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WO1998035960A1 - Inhibiteurs de prolylendopeptidase - Google Patents

Inhibiteurs de prolylendopeptidase Download PDF

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Publication number
WO1998035960A1
WO1998035960A1 PCT/HU1998/000016 HU9800016W WO9835960A1 WO 1998035960 A1 WO1998035960 A1 WO 1998035960A1 HU 9800016 W HU9800016 W HU 9800016W WO 9835960 A1 WO9835960 A1 WO 9835960A1
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group
carbon atoms
alkyl
atom
mean
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PCT/HU1998/000016
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Inventor
Sándor BÁTORI
Judit Bence
Erzsébet FEJÉR
István HERMECZ
ágnes Horváth
Zoltán Kapui
Károly KÁNAI
Zsolt MOLNÁR
Behr Ágnes PAPPNÉ
Judit Sipos
Edit SUSÁN
Zsuzsa SZAMOSVÖLGYI
Gábor SZELECZKY
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Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt.
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Priority to AU62251/98A priority Critical patent/AU6225198A/en
Publication of WO1998035960A1 publication Critical patent/WO1998035960A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to new compounds of the general formula (I), to pharmaceutical compositions containing them, and to the process for the preparation of these compounds.
  • a further aspect of our present invention is the use of the new compounds of the general formula I for the treatment of CNS diseases by inhibition of certain enzymes described later on on this page.
  • Alzheimer disease AIDS dementia
  • senile dementias of various origin hyperoxia, ischaemia
  • Prolyl endopeptidase PE or PEP is a post-proline cleaving enzyme (PPCE). It is widespread in mammalian species and can be found in various organs of the body. The level of the enzyme is the highest in the brain, testis and skeletal muscle (Yoshimoto T., Ogita K., Walter R., Koida M. and Tsuru D.: Biochim. Biophys. Acta, 569, (1979), 184-192).
  • PEP has some important role in the memory process due to the fact that its substrates are biologically active neuropeptides (substance P, thyrotropin-releasing hormone, Arg -Vasopressin). These neuropeptides exert characte ⁇ stic pharmacological effects on the central nervous system: they are capable of changing the performance of animals and humans in learning and memory tasks (Toide K., Iwamoto Z., Fujiwara T. and Abe H.: J. Pharm. Exp. Therapeutics, 274, (1995), 1370-1378; Riedel W. and Jolles J.: Drugs & Aging, 8, (1996), 245-274).
  • the neuropeptide sustance P prevents ⁇ -amyloid-induced neuronal loss and expression of Alz-50 proteins in cerebral cortex (Kowall N., Beal M.F., Busciglio J. and Duffy L.K.: Proc Natl. Acad. Sci., 88, (1991), 7247-7251). It is well known that in the brain of patients with Alzheimer's disease, the cerebral ACh content is decreased and the cerebral function suffers severe damage (O'Leary R. and O'Connor B.: J. Neurochem., 65, (1995), 953-963). A PEP inhibitor, through increasing the level of TRH, could induce ACh release in the brain which should result in a better cognitive performance. It can be supposed that a highly specific PEP inhibitor proves to be useful in the treatement of disorders of the central nervous system in neurodegenerative illnesses.
  • the new PEP inhibitor as a new drug would be a
  • nootropic drug having memory enhancing and anti-amnesic effect which could be used in the treatment of age-related cognitive decline
  • neuroprotective agent useful in therapy of a., acute events (ischemia/hypoxia) b., progressive neurodegenerative disorders -Alzheimer's disease -AIDS dementia
  • Senile dementia and Alzheimer ' s disease are becoming a serious and fastly outgrowing problem of the aging population.
  • a PEP inhibitor could be useful for the general treatment of the above mentioned serious diseases.
  • advantageous characteristics we mean a strong PEP - inhibitory effect, selectivity, easy transfer through the blood-brain barrier, long half-life, good oral resorption, enchanced chemical and biological stability and advantageous therapeutic profile including low toxicity and low probability of side effects.
