WO1998016224A1 - Pyrazolinones to treat disturbances of potency - Google Patents

Pyrazolinones to treat disturbances of potency Download PDF

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Publication number
WO1998016224A1
WO1998016224A1 PCT/EP1997/005532 EP9705532W WO9816224A1 WO 1998016224 A1 WO1998016224 A1 WO 1998016224A1 EP 9705532 W EP9705532 W EP 9705532W WO 9816224 A1 WO9816224 A1 WO 9816224A1
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WIPO (PCT)
Prior art keywords
dihydro
methylene
pyrazol
oxo
ethylanilino
Prior art date
Application number
PCT/EP1997/005532
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German (de)
French (fr)
Inventor
Michael Arlt
Rochus Jonas
Pierre Schelling
Maria Christadler
Franz-Werner Kluxen
Original Assignee
Merck Patent Gmbh
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 Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to BR9712307-2A priority Critical patent/BR9712307A/en
Priority to JP10517987A priority patent/JP2001501958A/en
Priority to AU49452/97A priority patent/AU4945297A/en
Priority to CA002268823A priority patent/CA2268823A1/en
Priority to EP97912141A priority patent/EP0930881A1/en
Priority to PL97332821A priority patent/PL332821A1/en
Priority to HU0000233A priority patent/HUP0000233A3/en
Publication of WO1998016224A1 publication Critical patent/WO1998016224A1/en
Priority to NO991734A priority patent/NO991734L/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • R 4 and R 5 together also represent a saturated, wholly or partly unsaturated, Q-saturated 4- to 5-membered alkylene chain in which 1 to 3 C-
  • R 2 A alkoxy-CO-alkylene or HO-alkylene
  • the invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
  • the invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of a medicament for the treatment and / or therapy of potent disorders.
  • Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal application, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants for parenteral use topical application ointments, creams or powder.
  • the new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables.
  • Example A Injection glasses
  • Example D ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • each capsule contains 20 mg of the active ingredient.

Abstract

The use of compounds having formula (I) wherein R?1, R2 and R3¿ have the meanings given in claim 1, for the treatment and/or therapy of disturbances of potency.

Description

Pyrazoiinone zur Behandlung von Potenzstörungen Pyrazoiinone for the treatment of erectile dysfunction
Die Erfindung betrifft die Verwendung von Verbindungen der Formel IThe invention relates to the use of compounds of the formula I.
Figure imgf000003_0001
worin
Figure imgf000003_0001
wherein
5 R1 unsubstituiert.es oder einfach durch Alkoxy substituiertes 5 R 1 unsubstituted or simply substituted by alkoxy
Benzyl, unsubstituiertes oder ein-, zwei- oder dreifach durch Hai, NO2, CN, COOH, CONH2, CONHA, CONAA', NH2, NH-CO-A, NH-SO2A, NA-SO2A', NH-CO-OA, SO3H, SO2NH-CO-A,SO2NR4R5, CO-NHSO3H, CO-NHSO2A, Tetra- zolyl oder PO3H substituiertes Phenyl oderBenzyl, unsubstituted or single, double or triple by shark, NO 2 , CN, COOH, CONH 2 , CONHA, CONAA ', NH 2 , NH-CO-A, NH-SO 2 A, NA-SO 2 A' , NH-CO-OA, SO 3 H, SO 2 NH-CO-A, SO 2 NR 4 R 5 , CO-NHSO 3 H, CO-NHSO 2 A, tetrazolyl or PO 3 H substituted phenyl or
Pyridyl,Pyridyl,
R2 A, Alkoxy-CO-alkylen, HO-CO-alkylen oder HO-alkylen,R 2 A, alkoxy-CO-alkylene, HO-CO-alkylene or HO-alkylene,
5 R3 H, A, Alkoxy, NH2, NHA, NAA', NH-CO-A oder SO2NR R5,5 R 3 H, A, alkoxy, NH 2 , NHA, NAA ', NH-CO-A or SO 2 NR R 5 ,
R4, R5 jeweils unabhängig voneinander H oder A,R 4 , R 5 each independently of one another H or A,
R4 und R5 zusammen auch eine gesättigte, ganz oder teilweise unge- Q sättigte 4- bis 5-giiedrige Alkylenkette, bei der 1 bis 3 C-R 4 and R 5 together also represent a saturated, wholly or partly unsaturated, Q-saturated 4- to 5-membered alkylene chain in which 1 to 3 C-
Atome durch N und/oder 1 bis 2 C-Atome durch 1 bis 2 O- und/oder 1 bis 2 S-Atome ersetzt sein können,Atoms can be replaced by N and / or 1 to 2 C atoms by 1 to 2 O and / or 1 to 2 S atoms,
A, A' jeweils unabhängig voneinander Alkyl mit 1 bis 6 C-Atomen, 5 wobei 1 bis 7 H-Atome durch F- und/oder Cl-Atome substituiert sein können, Hai F, Cl, Br oder IA, A 'each independently of one another alkyl having 1 to 6 C atoms, 5 where 1 to 7 H atoms can be substituted by F and / or Cl atoms, Shark F, Cl, Br or I
bedeuten,mean,
und ihre physiologisch unbedenklichen Salze zur Behandlung und/oder Therapie von Potenzstörungen.and their physiologically acceptable salts for the treatment and / or therapy of erectile dysfunction.
In der DE 195 18 082 sind die hier, gemäß der zweiten medizinischen In- dikation beanspruchten Pyrazol-3-on-Derivate bereits beschrieben. Die in DE 195 18 082 gemachte Offenbarung wird hiermit, durch Angabe des Aktenzeichens mit ihrem gesamten Inhalt in die vorliegende Erfindung mit einbezogen. Weiterhin wird dort die Verwendung dieser Verbindungen als selektive Inhibitoren der cGMP spezifischen Phosphodiesterase, zur Her- Stellung eines Arzneimittels zur Behandlung von Krankheiten des Herz- Kreislaufsystems, offenbart.DE 195 18 082 already describes the pyrazol-3-one derivatives claimed here in accordance with the second medical indication. The disclosure made in DE 195 18 082 is hereby incorporated into the present invention by indicating the file number with its entire content. Furthermore, the use of these compounds as selective inhibitors of cGMP-specific phosphodiesterase for the manufacture of a medicament for the treatment of diseases of the cardiovascular system is disclosed.
Überraschenderweise wurde gefunden, daß die in dieser Erfindung genannten Verbindungen zur Behandlung und/oder Therapie von Potenzstö- rungen (erektile Dysfunktion) verwendet werden können.It has surprisingly been found that the compounds mentioned in this invention can be used for the treatment and / or therapy of erectile dysfunction.
Die Verwendung von substituierten Pyrazolopyrimidinonen zur Behandlung von Impotenz ist z.B. in der WO 94/28902 beschrieben.The use of substituted pyrazolopyrimidinones for the treatment of impotence is e.g. described in WO 94/28902.
