metabolite, an enantio er, diastereoisomer, crystalline form, solvate, N-oxide or pharmaceutically acceptable salt of such a compound or prodrug, in admixture with a pharmaceutically acceptable diluent or carrier.
  • ⁇ ⁇ -adrenergic receptors such as blood vessels, prostate, urethra, etc. , as reported by A. L. Morrow et al., Mol . Pharmacol . , 29.- 321, 1986 and references cited therein in general and by M. Suzuki et al., Jap. J. Pharmacol . , 58., suppl. 1, 173P, 1992 for the human prostate
  • ⁇ ⁇ -adrenergic receptors such as blood vessels, prostate, urethra, etc.
  • antiadrenergic compounds within the invention established as such on the basis of their receptor binding profile, can be useful therapeutic agents for the treatment, for example, of micturition problems associated with obstructive disorders of the lower urinary tract, including but not limited to benign prostatic hypertrophy (BPH) , and of hypertension.
  • BPH benign prostatic hypertrophy
  • the compounds of the invention show high selectivity for the mammalian lower urinary tract, i.e., they are substantially more active in antagonizing urethral contractions than in lowering blood pressure.
  • 6- ⁇ 3-[4-(2-methoxyphenyl)-l-piperazinyl]-propylamino ⁇ -l,3- -dimethyl-2,4-(lH,3H)-pyrimidinedione shows a very small selectivity and low affinity for the c-i ⁇ -adrenoceptor.
  • those compounds of the invention that are not selective for the lower urinary tract are preferred as antihypertensive agents, but even the selective compounds can often be used as antihypertensives because of their low toxicity.
  • the majority of the compounds of the invention exhibit low toxicity. Thus they can be used in higher amounts, an advantage that often more than compensates for a relatively lower level of activity that some of these compounds have. Naturally, those exhibiting both high activity and low toxicity are preferred.
  • L represents a halogen atom or a leaving group such as a tosyloxy group.
  • M represents a group (CH 2 ) n wherein n is 0 to 2.
  • Q represents M-CO, S0 2 or PO(OC 2 H 5 ) ;
  • Q* represents CO or S0 .
  • X 1 represents G, S, N(alkyl) or NH.
  • Hal represents a halogen atom.
  • the compounds according to the invention may generally be prepared by condensation of compounds RRiPh-Y-W-L with compounds H-PzA.
  • the condensation is preferably, but not necessarily, carried out at a temperature of from 20 to 140°C in a polar solvent such as dimethyIformamide (DMF) or methanol or in absence of any solvent at 100-200°C, usually in the presence of a base such as potassium carbonate, see Gibson's chapter in Patai, The Chemistry of the Amino Group, p.45 et seq. , Wiley Interscience, New York, 1968. This alkylation is described in Example 31 below.
  • a polar solvent such as dimethyIformamide (DMF) or methanol
  • a base such as potassium carbonate
  • a compound RR Ph-Y-H can be condensed with a compound L-W-PzA.
  • This condensation is illustrated in Examples 1 to 5, 9, 10 and 30 below. A particular example of this case is reported in Example 8 below, in which a preformed RR PhCOONa is reacted with a compound L-W-PzA in refluxing acetonitrile.
  • this may be done by first reacting the amine RR Ph-NH 2 with an excess of trifluoroacetic anhydride, then reacting the obtained trifluoroacetyl derivative RR 1 PI1-NH-COCF 3 with an L-W-PzA reagent and finally deprotecting the resultant trifluoroacetyl derivative of the desired compound of the invention by treatment with potassium carbonate in aqueous methanol or with sodium borohydride in methanol or dimethylsulphoxide (DMSO) . Further details on the use of this technique are reported by T.W. Greene in Protective Groups in Organic Synthesis , page 353, Wiley Interscience, 1991 and references cited therein.
  • Another condensation method forms the group R by condensing a compound Z-(CH 2 ) p -L with a compound
  • This condensation can be carried out as above described or by operating in protic or aprotic solvents (e.g. ethanol, acetonitrile, DMF, toluene) in the presence of a base such as potassium carbonate, sodium or sodium hydride at 20-140°C.
  • a base such as potassium carbonate, sodium or sodium hydride at 20-140°C.
  • Some compounds of the invention can be prepared by addition reactions. For example, addition across a double bond is possible, as in:
  • aprotic solvents e.g., toluene, xylene, DMSO, DMF
  • RR l Ph-Q-Cl + R 2 -NH-W-PzA ⁇ RR ! Ph-Q-NR 2 -W-PzA (R 2 H, C 1 -C 4 alkyl) .
  • the amidification is carried out in aprotic solvents e..g. haloalkanes, toluene, DMF or pyridine, optionally in the presence of an organic base such as triethylamine, or in aqueous dioxane or lower alkanols in the presence of inorganic bases such as sodium hydroxide, sodium bicarbonate or potassium carbonate, according to Beckwith in Zabicky, The Chemistry of Amides , page 731-857, Wiley, 1970. Such a reaction is illustrated in Examples 7, 28, 29, 41 and 43 below.
