WO1992004045A1 - Nouveaux antagonistes de cholecystokinine, preparation et utilisation therapeutique de ces composes - Google Patents

Nouveaux antagonistes de cholecystokinine, preparation et utilisation therapeutique de ces composes Download PDF

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Publication number
WO1992004045A1
WO1992004045A1 PCT/US1991/006180 US9106180W WO9204045A1 WO 1992004045 A1 WO1992004045 A1 WO 1992004045A1 US 9106180 W US9106180 W US 9106180W WO 9204045 A1 WO9204045 A1 WO 9204045A1
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dec
tricyclo
methyl
amino
indol
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PCT/US1991/006180
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English (en)
Inventor
David Christopher Horwell
Jürgen KLEINSCHROTH
David Charles Rees
Reginald Stewart Richardson
William Howard Roark
Edward Roberts
Bruce David Roth
Bharat Kalidas Trivedi
Ann Holmes
Janak Khimchand Padia
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Warner-Lambert Company
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Priority to KR1019930700601A priority Critical patent/KR100222634B1/ko
Priority to AU87492/91A priority patent/AU651390C/en
Priority to JP3517185A priority patent/JPH06502627A/ja
Publication of WO1992004045A1 publication Critical patent/WO1992004045A1/fr
Priority to NO19930709A priority patent/NO312298B1/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/595—Gastrins; Cholecystokinins [CCK]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06156—Dipeptides with the first amino acid being heterocyclic and Trp-amino acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • CCK central cholecystokinin
  • CCK-peptides have been found in the brains of schizophrenic patients compared with controls (Roberts, Ferrier, Lee, Crow, Johnstone, Owens, Bacarese-Hamilton, McGregor, O'Shaughnessey, Polak, and Bloom, Brain Research 288:199-211, 1983). It has been proposed that changes in the activity of CCK neurones projecting to the nucleus accumbens may play a role in schizophrenic processes by influencing dopaminergic function (Totterdell and Smith,
  • agents modifying CCK receptor activity may have therapeutic value in conditions associated with disturbed function of central dopaminergic function such as schizophrenia and Parkinson's
  • CCK and gastrin peptides share a common carboxy terminal pentapeptide sequence and CCK peptides can bind to the gastrin receptor of the stomach mucosa and elicit acid secretion in many species including human (Konturek, Gastrointestinal Hormones, Ch. 23, pp 529- 564, 1980, ed. G. B. J. Glass, Raven Press, NY).
  • Antagonists of the CCK-B receptor would also be expected to be antagonists at the stomach gastrin receptor and this would also be of value for
  • CCK and gastrin peptides have trophic effects on the pancreas and various tissues of the gastrointestinal tract (Johnson, ibid., pp 507-527), actions which are associated with increased DNA and RNA synthesis.
  • gastrin secreting cells are associated with certain gastrointestinal tumors as in the Zollinger-Ellison syndrome (Stadil, ibid., pp 729- 739), and some colorectal tumors may also be
  • CCK/gastrin receptors could therefore be of
  • the CCK peptides are widely distributed in various organs of the body including the
  • CCK peptides The high concentrations of CCK peptides in many brain areas also indicate major brain functions for these peptides (G. J. Dockray, Br. Med. Bull.
  • appetite suppressant drugs either act peripherally, by increasing energy
  • Centrally acting appetite suppressants either potentiate central catecholamine pathways and tend to be stimulants (for example, amphetamine), or influence serotonergic pathways (for example, fenfluramine).
  • Other forms of drug therapy include bulking agents which act by filling the stomach, thereby inducing a "feeling" of satiety.
  • CCK is known to be present in some cortical interneurones which also contain gamma-aminobutyric acid (GABA) (H. Demeulemeester et al, J. Neuroscience 8:988-1000, 1988).
  • GABA gamma-aminobutyric acid
  • Agents that modify GABA action may have utility as anxiolytic or hypnotic agents
  • agents which modify CCK action may have parallel anxiolytic or hypnotic activities.
  • the role of CCK in anxiety is disclosed in TIPS 11:271-273, 1990.
  • the invention relates to novel compounds of the formula
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 12 , R 13 , R 20 , A, X, Y, E, Ar 1 , Ar 2 , n, m, p, q, r, s, t, u, and v are as defined hereinbelow.
  • the compounds are also useful as anxiolytics, antipsychotics, especially for treating schizophrenic behavior, as agents in treating disorders of the extrapyramidal motor system, as agents for blocking the trophic and growth stimulating actions of CCK and gastrin, and as agents for treating gastrointestinal motility.
  • Compounds of the invention are also useful as analgesics, and they potentiate the effect of
  • morphine can be used as an adjunct to morphine and other opioids in the treatment of severe pain such as cancer pain, and reduce the dosage of morphine required in the treatment of pain where morphine is contraindicated.
  • a suitable radiolabeled isotope gives an agent suitable for treatment of gastrin dependent tumors such as those found in colonic cancers.
  • radiolabeled compounds of the invention can also be used as diagnostic agents by localization of gastrin and CCK-B receptors in both peripheral and central tissue.