Die biologische Aktivität der Verbindungen der Formel I kann nach Methoden bestimmt werden, wie sie z.B in der WO 93/06104 beschrieben sind. Die Affinität der erfindungsgemäßen Verbindungen für cGMP- und cAMP- Phosphodiesterase wird durch die Ermittlung ihrer IC50-Werte (Konzentration des Inhibitors, die benötigt wird, um eine 50 %ige Inhibierung der En- zymaktivität zu erreichen) bestimmt.The biological activity of the compounds of the formula I can be determined by methods such as are described, for example, in WO 93/06104. The affinity of the compounds according to the invention for cGMP and cAMP phosphodiesterase is determined by determining their IC 50 values (concentration of the inhibitor which is required in order to achieve a 50% inhibition of the enzyme activity).
Zur Durchführung der Bestimmungen können nach bekannten Methoden isolierte Enzyme verwendet werden (z.B. W.J. Thompson et al., Biochem. 1971 , 0, 311). Zur Durchführung der Versuche kann eine modifizierte "batch"-Methode von W.J. Thompson und M.M. Appleman (Biochem. 1979, 18, 5228) angewendet werden. Ganz besonders wirksam sind die Verbindungen als Inhibitoren der Phenylephrin-induzierten Kontraktionen in Corpus cavernosum-Präpara- tionen von Hasen. Diese Wirkung kann z.B. nach der Methode nachgewiesen werden, die von F. Holmquist et al. in J. Urol., 15J), 1310-1315 (1993) beschrieben wird.Enzymes isolated according to known methods can be used to carry out the determinations (for example WJ Thompson et al., Biochem. 1971, 0, 311). A modified "batch" method by WJ Thompson and MM Appleman (Biochem. 1979, 18, 5228) can be used to carry out the experiments. The compounds are particularly effective as inhibitors of phenylephrine-induced contractions in corpus cavernosum preparations of rabbits. This effect can be demonstrated, for example, using the method described by F. Holmquist et al. in J. Urol., 15J), 1310-1315 (1993).
Die Inhibierung der Kontraktion, die die Wirksamkeit der erfindungsgemäßen Verbindungen zur Therapie und/oder Behandlung von Potenzstörungen aufzeigt, wurde für einige repräsentative Verbindungen der Formel I experimentell bewiesen. Die pharmakologischen Testdaten sind in Tabelle I zusammengefaßt.The inhibition of the contraction, which shows the effectiveness of the compounds according to the invention for the therapy and / or treatment of erectile dysfunction, has been experimentally proven for some representative compounds of the formula I. The pharmacological test data are summarized in Table I.
Die Verbindungen der Formel I können als Arzneimittelwirkstoffe in der Human- und Veterinärmedizin eingesetzt werden.The compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine.
A und A' bedeuten vorzugsweise jeweils unabhängig voneinander Alkyl mit 1-6 C-Atomen.A and A 'preferably each independently represent alkyl having 1-6 C atoms.
In den vorstehenden Formeln ist Alkyl vorzugsweise unverzweigt und hat 1 , 2, 3, 4, 5 oder 6 C-Atome, vorzugsweise 1 , 2, 3, 4 oder 5 C-Atome und bedeutet vorzugsweise Methyl, Ethyl oder Propyl, weiterhin bevorzugt Iso- propyl, Butyl, Isobutyl, sek.-Butyl oder tert.-Butyl, aber auch n-Pentyl, neo-In the above formulas, alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 carbon atoms, preferably 1, 2, 3, 4 or 5 carbon atoms and is preferably methyl, ethyl or propyl, more preferably iso propyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neo-
Pentyl oder Isopentyl.Pentyl or isopentyl.
A bedeutet ferner bevorzugt Trifluormethyl oder Pentafluorethyl.A also preferably denotes trifluoromethyl or pentafluoroethyl.
Alkylen ist vorzugsweise unverzweigt und bedeutet bevorzugt Methylen,Alkylene is preferably unbranched and preferably means methylene,
Ethylen, Propylen, Butylen oder Pentylen.Ethylene, propylene, butylene or pentylene.
Alkoxy bedeutet vorzugsweise Methoxy, Ethoxy, Propoxy, Butoxy, Penty- loxy oder Hexyloxy.Alkoxy preferably means methoxy, ethoxy, propoxy, butoxy, pentoxy or hexyloxy.
R4 und R5 bedeuten zusammen vorzugsweise -CH2-CH2-CH2-CH2-, -CH2-(CH2)3-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-CH2-NH-CH2-CH2-, -CH2-CH2-NA-CH2-CH2-, -CH2-O-CH2-CH2- oder -CH=CH-CH=CH-.R 4 and R 5 together preferably mean -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 - (CH 2 ) 3 -CH 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -CH 2 -NH-CH 2 -CH 2 -, -CH 2 -CH 2 -NA-CH 2 -CH 2 -, -CH 2 -O-CH 2 -CH 2 - or -CH = CH-CH = CH-.
Hai bedeutet vorzugsweise F, Cl oder Br, aber auch Für die gesamte Erfindung gilt, daß sämtliche Reste, die mehrfach auftreten, gleich oder verschieden sein können, d.h. unabhängig voneinander sind.Shark preferably means F, Cl or Br, but also It applies to the entire invention that all radicals which occur more than once can be the same or different, ie are independent of one another.
Gegenstand der Erfindung ist insbesondere die Verwendung derjenigen Verbindungen der Formel I, in denen mindestens einer der genannten Reste eine der vorstehend angegebenen bevorzugten Bedeutungen hat. Einige bevorzugte Gruppen von Verbindungen können durch die folgen- den Teilformeln la bis Id ausgedrückt werden, die der Formel I entsprechen und worin die nicht näher bezeichneten Reste die bei der Formel I angegebene Bedeutung haben, worin jedochThe invention relates in particular to the use of those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Id, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
