EP1208093A1 - Nitriles d'acide cinnamique, leurs procedes de preparation et d'utilisation - Google Patents

Nitriles d'acide cinnamique, leurs procedes de preparation et d'utilisation

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Publication number
EP1208093A1
EP1208093A1 EP00958512A EP00958512A EP1208093A1 EP 1208093 A1 EP1208093 A1 EP 1208093A1 EP 00958512 A EP00958512 A EP 00958512A EP 00958512 A EP00958512 A EP 00958512A EP 1208093 A1 EP1208093 A1 EP 1208093A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
piperazinyl
alkoxyphenyl
general formula
alkoxy
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00958512A
Other languages
German (de)
English (en)
Inventor
Hermann Hauer
Egon Koch
Shyam Sunder Chatterjee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Willmar Schwabe GmbH and Co KG
Original Assignee
Dr Willmar Schwabe GmbH and Co KG
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
Application filed by Dr Willmar Schwabe GmbH and Co KG filed Critical Dr Willmar Schwabe GmbH and Co KG
Publication of EP1208093A1 publication Critical patent/EP1208093A1/fr
Withdrawn legal-status Critical Current

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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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/18—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 acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • 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
    • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen 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
    • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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 no 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D227/00—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00
    • C07D227/02—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D227/04—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms
    • 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
    • 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

