Nothing Special   »   [go: up one dir, main page]

EP1824846A2 - Nouveaux composes pour le traitement de troubles neurologiques - Google Patents

Nouveaux composes pour le traitement de troubles neurologiques

Info

Publication number
EP1824846A2
EP1824846A2 EP05826439A EP05826439A EP1824846A2 EP 1824846 A2 EP1824846 A2 EP 1824846A2 EP 05826439 A EP05826439 A EP 05826439A EP 05826439 A EP05826439 A EP 05826439A EP 1824846 A2 EP1824846 A2 EP 1824846A2
Authority
EP
European Patent Office
Prior art keywords
group
compound according
alkyl
formula
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05826439A
Other languages
German (de)
English (en)
Inventor
André Johannes NIESTROJ
Ulrich Heiser
Ingo Schulz
Jens-Ulrich Rahfeld
Joachim Bär
Hans-Ulrich Demuth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vivoryon Therapeutics AG
Original Assignee
Probiodrug AG
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
Priority claimed from US10/976,677 external-priority patent/US20050137142A1/en
Priority claimed from US11/002,169 external-priority patent/US20050171112A1/en
Application filed by Probiodrug AG filed Critical Probiodrug AG
Publication of EP1824846A2 publication Critical patent/EP1824846A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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

  • This invention relates to heteroaryl-carbonyl compounds as inhibitors of prolyl endopeptidase (PEP, EC 3.4.21.26) and PEP-like enzymes.
  • PEP prolyl endopeptidase
  • Prolyl endopeptidase (PEP; EC 3.4.21.26; also called prolyl oligopeptidase) is a serine peptidase characterized by oligopeptidase activity. It is the name given to enzymes of family S9A, prolyl oligopeptidases, in clan SC (1). Enzymes belonging to clan SC are distinct from trypsin- or subtilisin-type serine peptidases by structure and by order of the catalytic triad residues in the primary sequence (2;3). The recently reported three dimensional structure of PEP revealed a two domain organization (4).
  • the catalytic domain displays an ⁇ / ⁇ hydrolase fold in which the catalytic triad (Ser554, His680, Asp641) is covered by a so-called ⁇ -propeller domain. Most likely, the propeller domain controls the access of potential substrates to the active site of the enzyme and excludes peptides having more than 30 amino acids.
  • PEP neuropeptide bioactivity
  • substance P and arginine-vasopressin (AVP) by limited proteolysis (12; 13).
  • Neuropeptides, such as substance P or AVP are known to influence learning and memory (14; 15).
  • LTP long-term potentiation
  • Binding of substance P to neurokinin 1 receptor stimulates a G-protein mediated increase in IP 3 concentration and a release of Ca 2+ from intracellular stores within the endoplasmic reticulum (ER) (17;18).
  • EP 0 172 458 discloses N-phenyl alkanoyl pyrrolidine derivatives useful as anti- amnesic agents.
  • EP 0 359 547 discloses pyridine compounds inhibiting prolylendo peptidase activity and useful for the treatment of amnesia.
  • US 5,340,832 discloses N-substituted carbamoyl-alkanoyl-prolinal derivatives useful as inhibitors of prolyl endopeptidase for treating amnesia.
  • US 5,763,576 discloses tetrapeptide alpha-ketoamides as selective and total inhibitors of serine and cysteine proteases. These compounds are useful in the treatment of tissue damage and various inflammatory conditions, such as blistering, and in the treatment of neurodegenerative diseases such as ischemia, stroke and Alzheimer's disease. The compounds are also inhibitors for blood coagulation enzymes and are useful anticoagulants for the treatment of thrombosis.
  • WO 91/18891 discloses aromatic pyrrolidine and thiazolidine amide(s) as prolyl endopeptidase inhibitors, which are useful for treating CNS disorders such as various memory or learning dysfunctions associated with disease e.g. Alzheimer's disease; amnesia; dementia; anxiety; ischemia; and damage caused by stroke.
  • WO 94/12474 discloses cyclic ketone compounds as prolyl endopeptidase inhibitors - including two nitrogen-containing heterocycles linked by a carbonyl group. These compounds inhibit the degradation and deactivation of TRH, substance P, neurotensin and vasopressin. They are useful for the treatment and prevention of amnesia and of dementia including Alzheimer's disease.
  • WO 95/03277 discloses N-substituted pyrrolidinyl-oxo-acetamide compounds as protease (especially PEP) inhibitors useful for treating memory loss e.g. Alzheimer's disease, and auto-immune disorders.