  • the invention further relates to a method of appetite suppression in mammals which comprises administering an amount effective to suppress appetite of the composition described above to a mammal in need of such treatment.
  • the invention also relates to a pharmaceutical composition for reducing gastric acid secretion containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for reducing gastric acid secretion.
  • the invention also relates to a method for reducing gastric acid secretion in mammals which comprises administering an amount effective for gastric acid secretion reduction of the composition described above to a mammal in need of such treatment.
  • the invention also relates to a method for reducing anxiety in mammals which comprises
  • the invention further relates to a method for treating gastrointestinal ulcers in mammals which comprises administering an amount effective for gastrointestinal ulcer treatment of the composition as described above to a mammal in need of such treatment.
  • the invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for treating psychosis, i.e., schizophrenia.
  • the invention further relates to a method for treating psychosis in mammals which comprises
  • the invention also relates to pharmaceutical compositions effective for stimulating or blocking CCK or gastrin receptors, for altering the activity of brain neurons, for schizophrenia, for treating
  • disorders of the extrapyramidal motor system for blocking the trophic and growth stimulating actions of CCK and gastrin, and for treating gastrointestinal motility.
  • the invention also relates to a pharmaceutical composition for preventing the withdrawal response produced by chronic treatment for abuse of drugs or alcohol.
  • the invention further relates to a method for treating the withdrawal response produced by
  • Such drugs include
  • benzodiazepines especially diazepam, cocaine, alcohol, and nicotine. Withdrawal symptoms are treated by administration of an effective withdrawal treating amount of a compound of the invention.
  • the invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a
  • the invention also relates to a method for treating and/or preventing panic in mammals which comprises administering an amount effective for panic treatment and/or prevention of the composition
  • the invention further relates to the use of the compounds of formula I to prepare pharmaceutical and diagnostic compositions for the treatment and
  • the invention further provides processes for the preparation of compounds of formula I.
  • the invention further provides novel
  • R 1 is a cyclo or polycycloalkyl hydrocarbon or mono- or polyheterocycle moiety (wherein the hetero atom(s) can be N, O, and/or S of from 3 to 12 carbon atoms with from 0 to 4 substituents each independently selected from a straight or branched alkyl of from 1 to 6 carbon atoms, halogen, CN, OR*, SR*, CO 2 R*, CF 3 , NR 5 R 6 , or (CH 2 ) n OR 5 wherein R*, R 5 , and R 6 are each independently hydrogen or a straight or branched alkyl of from 1 to about 6 carbon atoms;
  • n is as above,
  • A is a bond
  • Z is a bond, oxygen, sulphur, or -NR*- wherein R* is as defined above;
  • R 6 are as defined above, and Ar 1 and Ar 2 are as defined below;
  • X and Y are each independently:
  • R 3 and R 4 are each independently the same as R 2 or
  • n r is an integer of from 0 to 3;
  • R 7 and R 8 are each independently selected from hydrogen and R 2 or together form a ring (CH 2 ) m wherein m is an integer of from 1 to 5,
  • b is an integer of from 0 to 2
  • R*, R 2 , R 5 , and R 6 are as defined above;
  • R 9 is H, or a straight or branched alkyl of from one to six carbon atoms, - (CH 2 ) n CO 2 R*, (CH 2 ) n OAr',
  • Ar 1 and Ar 2 are each independently a mono- or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or carbo- or heteroaromatic moiety;
  • Preferred Ar 1 is substituted phenyl, fused aryl, heterocycle, fused heterocycle, or perhydroaryl.
  • Preferred Ar 1 is 2 or 3-thienyl, 2 or 3-furanyl,
  • E 1 and F are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, methoxy, trifluoromethyl, nitro, hydroxy, NH 2 , OCF 3 ,
  • substituents have from six to ten carbon atoms .
  • Preferred compounds of the instant invention are those wherein cycloalkyl is a substituted or
  • polycycloalkyl is selected from
  • W, X, Y, and Z are each independently
  • R is hydrogen or a straight or branched alkyl of from one to six carbon atoms and CF 3 , NR 5 R 6 , - (CH 2 ) n CO 2 R*, or CN, F, Cl, Br, OR*, SR*, wherein R is hydrogen or a straight or branched alkyl of from one to six carbon atoms and R 5 and R 6 are as defined above and n is an integer of from 1 to 3.
  • Preferred mono- or polyheterocyclic moieties wherein the heteroatom can be W, O, and/or mono- and polycyclic hydrocarbons include compounds wherein
  • R 1 is 2-adamantyl or 1-(S)-2-endobornyl
  • R 2 is -CH 3 , -CH 2 CO 2 CH 3 or -CH 2 C ⁇ CH;
  • R 3 is -(CH 2 ) n -B-D or H
  • R 4 is -(CH 2 ) n ,-B-D or H.
  • R 1 is 2-adamantyl or 1-(S)-2-endobornyl
  • A is -O-C-
  • R 2 is -CH 3 '
  • R 3 is H, -CH 2 OH, -CH 2 OCOCH 2 CH 2 CO 2 H,
  • R 2 is -CH 3 [D] configuration; 2.