Definitions

  • Cinnamic acid nitriles process for their preparation and use
  • Benign prostatic hyperplasia is by far the most important urological disease in men.
  • BPH is a benign growth of epithelial and stromal parts of the prostate, with enlargement of the organ leading to urinary drainage disorders that are accompanied by symptoms such as pollakiuria and nocturia, as well as incomplete and delayed bladder emptying.
  • urinary congestion can lead to renal failure and uremia.
  • LUTS Lower Urinary Tract Symptoms
  • alpha antagonists and 5-alpha reductase inhibitors are primarily used as medicines for the treatment of BPH (see Eckert, RE, et al., Cellular basis of dynamic, infravesical obstruction in the context of a benign prostatic hyperplasia; role of alpha-receptor blockers and cyclic nucleotides, Akt. Urol. 29, 252-260 (1998); Weckermann, D. and Wawroschek, F. Medicinal therapy of benign prostatic hyperplasia syndrome. Münch. med. Wschr. 141, 54- 58 (1999); Weckermann, D. and Wawroschek, F. Interventional therapy for benign prostatic hyperplasia, Münch. Med. Wschr., 141, 59-63 (1999).
  • Alphar antagonists are based on the view that the obstruction of the urinary tract in BPH is based not only on a static component, which is caused by the enlarged prostate, but also on a dynamic component, which is caused by an increased tone of the smooth prostatic muscles.
  • a large number of studies have shown that dynamic obstruction in BPH is apparently mediated by an increased release of norepinephrine from sympathetic neurons. It is generally accepted today that in the Prostate predominantly alpha 1A adrenoceptors are expressed.
  • the clinical effectiveness of blocking alpha-adrenoceptors in the treatment of BPH was originally demonstrated using the non-specific antagonist phenoxybenzamine.
  • alpha blockers Because of the significant cardiovascular side effects, a number of so-called uroselective alpha- A blockers have been developed in recent years, which are much better tolerated. The results of clinical studies show that these substances have a statistically and clinically significant improvement in symptoms and maximum urine flow compared to placebo.
  • the advantage of alpha blockers is their rapid onset of action, but the growth potential of the prostate remains unaffected by these substances (cf. Heimbach, D. and Müller, SC. Treatment of BPH with ⁇ adrenoceptor antagonists. Urologe [A] 36, 18-34 (1997); Eckert et al., Loc. Cit .; Weckermann and Wawroschek, loc. Cit.).
  • BPH only develops in the presence of biologically active male sex hormones. BPH is practically never observed in men who had to undergo castration before the age of 40 or who have no or only insufficient androgen formation in the gonads due to an underactive pituitary gland. Likewise, in the event of a congenital defect or a lack of androgen receptors (e.g. testicular feminization), the normal development of the prostate and the formation of hyperplastic changes with increasing age do not occur. The most biologically important androgen in the prostate is dihydrotestosterone (DHT), which is produced locally under the influence of 5-alpha reductase from testosterone.
  • DHT dihydrotestosterone
  • DHT mainly stimulates the epithelial parts of BPH
  • inhibition of 5-alpha reductase leads to growth arrest or atrophy of the glandular part, but the stromal component of BPH is practically unaffected.
  • taking the 5-alpha reductase inhibitor finasteride results in a reduction in the prostatic DHT concentration of up to 85%, but the reduction in prostate size is only about 20% on average and also requires a period of up to 12 months , This effect is only clinically relevant if the prostate volume at the beginning of therapy is over 40 ml (see Geller, J. Pathogenesis and medical treatment of benign prostatic hyperplasia. Prostate (Suppl.) 2, 95-104 (1989 ); Weckermann and Wawroschek, loc.cit.).
  • epidermal growth factor [EGFJ, transforming growth factor- ⁇ , [TGF- ⁇ ], TGF-ß, basic fibroblast growth factor (bFGF), keratinocyte growth factor [KGF], nerve growth Factor [NGF], Insulin-like Growth Factor I [IGF-1] etc.) and their receptors.
  • BPH basic fibroblast growth factor
  • KGF keratinocyte growth factor
  • NGF nerve growth Factor
  • IGF-1 Insulin-like Growth Factor I
  • Prostate 28 392-405 (1996); Peehl, DM Celluiar biology of prostatic growth factors. Prostate (Suppl.) 6: 74-78 (1996); Peehl, DM and Seilers, RG Basic FGF, EGF, and PDGF modify TGFß-induction of smooth muscle cell phenotype in human prostatic stromal cells. Prostate 35, 125-134 (1998).
  • the invention is therefore based on the object of providing substances which, by inhibiting alphar adrenoceptors ( ⁇ i-antagonistic action) and by suppressing the growth factor-mediated cell proliferation (proliferation-inhibiting action) of epithelial and stromal cells, both the dynamic and the static Affect components of BPH positively and thus allow comprehensive treatment of BPH syndrome.
  • the object of the invention is also the provision of medicaments for the prophylaxis and treatment of BPH and of processes for their production and use.
  • X CN, COOR 4 , CONR 5 R 6 , COAryl, COalkyl, aryl, heteroaryl,
  • R 1 H, alkyl, arylalkyl, [4- (2-alkoxyphenyl) -1-piperazinyl] alkyl,
  • R 2 and R 3 independently of one another H, hydroxy, alkoxy, benzyl,
  • R H, alkyl, [4- (2-alkoxyphenyl) -1-piperazinyl] alkyl,
  • R 5 H, alkyl, alkoxyalkyl, alkoxy-oxoalkyl, dialkylaminoalkyl, amino-oxoalkyl, aryl,
  • alkyl in all cases is a straight-chain or branched alkyl radical having 1 to 8 carbon atoms, preferably having 1 to 4 carbon atoms
  • alkoxy is an alkoxy group having 1 to 4 carbon atoms Atoms, preferably with one or two carbon atoms.
  • Aryl is also to be understood as meaning any substituted aryl radicals, for example halophenyl, alkylphenyl, alkoxyphenyl,
  • the compounds according to the invention are substituted by radicals or groups which contain basic nitrogen atoms, for example cyclic amine groups such as pyrrolidine, morpholine, piperidine, piperazine, these compounds can be present either in the form of free bases or in the form of addition salts with pharmacologically acceptable acids, for example in Form of their hydrochloride or trifluoroacetate.
  • cyclic amine groups such as pyrrolidine, morpholine, piperidine, piperazine
  • Preferred cinnamic acid nitrile derivatives are those compounds of general forms I in which the at least one [4- (2-alkoxyphenyl) -1-piperazinyl] alkyl radical is a [4- (2-methoxyphenyl) -1-piperazinyl] propyl radical is.
  • the compounds according to the invention are pharmacologically active; Their pharmacological effect is characterized by the simultaneous presence of an ⁇ T adrenoceptor-antagonistic active component and a proliferation-inhibiting active component.
  • the invention therefore also relates to medicaments which, as an active ingredient, contain, in addition to customary auxiliaries and additives, an amount of one or more of the compounds of general forms I according to the invention which is effective for the prophylaxis or treatment of BPH.
  • these medicaments can include, for example, water, vegetable oils, polyethylene glycols, glycerol esters, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, Vaseline®, preservatives, wetting agents, emulsifiers, physiologically acceptable salts, buffer substances, colorants, flavorings and flavorings contain.
  • the choice of excipients depends on the desired application form such as. B. tablets, dragees, juices, ampoules, suppositories, ointments or sprays.
  • the compounds according to the invention can also be administered in a mixture with other known active compounds.
  • the compound (E) -1 - [2-cyano-3- (3,4-dihydroxyphenyl) -1-oxo-2-propenyl] -4-phenylpiperazine is known from A. Gazit et al., J. Med Chem. 34, pp. 1896-1907 (1991) (there compound no. 68).