  • WO 95/15310 discloses prolyl peptide derivatives as prolyl endopeptidase inhibitors. These compounds can be used as memory enhancing agents to improve mental capacity, ability to recall cognitive events, and learned motor activities. Thus the compounds of WO 95/15310 may be used in patients suffering from aphasia, apraxia, agnosia, or any type of amnesias, benign forgetfulness and Korsakoff's syndrome. The compounds may also be used to prevent or slow memory deficits.
  • WO 97/07116 discloses PEP inhibitors for the use in treatment of acute events (such as ischemia and hypoxia) and progressive neurodegenerative disorders, including Alzheimer's disease, AIDS dementia and Huntington's disease.
  • WO 98/35960 discloses PEP inhibitors useful as nootropics having memory enhancing and anti-amnesic effects useful in the treatment of age-related cognitive decline and neuroprotectants useful for treatment of acute events (ischemia/hypoxia) and progressive neurodegenerative disorders such as Alzheimer's disease, AIDS related dementia and Huntington's disease.
  • WO 00/09542 discloses alpha-keto heterocycles inhibiting the enzymatic activity of a serine proteases.
  • the compounds can be used to inhibit microbial growth, reduce perioperative blood loss, preserve transplantation tissues or organs, inhibit cancer cell growth or tumor progression or tumor metastasis or invasion, treat pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or post-cardiac transplant coronary arteriopathy, atherosclerosis, reperfusion injury, Alzheimer's disease, hypoxia, ischemia and blood coagulation disorders.
  • PEP-inhibitor or "prolyl endopeptidase inhibitor” is generally known to a person skilled in the art and means enzyme inhibitors which inhibit the catalytic activity of prolyl endopeptidase (PEP, prolyl oligopeptidase, POP).
  • PEP activity is defined as the catalytic activity of an endoprotease that is capable to hydrolyze post proline bonds in peptides or proteins where the proline is in amino acid position 3 or higher counted from the N-terminus of a peptide or protein substrate.
  • PEP-like enzymes are enzymatically active proteins or peptides, which have PEP activity and are thereby inhibited by PEP-inhibitors.
  • the term "pharmaceutically acceptable” embraces both human and veterinary use: for example the term “pharmaceutically acceptable” embraces a veterinarily acceptable compound or a compound acceptable in human medicine and health care.
  • acyl denotes a C 1 - 12 acyl residue, preferably a Ci -8 acyl residue and especially preferred a Ci -4 acyl residue.
  • acyl include alkanoyl groups mentioned below and benzoyl.
  • alkyl denotes a Ci -I2 alkyl group, preferably a Ci -6 alkyl group.
  • Alkyl groups may be straight chain or branched. Suitable alkyl groups include, for example, methyl, ethyl, propyl (e.g. /7-propyl and isopropyl), butyl (e.g. n-butyl, terf-butyl and sec-butyl), pentyl, hexyl, heptyl (e.g. n-heptyl) and octyl (e.g. n-octyl).
  • alk for example in the expression “alkoxy”
  • alkan for example in the expression “alkanoyl”
  • alkoxy groups include methoxy, ethoxy, butoxy (e.g. n-butoxy), heptyloxy (e.g. ⁇ -heptyloxy) and octyloxy (e.g. n-octyloxy).
  • alkanoyl i.e. acyl groups
  • ethanoyl i.e. acetyl
  • propionyl i.e. acetyl
  • alkenyl denotes a C 2 - 12 alkenyl group, preferably a C 2 - 6 alkenyl group, which contains at least one double bond at any desired location.
  • Alkenyl groups may be straight chain or branched.
  • Exemplary alkenyl groups include ethenyl, propenyl and butenyl.
  • alkynyl unless specifically limited, denotes a C 2 - 1 2 alkynyl group, preferably a C 2-6 alkynyl group, which contains at least one triple bond at any desired location.
  • Alkynyl groups may be straight chain or branched.
  • Exemplary alkenyl groups include ethynyl, propynyl and butynyl.
  • cycloalkyl denotes a 0 3 . 12 cycloalkyl group, typically a C 3-8 cycloalkyl group.
  • exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Cycloalkyl groups may be branched in which case the number of carbons indicates the total number of carbons in the moiety.
  • a group such as cyclopentylmethyl- which contains a cycloalkyl group linked to alkylene is also embraced by the definition of "cycloalkyl", in which case the number of carbons indicates the total number of carbons in the moiety.
  • Alkyl groups including derivatives such as alkoxy together with alkenyl, alkynyl and cycloalkyl groups may optionally be halogen substituted e.g. substituted by fluoro.
  • halo substituted alkyl groups include trifluoromethyl and halo substituted alkoxy groups include trifluoromethoxy.
  • halogen comprises fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-1).
  • carbocylic or “carbocycle”, unless specifically limited, denotes a carbocylic group containing between 3 and 12 carbon atoms, more typically between 3 and 8 carbon atoms, which may optionally be branched.