  • R 3 is -CH 2 OCOCH 2 CH 2 CO 2 H or
  • L-Phenylalaninamide N-[[(1,1-dimet1ylethoxy)- carbonyl]- ⁇ -methyl]-L-tryptophyl]-L-methionyl-L- ⁇ - aspartyl-, Glycine, N-[2-methyl-N-[(tricyclo[3.3.1.I 3 ' 7 ]dec- 2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanyl-,
  • 2,4-Heptadienoic acid 6-[[3-(1H-indol-3-yl)-2- methyl-1-oxo-2- [[(tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy)- carbonyl]amino]propyl]amino]-7-phenyl-,
  • Table I illustrates representative compounds of the invention.
  • the numbers on the left-hand coluinn in Table I correspond to the compound numbers given above. All of the compounds shown in Table I have their stereochemical configurations shown.
  • the compounds of the present invention include compounds of formula I wherein the indole moiety is a 2-indolyl.
  • the compounds of the invention include solvates and hydrates and pharmaceutically acceptable salts of the compounds of formula I.
  • Phosphoric acid 2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)- 1-methyl-2-oxoethyl phenyl tricyclo[3.3.1.1 3 ' 7 ]dec-2-yl ester.
  • the compounds of the present invention can have multiple chiral centers including those designated in the above formula I by the symbol t, depending on their structures. For example, when R 3 taken with R 4 and R 12 taken with R 13 form double bonds to their carbon atoms, they are no longer chiral. In addition, centers of asymmetry may exist on the other
  • the compounds of the present invention may exist as diastereomers, mixtures of diastereomers, or as the mixed or the individual optical enantiomers.
  • the present invention
  • the compounds of the present invention can be formed by coupling individual substituted ⁇ -amino acids by methods well known in the art. (See, for example, standard synthetic methods discussed in the multi-volume treatise "The Peptides, Analysis,
  • R is selected from R 1 , 9-fluorenylmethyl, Bz and other suitable N-blocking groups. These are useful as intermediates in the preparation of
  • Example 2 (compound 5) was prepared in an exactly analogous manner.
  • the intermediate mixed anhydride described above was treated with Me 3 SiN 3 to make the acid azide which then reacted with jo-nitrobenzyl alcohol in the presence of DABCO to give the bis urethane 6 .
  • Example 4 saponification of the ester with LiOH in aqueous THF.
  • Example 4 compound 10 was prepared in three steps from 1 . Here the mixed anhydride of 1 was treated with diazomethane to give the diazoketone 8 . Reaction with HCl to the chloro ketone followed by reaction with sodium diethylbenzyl malonate gave a diester which, upon saponification, decarboxylated to the acid 10, Example 4.
  • DABCO 2,4-diazabicyclo[2.2.2]octane
  • Example 5 compound 12 was prepared by reduction of the amide in 11 using LiBH 4 and Me 3 SiCl.
  • Example 6 compound 14 was prepared from 13. 1 4 was treated with acetylchloride to give
  • Example 7 in the presence of base.
  • the major product was compound 15a, which was hydrolyzed to Example 8, compound 16, on treatment with lithium hydroxide.
  • Example 14 Compound 2 9 was modified further to 30, Example 16 by hydrolysis of the ester and subsequent condensation with aniline. Treatment of aldehyde 26 with the Grignard reagent 3-phenylpropyl magnesium bromide afforded the secondary alcohol 28 (Example 15).
  • the amide of 23b, 35 was prepared by bubbling ammonia gas through a solution of the
  • KEY Reagents i) isobutylchloroformate, NMM, THF; ii) CH 2 N 2 , EtOAc; iii) Ag + - OCOPh, Et 3 N, PhCH 2 OH; iv) H 2 /Pd/C; v) PFP, DCC, H 2 NCH (CH 2 OH) CH 2 Ph, EtOAc; vi) PFP, DCC, EtOAc; vii) NH 3 (g), THF;
  • 2-adamantyl oxycarbonyl ⁇ -methyltryptophan 23b (R isomer) or 38 (S isomer) is condensed with ⁇ -alanine ester in the usual manner.
  • This ester can then be hydrolyzed using standard methods (e.g., aqueous LiOH, etc) to afford the carboxylic acid 41 or 42.
  • Either of these two isomers may be condensed with an
  • Examples 23 and 24 using S-phenyl alaninol
  • Examples 25-28 inclusive using R and S. phenyl alaninamide
  • Examples 29-31 inclusive using phenylalanine ester.
  • Examples 29-31 and compound 52 may then be hydrolyzed using known methods to afford the products Examples 32-35 inclusive.
  • KEY Reagents i) PFP, DCC, ⁇ -Alanine Me ester, EtOAc;
  • KEY Reagents i) PFP, DCC, glycine benzyl ester hydrochloride, Et 3 N, EtOAc; ii) H 2 Pd/C, EtOH; iii) PFP , DCC, s-phenylalaninol, EtOAc.
  • Scheme 8 describes synthetic steps towards derivatives of ⁇ -methyltryptophyl- ⁇ -aminobutyric acids.
  • the carboxylic acid 23b may be condensed with ⁇ -aminobutyric acid methyl ester to give 60, hydrolysis of this with LiOH affords acid 61.