in la R1 unsubstituiert.es oder einfach durch Alkoxy substituier- tes Benzyl, unsubstituiert.es oder ein-, zwei- oder dreifach durch Hai, NO2> CN, COOH, CONH2, CONHA, CONAA', NH2, NH-CO-A, NH-SO2A, NA-SO2A', NH-CO-OA, SO3H, SO2NH-CO-A,SO2NR4R5, CO-NHSO3H, CO-NHSO2A oder Tetrazolyl sub- stituiert.es Phenyl oder Pyridyl,in la R 1 unsubstituted or monosubstituted by alkoxy, unsubstituted or single, double or triple by shark, NO 2> CN, COOH, CONH 2 , CONHA, CONAA ', NH 2 , NH- CO-A, NH-SO 2 A, NA-SO 2 A ', NH-CO-OA, SO 3 H, SO 2 NH-CO-A, SO 2 NR 4 R 5 , CO-NHSO 3 H, CO- NHSO 2 A or tetrazolyl substituted phenyl or pyridyl,
R2 A, Alkoxy-CO-alkylen oder HO-alkylen,R 2 A, alkoxy-CO-alkylene or HO-alkylene,
R3 A oder Alkoxy,R 3 A or alkoxy,
R4, R5 jeweils unabhängig voneinander H oder A, R4 und R5 zusammen auch eine gesättigte, ganz oder teilweise ungesättigte 4- bis 5-gliedrige Alkylenkette, bei der 1 bisR 4 , R 5 each independently of one another H or A, R 4 and R 5 together also a saturated, completely or partially unsaturated 4- to 5-membered alkylene chain in which 1 to
3 C-Atome durch N und/oder 1 bis 2 C-Atome durch 1 bis 2 O- und/oder 1 bis 2 S-Atome ersetzt sein können , A, A' jeweils unabhängig voneinander Alkyl mit 1 bis 6 C- Atomen, wobei 1 bis 7 H-Atome durch F- und/oder Cl- Atome substituiert sein können,3 C atoms can be replaced by N and / or 1 to 2 C atoms by 1 to 2 O and / or 1 to 2 S atoms, A, A 'each independently of one another alkyl having 1 to 6 C atoms, where 1 to 7 H atoms can be substituted by F and / or Cl atoms,
Hai F, Cl, Br oder I bedeuten;Shark means F, Cl, Br or I;
in I b R1 unsubstituiert.es oder einfach durch Alkoxy substituiertes Benzyl, unsubstituiert.es oder ein-, zwei- oder drei- fach durch Hai, NO2, CN, COOH, CONH2, CONHA,in I b R 1 unsubstituted or simply substituted by alkoxy, unsubstituted or single, double or triple by shark, NO 2 , CN, COOH, CONH 2 , CONHA,
CONAA', NH2, NH-CO-A, NH-SO2A, NA-SO2A, NH-CO-OA, SO3H, SO2NH-CO-A,SO2NR4R5, CO-NHSO3H, CO-NHSO2A oder Tetrazolyl substituiertes Phenyl oder Pyridyl, R2 A, Alkoxy-CO-alkylen oder HO-alkylen, R3 A oder Alkoxy,CONAA ', NH 2 , NH-CO-A, NH-SO 2 A, NA-SO 2 A, NH-CO-OA, SO 3 H, SO 2 NH-CO-A, SO 2 NR 4 R 5 , CO-NHSO 3 H, CO-NHSO 2 A or tetrazolyl substituted phenyl or pyridyl, R 2 A, alkoxy-CO -alkylene or HO-alkylene, R 3 A or alkoxy,
R4, R5 jeweils unabhängig voneinander H oder A, A, A' jeweils unabhängig voneinander Alkyl mit 1 bis 6 C- Atomen, wobei 1 bis 7 H-Atome durch F- und/oder Cl- Atome substituiert sein können, Hai F, Cl, Br oder I bedeuten;R 4 , R 5 each independently of one another H or A, A, A 'each independently of one another alkyl having 1 to 6 C atoms, where 1 to 7 H atoms can be substituted by F and / or Cl atoms, Hai F , Cl, Br or I mean;
in I c R1 unsubstituiertes oder einfach durch Alkoxy substituiertes Benzyl, unsubstituiertes oder ein-, zwei- oder dreifach durch Hai, NO2, CN, COOH, CONH2, CONHA, CONAA', NH2, NH-CO-A, NH-SO2A, NA-SO2A',in I c R 1 unsubstituted or monosubstituted by alkoxy, unsubstituted or mono-, di- or trisubstituted by shark, NO 2 , CN, COOH, CONH 2 , CONHA, CONAA ', NH 2 , NH-CO-A, NH -SO 2 A, NA-SO 2 A ',
NH-CO-OA, SO3H, SO2NH-CO-A,SO2NR R5, CO-NHSO3H, CO-NHSO2A oder Tetrazolyl substituiertes Phenyl oder Pyridyl, R2 A, Alkoxy-CO-alkylen oder HO-alkylen, R3 A oder Alkoxy,NH-CO-OA, SO 3 H, SO 2 NH-CO-A, SO 2 NR R 5 , CO-NHSO 3 H, CO-NHSO 2 A or tetrazolyl substituted phenyl or pyridyl, R 2 A, alkoxy-CO- alkylene or HO-alkylene, R 3 A or alkoxy,
R4 und R5 zusammen eine gesättigte, ganz oder teilweise ungesättigte 4- bis 5-gliedrige Alkylenkette, bei der 1 bis 3 C- Atome durch N und/oder 1 bis 2 C-Atome durch 1 bis 2 O- und/oder 1 bis 2 S-Atome ersetzt sein können , A, A' jeweils unabhängig voneinander Alkyl mit 1 bis 6 C-R 4 and R 5 together form a saturated, completely or partially unsaturated 4- to 5-membered alkylene chain, in which 1 to 3 carbon atoms are represented by N and / or 1 to 2 carbon atoms by 1 to 2 O and / or 1 up to 2 S atoms can be replaced, A, A 'each independently of one another alkyl having 1 to 6 carbon atoms
Atomen, wobei 1 bis 7 H-Atome durch F- und/oder Cl- Atome substituiert sein können, Hai F, Cl, Br oder I bedeuten;Atoms, where 1 to 7 H atoms can be substituted by F and / or Cl atoms, mean Shark F, Cl, Br or I;
in I d R1 einfach durch Alkoxy substituiertes Benzyl, unsubstituiertes oder ein- oder zweifach durch Hai, NO2, CN, COOH, CONH2, CONHA, CONAA', NH2, NH-CO-A, NH-SO2A, NA-SO2A, NH-CO-OA, SO3H, SO2NH-CO-A,SO2NR4R5, CO-NHSO3H, CO-NHSO2A oder Tetrazolyl substituiertes Phenyl oder Pyridyl,in I d R 1 benzyl substituted simply by alkoxy, unsubstituted or mono- or disubstituted by shark, NO 2 , CN, COOH, CONH 2 , CONHA, CONAA ', NH 2 , NH-CO-A, NH-SO 2 A, NA-SO 2 A, NH-CO-OA, SO 3 H, SO 2 NH-CO-A, SO 2 NR 4 R 5 , CO-NHSO 3 H, CO-NHSO 2 A or tetrazolyl substituted phenyl or pyridyl,
R2 A, Alkoxy-CO-alkylen oder HO-alkylen, R3 A oder Alkoxy,R 2 A, alkoxy-CO-alkylene or HO-alkylene, R 3 A or alkoxy,
R4, R5 jeweils unabhängig voneinander H oder A,R 4 , R 5 each independently of one another H or A,
R4 und R5 zusammen auch -CH2-CH2-CH2-CH2-,R 4 and R 5 together also -CH 2 -CH 2 -CH 2 -CH 2 -,
-CH2-(CH2)3-CH2-, -CH2-CH -O-CH2-CH2-, -CH2-CH2-NH-CH2-CH2-,-CH 2 - (CH 2 ) 3 -CH 2 -, -CH 2 -CH -O-CH 2 -CH 2 -, -CH 2 -CH 2 -NH-CH 2 -CH 2 -,
-CH2-CH2-NA-CH2-CH2-, -CH2-O-CH2-CH2- oder-CH 2 -CH 2 -NA-CH 2 -CH 2 -, -CH 2 -O-CH 2 -CH 2 - or
-CH=CH-CH=CH-, A, A' jeweils unabhängig voneinander Alkyl mit 1 bis 6 C--CH = CH-CH = CH-, A, A 'each independently of one another alkyl with 1 to 6 C-
Atomen, wobei 1 bis 7 H-Atome durch F- und/oder Cl- Atome substituiert sein können,Atoms, where 1 to 7 H atoms can be substituted by F and / or Cl atoms,
Hai F, Cl, Br oder I bedeuten.Shark F, Cl, Br or I.