  • a carbocyclic group refers to a group other than aryl or cycloalkyl which comprises at least one ring of carbon atoms without heteroatoms.
  • Examples of carbocylic groups include bridged ring systems (e.g. bicyclo[2.2.1]heptenyl) and partially unsaturated ring systems (e.g. cyclohexenyl). Such groups may be optionally substituted e.g. by alkyl, halo, oxo or hydroxyl.
  • heterocyclic or “heterocycle”, unless specifically limited, denotes a cycloalkyl residue or carbocylic residue, wherein one or more (e.g. 1 , 2 or 3) ring atoms are replaced by heteroatoms selected from N, S or O.
  • exemplary heterocyclic groups containing one hetero atom include pyrrolidine, tetrahydrofuran and piperidine.
  • exemplary heterocyclic groups containing two hetero atoms include morpholine and piperazine. Such groups may be optionally substituted e.g. by alkyl (eg methyl), halo, oxo or hydroxyl.
  • heterocyclic groups include oxirane (oxacyclopropane), aziridine (azacyclopropane), thiirane, oxetane, azetidine, thietane, thiolane, 1 ,3-dioxolane, thiazolidine, imidazolidine, oxazolidine, pyrazolidine, tetrahydropyran and piperazine.
  • Another example of a heterocycle is urotropine.
  • Other heterocyclic groups include lactams, lactones, cyclic imides and cyclic anhydrides.
  • substituted heterocyclic groups include 1 ,1-dioxo-thiolane, N-methyl-piperazine, 2-(N-methyl)- N ' -piperazinyl)-ethyl, 4-N-(2 ' -hydroxyethyl)-1-N-piperazinyl and 2-(N-morpholino)- ethyl.
  • aryl denotes a C 6- i2 aryl group, preferably a C ⁇ - ⁇ aryl group.
  • Aryl groups will contain at least one aromatic ring (e.g. one, two or three rings), but may also comprise partially or fully unsaturated rings.
  • An example of an aryl group with one aromatic ring is phenyl.
  • aromatic groups with two aromatic rings include naphthyl (e.g. 1-naphthyl-, or 2-naphthyl-).
  • aryl groups include 1-anthracenyl-, 2-anthracenyl- and 3-anthracenyk
  • aryl groups which contain partially or fully unsaturated rings include tetralin and indene.
  • a most typical aryl group is phenyl.
  • heteroaryl denotes as an aryl residue, wherein one or more (e.g. 1 , 2, 3, or 4, preferably 1 , 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O or else a 5-membered aromatic ring containing one or more (e.g. 1 , 2, 3, or 4, preferably 1 , 2 or 3) ring atoms selected from N, S and O.
  • heteroaryl groups may optionally be substituted.
  • exemplary heteroaryl groups include, pyridine (e.g. 2-, 3- or 4-pyridine), pyrimidine, quinoline, pyrrole, furan, thiophene, oxazole, pyrazole, benzodioxolane (benzodioxole), benzodioxane, benzothiophene, benzodioxepine, and thiazole, imidazole (e.g.
  • a most typical heteroaryl group is pyridine.
  • aryl and heteroaryl groups may, where appropriate, optionally be substituted by one or more (e.g. 1 , 2 or 3, typically 1 or 2) monovalent or multivalent functional groups.
  • Suitable substituent groups include alkyl, cycloalkyl, phenyl, pyridyl, furyl, carbocylic, heterocyclic, alkoxy, cycloalkoxy, phenyloxy, carbocyclicoxy, hetercyclicoxy, alkenyloxy, alkynyloxy, alkenyl, alkynyl, alkanoyl, alkoxyalkanoyl, alkoxyalkyl, nitro, -S-alkyl (e.g.
  • halo e.g. fluoro, chloro, bromo and iodo
  • cyano hydroxyl, -SO 2 alkyl, -SO2cycloalkyl -SO 2 heterocyclic, - CO 2 H, -CO 2 alkyl, -NH 2 , -NHalkyl, -N(alkyl) 2 (e.g. dimethylamino), -CO-N(alkyl) 2 and -CO-NH(alkyl).
  • Most typical substituent groups are selected from alkyl, alkoxy, halo, nitro and hydroxyl.
  • substituted aryl groups include 4-fluoro-phenyl, 3-fluoro-phenyl, pentafluoro-phenyl, 4-hydroxyphenyl-, 3-nitro-phenyl-, 4-(trifluoromethyl)-phenyl-, 4- anilinyl-, 2-biphenylyl-, 3-biphenylyl- and 4-biphenylyl-.