  • the product 62, Example 39 is produced when 61 is condensed with phenylalaninol via an active
  • KEY Reagents i) PFP, DCC, gamma-aminobutyric acid methylester hydrochloride, Et 3 N, EtOAc; ii) LiOH, aq 1,4-dioxan;
  • isonitrile 63 (prepared by the method described in Synthesis 465, 1990) in ethanol at -5°C was treated with ethanolic HCl to give the amine 64.
  • the product was formed by treatment of 67 with LiOH which abstracts the amide NH proton and cyclizes onto the ester group, liberating methoxide.
  • KEY Reagents i) EtOH-HCl, 67%; ii) 2-adamantyl-OCOCl, Et 3 N, EtOAc, 58%; iii) Pd/H 2 , EtOH, 88%; iv) H 2 NCH 2 CH 2 Ph, PFP, DCC, DMAP, EtOAc, 73%; v) LiOH(0.01M), 0°C, THF/H 2 O, 79%.
  • Scheme 10 outlines the synthetic steps towards ß-substituted tryptophan derivatives. Isopropylamine, when added to acetaldehyde and treated with KOH, gives 69 which reacts with indole in glacial acetic acid over 5 days to produce 70 .
  • ethylidene 70 then reacts with 71 in the presence of NaOMe in hot toluene, yielding 72 . Saponification and decarboxylation affords 7 4 as a mixture of separable diastereoisomers.
  • the amide 74 is dissolved in 4N sulphuric acid at reflux, then cooled to ambient temperature, and treated with 0.4N barium hydroxide until a pH of 8 is obtained, yielding the free amine 75 which reacts with 2-adamantyl chloroformate 76, yielding the urethane 77. This is then condensed with phenyl alaninol in the normal manner to give the product 78, Example 89.
  • Cyano acetic esters or substituted derivatives 1 are alkylated with gramine and a base, e.g., NaOH in toluene, to compounds 2 in analogy to known methods.
  • Compounds 2 are hydrogenated catalytically with Raney nickel alloy to the amino esters 3, which are reacted with chloro- or fluoroformates to the carbamic acid esters 4.
  • the esters 4 are hydrolyzed to the acids 5, which are converted to activated esters, e.g., with pentafluorophenol and dicyclohexylcarbodiimide to the pentafluorophenyl esters.
  • the activated esters are reacted with an appropriate amine to an amide of formula 6. Further conversions at the amide part of the molecules are done in analogy to known methods.
  • R 3 H, -CH 2 OH, -CH 2 O-CO-(CH 2 ) 2 CO 2 H
  • R 4 H, -NH-CO 2 -t-Bu
  • Cyano acetamides 8 are alkylated with gramine and a base, e.g., NaOH in toluene, to compounds 12 and 13, which are hydrogenated catalytically with Raney nickel alloy to the mono- or bis-(3-indolylmethyl)
  • Aminoesters 3 are reacted with carboxylic acid
  • the ester groups of compounds 18 are hydrolyzed with lithium hydroxide to the carboxylic acids 19, which are converted to activated esters, e.g., with pentafluorophenol and dicyclohexylcarbodiimide to the pentafluorophenyl esters.
  • the activated esters are reacted with an appropriate amine to an amide of formula 20. Further conversions at R 3 and R 4 are done in analogy to known methods.
  • 1-(3'-indolyl)-butan-3-one is converted with potassium cyanide and ammonium carbonate in a Bucherer synthesis to the hydantoin 21, which is hydrolyzed with aqueous sodium hydroxide to the amino acid 22 , which is consequently esterified with methanol and hydrogen chloride to 2 3.
  • Compound 23 is reacted with chloro- or fluoroformates to the carbamic acid esters 24.
  • the ester groups of compounds 24 are hydrolyzed with lithium hydroxide to the carboxylic acids 25.
  • Acids 25 are converted to activated esters, e.g., with pentafluorophenol and dicyclohexylcarbodiimide to the pentafluoro phenyl esters.
  • the activated esters are reacted with an appropriate amine to an amide of formula 26. Further conversions at R 3 or R 4 are done in analogy to known methods.
  • Diethyl methylmalonate 27 is alkylated with gramme and a base, e.g., NaOH in toluene, to compound 28 by known methods.
  • the diester 28 is hydrolyzed with potassium hydroxide to the mono acid 29 .
  • the ester group of 29 is selectively reduced with borane methyl sulfide complex to compound 30, which is esterified with methanol and sulfuric acid to the methyl
  • ester 31 The hydroxy compound 31 is reacted with p-toluene-sulfonyl chloride and pyridine to the tosylate 32 . Nucleophilic substitution with potassium cyanide gives the cyanoester 33, which is hydrogenated catalytically with Raney nickel alloy to the amino ester 34. The amino ester 34 is reacted with chloro- or fluoroformates to the carbamic acid esters 35. The ester groups of compounds 35 are hydrolyzed with lithium hydroxide to the carboxylic acids 36, which are converted to activated esters, e.g., with
  • the cerebral cortices taken from male CFLP mice weighing between 30-40 g were dissected on ice, weighed, and homogenized in 10 volumes of 50 mM Tris-HCl buffer (pH 7.4 at 0-4°C). The resulting suspension was centrifuged, the
  • the final pellet was resuspended in 20 volumes of 10 nM Hepes buffer (pH 7.2 at 23°C) containing 130 mM NaCl, 4.7 nM KCl, 5 nM MgCl 2 , 1 nM EDTA, 5 mg/mL bovine albumin, and bacitracin
  • membranes were incubated at 23°C for 120 minutes in a final volume of 500 ⁇ L of Hepes incubation buffer (pH 7.2) together with 0.2-20 nM tritiatedpentagastrin (Amersham International, England).