  • This known compound differs from the compounds of the general formula I according to the invention in that it contains a [4-phenyl-1-piperazinyl] radical, but not at least one [4- (2-alkoxyphenyl) -1-piperazinyl] alkyl -Rest.
  • a proliferation-inhibiting effect is described for the known compound, it is not known whether this compound also has an ⁇ i-antagonistic effect.
  • the invention finally also relates to processes for the preparation of the compounds of the general formula I in which a benzaldehyde of the general formula II, in which R 1 , R 2 and R 3 have the meanings given above, with a substituted acetonitrile of the general formula III, in which X has the meaning given above, is implemented under conditions known for Knoevenagel condensations, ie aldol condensations.
  • the Knoevenagel condensation can be carried out with or without a catalyst.
  • Piperidine, ammonium acetate, ⁇ -alanine or glacial acetic acid serve as catalysts.
  • R 1 [4- (2-alkoxyphenyl) -1-piperazinyl] alkyl
  • R 2 and R 3 independently of one another H, hydroxy, alkoxy with 1 - 4, preferably 1 - 2 C-
  • Atoms, benzyl are new reactive intermediates for the preparation of the compounds of general formula I, in which R 1 , R 2 and R 3 have the corresponding meanings. These intermediates are also the subject of the invention.
  • Process A The benzaldehyde of the general formula II correspondingly substituted with R 1 to R 3 , if appropriate released from its hydrochloride, 0.9 to 2.0 equivalents of the acetonitrile of the general formula III substituted with X and optionally a catalytic amount of piperidine are dissolved in ethanol, methanol , 2-propanol or TBME 2 h to 3 d at 50 ° C to boiling temperature.
  • the product is worked up by filtering off the product, by evaporation or by partitioning between ethyl acetate or chloroform and water. Purification is carried out by chromatography, recrystallization and / or salt formation using method C.
  • Process B The benzaldehyde of the general formula II substituted with R 1 to R 3 , if appropriate released from its hydrochloride, 0.9 to 1.1 equivalents of the Acetonitrile of the general formula III corresponding to X and optionally a catalytic amount of piperidine and / or glacial acetic acid are stirred in toluene for 2 to 24 hours on a water separator under reflux. The mixture is worked up by evaporating the reaction solution. Purification is carried out by chromatography, recrystallization and / or salt formation using method C.
  • Process C The base prepared by process A or B is dissolved in ethanol, 2-propanol or acetone and 1 to 3 equivalents of a solution of hydrogen chloride in 2-propanol or aqueous hydrochloric acid are added.
  • the hydrochloride is suctioned off or concentrated and purified by recrystallization.
  • Method E 2.0 to 2.4 equivalents of potassium hydroxide are added to 1.0 to 1.2 equivalents of the appropriately substituted 1- (3-chloropropyl) -4- (2-alkoxyphenyl) piperazine dihydrochloride in ethanol or 1-propanol.
  • potassium iodide 1.0 to 1.2 equivalents of potassium carbonate
  • the inorganic material is filtered off and the filtrate is spun in.
  • Working up is carried out by extraction with ethyl acetate or TBME and renewed filtration and / or by partitioning between ethyl acetate or TBME and water. It is cleaned by recrystallization or salt formation according to method C.
  • Process F 1.0 equivalent of isovanillin, 1.5 equivalents of 1-bromo-2-chloroethane or 1, 4-dibromobutane and 1.5 equivalents of potassium carbonate are stirred in 2-butanone at boiling temperature for 4 to 20 h. The inorganic material is filtered off and the filtrate is spun in. The purification is carried out by chromatography and / or recrystallization.
  • Process G The amine HNR 5 R 6 , optionally released from its hydrochloride, is reacted with 1.0 to 1.05 equivalents of methyl cyanoacetate in methanol, ethanol or without solvent for 15 min to 28 h at room temperature to 100 ° C. After cooling, the mixture is optionally rotated in and purified by recrystallization.
  • Method H The alcohol H ⁇ R 4 is heated with 5 equivalents of methyl cyanoacetate to 80 ° C. for 7 hours at a slightly reduced pressure. After cooling, it is purified by column chromatography and subsequent recrystallization.
  • the cell homogenate was centrifuged for 10 min at 50,000 g (4 ⁇ C) and the pellet resuspended in ice-cold homogenization buffer. After renewed centrifugation (10 min at 4 ° C. and 50,000 g), the cell membranes were in a 10-fold volume of binding buffer (50 mM Tris-HCl, 0.5 mM Na-EDTA, 0.01% ascorbic acid, 10 ⁇ M pargyline, pH 7, 4) and stored in portions (1 ml) at -80 ° C
  • the substances were dissolved in 150 ⁇ l binding buffer using DMSO and together with 50 ⁇ l brain cell membranes (2.5 mg / ml protein) and 50 ⁇ l 3 H-Prazos ⁇ n (300 pM, specific activity 80 Ci / mmol) in Binding buffer incubated for 45 min at room temperature. The non-specific binding was determined in the presence of 2 ⁇ M phentolamine.
  • the reaction mixture was then filtered through glass fiber filters (type GF / B) which had been pretreated overnight with polyethyleneimine (0.2% in distilled water). After washing four times with 3 ml of ice-cold binding buffer, the filters were dried at 60 ° C. for 1 h.
  • DMEM modified Eagle's Medium
  • FCS fetal calf serum
  • FCS fetal calf serum
  • FCS fetal calf serum
  • the cells were detached from the ground with trypsin / EDTA and then harvested with a cell harvester (Inotech) on glass fiber filter (type G-10, ICH-201).
  • a cell harvester Inotech
  • the incorporation of 3 H-thymid into newly synthesized DNA was carried out with the aid of a linear analyzer (LB 2842, Berthold).
  • the degree of the anti-proactive effect of the substances was determined in each case in comparison to the solvent controls examined at the same time
  • the finely powdered substances are mixed homogeneously and filled into size 2 hard gelatin capsules in an amount of 200 mg per capsule.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne des nitriles d'acide cinnamique substitués de formule (I) dans laquelle: X = CN, COOR?4, CONR5R6¿, COaryle, COalkyle, aryle, hétéroaryle; R1 = H, alkyle, arylalkyle, [4-(2-alkoxyphényl)-1-pipérazinyl]alkyle; R2 et R3 sont indépendamment H, hydroxy, alkoxy, benzyle; R4 = H, alkyle, [4-(2-alkoxyphényl)-1-pipérazinyl]alkyle; R5 = H, alkyle, alkoxyalkyle, alkoxy-oxoalkyle, dialkylaminoalkyle, amino-oxoalkyle, aryle, arylalkyle, [4-(2-alkoxyphényl)-1-pipérazinyl]alkyle, morpholinoalkyle, furanylalkyle, thiénylalkyle; R6 = H, alkyle, ou NR5R6 forment ensemble une amine cyclique telle que pyrrolidine, morpholine, pipéridine, pipérazine substituée; l'un des restes R?1, R4 ou R5¿ est un reste [4-(2-alkoxyphényl)-1-pipérazinyl]alkyle. Cette invention concerne également leurs sels d'addition avec des acides pharmaceutiquement tolérés. Les composés peuvent être utilisés comme produits pharmaceutiques pour la prévention et le traitement de l'hyperplasie prostatique bénigne. L'invention concerne également des procédés de préparation des nitriles d'acide cinnamique. Pour cela, un benzaldéhyde substitué correspondant et un acétonitrile substitué approprié sont soumis ensemble à une condensation de Knoevenagel.
EP00958512A 1999-09-01 2000-08-29 Nitriles d'acide cinnamique, leurs procedes de preparation et d'utilisation Withdrawn EP1208093A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19941657 1999-09-01
DE1999141657 DE19941657A1 (de) 1999-09-01 1999-09-01 Zimtsäurenitrile, Verfahren zu ihrer Herstellung und Verwendung
PCT/EP2000/008419 WO2001016124A1 (fr) 1999-09-01 2000-08-29 Nitriles d'acide cinnamique, leurs procedes de preparation et d'utilisation