  • N,N'-carbonyldiimidazole or diethyl cyanophosphonate optionally in the presence of a promoting agent (e.g. 4-dimethylaminopyridine or N-hydroxybenzotriazole or N-hydroxysuccinimide) in an aprotic or a chlorinated solvent (e.g. DMF, chloroform) at from -10 to 140°C (Albertson, Org. React . , .12., 205-218, 1962; Doherty et al., J. Med. Chem . , 35. 9, 1992; Staab et al., Newer Methods Prep. Org. Chem . , 5 , 61, 1968; Ishihara, Chem . Pharm . Bull . , .39., 3236, 1991). It is illustrated in Examples 6, 25 to 27, 32 to 35, 37, 40, 44 and 45 below.
  • a promoting agent e.g. 4-dimethylamino
  • RR l Ph-M-COOH + alkylchloroformate in the presence of a tertiary amine (e.g. triethylamine) followed by addition of R -NH-W-PzA at from 0 to 80°C; optionally a promoting agent (e.g. 1-hydroxypyridine) may be added before the amine addition (Albertson, Org. React . , .12., 157, 1962).
  • a promoting agent e.g. 1-hydroxypyridine
  • This reaction can be carried out without a solvent at from
  • the temperatures of the above reactions will be from 20°C to 100°C (J. March, Advanced Organic Chemistry, III Ed., page 1103, Wiley Interscience, 1985).
  • R or R3 represents an amino group
  • an alkylating agent L-alkyl for monoalkylation, the amino group may be protected before the alkylation and deprotected afterwards, as above described.
  • An alternative alkylation method comprises reacting such compounds with an appropriate aldehyde in the presence of a reducing agent, such as sodium cyanoborohydride, in a lower alkanol as solvent at from 20 to 100°C.
  • R or R3 represents an alkanoylamino or alkylsulphonyla ino group
  • Ri or R3 represents an amino group
  • a non-protic solvent such as chloroform, 1,2-dichloroethane, toluene, acetone or pyridine
  • a base such as potassium carbonate or triethylamine at from 20 to 120°C.
  • Ri or R 3 represents a hydroxy group
  • BBr 3 in dichloromethane at from 0 to 40°C (T.W. Greene, Protective Groups in Organic Synthesis , page 87, Wiley Interscience, 1981) or according to other methods described in the same reference.
  • R represents an ⁇ -hydroxyalkyl group
  • Ri represents an alkanoyl group
  • Such reduction may be effected with sodium borohydride or sodium cyanoborohydride in a lower alkanol as solvent at from 0 to 90°C.
  • N-oxides of the compounds of the invention may be formed by oxidising the basic nitrogen atom(s) present, mainly, but not necessarily only, that at position 1 of the piperazine ring.
  • the oxidation can be performed by reacting compounds of formula I with hydrogen peroxide at from 20 to 60°C in acetic acid or with m-chloroperbenzoic acid or magnesium mono-peroxyphthalate at from 0 to 50°C, according to Broughan et al., Synthesis , ⁇ , 1015, 1987.
  • Prodrugs as above defined may be prepared from the corresponding hydroxy compounds of the invention by the following methods:
  • a chloroformate e.g. a chlorinated solvent, DMF, tetrahydrofuran, dioxane, acetonitrile, pyridine
  • a suitable solvent e.g. a chlorinated solvent, DMF, tetrahydrofuran, dioxane, acetonitrile, pyridine
  • a base such as triethylamine, pyridine, 4-dimethylaminopyridine, sodium hydroxide, potassium carbonate or 1,10-diazabicycloundecene at from -20 to 100°C;
  • the crude product was purified by flash chromatography on silica gel eluting with ethyl acetate. Evaporation in vacuo of the collected fractions yielded 2.1 g of the base of the title compound. This was dissolved in diethyl ether and acidified with 3.8N hydrochloric acid in diethyl ether. The title compound was recovered by suction filtration and melted at 181-183°C.
  • This compound was prepared according to the method described in Example 11 but using 3-chlorobenzyl chloride instead of 2-chlorobenzyl chloride and the reaction lasted 20 hours.
  • the title compound was crystallized from ethanol:diethyl ether and melted at 140-143°C.
  • This compound was prepared according to the method described in Example 11 but using 4-chlorobenzyl chloride instead of 2-chlorobenzyl chloride and the reaction lasted 16 hours.
  • the title compound was crystallized from ethanol:diethyl ether and melted at 143-146°C.
  • This compound was prepared according to Example 11 but using 3-methoxybenzyl chloride instead of 2-chlorobenzyl chloride.
  • the title compound was crystallized from ethanol:diethyl ether and melted at 125-126.5°C.
  • This compound was prepared according to Example 11 but using 4-methoxybenzyl chloride instead of 2-chlorobenzyl chloride and the reaction lasted 7 hours.
  • the title compound was crystallized from ethanol:diethyl ether and melted at 128-132°C.
  • This compound was prepared according to Example 11 but using 2,3-dimethoxybenzyl chloride instead of 2-chlorobenzyl chloride and the reaction lasted 2 hours.
  • the title compound was crystallized from ethanol:diethyl ether and melted at 141-143°C.
  • This compound was prepared according to Example 11 but using 3,4,5-trimethoxybenzyl chloride instead of 2-chlorobenzyl chloride and the reaction lasted 2 hours.
  • the title compound was crystallized from ethanol:diethyl ether and melted at 97-103°C.