  • membranes were incubated with a single concentration (2 nM) of ligand, together with increasing concentrations (10 -11 to 10 -14 M) of competitive test compound.
  • the nonspecific binding was defined as that persisting in the presence of the unlabeled octapeptide CCK 26-33 (10 -6 M).
  • the specific binding to CCK receptor sites was defined as the total bound tritiated-pentagastrin minus the amount of tritiated-pentagastrin bound in the presence of 10 -6 octapeptide, CCK 26-33 .
  • K i The inhibition constant (K i ) of the test compound was then calculated according to the Cheng-Prusoff equation: where [L] is the concentration of radiolabel and K a is the equilibrium dissociation constant.
  • [L] is the concentration of radiolabel
  • K a is the equilibrium dissociation constant.
  • the compounds of the instant invention are administered to the patient at dosage levels of from about 200 to about 2800 mg per day.
  • Table III shows the binding data for Male Hooded Lister rats (175-250 g) are housed individually and are caused to fast overnight (free access to water). They are anesthetized with urethane (1.5 g/kg IP) and the trachea cannulated to aid spontaneous respiration. The stomach is perfused continuously using a modification of the original method of Ghosh & Schild in "Continuous recording of acid secretion in the rat", Brit. J. Pharmac. 13:54- 61, 1956 as described by Parsons in "Quantitative studies of drug-induced gastric acid secretion".
  • the perfusion fluid is collected by the fundic collecting funnel and passed to a pH electrode connected to a Jenway pH meter (PHM6). An output is taken from the pH meter to a Rikadenki chart recorder for the on-line recording of the pH of the gastric perfusate.
  • Pentagastrin is stored as a frozen aliquot and diluted to the required concentrations with sterile 0.9% w/v NaCl. Novel compounds are dissolved in sterile 0.9% w/v NaCl on the day of the experiment. Drugs are administered IV through a cannulated jugular vein as a bolus in a dose volume of 1 mL/kg washed in with 0.15 mL 0.9% w/v NaCl. Basal pH is allowed to stabilize before administration of compounds is begun. Typically 30 minutes elapses between surgery and the first compound administration.
  • the compounds of the instant invention are also useful as antiulcer agents as discussed hereinbelow. Aspirin-induced gastric damage is assessed in groups of 10 rats each.
  • CMC carboxymethylcellulose
  • the animals are sacrificed 5 hours after aspirin administration and the stomachs removed and opened for examination.
  • the compounds of the instant invention are also useful as anxiolytic agents as described and discussed below. Anxiolytic activity is assessed in the
  • the apparatus used is an open-topped box, 45 cm long, 27 cm wide, and 27 cm high, divided into a small (2/5) area and a large (3/5) area by a partition that extended 20 cm above the walls. There is a
  • the small compartment is painted black and the large compartment white.
  • the floor of each compartment is marked into 9 cm squares.
  • the white compartment is illuminated by a 100-watt tungsten bulb 17 cm above the box and the black compartment by a similarly placed 60-watt red bulb.
  • the laboratory is
  • the compounds of the instant invention are useful as antipsychotic agents and can be tested for their ability to reduce the effects of intra-accumbens amphetamine in the rat as described hereinafter.
  • Rats are fed CRM diet (Labsure) and allowed water ad libitum.
  • Rats are anesthetized with chloral hydrate
  • Rats are manually restrained and the stylets removed.
  • Intracerebral injection cannulae 0.3 mm diameter, are inserted and drugs delivered in a volume of 0.5 ⁇ L over 5 seconds (a further 55 seconds was allowed for deposition) from Hamilton syringes attached via polythene tubing to the injection units. Animals Are used on a single occasion only.
  • Rats are taken from the holding room and allowed 1 hour to adapt to the new environment.
  • Locomotor activity is assessed in individual screened Perspex cages (25 x 15 x 15 cm (high) (banked in groups of 30) each fitted with one photocell unit along the longer axis 3.5 cm from the side; this position has been found to minimize spurious activity counts due to, for example, preening and head movements when the animal is stationary.
  • the compounds of the instant invention prevent and treat the withdrawal response produced when chronic treatment by a drug is stopped or when alcohol abuse is stopped. These compounds are therefore useful as therapeutic agents in the treatment of chronic drug or alcohol abuse as discussed and described below.
  • compound (20) is given at 1.0 mg/kg i.p. b.d.
  • the increased time spent in the light area is a sensitive measure of the effect of compound (20) as an agent to treat withdrawal effects from nicotine.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material .
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding
  • a low- melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
  • the powders and tablets preferably contain 5% to about 70% of the active component.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • Preferred pharmaceutically acceptable salts are the N-methyl glucamine salt and sodium.
  • salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate,
  • estolate estolate
  • esylate fumarate
  • glucaptate gluconate
  • glutamate glycollylarsanilate
  • hydrochloride hydrochloride, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate mesylate, methylbromide,
  • ethylenediamine, meglumine, procaine aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
  • preparation is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.
  • Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral
  • Liquid form preparations include solutions, suspensions, and emulsions.
  • Sterile water or water- propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration.
  • Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is divided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • Lithium aluminum hydride (45 mg, 1.2 mmol) was added portionwise over a period of 30 minutes to a solution of the hydroxamate (2) (197 mg, 0.460 mmol) in THF (3 mL) at 0°C. The mixture was stirred for a further 30 minutes, then ether (30 mL) was added followed by an ice cold solution of 10% citric acid (40 mL). The mixture was stirred vigorously for
  • N-methylmorpholine (1.15 mL, 10.4 mmol) and n-isobutyl chloroformate (1.35 mL, 10.4 mmol). This mixture was stirred for 20 minutes at -10°C then filtered.
  • Trimethylsilyl azide [Aldrich] (1.89 mL, 14.2 mmol) was added to the filtrate and the resulting solution stirred at -10°C for 1 hour. The solvent was then removed in vacuo at 25°C and the residue partitioned between ethyl acetate (100 mL) and saturated sodium hydrogen carbonate (100 mL). The layers were
  • the urethane (6) (190 mg, 0.357 mmol) in ethyl acetate (36 mL) was hydrogenated over palladium hydroxide on carbon (Pearlman's catalyst) at 45 psi and 30°C for 1 hour.
  • the mixture was filtered through celite to remove the catalyst into a flask containing the HOBT ester of 2-(acetoxymethyl)-3-phenylpropionic acid [the latter was generated via the reaction of 2-(acetoxymethyl)-3-phenylpropionic acid (81 mg,
  • DIAZOMETHANE IS HIGHLY TOXIC AND EXPLOSIVE (NO GROUND GLASS JOINTS). HANDLE WITH CARE IN A FUME HOOD.
  • n-METHYLNITROSUREA IS HIGHLY TOXIC AND CARCINOGENIC. HANDLE IN A FUME HOOD USING A FULL FACE MASK AND GLOVES.
  • N-methylnitrosurea 1.5 g, 15 mmol
  • ether 25 mL
  • ethereal solution of diazomethane was dried over solid potassium hydroxide. This drying process was repeated twice more and the diazomethane used immediately.
  • diethylbenzylmalonate (950 ⁇ L, 4.0 mmol) at room temperature] was added. The resulting solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo, the residue taken up in
  • ketoacid 10 (83 mg, 78%) as a yellow foam, m.p. 66-80°C.
  • 1 H NMR 300 m Hz: ⁇ 1.38-2.22 (m, 16H, adamantyl + H 2 O), 2.55-3.25 (vbr m, 12H, CH 2 ind, CH 2 Ph CO, CH 2 CH +
  • the residue was purified by flash chromatography on normal phase silica gel using hexane/ethyl acetate eluant (a gradient elution technique was employed, ranging from 80% hexane: 20% ethyl acetate to 100% ethyl acetate).
  • a mono-4-toluenesulphonate salt was prepared by dissolving (14) (0.2 g, 0.4 mmol) and
  • a mono-4-toluenesulphonate salt was prepared by dissolving (15) (0.02 g, 0.04 mmol) and
  • N,N'-dicyclohexylcarbodiimide 80 mg, 0.39 mmol
  • EtOAc 5 mL
  • S-phenyl alaninol 121 mg, 0.8 mmol
  • Trimethylsilylchloride (4.34 g, 40 mmol) was added dropwise to a solution of LiBH 4 (11 mL of a 2M
  • Example 26 The acid from Example 30, Step 2 (117 mg, 0.25 mmol) and pentafluorophenol (46 mg, 0.25 mmol) as a solution in EtOAc (10 mL) was treated with
  • Step 1 Glycine, N-[3-(1H-indol-3-yl)-2-methyl-1-oxo- 2-[[(tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy)carbonyl]amino]- propyl-, (R) - AdOC- ( ⁇ -Me) DTrp-Gly
  • Butanoic acid 4-[[3-(1H-indol-3-yl)-2- methyl-1-oxo-2-[[(tricyclo[3.3.1.1 3 ' 7 ]dec-2-yloxy) carbonyl]amino]propyl]amino]-, (R)-
  • Triethylamine (55 ⁇ L, 0.40 mmol) was injected.
  • the solution was cooled to 0°C in an ice- alt bath and 2-adamantyl chloride (77 mg, 0.36 mmol) dissolved in THF (5 mL) was injected.
  • the solution was stirred for 12 hours at room temperature before triethylamine hydrochloride was filtered off.