  • substituted heteroaryl groups include N-methyl-2-pyrrolyl, 2-methyl-1-pyrrolyl, 3-methyl-2-pyrrolyl and 3-phenyl-1-pyrrolyl.
  • Examples of -alkylaryl include phenylmethyl- (i.e. benzyl) and phenylethyl, 2- phenyleth-1-yl, p-tolyl-methyl-, p-tolyl-ethy!-, m-tolyl-methyl-, m-tolyl-ethyl-, o-tolyl- methyl-, o-tolyl-ethyl-, 2-(4-ethyl-phenyl)-eth-1-yl-, 2,3-dimethyl-phenyl-methyl-, 2,4- dimethyl-phenyl-methyl-, 2,5-dimethyl-phenyl-methyl-, 2,6-dimethyl-phenyl-methyl-, 3,4-dimethyl-phenyl-methyl-, 3,5-dimethyl-phenyl-methyl-, 2,4,6-trimethyl-phenyl- methyl-, 2,3-dimethyl-phenyl-ethyl-, 2,4-
  • diphenyl-methyl diphenyl-ethyl
  • trityl i.e. thphenyl-methyl
  • triphenyl-ethyl cumyl (i.e. 1-methyl-1 -phenylethyl), 2- ethyl-phenyl-methyl-, 3-ethyl-phenyl-methyl-, 4-ethyl-phenyl-methyl-, 2-ethyl-phenyl- ethyl-, 3-ethyl-phenyl-ethyl-, 4-ethyl-phenyl-ethyl-, 2-fluoro-benzyl, 1-methyl-2-fluoro- phen-6-yl-methyl-, 1-methyl-2-fluoro-phen-4-yl-methyl-, 1 -methyl-2-fluoro-phen-6-yl- ethyl-, 1-methyl-2-fluoro-phen-4-yl-ethyl-, 1 H-indenyl-methyl-, 2H
  • Examples of -alkylheteroaryl include pyridinylmethyl- (eg 2-pyridinylmethyl), N- methyl-pyrroI-2-methyl- N-methyl-pyrrol-2-ethyl-, N-methyl-pyrrol-3-methyl-, N- methyl-pyrrol-3-ethyl-, 2-methyl-pyrrol-1 -methyl-, 2-methyl-pyrrol-1 -ethyl-, 3-methyl- pyrrol-1 -methyl-, 3-methyl-pyrrol-1 -ethyl-, 4-pyridino-methyl-, 4-pyridino-ethyl-, 2- (thiazol-2-yl)-ethyl-, tetrahydroisochinolinyl-methyl-, tetrahydroisochinolinyl-ethyl-, 2- ethyl-indol-1 -methyl-, 2-ethyl-indol-1 -ethyl-, 3-ethyl-indo
  • Amino acids which can be used in the present invention are L and D-amino acids, N- alkylated amino acids, N-methyl-amino acids, allo- and f ⁇ reo-forms of lie and Thr, which can, e.g. be ⁇ -, ⁇ - or ⁇ -amino acids, whereof ⁇ -amino acids are preferred.
  • amino acids are: aspartic acid (Asp), glutamic acid (GIu), arginine (Arg), lysine (Lys), histidine (His), glycine (GIy), serine (Ser), cysteine (Cys), threonine (Thr), asparagine (Asn), glutamine (GIn), tyrosine (Tyr), alanine (Ala), proline (Pro), valine (VaI), isoleucine (lie), leucine (Leu), methionine (Met), phenylalanine (Phe), tryptophan (Trp), hydroxyproline (Hyp), beta-alanine (beta-Ala), 2-aminooctanoic acid (Aoa), acetidine- (2)-carboxylic acid (Ace), pipecolic acid (Pip), 3-aminopropionic acid, 4-aminobutyric acid and so forth, alpha-aminoisobutyl
  • t ⁇ -amino acids are e.g.: 5-Ara (aminoraleric acid), 6-Ahx (aminohexanoic acid), 8-Aoc (aminooctanoic acid), 9-Anc (aminovanoic acid), 10-Adc (aminodecanoic acid), 11- Aun (aminoundecanoic acid), 12-Ado (aminododecanoic acid).
  • amino acids are: indanylglycine (IgI), indoline-2-carboxylic acid (Idc), octahydroindole-2-carboxylic acid (Oic), diaminopropionic acid (Dpr), diaminobutyric acid (Dbu), naphtylalanine (1- NaI) and (2-NaI), 4-aminophenylalanine (Phe(4-NH 2 )), 4-benzoylphenylalanine (Bpa), diphenylalanine (Dip), 4-bromophenylalanine (Phe(4-Br)), 2-chlorophenylaIanine (Phe(2-CI)), 3-chlorophenylalanine (Phe(3-CI)), 4-chlorophenylaIanine (Phe(4-CI)), 3,4-chlorophenylalanine (Phe (3,4-Cl 2 )), 3-fluorophenylalanine (Phe
  • aza-amino acid is defined as an amino acid where the chiral ⁇ -CH group is replaced by a nitrogen atom.