  • This compound was prepared according to Example 11 but using 1-bromooctane instead of 2-chlorobenzyl chloride and the reaction lasted 15 hours.
  • the title compound was crystallized from ethanol:diethyl ether and melted at 75-77°C.
  • This compound was prepared according to Example 11 but using 1-bromobutane instead of 2-chlorobenzyl chloride and the reaction lasted 11 hours.
  • the title compound was crystallized from ethanol:diethyl ether and melted at 69-72 °C .
  • This compound was prepared according to Example 11 but using cyclohexylmethyl bromide instead of 2-chlorobenzyl chloride and the reaction lasted 33 hours.
  • the title compound was crystallized from ethanol:diethyl ether and melted at 104-106°C.
  • This compound was prepared according to Example 11 but using 2-bromomethylnaphthalene instead of 2-chlorobenzyl chloride and the reaction lasted 30 hours.
  • the title compound was crystallized from ethanol:diethyl ether and melted at 101-103°C.
  • the title compound was prepared by the method described in Example 25 but using 2-benzylbenzoic acid instead of 2-phenylthio-benzoic acid. It was purified by crystallization from ethanol:diethyl ether and melted at 184-188°C.
  • the title compound was prepared by the method described in Example 28 but using 1-(2-methoxyphenyl)-4-(3-methylamino- -propyl)-piperazine (prepared as described in WO 93/17007) instead of l-(3-aminopropyl)-4-(2-methoxyphenyl)-piperazine.
  • the crude base was dissolved in ethanol and 2 equivalents of a 2N ethanolic solution of methanesulphonic acid were added. The mixture was evaporated to dryness in vacuo. The residue was rinsed with ethyl acetate, stirred at reflux temperature for 1% hours, filtered, and crystallized from acetonitrile to give the title compound.
  • the title compound was prepared according to the method described in Example 1 but using phenylacetic acid instead of benzoic acid and 1-(2-chloroethyl)-4-(2-methoxyphenyl)- -piperazine instead of l-(3-chloropropyl)- -4-(2-methoxyphenyl)-piperazine.
  • the reaction was conducted for 4 hours at 100°C.
  • the crude product was purified by flash chromatography on silica gel, eluting with a dichloromethane:methanol 100:3 mixture.
  • the crude was dissolved in diethyl ether, treated with charcoal, filtered, and evaporated to dryness to give the title compound as an oily residue.
  • the title compound was prepared according to the procedure of Example 36, but using 73% 4-benzoylbenzyl bromide (prepared as reported in Intermediate VIII) instead of 4-nitrobenzyl chloride and DMF as a solvent., stirring at room temperature.
  • the crude was purified by flash chromatography eluting with an ethyl acetate:methanol mixture graduated from 85:5 to 90:20, yielding the base of the title compound. This was dissolved in isopropanol and converted to its hydrochloride by adding 5.8N isopropanolic hydrogen chloride. The solid was filtered and recrystallized from aqueous 0.1N hydrochloric acid. M.p. 165-169°C.
  • the title compound was prepared by the method described in Example 39 but using 3-phenylpropyl bromide instead of phenethyl bromide.
  • the crude product was purified by crystallization from isopropanol; m.p. 86-88°C.
  • the title compound was prepared by the method described in Example 25 but using 2-phenoxybenzoic acid instead of 2-phenylthiobenzoic acid.
  • the title compound melted at 176-182°C after crystallization from a 1:4 mixture of ethanol:diethyl ether.
  • c-i-blockers i.e., to be within a class of substances widely used as agents that can be used fo the relief of symptoms associated with obstructive disorders of the lower urinary tract, including (but not limited to) benign prostatic hypertrophy (BPH) , and as antihypertensives.
  • BPH benign prostatic hypertrophy
  • antihypertensives See, e.g., W. H. Frish an et al., Medical Clinics of N. Jiemerica , 12., 427, 1988 and references cited therein.
  • the acute toxicity of the compounds of the invention was evaluated in female Albino Swiss mice after intraperitoneal and oral administration.
  • Four logarithmic scaled doses of the compounds were dissolved or suspended in 0.5% Methocel and each dose was administered in a volume of 10 ml/kg to groups of 4 mice. Mortality was recorded 7 days after the administration.
  • Data analysis the LD5 0 values and their fiducial limits were calculated according to the method of Weil (Biometrics , 8, 249, 1952).
  • the affinity of the compounds of the invention for the ⁇ iA-adrenoceptor was investigated by utilizing [ 3 H]prazosin as radioligand and rat hippocampal membranes, after irreversible inactivation of ⁇ i ⁇ -adrenoceptors with chloroethylclonidine, as source of the ⁇ - ⁇ -adrenoceptors (C. Han et al., Mol . Pharmacol . , 3 , 505, 1987). Male rats were killed and their hippocampus was dissected, immediately frozen on dry ice and then stored at -70°C until use.
  • the homogenates were incubated for 30 min at 25°C with 0.25-0.35 nM [ 3 H]prazosin in the absence or presence of the displacing compound to be tested, concentration ranging from 10 ⁇ 4 to 5xl0 ⁇ 12 M, in a final volume of 2 ml.
  • Non-specific binding was defined by 10 ⁇ M phentolamine.