  • Dichloromethane (50 mL) was added and the solution was washed with water (2 x 25 mL). The organic payer was dried
  • phenylethylamine 60 mg, 0.50 mmol was injected to the solution. The mixture was left stirring
  • a suspension of powdered sodium hydroxide (2 g, 50 mmol) and ethyl 2-cyanopropionate (20 g, 157 mmol) in 150 mL toluene was heated under nitrogen atmosphere to 100°C and gramine (30.1 g, 172 mmol) added in portions. After 30 minutes the temperature was raised to 130°C (oil bath) and the mixture gently refluxed for 16 hours. Then 100 mL water and 200 mL ethyl acetate were added, the mixture neutralized with acetic acid, the organic layer separated, washed with water (100 mL), dried (sodium sulfate) and evaporated.
  • Butanoic acid 4-[[2-[[2-(1H-indol-3-ylmethyl)-2- methyl-1-oxo-3-[[(tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy)carbonyl]amino]-propyl]amino]-1- phenylethyl]amino]-4-oxo-, [R-(R*,R*)]- m.p. 110-125oC, CI-MS (CH 4 ) : m/z 628 (M-, 21), 164 (100)
  • Butanedioic acid mono 2-[[2-(1H-indol-3-ylmethyl)-2- methyl-1-oxo-3-[[(1,7,7-trimethylbicyclo[2.2.1]hept-2- yloxy)carbonyl]-amino]propyl]amino]-3-phenylpropyl ester (Bicyclo system is 1S-endo, phenylmethyl center is S, other center is RS)
  • Butanedioic acid [2-[[2-(1H-indol-3-ylmethyl)-2- methyl-1-oxo-3-[[(tricyclo[3.3.1.1 3 ' 7 ]dec-2- yloxy)carbonyl]amino]propyl]-amino]-3 phenylpropyl ester (Trp center RS; other center S)
  • MS (70eV) m/z 446 (M + , 4), 130 (100).
  • MS (70eV) m/z 317 (M + , 18), 130 (100).

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Abstract

L'invention se rapporte à de nouveaux antagonistes de cholécystokinine, qui sont utiles comme agents de traitement de l'obésité, de l'hypersécrétion d'acide gastrique dans l'intestin, de tumeurs dépendantes de la gastrine ou comme neuroleptiques. Ces composés peuvent en outre servir d'anxiolytiques et d'agents anti-ulcéreux. Ils sont utiles pour empêcher la réaction à l'arrêt d'un traitement chronique avec utilisation de nicotine, de diazépam, d'alcool, de cocaïne, de caféine ou d'opioïdes. Ces composés sont également utiles dans le traitement et/ou la prévention des peurs paniques. La présente invention décrit aussi des compositions pharmaceutiques et des procédés de traitement qui utilisent ces antagonistes, ainsi que des procédés de préparation de ces antagonistes et de nouveaux intermédiaires utiles dans leur préparation. Une autre caractéristique de la présente invention est l'utilisation de ces composés dans des compositions diagnostiques.
PCT/US1991/006180 1990-08-31 1991-08-29 Nouveaux antagonistes de cholecystokinine, preparation et utilisation therapeutique de ces composes WO1992004045A1 (fr)

Priority Applications (4)

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KR1019930700601A KR100222634B1 (ko) 1990-08-31 1991-08-29 콜레시스토키닌길항제,그의제조방법및치료학적용도
AU87492/91A AU651390C (en) 1990-08-31 1991-08-29 Novel cholecystokinin antagonists, their preparation and therapeutic use
JP3517185A JPH06502627A (ja) 1990-08-31 1991-08-29 新規コレシストキニンアンタゴニスト、その製造および治療用使用
NO19930709A NO312298B1 (no) 1990-08-31 1993-02-26 Analogifremgangsmåte for fremstilling av terapeutisk aktive indolderivater

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993003721A1 (fr) * 1991-08-20 1993-03-04 Warner-Lambert Company Antagonistes de la cholecystokinine utiles dans le traitement de la depression
WO1994018229A1 (fr) * 1993-02-03 1994-08-18 Fisons Corporation Derives de 1,2,4 triazone et leur utilisation en therapeutique
US5380872A (en) * 1992-07-14 1995-01-10 Glaxo Inc. Modulators of cholecystokinin
US5686461A (en) * 1993-03-05 1997-11-11 Glaxo Wellcome S.P.A. Indole derivatives
US6194437B1 (en) 1996-08-22 2001-02-27 Warner-Lambert Company Non-peptide bombesin receptor antagonists
US6645968B2 (en) 1999-08-03 2003-11-11 Abbott Laboratories Potassium channel openers
US6846836B2 (en) 2003-04-18 2005-01-25 Bristol-Myers Squibb Company N-substituted phenylurea inhibitors of mitochondrial F1F0 ATP hydrolase
US7491743B2 (en) 2003-08-29 2009-02-17 President And Fellows Of Harvard College Inhibitors of cellular necrosis
US8445714B2 (en) 2006-09-15 2013-05-21 Reviva Pharmaceuticals, Inc. Cycloalkylmethylamines
US8809280B2 (en) 2009-11-02 2014-08-19 Lytix Biopharma As Therapeutic peptides
US9296681B2 (en) 2006-09-15 2016-03-29 Reviva Pharmaceuticals, Inc. Cycloalkylmethylamines