Ganz besonders bevorzugt ist die Verwendung der nachstehenden Verbindungen:The use of the following compounds is very particularly preferred:
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazoI-1 -yl)-benzoesäure;4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1 H -pyrazoI-1-yl) -benzoic acid;
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-propyl-1 H-pyrazol- 1-yl)-benzoesäure;4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl) benzoic acid;
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-benzamid;4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) benzamide;
N-(4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-phenyl)-acetamid;N- (4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1 H -pyrazol-1-yl) phenyl) acetamide;
2-(1-(4-Methoxycarbonylaminophenyl)-4-(2-ethylanilino-methylen)- 4,5-dihydro-5-oxo-1 H-pyrazol-3-yl)-essigsäureethylester;Ethyl 2- (1- (4-methoxycarbonylaminophenyl) -4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-1H-pyrazol-3-yl);
2-(4-(2-Ethylanilino-methylen)-4,5-dihydro-1-(4-methansulfonamido- phenyl)-5-oxo-1 H-pyrazol-3-yl)-essigsäureethylester;Ethyl 2- (4- (2-ethylanilino-methylene) -4,5-dihydro-1- (4-methanesulfonamido-phenyl) -5-oxo-1H-pyrazol-3-yl);
2-(4-(2-Ethylaniiino-methylen)-4,5-dihydro-1-(4-(N,N-diethylsulfon- amido)-phenyl)-5-oxo-1 H-pyrazol-3-yl)-essigsäureethylester; N-(4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-3-methyl-5-oxo-1 H- pyrazol-1-yl)-phenyl)-N-methyl-methylsulfonamid;2- (4- (2-Ethylaniiino-methylene) -4,5-dihydro-1- (4- (N, N-diethylsulfonamido) phenyl) -5-oxo-1 H-pyrazol-3-yl) -ethyl acetate; N- (4- (4- (2-ethylanilino-methylene) -4,5-dihydro-3-methyl-5-oxo-1 H -pyrazol-1-yl) phenyl) -N-methyl-methylsulfonamide;
2-(1-(4-(N,N-Diethylsulfamoyl)-phenyl)-4-(2-ethylanilino-methylen)- 4,5-dihydro-5-oxo-1 H-pyrazol-3-yl)-essigsäureethylester;Ethyl 2- (1- (4- (N, N-diethylsulfamoyl) phenyl) -4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-1H-pyrazol-3-yl) -acetate ;
4-[(2-Methoxy-phenylamino)-methylen]-2,4-dihydro-5-methyl-2- phenyl-pyrazol-3-on;4 - [(2-methoxyphenylamino) methylene] -2,4-dihydro-5-methyl-2-phenylpyrazol-3-one;
4-[(2-Propoxy-phenylamino)-methylen]-2,4-dihydro-5-methyl-2- phenyl-pyrazol-3-on;4 - [(2-propoxyphenylamino) methylene] -2,4-dihydro-5-methyl-2-phenylpyrazol-3-one;
4-(2-Ethylanilino-methylen)-2,4-dihydro-5-propyl-2-(4-methoxy- benzyl)-pyrazol-3-on;4- (2-ethylanilino-methylene) -2,4-dihydro-5-propyl-2- (4-methoxy-benzyl) pyrazol-3-one;
4-(2-Ethylanilino-methylen)-2,4-dihydro-5-(2-hydroxyethyl)-2-phenyl- pyrazol-3-on;4- (2-ethylanilino-methylene) -2,4-dihydro-5- (2-hydroxyethyl) -2-phenylpyrazol-3-one;
4-(2-Ethylanilino-methylen)-2,4-dihydro-5-propyl-2-(4-bromphenyl)- pyrazol-3-on;4- (2-ethylanilino-methylene) -2,4-dihydro-5-propyl-2- (4-bromophenyl) pyrazol-3-one;
4-(2-Ethylanilino-methylen)-2,4-dihydro-5-propyl-2-(4-nitrophenyl)- pyrazol-3-on;4- (2-ethylanilino-methylene) -2,4-dihydro-5-propyl-2- (4-nitrophenyl) pyrazol-3-one;
3-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-3- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-propyl-1H-pyrazole-
1 -yl)-benzolsulfonsäure;1 -yl) -benzenesulfonic acid;
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-propyl-1 H-pyrazol- 1 -yl)-benzolsulfonsäure;4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-propyl-1 H-pyrazole-1-yl) -benzenesulfonic acid;
4-(2-Ethylanilino-methylen)-2,4-dihydro-5-methyl-2-(4-nitrophenyl)- pyrazol-3-on;4- (2-ethylanilino-methylene) -2,4-dihydro-5-methyl-2- (4-nitrophenyl) pyrazol-3-one;
2-(4-(2-Ethylanilino-methylen)-4,5-dihydro-1-(4-nitrophenyl)-5-oxo- H-pyrazol-3-yl)-essigsäureethylester; 4-(2-Ethylanilino-methylen)-2,4-dihydro-5-propyl-2-(2-pyridyl)-pyrazol- 3-on;Ethyl 2- (4- (2-ethylanilino-methylene) -4,5-dihydro-1- (4-nitrophenyl) -5-oxo-H-pyrazol-3-yl); 4- (2-ethylanilino-methylene) -2,4-dihydro-5-propyl-2- (2-pyridyl) pyrazol-3-one;
4-(2-Ethylaniiino-methylen)-2,4-dihydro-5-methyl-2-(2-pyridyl)-pyra- zol-3-on;4- (2-ethylaniinomethylene) -2,4-dihydro-5-methyl-2- (2-pyridyl) pyrazol-3-one;
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-N-hexylbenzamid;4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) -N-hexylbenzamide;
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-N,N-diethylbenzamid;4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) -N, N-diethylbenzamide;
4-(2-Ethylanilino-methyien)-2,4-dihydro-5-propyl-2-(4-pyridyl)-pyrazol- 3-on;4- (2-ethylanilinomethyl) -2,4-dihydro-5-propyl-2- (4-pyridyl) pyrazol-3-one;
4-(2-Ethylanilino-methylen)-2,4-dihydro-5-methyl-2-(4-chlorphenyl)- pyrazol-3-on;4- (2-ethylanilino-methylene) -2,4-dihydro-5-methyl-2- (4-chlorophenyl) pyrazol-3-one;
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol- 1-yl)-N,N-diethylbenzamid;4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl) -N, N-diethylbenzamide;
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-propyl-1 H-pyrazol- 1-yl)-N-hexylbenzamid;4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl) -N-hexylbenzamide;
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-propyl-1 H-pyrazol-4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-propyl-1 H-pyrazole-
1-yl)-benzamid;1-yl) benzamide;
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-propyl-1 H-pyrazol- 1-yl)-benzonitril;4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl) benzonitrile;
3-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-propyl-1 H-pyrazol- 1-yl)-N,N-diethyl-4-methoxy-benzolsulfonamid;3- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl) -N, N-diethyl-4-methoxy-benzenesulfonamide;
3-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-benzonitril; 4-(2-Ethylanilino-methylen)-2,4-dihydro-5-methyl-2-(4-(4- morpholinylsulfonyl)-phenyl)-pyrazol-3-on;3- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) benzonitrile; 4- (2-ethylanilino-methylene) -2,4-dihydro-5-methyl-2- (4- (4-morpholinylsulfonyl) phenyl) pyrazol-3-one;
3-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-ylmethyl)-N-hexyl-4-propoxy-benzolsulfonamid;3- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-ylmethyl) -N-hexyl-4-propoxy-benzenesulfonamide;