  • A means a mono or multiple substituted or unsubstituted organic cyclic group containing one nitrogen atom with one free valency and optionally one or more further heteroatom, selected from a group consisting of nitrogen atom, sulfuratom or oxigenatom, especially a group having the general formula (1), (la), (2), (2a), (3), (3a), (4a), (4b), (5), (6), (7), (8), (9), (10), (11a), (l ib), (12), (12a), (12b), (13), (13a), (14), (15), (16), (17), (18), (19), (19a), (20), (20a), (21), (22), (23), (23a), (23b), (24), (25), (25a), (26), (27), (28), (28a), (28b), (29), (29a), (30), (31), (32), (32a), (33), (34), (35), (3
  • R means hydrogen atom alkyl group of 1-4 carbon atoms or aryl or aralkyl group of 6-12 carbon atoms;
  • Rl, R2, R3 and R4 mean independently from each other hydrogen atom, halogen atom, hydroxyl group, straight chain or branched chain alkyl- or alkenyl- or alkinyl- or alkoxy- or alkenyloxy- or alkinyloxy groups containing 1-6 carbon atoms, nitro group, amino group, monoalkylamino- or monoacylamino group of 1- 12 carbon atoms, dialkylamino- or diacylamino group of 2-24 carbon atoms - where the acyl group is an alkyl-, aralkyl-, cycloalkyl- or aryl type -, cyano group, mercapto group, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group, anilino group,
  • R5 and R ⁇ mean independently from each other hydrogen atom, hydroxyl group phenyl group or alkyl group of 1- 4 carbon atoms or R ⁇ and R ⁇ together mean oxo group;
  • R means hydrogen atom or alkyl group of 1-6 carbon atoms
  • R8 means hydrogen atom or alkyl group of 1-6 carbon atoms or aralkyl group of 7-10 carbon atoms or alkoxycarbonyl-alkyl group of 3-6 carbon atoms; or aliphatic or aromatic acyl group of 1-7 carbon atoms or difluoro- or trifluoro- or polyfluoro acyl group of 2-6 carbon atom, the dotted line means an optional chemical bond
  • n is zero 1, 2 or 3;
  • X means-CH.2-group, -NH-group, carbon atom, hydrogen atom, oxygen atom or amino group; or R 9
  • B means -(CH 2 ) m - C - group - wherein m is an integer of 1 to 21; or O R s
  • R means the same substituents as defined above, or -O-(CH 2 ) p - C - group wherein p is an integer of 1 to 3; or
  • R 9 , R 10 , R 1 1 , R 12 , R 13 and R 14 mean independently from each other hydrogen atom, alkyl or alkoxy group of 1-6 carbon atoms, halogen atom, amino group optionally substituted with one or two alkyl group of 1-6 carbonatoms; or phenyl, phenoxy, aryl-alkyl group of 7-12 carbon atoms or aryl-alkoxy group of 7- 12 carbon atoms each of them optionally containing 1, 2 or 3 of the same or different substituents identical to R 1 , R 2 , R 3 or R 4 ; or two of R 9 , R 10 , R 11 , R 12 ', R 13 and R 14 mean together an oxo or epoxy group or further chemical bond, or four of them mean together two further chemical bonds and the remaining groups stand for hydrogen atoms; or
  • R 9 , R 10 , R 11 , R 12 ', R 13 and R 14 mean together with the chain carbon atoms a saturated or unsaturated homocycle containing 3-8 carbon atoms or a saturated or unsaturated heterocycle containing 2-7 carbon atoms and a nitrogen or sulfur or oxygen atom, to which optionally an aromatic ring of 6-10 carbon atoms is o condensed;
  • R means the same substituents as defined above, and w is zero or 1 ;
  • C means prolyl group or one of the groups of formula (37), (38), (39), (40) or (41)
  • Hlg means fluoro, chloro, bromo, or iodo atom
  • R and R mean independently from each other hydrogen atom, hydroxyl group phenyl group or alkyl group of 1-4 carbonatoms or R 5 and R 6 together mean oxo- group;
  • Rl6 means an alkoxy group of 1-4 carbon atoms, or -NH- CFf? -CN group, or - NH-CH2-CO2R group - where R ⁇ is defined as above; or D or L structural unit; or one of the groups of the formula (42) or (43) or (43a)
  • R 5 means hydrogen atom, alkyl group of 1-6 carbon atoms, phenyl or naphthyl group; or a group of the formula (45) - wherein Z means NH - group, oxygen atom or sulfur atom;
  • D means a covalent chemical bond or prolyl- or thioprolyl group, or one of the groups of formula (37) or (38), (39), (40) or (41);