US9499521B2 (en) 2014-12-11 2016-11-22 President And Fellows Of Harvard College Inhibitors of cellular necrosis and related methods
US9586880B2 (en) 2008-12-23 2017-03-07 President And Fellows Of Harvard College Small molecule inhibitors of necroptosis
US9725452B2 (en) 2013-03-15 2017-08-08 Presidents And Fellows Of Harvard College Substituted indoles and pyrroles as RIP kinase inhibitors

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EP0227173A2 (fr) * 1985-12-23 1987-07-01 Janssen Pharmaceutica N.V. Procédé pour la détection des agents liants spécifiques et leurs substances liables correspondantes
US4757157A (en) * 1986-11-14 1988-07-12 Alcatel Cit Housing for an undersea repeater

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US4814463A (en) * 1985-12-31 1989-03-21 Biomeasure, Inc. CCK antagonists
WO1989010355A1 (fr) * 1988-04-05 1989-11-02 Abbott Laboratories Derives de tryptophan utilises comme antagonistes cck
NZ234264A (en) * 1989-06-29 1993-05-26 Warner Lambert Co N-substituted cycloalkyl and polycycloalkyl alpha-substituted trp-phe- and phenethylamine derivatives, and pharmaceutical compositions
US5244915A (en) * 1990-08-31 1993-09-14 Warner-Lambert Company Amico acid derivatives cyclized at the c-terminal

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EP0227173A2 (fr) * 1985-12-23 1987-07-01 Janssen Pharmaceutica N.V. Procédé pour la détection des agents liants spécifiques et leurs substances liables correspondantes
US4757157A (en) * 1986-11-14 1988-07-12 Alcatel Cit Housing for an undersea repeater

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See also references of EP0547178A4 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993003721A1 (fr) * 1991-08-20 1993-03-04 Warner-Lambert Company Antagonistes de la cholecystokinine utiles dans le traitement de la depression
US5380872A (en) * 1992-07-14 1995-01-10 Glaxo Inc. Modulators of cholecystokinin
US5508432A (en) * 1992-07-14 1996-04-16 Glaxo Wellcome Inc. Modulators of cholecystokinin
WO1994018229A1 (fr) * 1993-02-03 1994-08-18 Fisons Corporation Derives de 1,2,4 triazone et leur utilisation en therapeutique
US5686461A (en) * 1993-03-05 1997-11-11 Glaxo Wellcome S.P.A. Indole derivatives
US6194437B1 (en) 1996-08-22 2001-02-27 Warner-Lambert Company Non-peptide bombesin receptor antagonists
US6645968B2 (en) 1999-08-03 2003-11-11 Abbott Laboratories Potassium channel openers
US6846836B2 (en) 2003-04-18 2005-01-25 Bristol-Myers Squibb Company N-substituted phenylurea inhibitors of mitochondrial F1F0 ATP hydrolase
US8741942B2 (en) 2003-08-29 2014-06-03 President And Fellows Of Harvard College Inhibitors of cellular necrosis
US7491743B2 (en) 2003-08-29 2009-02-17 President And Fellows Of Harvard College Inhibitors of cellular necrosis
US8143300B2 (en) 2003-08-29 2012-03-27 President And Fellows Of Harvard College Inhibitors of cellular necrosis
US8445714B2 (en) 2006-09-15 2013-05-21 Reviva Pharmaceuticals, Inc. Cycloalkylmethylamines
US9296681B2 (en) 2006-09-15 2016-03-29 Reviva Pharmaceuticals, Inc. Cycloalkylmethylamines
US9302981B2 (en) 2006-09-15 2016-04-05 Reviva Pharmaceuticals, Inc. Synthesis, methods of using, and compositions of cycloalkylmethylamines
US9586880B2 (en) 2008-12-23 2017-03-07 President And Fellows Of Harvard College Small molecule inhibitors of necroptosis
US8809280B2 (en) 2009-11-02 2014-08-19 Lytix Biopharma As Therapeutic peptides
US9725452B2 (en) 2013-03-15 2017-08-08 Presidents And Fellows Of Harvard College Substituted indoles and pyrroles as RIP kinase inhibitors
US9499521B2 (en) 2014-12-11 2016-11-22 President And Fellows Of Harvard College Inhibitors of cellular necrosis and related methods
US9944628B2 (en) 2014-12-11 2018-04-17 President And Fellows Of Harvard College Inhibitors of cellular necrosis and related methods
US10508102B2 (en) 2014-12-11 2019-12-17 President And Fellows Of Harvard College Inhibitors of cellular necrosis and related methods

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CA2088195A1 (fr) 1992-03-01
NO312298B1 (no) 2002-04-22
EP0547178A4 (en) 1994-07-06
NZ239595A (en) 1994-06-27
AU651390B2 (en) 1994-07-21
JPH06502627A (ja) 1994-03-24
KR930703349A (ko) 1993-11-29
PT98842A (pt) 1992-08-31
KR100222634B1 (ko) 1999-10-01
IE67290B1 (en) 1996-03-20
PT98842B (pt) 1999-01-29
IE913077A1 (en) 1992-03-11
EP0547178A1 (fr) 1993-06-23
NO930709L (no) 1993-04-15
AU8749291A (en) 1992-03-30

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