  • a collateral of the left femoral vein was cannulated for infusion of anaesthetic, and the right femoral vein was cannulated for administration of drugs.
  • a PE catheter was introduced into the lower portion of the abdominal aorta via the right external iliac artery.
  • NA was selectively distributed to the lower urinary tract.
  • the urinary bladder and proximal urethra were exposed. In order to prevent the filling of the bladder, the two ureters were cannulated and the urine led outside.
  • a Mikro-tip catheter (6 F) was introduced into the bladder via the external urethral meatus, and withdrawn until the pressure transducer was positioned in the prostatic urethra.
  • a ligature was secured between the neck of the bladder and urethra to isolate the response of the latter and avoid any interaction with the bladder.
  • Another ligature was put around the Mikro-tip catheter at the external urethral meatus, to secure the catheter itself.
  • test compounds were administered i.v. in a cumulative manner with intervals of 15-20 min between administrations. I.a. injections of NA were repeated approximately 5 minutes after every dosing of test compound.
  • Dose response curves were constructed computing the percentage inhibition to the increase in urethral pressure (NA induced) , and the percentage drop in blood pressure produced by the test compound.
  • ED 2 5 for diastolic blood pressure (dose inducing a 25% decrease) and ID 50 (dose inducing a 50% inhibition of NA-induced increase in urethral pressure) were computed by means of linear regression analysis.
  • Urethra active dose in inhibiting by 50% the noradrenaline induced contraction of urethra
  • DBP active dose in lowering diastolic blood pressure by 25%
  • DBP/urethra ratio between the active doses
  • the active compounds of the invention may be orally administered, for example, with an inert diluent or with an edible carrier, or they may be enclosed in gelatin capsules, or they may be compressed into tablets.
  • the active compounds of the invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like. These preparations should contain at least 0.5% of active compounds, but the amount of active ingredient may be varied depending upon the particular form and may conveniently be from about 5% to about 70% of the weight of the unit.
  • compositions and preparations according to the invention are prepared so that an oral dosage unit form contains from 2 to 600 mg of active compound.
  • the tablets, pills, capsules, troches and the like may optionally contain any of the following ingredients: a binder such as micro-crystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, cornstarch and the like; a lubricant such as magnesium stearate or Sterotex; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, or orange flavouring.
  • a binder such as micro-crystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose
  • a disintegrating agent such as alginic acid, Primogel, cornstarch and the like
  • a lubricant such as magnesium stearate or Sterotex
  • a glidant such as colloidal silicon dioxide
  • dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
  • tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, colourings and flavours. Materials used in preparing these various compositions should be pharmaceutically acceptable and non-toxic in the amounts used.
  • the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.2% of active compound, but may be varied between 0.5 and about 30% of the weight thereof. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains from 0.4 to 200 mg of active compound.
  • the solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulphite; chelating agents _such as ethylenediaminetetraacetic acid; buffers such as acetates; citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral multiple dose vials may be of glass or plastics material. Additional compositions suitable for administration by various routes and containing compounds according to the invention are also within the scope of the invention. Dosage forms, additional ingredients and routes of administration contemplated herein include those disclosed in US 4089969 and 5091182.

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Abstract

Composés répondant à la formule générale (I), dans laquelle Y représente un groupe de liaison, choisi dans une large gamme, mais comprenant -COO-, -CH2COO-, -CONH-, -CON(CH3)-, -CH2CONH-, SO2NH-, -SO2N(CH3)- et -PO(OC2H5)NH-; W représente une chaîne alkylène; A représente un groupe phénylique substitué ou un groupe benzofurane ou benzodioxane; et R et R1 peuvent avoir plusieurs valeurs, mais R est de préférence un groupe volumineux. Ces composés et leurs promédicaments, énantiomères, diastéréoisomères, N-oxydes et leurs sels pharmaceutiquement acceptables bloquent les récepteurs α1a-adrénergiques et sont de ce fait utilisables dans la prophylaxie des contractions de la prostate, de l'urètre et de la partie inférieure du tractus urinaire, et ce sans intervenir sur la tension artérielle.