3-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol- 1-yl)-benzoesäure;3- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl) benzoic acid;
N-(3-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-phenyl)-acetamid;N- (3- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) phenyl) acetamide;
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1H- pyrazol-1-yl)-N,N-diethyl-benzolsulfonamid;4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) -N, N-diethyl-benzenesulfonamide;
4-(2-Ethylanilino-methylen)-2,4-dihydro-5-propyl-2-(4-(1H-tetrazol-5- yl)-phenyl)-pyrazol-3-on;4- (2-ethylanilino-methylene) -2,4-dihydro-5-propyl-2- (4- (1H-tetrazol-5-yl) phenyl) pyrazol-3-one;
4-(2-Ethylanilino-methylen)-2,4-dihydro-5-propyl-2-(3-pyridyl)-pyrazol- 3-on;4- (2-ethylanilino-methylene) -2,4-dihydro-5-propyl-2- (3-pyridyl) pyrazol-3-one;
4-(2-Ethylanilino-methylen)-2,4-dihydro-5-methyl-2-(3-(1H-tetrazol-5- yl)-phenyl)-pyrazol-3-on;4- (2-ethylanilino-methylene) -2,4-dihydro-5-methyl-2- (3- (1H-tetrazol-5-yl) phenyl) pyrazol-3-one;
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-N-ethyl-benzolsulfonamid;4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) -N-ethyl-benzenesulfonamide;
4-(2-Butoxyanilino-methylen)-2,4-dihydro-5-methyl-2-(4-(4- morpholinylsulfonyl)-phenyl)-pyrazol-3-on;4- (2-butoxyanilino-methylene) -2,4-dihydro-5-methyl-2- (4- (4-morpholinylsulfonyl) phenyl) pyrazol-3-one;
4-(2-Ethoxyanilino-methylen)-2,4-dihydro-5-methyl-2-(4-(4- morpholinylsulfonyl)-phenyl)-pyrazol-3-on;4- (2-ethoxyanilino-methylene) -2,4-dihydro-5-methyl-2- (4- (4-morpholinylsulfonyl) phenyl) pyrazol-3-one;
4-(2-Ethylanilino-methylen)-2,4-dihydro-5-methyl-2-(4-(4-methyl-1- piperazinylsulfonyl)-phenyl)-pyrazol-3-on; N-(3-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-phenyl)-methansulfonamid;4- (2-ethylanilino-methylene) -2,4-dihydro-5-methyl-2- (4- (4-methyl-1-piperazinylsulfonyl) phenyl) pyrazol-3-one; N- (3- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) phenyl) methanesulfonamide;
N-(3-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1H- pyrazol-1 -yl)-phenyl)-carbaminsäuremethylester;N- (3- (4- (2-Ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) -phenyl) -carbamic acid methyl ester;
N-(2-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-phenyl)-methansulfonamid;N- (2- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) phenyl) methanesulfonamide;
N-(3-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-phenyl)-trifluoracetamid;N- (3- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) phenyl) trifluoroacetamide;
4-(4-(2-Ethoxyanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-N,N-diethyl-benzolsulfonamid;4- (4- (2-ethoxyanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) -N, N-diethyl-benzenesulfonamide;
4-(4-(2-Methoxyanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1H- pyrazol-1-yl)-N,N-diethyl-benzolsulfonamid;4- (4- (2-methoxyanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) -N, N-diethyl-benzenesulfonamide;
4-(4-(2-EthoxyaniIino-methylen)-4,5-dihydro-5-oxo-3-methyl-1H- pyrazol-1-yl)-N-ethyl-benzolsulfonamid;4- (4- (2-Ethoxyaniino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) -N-ethyl-benzenesulfonamide;
N-(4-(4-(2-Methoxyanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-phenyl)-carbaminsäureethylester;Ethyl N- (4- (4- (2-methoxyanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) phenyl) carbamic acid;
4-(4-(2-Trifluormethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-4- (4- (2-trifluoromethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-
1 H-pyrazol-1-yl)-benzoesäure;1 H-pyrazol-1-yl) benzoic acid;
4-(4-(2-Ethyianilino-methylen)-4,5-dihydro-5-oxo-3-ethoxycarbonyl- methyl-1H-pyrazol-1-yl)-benzoesäure;4- (4- (2-Ethyianilino-methylene) -4,5-dihydro-5-oxo-3-ethoxycarbonylmethyl-1H-pyrazol-1-yl) benzoic acid;
4-(4-(2-Propoxyanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1 -yl)-benzoesäure;4- (4- (2-propoxyanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) -benzoic acid;
N-(4-(4-(2-Ethoxyanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1H- pyrazol-1-yl)-propionamid; 4-(4-(2-Methoxyanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1 -yl)-benzoesäure;N- (4- (4- (2-ethoxyanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) propionamide; 4- (4- (2-methoxyanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) -benzoic acid;
4-(4-(2-lsopropylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-benzoesäure;4- (4- (2-isopropylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) benzoic acid;
4-(2-Ethoxyanilino-methylen)-2,4-dihydro-5-methyl-2-(4-(1- piperidylsulfonyl)-phenyl)-pyrazol-3-on;4- (2-ethoxyanilino-methylene) -2,4-dihydro-5-methyl-2- (4- (1-piperidylsulfonyl) phenyl) pyrazol-3-one;
4-(4-(2-Ethoxyanilino-methylen)-4,5-dihydro-5-oxo-3-propyl-1 H- pyrazol-1-yl)-N-tert.-butyl-benzolsulfonamid;4- (4- (2-ethoxyanilino-methylene) -4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl) -N-tert-butyl-benzenesulfonamide;
4-(4-(2-Ethoxyanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1H- pyrazol-1-yl)-N-acetyl-benzolsulfonamid;4- (4- (2-ethoxyanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) -N-acetyl-benzenesulfonamide;
4-(4-(2-Ethoxyanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1H- pyrazol-1-yl)-benzolsulfonamid;4- (4- (2-ethoxyanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) benzenesulfonamide;
2-(1-(4-(N,N-Diethylsulfamoyl)-phenyl)-4-(2-ethoxyanilino-methylen)- 4,5-dihydro-5-oxo-1 H-pyrazol-3-yl)-essigsäureethylester;Ethyl 2- (1- (4- (N, N-diethylsulfamoyl) phenyl) -4- (2-ethoxyanilino-methylene) -4,5-dihydro-5-oxo-1H-pyrazol-3-yl) -acetate ;
2-(1-(4-Acetamidophenyl)-4-(2-ethylanilino-methylen)-4,5-dihydro-5- oxo-1 H-pyrazol-3-yl)-essigsäureethylester;Ethyl 2- (1- (4-acetamidophenyl) -4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-1H-pyrazol-3-yl);
2-(1-(4-Trifluoracetamidophenyl)-4-(2-ethylanilino-methylen)-4,5- dihydro-5-oxo-1 H-pyrazol-3-yl)-essigsäureethylester.Ethyl 2- (1- (4-trifluoroacetamidophenyl) -4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-1H-pyrazol-3-yl) -acetate.