Publications (1)

Publication Number Publication Date
EP1208093A1 true EP1208093A1 (fr) 2002-05-29

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Application Number Title Priority Date Filing Date
EP00958512A Withdrawn EP1208093A1 (fr) 1999-09-01 2000-08-29 Nitriles d'acide cinnamique, leurs procedes de preparation et d'utilisation

Country Status (4)

Country Link
EP (1) EP1208093A1 (fr)
AU (1) AU7000600A (fr)
DE (1) DE19941657A1 (fr)
WO (1) WO2001016124A1 (fr)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2623314C2 (de) * 1976-05-25 1984-08-02 Hoechst Ag, 6230 Frankfurt 1-Aryloxy-2-Hydroxy-3-aminopropane, Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel
US4689327A (en) * 1984-06-30 1987-08-25 Tanabe Seiyaku Co., Ltd. N-substituted-2-[2-[2-(4-phenylpiperazine-1-yl)ethoxy]phenyl]-thiazolidine-3-carboxamides useful as cardiotonic agent
HRP930210A2 (en) * 1992-02-25 1995-06-30 Recordati Chem Pharm Heterobicyclic compounds and pharmaceutical preparations containing them
JPH08143557A (ja) * 1994-11-24 1996-06-04 Toyobo Co Ltd 新規なフェニルピペラジン誘導体、その塩及びその溶媒和物
JPH0912563A (ja) * 1995-06-30 1997-01-14 Toyobo Co Ltd 新規ベンジルアルコ−ル誘導体、その製造方法およびその用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0116124A1 *

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AU7000600A (en) 2001-03-26
DE19941657A1 (de) 2001-03-08
WO2001016124A1 (fr) 2001-03-08

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