  • Proteinogenic amino acids are defined as natural protein-derived ⁇ -amino acids (e.g. the 20 common natural L-amino acids i.e.: L-Asp (aspartic acid), L-GIu (glutamic acid), L-Arg (arginine), L-Lys (lysine), L-His (histidine), GIy (glycine), L-Ser (serine), L-Cys (cysteine), L-Thr (threonine), L-Asn (asparagine), L-GIn (glutamine), L-Tyr (tyrosine), L-AIa (alanine), L-Pro (proline), L- VaI (valine), L-IIe (isoleucine), L-Leu (leucine), L-Met (methionine), L-Phe (phenyla
  • Non-cyclic amino acids include the above mentioned amino acids but excluding cyclic amino acids such as Pro and the various derivatives thereof (eg 3,4- dehydroproline (A-Pro), 4-ketoproline (Pro(4-keto)) and thioproline (Thz)).
  • Non cyclic aza amino acids include the aza derivatives of those amino acids and excluding the cyclic aza amino acids such as the aza derivative of Pro and its various derivatives (eg the aza derivatives of 3,4-dehydroproline (A-Pro), 4-ketoproline (Pro(4-keto)) and thioproline (Thz)).
  • the pharmaceutically acceptable salt may take a form in which a basic side chain is protonated with an inorganic or organic acid.
  • organic or inorganic acids include hydrochloric, hydrobromic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid.
  • an acidic side chain forms a salt with a metal ion (eg sodium, potassium ions and the like) or other positive ion such as ammonium.
  • a metal ion eg sodium, potassium ions and the like
  • other positive ion such as ammonium.
  • Polymorph crystal forms and solvates Furthermore, some of the crystalline forms of the compounds may exist in more than one polymorphic form and as such all forms are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the present invention further includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound.
  • the term “administering” shall encompass the treatment of the various disorders described with prodrug versions of one or more of the claimed compounds, but which converts to the above specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H.
  • composition is intended to encompass a product comprising the claimed compound(s) in the therapeutically effective amounts, as well as any product which results, directly or indirectly, from combinations of the claimed compounds.
  • the present invention provides compounds acting as inhibitors of prolyl endopeptidase (PEP, EC 3.4.21.26) and PEP-like enzymes. These compounds, together with their pharmaceutically acceptable salts and stereoisomers thereof, are represented by the general formula 1
  • W-KCONH-X-CON-Y-CO-Z formula 1 wherein W represents alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, carbocyclyl, aryl, - alkylaryl or -alkylheteroaryl;
  • K represents O, NH or CH 2 ; or K is absent and W-CO represents the moiety of an amino acid or aza-amino acid;
  • NH-X-CO represents the moiety of non-cyclic amino acid or non-cyclic aza-amino acid, wherein when NH-X-CO represents the moiety of Asp or GIu the acid side chain of said Asp or GIu may optionally be joined via a peptide bond to another amino acid or aza-amino acid;
  • N-Y-CO- is selected from a moiety of formula 2a, 2b, 2c, 2d, 2e, 2f and 2g:
  • R 1 -R 15 and R 17 -R 19 are independently H or an alkyl chain, alkenyl chain, alkynyl chain, cycloalkyl, a carbocycle, aryl, heteroaryl, heterocycle, or a group selected from halogen, amino, -CONH 2 , CONH(alkyl), -CON(alkyl) 2 , nitro, hydroxyl, - CN and -SCN; or else R 2 /R 3 , R 4 /R 5 , R 6 /R 7 , R 9 /R 10 , R 11 /R 12 together with the carbon atom to which they are attached independently represent oxo; or else R 3 and R 5 are connected to form a benzene ring fused to the azetidine ring (in which case R and R are absent) or R ,10 and R 11 are connected to form a benzene ring fused to the piperidine ring (in which case R 9 and R 12 are absent);
  • R 16 is the side chain of an amino acid moiety
  • X 1 is CR 20 R 21 , O, S, SO, SO 2 or NR 22
  • X 2 is CR 23 R 24 , O, S, SO, SO 2 or NR 25
  • X 3 is CR 26 R 27 , O, S, SO, SO 2 or NR 28