  • L means pyrrolidino or 2-cyanopyrrolidino, thiazolidino or 2-cyanothiazolidino or piperidino group optionally substituted with one halogen atom or geminally with two halogen atoms; or a group of the formula (46) - wherein Rl means hydrogen atom or cyano group, n is 0, 1 or 2 ; or a group of the formula (47) or (48) or (49); or a group of formula (46) - wherein
  • R 17 means - CF 2 H group or a group of the formula (50) or formula (51) - wherein
  • R means hydrogen atom, halogen atom, l,3-dioxolan-2-yl group or -OR group wherein R stands for hydrogen atom or alkyl group of 1-6 carbon atom or phenyl group optionally substituted by one or two alkoxy group of 1-4 carbon atom or alkyl group of 1-4 carbon atom or nitro groups; n is 0, 1 or 2
  • R 19 means hydrogen atom halogen atom l,3-dioxolan-2-yl group or - OR group
  • R stands for alkyl group of 1-6 carbon atoms or phenyl group optionally substituted by one or two alkoxy group of 1-4 carbon atoms or alkyl group of 1-4 carbon atoms or nitro groups, or
  • R 18 and R 1 form together an oxo-group
  • R means a - (CH 2 ) t - T - R group - wherein t is 0, 1 or 2, T is an oxygen or sulphur
  • R means hydrogen atom, phenyl, 2- thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyrrolyl, thienyl, 2-benzothiazolyl, 2- benzoxazolyl, 2- benzimidazolyl, 2-indolyl, 2-thiazolo[5,4-b]pyridinyl, 2- oxazolo[4,5-b]pyridinyl, 2-imidazolo[4,5-b]pyridinyl, 5-thiazolyl, 2-thiazolinyl,
  • R means hydroxy group, alkoxy group of 1-6 carbon atoms or - NR
  • R -group - wherein R is alkyl group of 1-6 carbon atoms, R is alkyl group of 1- 6 carbon atoms or R and R form together a alkylene group of 1-5 carbon atoms with the proviso that if a.)
  • B means -(CH 2 ) m - C - group - wherein m is an integer of 1 to 21; or
  • Rl3 and R 14 mean independently from each other hydrogen atom, alkyl or alkoxy group of 1-6 carbon atoms, halogen atom, amino group optionally substituted with one or two alkyl groups of 1-6 carbon atoms; or phenyl group, phenoxy group, aryl-alkyl group of 7-12 carbon atoms or aryl-alkoxy group of 7-12 carbon atoms each of them optionally containing 1, 2 or 3 of the same or different substituents identical to R ,
  • R , R , R , R ', R and R mean together with the chain carbon atoms a saturated or unsaturated homocycle containing 3-8 carbon atoms or a saturated or unsaturated heterocycle containing 2-7 carbon atoms and a nitrogen or sulfur or oxygen atom, to which optionally an aromatic ring of 6-10 carbon atoms is condensed; and w is zero or 1 ;
  • L cannot mean pyrrolidino- or 2-cyanopyrrolidino, thiazolidino or 2- cyanothiazolidino or piperidino group optionally substituted with one halogen atom or geminally with two halogen atoms; or a group of the formula (46) - where R 1 ⁇ means hydrogen atom or cyano group, n is 0, 1 or 2 ; or a group of the formula (47) or (48) or (49); or if b.) L means pyrrolidino- or 2-cyanopyrrolidino, thiazolidino or 2- cyanothiazolidino or piperidino group optionally substituted with one halogen atom or geminally with two halogen atoms; or a group of the formula (46) - where R 1 # 7 means hydrogen atom or cyano group, n is 0, 1 or 2 ; or a group of the formula (47) or (48) or (49);
  • B cannot mean -(CH 2 ) m - C - group - wherein m is an integer of 1 to 21;
  • R 9 , R10, RU , R12, R 13 and R 14 mean II O independently from each other hydrogen atom, alkyl or alkoxy group of 1-6 carbon atoms, halogen atom, amino group optionally substituted with one or two alkyl groups of 1-6 carbon atoms; or phenyl group, phenoxy group, aryl-alkyl group of
  • R , R , R , R ', R and R mean together with the chain carbon atoms a saturated or unsaturated homocycle containing 3-8 carbon atoms or a saturated or unsaturated heterocycle containing 2-7 carbon atoms and a nitrogen or sulfur or oxygen atom, to which optionally an aromatic ring of 6-10 carbon atoms is condensed; and w is zero or 1; - and optical , cis-trans, geometric isomers , epimers, tautomers, salts, prodrugs and human and mammalian metabolites of them having significant prolylendopeptidase inhibiting effect and they show one or more of the advantages mentioned above.