PCT/EP1994/002437 1993-07-30 1994-07-22 DERIVES DE PIPERAZINE UTILISES COMME ANTAGONISTES DES RECEPTEURS α1A-ADRENERGIQUES WO1995004049A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU75323/94A AU680037B2 (en) 1993-07-30 1994-07-22 Piperazine derivatives as alpha1a-adrenergic receptor antagonists
EP94925382A EP0711288A1 (fr) 1993-07-30 1994-07-22 Derives de piperazine utilises comme antagonistes des recepteurs alpha 1a-adrenergiques
JP7505546A JPH09500883A (ja) 1993-07-30 1994-07-22 α１Ａ−アドレナリン受容体アンタゴニストとしてのピペラジン誘導体
KR1019960700460A KR960703884A (ko) 1993-07-30 1994-07-22 α₁_A-아드레날린 수용체 길항제로써 피페라진 유도체들(PIPERAZINE DERIVATIV ES AS α₁_A-ADRENERGIC RECEPTOR ANTAGONISTS)
NO960371A NO960371L (no) 1993-07-30 1996-01-29 Piperazinderivater som ter

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ITMI93A001717 1993-07-30
IT93MI001717A IT1266582B1 (it) 1993-07-30 1993-07-30 Derivati (di)azacicloesanici e diazacicloeptanici

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EP (1) EP0711288A1 (fr)
JP (1) JPH09500883A (fr)
KR (1) KR960703884A (fr)
CN (1) CN1132508A (fr)
AU (1) AU680037B2 (fr)
CA (1) CA2168443A1 (fr)
IL (1) IL110348A0 (fr)
IT (1) IT1266582B1 (fr)
MX (1) MXPA94005805A (fr)
NO (1) NO960371L (fr)
NZ (1) NZ271634A (fr)
SG (1) SG46281A1 (fr)
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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997010229A1 (fr) * 1995-09-13 1997-03-20 Neurogen Corporation Nouveaux n-aminoalkylfluorenecarboxamides; nouvelle classe de ligands specifiques de sous-types de recepteurs dopaminergiques
WO1997037983A1 (fr) * 1996-04-05 1997-10-16 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) ANTAGONISTES DU RECEPTEUR α1-ADRENERGIQUE
EP0802196A1 (fr) * 1996-04-18 1997-10-22 Shiseido Company Limited Dérives d'amides des acides N-(1-piperidinylalkyl)-alkoxybenzoique ayant une activité contre l'heliobacter pyroli et leur application comme des médicaments anti-ulcères
EP0831823A1 (fr) * 1995-06-07 1998-04-01 Merck & Co., Inc. ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a
EP0833637A1 (fr) * 1995-06-07 1998-04-08 Merck & Co., Inc. ANTAGONISTES DU RECEPTEUR ALPHA ADRENERGIQUE 1a
US5807856A (en) * 1995-11-15 1998-09-15 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonist
WO1999006384A1 (fr) * 1997-08-01 1999-02-11 Recordati S.A., Chemical And Pharmaceutical Company Derives de 1-(n-phenylaminoalkyl)-piperazine substitues a la position 2 du cycle phenyle
WO1999006382A1 (fr) * 1997-08-01 1999-02-11 Recordati S.A., Chemical And Pharmaceutical Company Piperazines 1,4-disubstituees
US5977141A (en) * 1995-11-17 1999-11-02 Warner-Lambert Company Sulfonamide inhibitors of matrix metalloproteinases
EP0984777A1 (fr) * 1997-05-12 2000-03-15 Ortho-Mcneil Pharmaceutical, Inc. Piperazines a substitution aryle utiles dans le traitement de l'adenome prostatique
US6057451A (en) * 1995-12-29 2000-05-02 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-herpesvirus compounds and methods for identifying, making and using same
US6211215B1 (en) 1996-07-19 2001-04-03 Takeda Chemical Industries, Ltd. Heterocyclic compounds, their production and use
WO2001049683A1 (fr) * 1999-12-30 2001-07-12 H. Lundbeck A/S Nouveaux derives d'heteroaryle, preparation et utilisation desdits derives
US6271234B1 (en) 1997-08-01 2001-08-07 Recordati S.A., Chemical And Pharmaceutical Company 1,4-disubstituted piperazines
US6288091B1 (en) 1995-12-29 2001-09-11 Boehringer Ingelheim Ltd. Antiherpes virus compounds and methods for their preparation and use
WO2001029015A3 (fr) * 1999-10-18 2001-11-01 Recordati Chem Pharm Derives d'isoxazolecarboxamide
US6399614B1 (en) 1997-08-01 2002-06-04 Recordati S.A. Chemical And Pharmaceutical Company 1-(N-phenylaminoalkyl)piperazine derivatives substituted at position 2 of the phenyl ring
EP1219614A1 (fr) * 2000-12-22 2002-07-03 The Jordanian Pharmaceutical Manufacturing and Medical Equipment Co.Ltd. Sulfonamides de benzene comme inhibiteurs de la PDE-V utilisables contre la dysérection
WO2002055496A1 (fr) * 2001-01-15 2002-07-18 Glaxo Group Limited Derives aryle de piperidine et de piperazine comme inducteurs de l'expression du recepteur ldl
US6680319B2 (en) 1999-10-18 2004-01-20 Recordati S.A. Isoxazolecarboxamide derivatives
US6743815B2 (en) 1998-08-07 2004-06-01 Chiron Corporation Estrogen receptor modulators
AU2002300904B2 (en) * 1997-05-12 2004-12-23 Ortho-Mcneil Pharmaceutical, Inc. Arylsubstituted piperazines useful in the treatment of benign prostatic hyperplasia
US6894052B1 (en) 1997-08-01 2005-05-17 Recordati S.A. Chemical And Pharmaceutical Company Diarylalkylpiperazines active on the lower urinary tract
EP1592425A2 (fr) * 2003-01-31 2005-11-09 Predix Pharmaceuticals Holdings, Inc. Nouveaux composes d'arylpiperazinyle
US7084144B2 (en) 2000-12-22 2006-08-01 The Jordanian Pharmaceutical Mfg & Medical Equipment Co Ltd Sulfonyl group containing compounds and their use for the treatment of erectile dysfunction
WO2013102249A1 (fr) * 2012-01-05 2013-07-11 Universidade Federal Do Rio De Janeiro-Ufrj Dérivés n-phénylpipéraziniques antagonistes d'adrénorécepteurs α1a, α1d et de récepteurs 5-ht1a dans le traitement de l'hyperplasie bénigne de la prostate, et compositions pharmaceutiques les contenant
US9149527B2 (en) 2010-06-07 2015-10-06 Novomedix, Llc Furanyl compounds and the use thereof
US9241942B2 (en) 2007-06-08 2016-01-26 Mannkind Corporation IRE-1α inhibitors
US11827610B2 (en) 2021-09-15 2023-11-28 Enko Chem, Inc. Protoporphyrinogen oxidase inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA991315B (en) * 1998-02-20 2000-11-20 Ortho Mcneil Pharm Inc Novel substituted pyridino arylpiperazines useful in the treatment of benign prostatic hyperplasia.