  • R 22 , R 25 and R 28 independently of each other, are H, alkyl, alkenyl, alkynyl, cycloalkyl, carbocycle, heterocycle, aryl, heteroaryl, aryl-alkyl or a heteroaryl-alkyl group;
  • R 20 , R 21 , R 23 , R 24 , R 26 and R 27 are H, alkyl, alkenyl, alkynyl, cycloalkyl, carbocycle heterocycle, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl group or, a carbaldehyde (-CHO), a ketone group (-CO-R 29 ), a boronic acid group (-B(OH) 2 ), a cyano group (-C ⁇ N), a carboxylic acid group (-COOH), a carboxylic acid ester group (-COOR 30 ), a carboxylic acid anhydride group (-CO-O-CO-R 31 ), a hydroxamic acid group (-CO-NH(OH)), a N-substituted hydroxamic acid group (-CO- NR 32 (OH)), a O-substituted hydroxamic acid group (-CO-NH(OR 33
  • X 4 is CR 52 or N;
  • X 5 is CR 53 or N;
  • R 52 and R 53 independently of each other, are H, alkyl, alkenyl, alkynyl, cycloalkyl, carbocycle, heterocycle, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl, aryl-heteroalkyl, heteroaryl-heteroalkyl group or, a carbaldehyde (-CHO), a ketone group (-CO-R 54 ), a boronic acid group (-B(OH) 2 ), a cyano group (-C ⁇ N), a carboxylic acid group (-COOH), a carboxylic acid ester group (-COOR 55 ), a carboxylic acid anhydride group (-CO-O-CO-R 56 ), a hydroxamic acid group (-CO-NH(OH)), a N-substituted hydroxamic acid group ( : CO
  • Figure 1 Quantification of basal medium IL-6 in human glial U-343 cells treated with different PEP inhibitors.
  • the conditioned medium of human glial U343 cells, treated with PEP inhibitors over 24 hours contained only 15% to 60% of IL-6 amount measured in untreated control samples. Values are presented as mean ⁇ SD of quadruplicate wells and were analyzed for statistical significance by unpaired t test ( * * * p ⁇ 0.001).
  • Figure 2 Quantification of basal A ⁇ 1-42 value in human neuroblastoma SH-SY5Y cells treated with different PEP inhibitors.
  • the conditioned medium of human glial U343 cells, treated with PEP inhibitors over 24 hours contained 87.5% to 546% of A ⁇ 1-42 amount measured in untreated control samples. Values are presented as mean + SD of quadruplicate wells and were analyzed for statistical significance by unpaired f test ( * * * p ⁇ 0.001).
  • Figure 3 PEP catalysed degradation of humanin - positive control without inhibitor. The cleavage products are determined by matrix-assisted laser desorption mass spectrometry.
  • HN 1-24 represents full length humanin.
  • HN 9-24 represents post cysteine cleaved humanin 9-24.
  • Figure 4 PEP catalysed degradation of humanin - PEP inhibitor Example 2 present. The cleavage products are determined by matrix-assisted laser desorption mass spectrometry.
  • HN 1-24 represents full length humanin.
  • HN 9-24 represents post cysteine cleaved humanin 9-24.
  • Figure 5 PEP catalysed degradation of humanin - PEP inhibitor Example 2 present.
  • the cleavage products are determined by matrix-assisted laser desorption mass spectrometry.
  • HN 1-24 represents full length humanin.
  • HN 9-24 represents post cysteine cleaved humanin 9-24.
  • W represents -alkylaryl (eg -methylaryl), -alkylheteroaryl (eg methylheteroaryl), alkyl, alkenyl, alkynyl or cycloalkyl. More preferably W represents alkenyl- (eg C 2-6 alkenyl), alkyl- (eg C 2-6 alkyl) or arylalkyl- (eg arylmethyl-), especially arylalkyl- (eg arylmethyl).
  • aryl may for example represent phenyl optionally substituted by alkyl and/or halo.
  • heteroaryl may for example represent pyridyl optionally substituted by alkyl and/or halo.
  • W -CO When K is absent and W -CO represents the moiety of an amino acid or aza amino acid, W -CO may for example represent the moiety of L- Phe (i.e W is - CH(NH 2 )(CH 2 Ph) or L-Tyr (i.e. W is -CH(NH 2 )(CH 2 PhOH)
  • K represents O or CH 2 , especially O.
  • W-K-CO represents aliyloxycarbonyl (Aloe), f-butyloxycarbonyl (Boc) or benzyloxycarbonyl (Cbz), particularly benzyloxycarbonyl.
  • L-Lys i.e. X is (CHz) 4 NH 2 ).
  • R 16 will represent the sidechain of a proteinogenic amino acid.
  • groups of group R 16 include H, methyl, -CH 2 OH, -CH(Me)OH, CHMe 2 , CH 2 CHMe 2 , CH(Me)CH 2 Me, CH 2 CH 2 CONH 2 , -CH 2 COOH, -CH 2 CONH 2 and CH 2 CH 2 COOH.