  • ordinalkyl group of 1-6 carbon atoms means a straight chain or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.
  • Theticianaryl group of 6-10 carbon atoms means for example phenyl, tolyl or naphthyl groups.
  • the dormitoryl group of 6-10 carbon atoms means for example benzyl-, 1- phenylethyl-, 2-phenylethyl-, 1-phenylpropyl groups.
  • the alkenyl group of 1-6 carbon atoms means a straight chain or branched alkenyl group such as vinyl, allyl, methacryl, crotyl, 3-butenyl, 2-pentenyl-, 4-pentenyl-, 2-hexenyl-, 5-hexenyl.
  • the dormitoryl group of 1-6 carbon atoms means a straight-chain or branched alkinyl group such as ethynyl, propargyl, 2-butynyl-, 3-butynyl, 2-pentynyl, 4-pentynyl, 2- hexynyl 5-hexynyl 4-methyl-2-hexynyl.
  • the cycloalkyl part of theticianacyl group of 1-12 carbonatoms means for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group.
  • Halogen atom means fluoro, chloro, brom or iodo atom, preferably fluoro atom.
  • Acyl group means acetyl, formyl, benzoyl group, difluoro- trifluoro- or polyfluoro acyl group e.g. trifluoroacetyl group or pentafluoropropionyl group.
  • the supernatant was thawn just before activity measurement and diluted in a 1 :15 ratio with PEP buffer.
  • the enzyme activity was measured by using fluorometric method described by J. R. Atack et al. (Eur J. Pharmacol., 205, (1991), 157-163). Enzyme reaction was performed at room temperature for 15 minutes in the presence of 62.5 ⁇ M Z-glycyl-prolyl-7- amino-4-methyl-coumarin (Bachem Biochem.) as a highly specific synthetic substrate of the PEP.
  • the inhibitory effect of the compounds was tested under the same conditions in the presence of 100 to 0.001 nM of the compound.
  • IC 50 50% inhibition concentration values of the compounds (IC 50 ) were calculated by curve fitting of the % inhibition of the enzyme versus inhibitor concentration (M) using Hill- equation. IC 50 values of the compounds of the general formula (I) are in the range of lOOnM - lpM.
  • pig brain prolyl endopeptidase was a kind gift from Laszl ⁇ Polgar (Enzymology Institute of the Hungarian Academy of Sciences). Enzyme solution was diluted in the reaction mixture 400000 times. Measurements were performed under the same conditions as in the case of the in vitro measurements on rat brain preparation. The compounds of the general Formula I were shown to be active also on pig brain PEP activity test.
  • Some compounds of the general (I) had half-life on human liver microsomes of more than 7 hours. Such good biological stabilities favour an long lasting effect in vivo and are an advantage over other peptidic-type PEP-inhibitors which are known to be biologically unstable.
  • the published European Patent Application No 0 232 849 A2 describes numerous PEP-inhibitors including SUAM-1221 (N-[N-( ⁇ -phenyl)butyryl-L- prolyl]pyrrolidine).