Gegenstand der Erfindung ist ferner die Verwendung der Verbindungen der Formel I und/oder ihrer physiologisch unbedenklichen Salze zur Herstellung pharmazeutischer Zubereitungen, insbesondere auf nichtchemischem Wege. Hierbei können sie zusammen mit mindestens einem festen, flüssigen und/oder halbflüssigen Träger- oder Hilfsstoff und gegebenenfalls in Kombination mit einem oder mehreren weiteren Wirkstoffen in eine geeignete Dosierungsform gebracht werden. Gegenstand der Erfindung ist ferner die Verwendung der Verbindungen der Formel I und/oder ihrer physiologisch unbedenklichen Salze zur Herstellung eines Arzneimittels zur Behandlung und/oder Therapie von Potentstörungen.The invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients. The invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of a medicament for the treatment and / or therapy of potent disorders.
Gegenstand der Erfindung sind ferner pharmazeutische Zubereitungen zur Behandlung und/oder Therapie von Potentstörungen, enthaltend mindestens eine Verbindung der Formel I und/oder eines ihrer physiologisch unbedenklichen Salze.The invention further relates to pharmaceutical preparations for the treatment and / or therapy of potent disorders, comprising at least one compound of the formula I and / or one of its physiologically acceptable salts.
Gegenstand der Erfindung ist auch die Verwendung einer pharmazeutischen Zubereitung enthaltend mindestens eine Verbindung der Formel I und/oder mindestens eines ihrer physiologisch unbedenklichen Salze zur Behandlung und zur Therapie von Potenzstörungen.The invention also relates to the use of a pharmaceutical preparation containing at least one compound of the formula I and / or at least one of its physiologically acceptable salts for the treatment and therapy of erectile dysfunction.
Diese Zubereitungen können als Arzneimittel in der Human- oder Veterinärmedizin verwendet werden. Als Trägerstoffe kommen organische oder anorganische Substanzen in Frage, die sich für die enterale (z.B. orale), parenterale oder topische Applikation eignen und mit den neuen Verbin- düngen nicht reagieren, beispielsweise Wasser, pflanzliche Öle, Benzylal- kohole, Alkylenglykole, Polyethylenglykole, Glycerintriacetat, Gelatine, Kohlehydrate wie Lactose oder Stärke, Magnesiumstearat, Talk, Vaseline. Zur oralen Anwendung dienen insbesondere Tabletten, Pillen, Dragees, Kapseln, Pulver, Granulate, Sirupe, Säfte oder Tropfen, zur rektalen An- endung Suppositorien, zur parenteralen Anwendung Lösungen, vorzugsweise ölige oder wässrige Lösungen, ferner Suspensionen, Emulsionen oder Implantate, für die topische Anwendung Salben, Cremes oder Puder. Die neuen Verbindungen können auch lyophilisiert und die erhaltenen Lyophilisate z.B. zur Herstellung von Injektionspräparaten verwendet werden. Die angegebenen Zubereitungen können sterilisiert sein und/oder Hilfsstoffe wie Gleit-, Konservierungs-, Stabilisierungs- und/oder Netzmittel, Emulgatoren, Salze zur Beeinflussung des osmotischen Druckes, Puffersubstanzen, Färb-, Geschmacks- und /oder mehrere weitere Wirkstoffe enthalten, z.B. ein oder mehrere Vitamine. Die Verbindungen der Formel I und ihre physiologisch unbedenklichen Salze können bei der Bekämpfung von Krankheiten, bei denen eine Erhöhung des cGMP(cyclo-Guanosin-monophosphat)-Spiegels zu Entzündungshemmung oder -Verhinderung und Muskelentspannung führt, eingesetzt werden. Besondere Verwendung können die erfindungsgemäßen Verbindungen bei der Behandlung von Krankheiten des Herz- Kreislaufsystems und zur Behandlung und Therapie von Potenzstörungen finden.These preparations can be used as medicinal products in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate , Gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal application, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants for parenteral use topical application ointments, creams or powder. The new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables. The specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, for example one or more vitamins. The compounds of the formula I and their physiologically acceptable salts can be used in combating diseases in which an increase in the cGMP (cyclo-guanosine monophosphate) level leads to inhibition or prevention of inflammation and muscle relaxation. The compounds according to the invention can be used particularly in the treatment of diseases of the cardiovascular system and for the treatment and therapy of erectile dysfunction.
Dabei werden die Substanzen in der Regel vorzugsweise in Dosierungen zwischen etwa 1 und 500 mg, insbesondere zwischen 5 und 100 mg pro Dosierungseinheit verabreicht. Die tägliche Dosierung ligt vorzugsweise zwischen etwa 0,02 und 10 mg/kg Körpergewicht. Die spezielle Dosis für jeden Patienten hängt jedoch von den verschiedensten Faktoren ab, bei- spielsweise von der Wirksamkeit der eingesetzten speziellen Verbindung, vom Alter, Körpergewicht, allgemeinen Gesundheitszustand, Geschlecht, von der Kost, vom Verabreichungszeitpunkt und -weg, von der Ausscheidungsgeschwindigkeit, Arzneistoffkombination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die orale Applikation ist bevorzugt.The substances are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg / kg body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion and combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.
Die Synthese der Verbindungen ist in DE 195 18 082 beschrieben. Es wird in dieser Hinsicht auf die genannte Anmedlung verwiesen und die präpa- rativen Grundlagen hier nicht mehr wiederholt.The synthesis of the compounds is described in DE 195 18 082. In this regard, reference is made to the aforementioned registration and the preparative basis is no longer repeated here.
Beispiel 1example 1
Die Testergebnisse der Inhibierung von Phenylephrin-induzierten Kontraktionen in Corpus cavernosum-Präparationen von Hasen durch einige repräsentative Verbindungen der Formel I sind in der nachfolgenden Tabelle I zusammengefaßt. Für die Relaxationstests sind die IC50-Werte angegeben, d.h. die Konzentrationen in μMol/Liter, die 50 % der durch Phenyle- phrin induzierten Spasmen (Kontraktionen) inhibieren.The test results of the inhibition of phenylephrine-induced contractions in corpus cavernosum preparations by some representative compounds of formula I are summarized in Table I below. The IC 50 values are given for the relaxation tests, ie the concentrations in μmol / liter which inhibit 50% of the spasms (contractions) induced by phenylphenin.
Tabelle ITable I
IC50-Werte (Konzentrationen in μMol/Liter) repräsentativer Verbindungen der Formel I, die analog der Methode von F. Holmquist et al. in J. Urol., 150, 1310-1315 (1993) erhalten wurden, sowie die gemessenen Schmelzpunkte der Substanzen.IC 50 values (concentrations in μmol / liter) of representative compounds of the formula I, which are analogous to the method of F. Holmquist et al. in J. Urol., 150, 1310-1315 (1993) and the measured melting points of the substances.
Figure imgf000016_0001
Figure imgf000016_0001
Figure imgf000016_0005
Figure imgf000016_0005
Figure imgf000016_0002
Figure imgf000016_0002
Figure imgf000016_0003
Figure imgf000016_0003
Figure imgf000016_0004
Me = Methyl Et = Ethyl Pr = Propyl
Figure imgf000016_0004
Me = methyl Et = ethyl Pr = propyl
Die pharmakologischen Daten beweisen die inhibitorische Aktivität der Verbindungen der Formel I und ihre Wirksamkeit in der Therapie und/oder zur Behandlung von Potenzstörungen.The pharmacological data demonstrate the inhibitory activity of the compounds of the formula I and their effectiveness in the therapy and / or for the treatment of erectile dysfunction.
Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen:The following examples relate to pharmaceutical preparations:
Beispiel A: InjektionsgläserExample A: Injection glasses
Eine Lösung von 100 g eines Wirkstoffes der Formel I und 5 g Dinatrium- hydrogenphosphat wird in 3 I zweifach destilliertem Wasser mit 2 n Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes In- jektionsglas enthält 5 mg Wirkstoff.A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection glass contains 5 mg of active ingredient.
Beispiel B: SuppositorienExample B: Suppositories
Man schmilzt ein Gemisch von 20 g eines Wirkstoffes der Formel I mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
Beispiel C: LösungExample C: solution
Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I, 9,38 g NaH2PO4 • 2 H2O, 28,48 g Na2HPO4 • 12 H2O und 0,1 g Benzalkonium- chlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
Beispiel D: SalbeExample D: ointment
Man mischt 500 mg eines Wirkstoffes der Formel I mit 99,5 g Vaseline unter aseptischen Bedingungen.500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
Beispiel E: Tabletten Ein Gemisch von 1 kg Wirkstoff der Formel I, 4 kg Lactose, 1 ,2 kg Kartoffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält.Example E: tablets A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
Beispiel F: DrageesExample F: coated tablets
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
Beispiel G: KapselnExample G: capsules
2 kg Wirkstoff der Formel I werden in üblicher Weise in Hartgelatinekapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.
Beispiel H: AmpullenExample H: ampoules
Eine Lösung von 1 kg Wirkstoff der Formel I in 60 I zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff.A solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.
Beispiel I: Inhalations-SprayExample I: Inhalation spray
Man löst 14 g Wirkstoff der Formel I in 10 I isotonischer NaCI-Lösung und füllt die Lösung in handelsübliche Sprühgefäße mit Pump-Mechanismus. Die Lösung kann in Mund oder Nase gesprüht werden. Ein Sprühstoß (etwa 0,1 ml) entspricht einer Dosis von etwa 0,14 mg. 14 g of active ingredient of the formula I are dissolved in 10 I of isotonic NaCI solution and the solution is filled into commercially available spray vessels with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Claims

Patentansprüche claims
1. Verwendung von Verbindungen der Formel I1. Use of compounds of formula I.
Figure imgf000019_0001
worin
Figure imgf000019_0001
wherein
R1 unsubstituiertes oder einfach durch Alkoxy substituiertes Benzyl, unsubstituiertes oder ein-, zwei- oder dreifach durch Hai, NO2, CN, COOH, CONH2, CONHA, CONAA', NH2, NH-CO-A, NH-SO2A, SO2NH-CO-A, NA-SO2A', NH-CO-OA, SO3H, SO2NR4R5, CO- NHSO3H,R 1 unsubstituted or monosubstituted by alkoxy, unsubstituted or mono-, di- or triple by shark, NO 2 , CN, COOH, CONH 2 , CONHA, CONAA ', NH 2 , NH-CO-A, NH-SO 2 A, SO 2 NH-CO-A, NA-SO 2 A ', NH-CO-OA, SO 3 H, SO 2 NR 4 R 5 , CO-NHSO 3 H,
CO-NHSO2A, Tetrazolyl oder PO3H substituiertesCO-NHSO 2 A, tetrazolyl or PO 3 H substituted
Phenyl oderPhenyl or
Pyridyl,Pyridyl,
5 R2 A, Alkoxy-CO-alkylen, HO-CO-alkylen oder HO-alkylen,5 R 2 A, alkoxy-CO-alkylene, HO-CO-alkylene or HO-alkylene,
R3 H, A, Alkoxy, NH2, NHA, NAA',R 3 H, A, alkoxy, NH 2 , NHA, NAA ',
NH-CO-A oder SO2NR4R5,NH-CO-A or SO 2 NR 4 R 5 ,
Q R4, R5 jeweils unabhängig voneinander H oder A,QR 4 , R 5 each independently of one another H or A,
R4 und R5 zusammen auch eine gesättigte, ganz oder teilweise ungesättigte 4- bis 5-gliedrige Alkylenkette, bei der 1 bis 3 C-Atome durch N und/oder 1 bis 2 C-Atome durch 1 5 bis 2 O- und/oder 1 bis 2 S-Atome ersetzt sein können, A, A' jeweils unabhängig voneinander Alkyl mit 1 bis 6 C-R 4 and R 5 together also form a saturated, completely or partially unsaturated 4- to 5-membered alkylene chain, in which 1 to 3 C atoms are represented by N and / or 1 to 2 C atoms are represented by 1 5 to 2 O and / or 1 to 2 S atoms can be replaced, A, A 'each independently of one another alkyl with 1 to 6 C-
Atomen, wobei 1 bis 7 H-Atome durch F- und/oder Cl- Atome ersetzt sein können,Atoms, where 1 to 7 H atoms can be replaced by F and / or Cl atoms,
Hai F, Cl, Br oder IShark F, Cl, Br or I
bedeuten,mean,
und ihre physiologisch unbedenklichen Salze zur Behandlung und/oder Therapie von Potenzstörungen.and their physiologically acceptable salts for the treatment and / or therapy of erectile dysfunction.
2. Verwendung von Verbindungen der Formel I gemäß Anspruch 1 zur Herstellung eines Arzneimittels zur Behandlung und/oder Therapie von Potenzstörungen.2. Use of compounds of formula I according to claim 1 for the manufacture of a medicament for the treatment and / or therapy of erectile dysfunction.
3. Verwendung nach Anspruch 1 von Verbindungen der Formel I ausgewählt aus der Gruppe:3. Use according to claim 1 of compounds of the formula I selected from the group:
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-benzoesäure;4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) benzoic acid;
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-propyl-1 H- pyrazol-1 -yl)-benzoesäure;4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl) -benzoic acid;
4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1-yl)-benzamid;4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1H-pyrazol-1-yl) benzamide;
N-(4-(4-(2-Ethylanilino-methylen)-4,5-dihydro-5-oxo-3-methyl-1 H- pyrazol-1 -yl)-phenyl)-acetamid;N- (4- (4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-3-methyl-1 H -pyrazol-1-yl) phenyl) acetamide;
2-(1-(4-Methoxycarbonylaminophenyl)-4-(2-ethylanilino- methylen)-4,5-dihydro-5-oxo-1 H-pyrazol-3-yl)-essigsäureethylester;Ethyl 2- (1- (4-methoxycarbonylaminophenyl) -4- (2-ethylanilino-methylene) -4,5-dihydro-5-oxo-1H-pyrazol-3-yl);
2-(4-(2-Ethylanilino-methylen)-4,5-dihydro-1-(4-methansulfon- amidophenyl)-5-oxo-1 H-pyrazol-3-yl)-essigsäureethylester; 2-(4-(2-Ethylanilino-methylen)-4,5-dihydro-1-(4-(N,N- diethylsulfonamido)-phenyl)-5-oxo-1H-pyrazol-3-yl)-essig- säureethylester;Ethyl 2- (4- (2-ethylanilino-methylene) -4,5-dihydro-1- (4-methanesulfonamidophenyl) -5-oxo-1H-pyrazol-3-yl); 2- (4- (2-ethylanilino-methylene) -4,5-dihydro-1- (4- (N, N-diethylsulfonamido) phenyl) -5-oxo-1H-pyrazol-3-yl) -acetic acid- acid ethyl ester;
zur Behandlung und/oder Therapie von Potenzstörungen.for the treatment and / or therapy of erectile dysfunction.