JP5260627B2 (ja) * 2007-03-30 2013-08-14 カウンスィル オブ サイエンティフィック アンド インダストリアル リサーチ ベンゾフェノン化合物及びその作製方法
CA2858752C (fr) 2011-12-09 2019-12-31 Research Triangle Institute 4-arylpiperazine 1-substitue a titre d'antagoniste du recepteur opioide kappa

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1537901A (fr) * 1967-07-19 1968-08-30 Bruneau & Cie Lab Dérivés amidés d'acides halogéno et nitro benzoïques et leur préparation
FR1543944A (fr) * 1967-03-10 1968-10-31 Bruneau & Cie Lab Dérivés amidés de l'acide salicylique et leur préparation
FR6452M (fr) * 1967-03-10 1968-11-12
FR6924M (fr) * 1967-10-18 1969-05-05
US3557107A (en) * 1967-05-01 1971-01-19 Shulton Inc Phenylpiperazinylalkyl alkoxy anthranilates
US3846430A (en) * 1968-01-12 1974-11-05 Bruneau & Cie Lab 1-(2-methoxy-phenyl)-4-{8 2-(4-fluoro-benzamido)-ethyl{9 -piperazine
EP0048045A1 (fr) * 1980-09-12 1982-03-24 Duphar International Research B.V Dérivés de phényl-pipérazine ayant une activité antiagressive
EP0104614A1 (fr) * 1982-09-24 1984-04-04 Chugai Seiyaku Kabushiki Kaisha Dérivés du phénylpipérazine et leur procédé de préparation
JPS60169467A (ja) * 1984-02-10 1985-09-02 Chugai Pharmaceut Co Ltd 新規なフエニルピペラジン誘導体
US4857644A (en) * 1988-06-09 1989-08-15 American Home Products Corporation Aryl sulfonopiperazines as anti-inflammatory agents
EP0330065A1 (fr) * 1988-02-18 1989-08-30 Kowa Company, Ltd. Composés de sulfonamides
EP0496692A1 (fr) * 1991-01-24 1992-07-29 Fabrica Espanola De Productos Quimicos Y Farmaceuticos, S.A. (Faes) Dérivés de 2-méthoxyphénylpipérazine
WO1993017007A1 (fr) * 1992-02-25 1993-09-02 Recordati Industria Chimica E Farmaceutica S.P.A. Composes heterobicycliques
WO1993021179A1 (fr) * 1992-04-09 1993-10-28 Aktiebolaget Astra Nouvelle piperazine d'aminoalkyle et d'iminoalkyle

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2997472A (en) * 1961-08-22 Certificate of correction
US4642291A (en) * 1982-09-01 1987-02-10 Sloan-Kettering Institute For Cancer Research Cell surface antigens of human astrocytoma

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1543944A (fr) * 1967-03-10 1968-10-31 Bruneau & Cie Lab Dérivés amidés de l'acide salicylique et leur préparation
FR6452M (fr) * 1967-03-10 1968-11-12
US3557107A (en) * 1967-05-01 1971-01-19 Shulton Inc Phenylpiperazinylalkyl alkoxy anthranilates
FR1537901A (fr) * 1967-07-19 1968-08-30 Bruneau & Cie Lab Dérivés amidés d'acides halogéno et nitro benzoïques et leur préparation
FR6924M (fr) * 1967-10-18 1969-05-05
US3846430A (en) * 1968-01-12 1974-11-05 Bruneau & Cie Lab 1-(2-methoxy-phenyl)-4-{8 2-(4-fluoro-benzamido)-ethyl{9 -piperazine
EP0048045A1 (fr) * 1980-09-12 1982-03-24 Duphar International Research B.V Dérivés de phényl-pipérazine ayant une activité antiagressive
EP0104614A1 (fr) * 1982-09-24 1984-04-04 Chugai Seiyaku Kabushiki Kaisha Dérivés du phénylpipérazine et leur procédé de préparation
JPS60169467A (ja) * 1984-02-10 1985-09-02 Chugai Pharmaceut Co Ltd 新規なフエニルピペラジン誘導体
EP0330065A1 (fr) * 1988-02-18 1989-08-30 Kowa Company, Ltd. Composés de sulfonamides
US4857644A (en) * 1988-06-09 1989-08-15 American Home Products Corporation Aryl sulfonopiperazines as anti-inflammatory agents
EP0496692A1 (fr) * 1991-01-24 1992-07-29 Fabrica Espanola De Productos Quimicos Y Farmaceuticos, S.A. (Faes) Dérivés de 2-méthoxyphénylpipérazine
WO1993017007A1 (fr) * 1992-02-25 1993-09-02 Recordati Industria Chimica E Farmaceutica S.P.A. Composes heterobicycliques
WO1993021179A1 (fr) * 1992-04-09 1993-10-28 Aktiebolaget Astra Nouvelle piperazine d'aminoalkyle et d'iminoalkyle

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ACTA PHYS. CHEM., vol. 28, no. 3, 1982, HUNGARIA, pages 225 - 244 *
CHEMICAL ABSTRACTS, vol. 104, no. 17, 28 April 1986, Columbus, Ohio, US; abstract no. 148910, page 701; column L; *