  • the compounds of the general formula (I) exert high inhibition activity on prolyl endopeptidase their effect is greater than that of the above reference compound, SUAM- 1221 , measured in our test-system described above.
  • the preparation of compounds of the general formula (I) is carried out by methods well known from the literature or by obvious chemical equivalents thereof related to the synthesis of peptide type substances.
  • the A and B units of compounds of the general formula A - B - C - D - L (I) - where the meanings of A , B , C , D , and L are as described above - are coupled by the reaction of the appropriate acid anhydride or other activated acid derivative and an arnine, yielding compounds of the general formula (II) - where the meanings of A and B are as described above.
  • the coupling of units C and D happens likewise by coupling the appropriate activated acid derivative e.g. acid anhydride and an amine.
  • the coupling of units CD and L to yield compounds of the general formula (III) - where the meanings of CD and L are as described above - is carried out by reacting the appropriate mixed anhydride and amine resp. ester and metallo - organic compound.
  • the starting compounds corresponding to units A, B, C, D, and L are commercially available or readily producible by known transformations of them or as described in Chem. Pharm. Bulletin 41 (9) p 1583-1588 (1993.)
  • the compound (IV) can be prepared from the commercially available /-proline by a known route according to the process described by Azami et. al. (Bioorg.Med. Chem.Letters 1995, 5, 2199.
  • the compounds of formula (III) can be prepared from (IV) by one of the reaction routes shown below. All the abbreviations have the same meaning as defined previously.
  • the epoxide compound (V) is obtained from the protected /-prolinal (IV) by a conventional method described by Corey and Chaykovsky (J. Am. Chem. Soc.
  • the compound of the formula (VI) may be obtained by treating the epoxide (V) with an appropriate phenolic compound in the presence of a base such as sodium methoxide at reflux temperature in methanol.
  • the keto derivatives (IX) or (XII) could be obtained by treating the compound (VI) or (XI) separately with an oxidizing agent, preferable oxalyl chloride and dimethyl- sulfoxide in the presence of triethylamine at a temperature between 0°C and -60°C.
  • N-protected prolinal (IV) is reacted with heterocycles in the presence of a strong base (butyllithium or the like) in an inert solvent, such as THF, at -75°C to yield a compound of the general formula (XI).
  • a strong base butyllithium or the like
  • an inert solvent such as THF
  • a compound of the formula (IX) or (XII) is reacted with DAST [(diethylamino)sulfur trifluoride] in a suitable solvent such as benzene at the room temperature to give compound (X) or (XIV) respectively.
  • DAST diethylamino)sulfur trifluoride
  • a suitable solvent such as benzene
  • R in (IX), (X) or (XI) by cerium ammonium nitrate in aqueous acetonitrile-pyridine mixture preferable at room temperature could give useful intermediate to the compound of formula (III) as well.
  • the activated derivatives of compounds having general formula (II) were e.g. acid chlorides, which can be synthesized by applying halogenating agents (e.g. thionyl chloride). Active esters can be produced by 1-hydroxybenzotriazole in the presence of N,N'-dicyclohexylcarbodiimid (Chem. Ber. 103, 788/1970/).
  • the coupling reaction can favourably be carried out in organic solvents (preferably at a temperature between - 25°C and the boiling point of the reaction mixture).
  • Use of acid binding agents e.g. organic amines is favourable during the reaction.
  • a compound of formula (I) can also be prepared by other condensation method. According to this an amine component (III) is coupled to an isocyanate formed in situ from an acid (II) via a modified Curtius degradation [Eaton et.al. J.Org.Chem. 1984, 49, 185.] to give (I) in very good yield. Diphenyl phosphorazidate is a commonly used reagent in this proccess.
  • Preferable solvents for this reaction are toluene, xylene, THF or DMF.
  • the reaction temperature may vary from room temperature to 120°C, preferably a range from 80 to 120°C is applied.
  • the compounds of the general formula (I) can be purified, if appropriate, by a conventional purification technique, its isomers, if desired, may be separated by a conventional separation technique, and they are converted, if necessary, to their addition salts with a pharmaceutically acceptable acid.