4. Verfahren zur Herstellung pharmazeutischer Zubereitungen zur Behandlung und/oder Therapie von Potenzstörungen, dadurch gekennzeichnet, daß man eine Verbindung der Formel I nach Anspruch 1 und/oder eines ihrer physiologischen unbedenklichen Salze zusammen mit mindestens einem festen, flüssigen oder halbflüssigen Träger- oder Hilfsstoff in eine geeignete Dosierungsform bringt.4. A process for the preparation of pharmaceutical preparations for the treatment and / or therapy of erectile dysfunction, characterized in that a compound of formula I according to claim 1 and / or one of its physiologically acceptable salts together with at least one solid, liquid or semi-liquid carrier or auxiliary into a suitable dosage form.
5. Pharmazeutische Zubereitung zur Behandlung und/oder Therapie von Potenzstörungen, gekennzeichnet durch einen Gehalt an mindestens einer Verbindung der Formel I nach Anspruch 1 und/oder einem ihrer physiologisch unbedenklichen Salze.5. Pharmaceutical preparation for the treatment and / or therapy of erectile dysfunction, characterized by a content of at least one compound of the formula I according to claim 1 and / or one of its physiologically acceptable salts.
6. Verwendung einer pharmazeutischen Zubereitung enthaltend min- destens eine Verbindung der Formel I und/oder mindestens eines ihrer physiologisch unbedenklichen Salze gemäß Anspruch 1 zur Behandlung und/oder Therapie von Potenzstörungen. 6. Use of a pharmaceutical preparation containing at least one compound of formula I and / or at least one of its physiologically acceptable salts according to claim 1 for the treatment and / or therapy of erectile dysfunction.
PCT/EP1997/005532 1996-10-14 1997-10-08 Pyrazolinones to treat disturbances of potency WO1998016224A1 (en)

Priority Applications (8)

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BR9712307-2A BR9712307A (en) 1996-10-14 1997-10-08 Pyrazolinones for the treatment of weakened potency
JP10517987A JP2001501958A (en) 1996-10-14 1997-10-08 Pyrazolinone compounds for the treatment of sexual dysfunction
AU49452/97A AU4945297A (en) 1996-10-14 1997-10-08 Pyrazolinones to treat disturbances of potency
CA002268823A CA2268823A1 (en) 1996-10-14 1997-10-08 Pyrazolinones to treat disturbances of potency
EP97912141A EP0930881A1 (en) 1996-10-14 1997-10-08 Pyrazolinones to treat disturbances of potency
PL97332821A PL332821A1 (en) 1996-10-14 1997-10-08 Pyrazolydinones for treating potency disorders
HU0000233A HUP0000233A3 (en) 1996-10-14 1997-10-08 Use of pyrazolinone derivatives for producing pharmaceutical compositions useful for treating disturbances of potency
NO991734A NO991734L (en) 1996-10-14 1999-04-13 Pyrazolinones for the treatment of potency disorders

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DE19642284A DE19642284A1 (en) 1996-10-14 1996-10-14 Pyrazolinones for the treatment of erectile dysfunction
DE19642284.1 1996-10-14

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US6020379A (en) * 1999-02-19 2000-02-01 Cell Pathways, Inc. Position 7 substituted indenyl-3-acetic acid derivatives and amides thereof for the treatment of neoplasia
US6034099A (en) * 1998-11-24 2000-03-07 Cell Pathways, Inc. Method for inhibiting neoplastic lesions by administering 4-(arylmethylene)- 2, 3- dihydro-pyrazol-3-ones
US6077842A (en) * 1998-11-24 2000-06-20 Cell Pathways, Inc. Method of inhibiting neoplastic cells with pyrazolopyridylpyridazinone derivatives
US6133271A (en) * 1998-11-19 2000-10-17 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure thienopyrimidine derivatives
US6187779B1 (en) 1998-11-20 2001-02-13 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to 2,8-disubstituted quinazoline derivatives
US6200771B1 (en) 1998-10-15 2001-03-13 Cell Pathways, Inc. Method of using a novel phosphodiesterase in pharmaceutical screeing to identify compounds for treatment of neoplasia
US6369092B1 (en) 1998-11-23 2002-04-09 Cell Pathways, Inc. Method for treating neoplasia by exposure to substituted benzimidazole derivatives
US6486155B1 (en) 1998-11-24 2002-11-26 Cell Pathways Inc Method of inhibiting neoplastic cells with isoquinoline derivatives
US6875575B1 (en) 1998-11-25 2005-04-05 Osi Pharmaceuticals, Inc. Diagnostic methods for neoplasia
US7115647B2 (en) 1998-01-14 2006-10-03 Osi Pharmaceuticals, Inc. Method of inhibiting neoplastic cells with indole derivatives

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7115647B2 (en) 1998-01-14 2006-10-03 Osi Pharmaceuticals, Inc. Method of inhibiting neoplastic cells with indole derivatives
US6200771B1 (en) 1998-10-15 2001-03-13 Cell Pathways, Inc. Method of using a novel phosphodiesterase in pharmaceutical screeing to identify compounds for treatment of neoplasia
US6133271A (en) * 1998-11-19 2000-10-17 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure thienopyrimidine derivatives
US6187779B1 (en) 1998-11-20 2001-02-13 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to 2,8-disubstituted quinazoline derivatives
US6369092B1 (en) 1998-11-23 2002-04-09 Cell Pathways, Inc. Method for treating neoplasia by exposure to substituted benzimidazole derivatives
US6034099A (en) * 1998-11-24 2000-03-07 Cell Pathways, Inc. Method for inhibiting neoplastic lesions by administering 4-(arylmethylene)- 2, 3- dihydro-pyrazol-3-ones
US6077842A (en) * 1998-11-24 2000-06-20 Cell Pathways, Inc. Method of inhibiting neoplastic cells with pyrazolopyridylpyridazinone derivatives
US6486155B1 (en) 1998-11-24 2002-11-26 Cell Pathways Inc Method of inhibiting neoplastic cells with isoquinoline derivatives
US6875575B1 (en) 1998-11-25 2005-04-05 Osi Pharmaceuticals, Inc. Diagnostic methods for neoplasia
US6020379A (en) * 1999-02-19 2000-02-01 Cell Pathways, Inc. Position 7 substituted indenyl-3-acetic acid derivatives and amides thereof for the treatment of neoplasia

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CN1233178A (en) 1999-10-27
HUP0000233A3 (en) 2001-06-28
KR20000049086A (en) 2000-07-25
CA2268823A1 (en) 1998-04-23
HUP0000233A2 (en) 2001-04-28
DE19642284A1 (en) 1998-04-16
AR008494A1 (en) 2000-01-19
PL332821A1 (en) 1999-10-11
BR9712307A (en) 1999-08-31
EP0930881A1 (en) 1999-07-28
AU4945297A (en) 1998-05-11

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