  • N-Y-CO represents a moiety of formula 2a, 2e, 2f or 2g.
  • N-Y-CO represents a moiety of formula 2b or 2c.
  • N-Y-CO represents a moiety of formula 2d, especially wherein R 16 represents alkyl eg methyl (i.e. the moiety of Ala, especially L-AIa).
  • N-Y-CO represents a moiety of formula of 2h or 2i:
  • R 77 and R 78 independently represent H, halogen, CN or alkyl eg H, CN or Me.
  • R 77 and R 78 may for example independently represent CN. Alternatively they may independently represent Me. Preferably they independently represent H.
  • N-Y-CO represents a moiety of formula 2j or 2k:
  • R 77 and X 1 are as defined above and R 80 and R 81 are independently H or fluoro.
  • N-Y-CO represents L-Pro in which the pyrrolidine ring is optionally substituted by methyl, eg a moiety of formula 2j in which R 77 represents H or methyl and X 1 represents CH 2 , especially unsubstituted L-Pro.
  • R 1 -R 15 and R 17 -R 19 independently represent H, halogen (eg F), CN or alkyl (eg Me) eg H, CN or Me, especially H.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 17 , R 18 and R 19 are halogen (eg F) or H, especially H.
  • R 20 , R 21 , R 23 , R 24 , R 26 , R 27 , R 28 , R 52 and R 53 are H.
  • groups R 29 -R 51 represent H.
  • R 54 -R 76 represent H.
  • X 1 represents CH 2 or CHMe, particularly CH 2 .
  • X 2 represents CH 2 or CHMe, particularly CH 2 .
  • X 3 represents CH 2 or CHMe, particularly CH 2 .
  • X 4 represents CH or CMe, particularly CH.
  • X 5 represents CH or CMe, particularly CH.
  • n represents 0 or 1, particularly 0.
  • m represents 0 or 1 , particularly 0.
  • Z represents a 5-membered heteroaryl ring optionally fused to a benzene ring (especially when linked to the remainder of the molecule through the 5- membered heteroaryl ring) more preferably 2-furan, 2-imidazole, 2-thiazole, 4- thiazole, 5-thiazole, 2-thiophene, 3-thiophene, 2-oxazole, 4-oxazole, 5-oxazole, 2- pyrrole, 3-pyrrole, 2-benzo[d]imidazole, 2-benzo[d]thiazole, 2-benzo[b]thiophene, 3- benzo[b]thiophene, 2-benzo[d]oxazole, 2-indole, 3-indole, or is selected from a moiety of formula 3a, 3b, 3c, 3d or 3e:
  • R 82 ,R 83 , R 84 , R 85 and R 86 are independently H or an alkyl chain, alkenyl chain, alkynyl chain, cycloalkyl, a carbocycle, aryl, heteroaryl, heterocycle, or a group selected from halogen, amino, -CONH 2 , CONH(alkyl), -CON(alkyl) 2 , nitro, hydroxyl, oxo, -CN and -SCN.
  • Groups R ⁇ 82 , DR83 , D R84 , D R8 o 5 s and R 5 8 b 6 b are typically H or alkyl (eg methyl), more typically H.
  • Z more preferably is 2-imidazole, 2-thiazole, 4-thiazole, 5-thiazole, 2-thiophene, 3- thiophene, 2-oxazole, 4-oxazole, 5-oxazole, 3-pyrazole, 4-pyrazoIe, 5-pyrazole, 2- pyrrole, 3-pyrrole, 3-triazole, 2-benzo[d]imidazole, 2-benzo[d]thiazole, 2- benzo[b]thiophene, 3-benzo[b]thiophene, 2-benzo[d]oxazole, 2-indole or 3-indole, especially 2-thiazole or 2-benzo[d]thiazole.
  • Another group of particular interest is pyrrole eg 2-pyrrole.
  • the PEP-inhibitors of the present invention are shown to be surprisingly effective to modulate the basal level of interleukin-6 (IL-6) in human glial cells. These compounds show a significant suppression of IL-6 secretion. This is not known for any PEP-inhibitor described in the prior art.
  • IL-6 interleukin-6
  • IL-6 a pleiotropic cytokine
  • Overexpression of IL-6 has been implicated in the pathology of multiple myeloma, solid tumors, prostatic cancers, bladder cancers, neurological cancers, Castleman ' s disease, inflammation, myocardial infarction, Pagef s disease, ischemia, asthma, rheumatoid arthritis, psoriasis, Alzheimer ' s disease, multiple sclerosis, meningitis, stroke, osteoporosis, insulin resistance, obesity, impaired glucose tolerance, type 2 diabetes, cancer-related anorexia and cachexia as well as multidrug resistance. Therefore, reduct on of pathological IL-6 concentrations by compounds which are described here may be useful in treatment of IL-6 related diseases, for instance those mentioned above.