  • Pharmaceutically acceptable acids may be for example hydrochloric, sulfuric, tartaric, fumaric, methanesulfonic acid and the like.
  • compositions containing, as active principle, at least one compound of general formula (I) or one of its addition salts with a pharmaceutically acceptable acid, alone or in combination with one or more inert and nontoxic excipients or vehicles. Mention may more particularly be made, among pharmaceutical compositions according to the invention, of those which are suitable for oral, parenteral, rectal or nasal administration, simple or sugar-coated tablets, sublingual tablets, injectable compositions, infusions, packets, gelatin capsules, suppositories, creams, ointments, dermal gels, and the like.
  • the dose varies according to the age and weight of the patient, the nature and the severity of the ailment and on the administration route.
  • the latter can be oral, nasal, rectal or parenteral.
  • the unit dose generally varies between 0,1 and 50 mg/body weight kg for a treatment taken 1 to 3 times per 24 hours.
  • the reaction mixture was stirred at room temperature for 4 hours, then it was washed successively with water, 30% cc. citric acid solution, saturated aqueous sodium hydrogene carbonate solution, water and finally with saturated sodium chloride solution.
  • the organic phase was dried on calcinated magnesium sulphate and it was evaporated.
  • the residue was purified by silica gel chromatography (eluent chloroform-methanol) to give the title compound (2,9 g, 59%) as a white waxy solid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne de nouveaux inhibiteurs de prolylendopeptidase répondant à la formule générale I.
PCT/HU1998/000016 1997-02-14 1998-02-13 Inhibiteurs de prolylendopeptidase WO1998035960A1 (fr)

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AU62251/98A AU6225198A (en) 1997-02-14 1998-02-13 Prolylendopeptidase inhibitors

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HU9700442A HUP9700442A1 (hu) 1997-02-14 1997-02-14 Gyűrűs amidszármazékok, e vegyületeket tartalmazó gyógyászati készítmények, eljárás előállításukra és alkalmazásuk
HUP9700442 1997-02-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006058720A2 (fr) 2003-11-03 2006-06-08 Probiodrug Ag Nouveaux composes pour le traitement de troubles neurologiques

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EP0355409A2 (fr) * 1988-07-25 1990-02-28 Kabushiki Kaisha Yakult Honsha L'utilisation d'un inhibiteur de prolylendopeptidase pour le traitement du SIDA
EP0372484A2 (fr) * 1988-12-08 1990-06-13 Zeria Pharmaceutical Co., Ltd. Benzènes condensés
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EP0468469A2 (fr) * 1990-07-27 1992-01-29 Japan Tobacco Inc. Dérivés de proline
WO1993013065A1 (fr) * 1991-12-27 1993-07-08 Japan Tobacco Inc. Derive de proline
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EP0232849A2 (fr) * 1986-02-04 1987-08-19 Suntory Limited Dérivés pyrrolidineamide d'amino-acides acylés, composition pharmaceutique et usage
EP0355409A2 (fr) * 1988-07-25 1990-02-28 Kabushiki Kaisha Yakult Honsha L'utilisation d'un inhibiteur de prolylendopeptidase pour le traitement du SIDA
EP0372484A2 (fr) * 1988-12-08 1990-06-13 Zeria Pharmaceutical Co., Ltd. Benzènes condensés
EP0419683A1 (fr) * 1989-04-13 1991-04-03 Japan Tobacco Inc. Nouveaux derives aminoacides possedant une activite d'inhibiteur de la prolylendopeptidase
EP0468469A2 (fr) * 1990-07-27 1992-01-29 Japan Tobacco Inc. Dérivés de proline
WO1993013065A1 (fr) * 1991-12-27 1993-07-08 Japan Tobacco Inc. Derive de proline
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WO1997007116A1 (fr) * 1995-08-17 1997-02-27 Chinoin Gyógyszer És Vegyészeti Inhibiteurs de la propylendopeptidase

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006058720A2 (fr) 2003-11-03 2006-06-08 Probiodrug Ag Nouveaux composes pour le traitement de troubles neurologiques

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