CHEMICAL ABSTRACTS, vol. 113, no. 13, 24 September 1990, Columbus, Ohio, US; abstract no. 115251b, page 690; column L; *
CHEMICAL ABSTRACTS, vol. 99, no. 9, 29 August 1983, Columbus, Ohio, US; abstract no. 70678v, page 624; column R; *
COLLECT. CZECH . CHEM. COMMUN., vol. 55, no. 3, 1990, PRAGUE, pages 797 - 808 *

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US6075038A (en) * 1995-06-07 2000-06-13 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
US6274583B1 (en) 1995-06-07 2001-08-14 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
EP0831823A1 (fr) * 1995-06-07 1998-04-01 Merck & Co., Inc. ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a
EP0833637A1 (fr) * 1995-06-07 1998-04-08 Merck & Co., Inc. ANTAGONISTES DU RECEPTEUR ALPHA ADRENERGIQUE 1a
EP0833637A4 (fr) * 1995-06-07 1998-07-08 Merck & Co Inc ANTAGONISTES DU RECEPTEUR ALPHA ADRENERGIQUE 1a
EP0831823A4 (fr) * 1995-06-07 1998-10-21 Merck & Co Inc ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a
US5977115A (en) * 1995-06-07 1999-11-02 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
WO1997010229A1 (fr) * 1995-09-13 1997-03-20 Neurogen Corporation Nouveaux n-aminoalkylfluorenecarboxamides; nouvelle classe de ligands specifiques de sous-types de recepteurs dopaminergiques
US6015900A (en) * 1995-09-13 2000-01-18 Neurogen Corporation N-aminoalkylfluorenecarboxamides
US5932734A (en) * 1995-09-13 1999-08-03 Neurogen Corporation N-aminoalkylfluorenecarboxamides
US5807856A (en) * 1995-11-15 1998-09-15 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonist
US6153612A (en) * 1995-11-17 2000-11-28 Warner-Lambert Company Sulfonamide inhibitors of matrix metalloproteinases
US5977141A (en) * 1995-11-17 1999-11-02 Warner-Lambert Company Sulfonamide inhibitors of matrix metalloproteinases
US6288091B1 (en) 1995-12-29 2001-09-11 Boehringer Ingelheim Ltd. Antiherpes virus compounds and methods for their preparation and use
US6458959B1 (en) 1995-12-29 2002-10-01 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-herpesvirus compounds and methods for identifying, making and using same
US6348477B1 (en) 1995-12-29 2002-02-19 Boehringer Ingelheim(Canada) Ltd. Anti-herpesvirus compounds and methods for identifying, making and using same
US6057451A (en) * 1995-12-29 2000-05-02 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-herpesvirus compounds and methods for identifying, making and using same
WO1997037983A1 (fr) * 1996-04-05 1997-10-16 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) ANTAGONISTES DU RECEPTEUR α1-ADRENERGIQUE
US5814634A (en) * 1996-04-18 1998-09-29 Shiseido Co. Ltd. Alkylenediamine derivative anti-ulcer drug and antibacterial drug
AU711954B2 (en) * 1996-04-18 1999-10-28 Shiseido Company Ltd. Alkylenediamine derivative, anti-ulcer drug, and antibacterial drug
EP0802196A1 (fr) * 1996-04-18 1997-10-22 Shiseido Company Limited Dérives d'amides des acides N-(1-piperidinylalkyl)-alkoxybenzoique ayant une activité contre l'heliobacter pyroli et leur application comme des médicaments anti-ulcères
US6211215B1 (en) 1996-07-19 2001-04-03 Takeda Chemical Industries, Ltd. Heterocyclic compounds, their production and use
US6593474B1 (en) 1997-05-12 2003-07-15 Ortho-Mcneil Pharmaceutical, Inc. Arylsubstituted piperazines useful in the treatment of benign prostatic hyperplasia
EP0984777A1 (fr) * 1997-05-12 2000-03-15 Ortho-Mcneil Pharmaceutical, Inc. Piperazines a substitution aryle utiles dans le traitement de l'adenome prostatique
EP0984777A4 (fr) * 1997-05-12 2001-04-25 Ortho Mcneil Pharm Inc Piperazines a substitution aryle utiles dans le traitement de l'adenome prostatique
US6890921B1 (en) 1997-05-12 2005-05-10 Ortho-Mcneil Pharmaceutical, Inc. Arylsubstituted piperazines useful in the treatment of benign prostatic hyperplasia
AU2002300904B2 (en) * 1997-05-12 2004-12-23 Ortho-Mcneil Pharmaceutical, Inc. Arylsubstituted piperazines useful in the treatment of benign prostatic hyperplasia
US6271234B1 (en) 1997-08-01 2001-08-07 Recordati S.A., Chemical And Pharmaceutical Company 1,4-disubstituted piperazines
US6399614B1 (en) 1997-08-01 2002-06-04 Recordati S.A. Chemical And Pharmaceutical Company 1-(N-phenylaminoalkyl)piperazine derivatives substituted at position 2 of the phenyl ring
US6894052B1 (en) 1997-08-01 2005-05-17 Recordati S.A. Chemical And Pharmaceutical Company Diarylalkylpiperazines active on the lower urinary tract
WO1999006384A1 (fr) * 1997-08-01 1999-02-11 Recordati S.A., Chemical And Pharmaceutical Company Derives de 1-(n-phenylaminoalkyl)-piperazine substitues a la position 2 du cycle phenyle
US6071920A (en) * 1997-08-01 2000-06-06 Recordati S.A. Chemical And Pharmaceutical Company 1-(N-phenylaminoalkyl)piperazine derivatives substituted at position 2 of the phenyl ring
WO1999006382A1 (fr) * 1997-08-01 1999-02-11 Recordati S.A., Chemical And Pharmaceutical Company Piperazines 1,4-disubstituees
US6869969B2 (en) 1998-08-07 2005-03-22 Chiron Corporation Estrogen receptor modulators
US6743815B2 (en) 1998-08-07 2004-06-01 Chiron Corporation Estrogen receptor modulators
WO2001029015A3 (fr) * 1999-10-18 2001-11-01 Recordati Chem Pharm Derives d'isoxazolecarboxamide
US6680319B2 (en) 1999-10-18 2004-01-20 Recordati S.A. Isoxazolecarboxamide derivatives
WO2001049683A1 (fr) * 1999-12-30 2001-07-12 H. Lundbeck A/S Nouveaux derives d'heteroaryle, preparation et utilisation desdits derives
US7084144B2 (en) 2000-12-22 2006-08-01 The Jordanian Pharmaceutical Mfg & Medical Equipment Co Ltd Sulfonyl group containing compounds and their use for the treatment of erectile dysfunction
EP1219614A1 (fr) * 2000-12-22 2002-07-03 The Jordanian Pharmaceutical Manufacturing and Medical Equipment Co.Ltd. Sulfonamides de benzene comme inhibiteurs de la PDE-V utilisables contre la dysérection
WO2002055496A1 (fr) * 2001-01-15 2002-07-18 Glaxo Group Limited Derives aryle de piperidine et de piperazine comme inducteurs de l'expression du recepteur ldl
US7491727B2 (en) 2003-01-31 2009-02-17 Epix Delaware, Inc. Arylpiperazinyl compounds
EP1592425A4 (fr) * 2003-01-31 2007-01-24 Epix Delaware Inc Nouveaux composes d'arylpiperazinyle
US7488731B2 (en) 2003-01-31 2009-02-10 Epix Delaware, Inc. Arylpiperazinyl compounds
EP1592425A2 (fr) * 2003-01-31 2005-11-09 Predix Pharmaceuticals Holdings, Inc. Nouveaux composes d'arylpiperazinyle
US9241942B2 (en) 2007-06-08 2016-01-26 Mannkind Corporation IRE-1α inhibitors
US9546149B2 (en) 2007-06-08 2017-01-17 Mannkind Corporation IRE-1α inhibitors
US9981901B2 (en) 2007-06-08 2018-05-29 Fosun Orinove Pharmatech, Inc. IRE-1α inhibitors
US9149527B2 (en) 2010-06-07 2015-10-06 Novomedix, Llc Furanyl compounds and the use thereof
US9663483B2 (en) 2010-06-07 2017-05-30 Novomedix, Llc Furanyl compounds and the use thereof
WO2013102249A1 (fr) * 2012-01-05 2013-07-11 Universidade Federal Do Rio De Janeiro-Ufrj Dérivés n-phénylpipéraziniques antagonistes d'adrénorécepteurs α1a, α1d et de récepteurs 5-ht1a dans le traitement de l'hyperplasie bénigne de la prostate, et compositions pharmaceutiques les contenant
US11827610B2 (en) 2021-09-15 2023-11-28 Enko Chem, Inc. Protoporphyrinogen oxidase inhibitors

Also Published As

Publication number Publication date
SG46281A1 (en) 1998-02-20
ITMI931717A0 (it) 1993-07-30
ZA945625B (en) 1995-03-07
IL110348A0 (en) 1994-10-21
ITMI931717A1 (it) 1995-01-30
NO960371L (no) 1996-03-29
NZ271634A (en) 1996-09-25
NO960371D0 (no) 1996-01-29
JPH09500883A (ja) 1997-01-28
AU7532394A (en) 1995-02-28
EP0711288A1 (fr) 1996-05-15
KR960703884A (ko) 1996-08-31
IT1266582B1 (it) 1997-01-09
CN1132508A (zh) 1996-10-02
MXPA94005805A (es) 2004-08-20
CA2168443A1 (fr) 1995-02-09
AU680037B2 (en) 1997-07-17

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