  • the PEP-inhibitors of the present invention are shown to be surprisingly effective at modulating the basal level of ⁇ -amyloid peptides, especially of APi -4O and APi -42 in different human cell lines, e.g. neuronal cells.
  • the compounds of the present invention show a significant increase of the secretion of ⁇ -amyloid peptides. This is not known for any PEP-inhibitor described in the prior art.
  • ⁇ -amyloid peptides are considered to be the cause of neurodegeneration and neuronal cell death in patients faced with MCI (Mild Cognitive Impairment)
  • AD Alzheimer's disease
  • MCI MCI-associated cognitive dysfunction
  • AD Alzheimer's disease
  • ⁇ -amyloid species which are involved in the onset of MCI and AD, are formed intracellular ⁇ .
  • N-terminally truncated and N-terminally modified forms of ⁇ -amyloid peptides e.g. A ⁇ 3-40 , A ⁇ 3-42 , pGlu-A ⁇ 3-4 o, pGlu-A ⁇ 3-42 , A ⁇ 11-42 and pGlu-A ⁇ i 1-42 are discussed as the toxic forms (Piccini et al., J. Biol. Chem. 280 (40), 2005, pp. 34186-34192).
  • the compounds of the present invention should therefore be useful to prevent the formation of neurotoxic ⁇ -amyloid peptides, e.g. A ⁇ 3-40 , A ⁇ 3-42 , pGlu-A ⁇ 3-40 , pGlu-A ⁇ 3- 42 , A ⁇ 11-42 and pGlu-A ⁇ n -42 by enhancement of the secretion of full-length A ⁇ i -40 and A ⁇ i -42 before N-terminal truncation and modification.
  • neurotoxic ⁇ -amyloid peptides e.g. A ⁇ 3-40 , A ⁇ 3-42 , pGlu-A ⁇ 3-40 , pGlu-A ⁇ 3- 42 , A ⁇ 11-42 and pGlu-A ⁇ n -42 by enhancement of the secretion of full-length A ⁇ i -40 and A ⁇ i -42 before N-terminal truncation and modification.
  • a protease is able to cleave a substrate after a cysteine residue in the peptide chain.
  • the peptide humanin is a substrate for PEP.
  • prolyl endopeptidase is able to cleave the peptide humanin at two positions in the peptide sequence, after the proline residue in position 3 and after the cysteine residue at position 8. This cleavage pattern can be completely inhibited by the use of specific PEP inhibitors.
  • Humanin was originally discovered by means of a unbiased functional screening for genes suppressing FAD (familial Alzheimer's disease) and A ⁇ induced neuronal cell death, respectively [30, 32].
  • the peptide is an unusually 75 bp gene product of the mitochondrial 16S ribosomal RNA [27,30].
  • the evidence for a cellular expression of this gene product was given by Western blots using a peptide-antibody [33].
  • a detailed analysis of the physiological activity revealed the existence of a humanin core domain (residues 3 to 19) [34,35].
  • PEP-inhibitors are useful for the prevention of the degradation of peptide substrates, which can be degraded by post cysteine cleavage, e.g. the peptide humanin.
  • the present invention provides a method for the prevention of the degradation of peptide substrates, which can be degraded by post cysteine cleavage, e.g. the peptide humanin.
  • the compounds of formula (I) are especially suitable for use in this method.
  • the compounds of the present invention have several unique and surprising properties and are expected to be useful for the treatment of neurodegenerative diseases, e.g. MCI, AD, Down Syndrome, Parkinson disease and Chorea Huntington.
  • neurodegenerative diseases e.g. MCI, AD, Down Syndrome, Parkinson disease and Chorea Huntington.
  • a process for preparing compounds of formula 1 comprises reacting a compound of formula A with a compound of formula B under conditions of metallation.
  • Dipeptides of formula A are activated molecules (Weinrebamides), which may be reacted with a organometallic (eg organolithium) derivatives of compounds of formula B.
  • Dipeptides of formula A may be prepared by reacting a dipeptide of formula C (usually activated eg as a mixed anhydride) with a compound of formula D (Weinreb activating group).
  • Compounds of formula C may be prepared by hydrolysing a compound of formula E (ester).
  • Compounds of formula E may be prepared by reacting a compound of formula F ( ⁇ /-protected amino acid derivative) (typically activated eg as the mixed anhydride) with a compound of formula G (C-protected amino acid derivative).
  • a process for preparing compounds of formula 1 comprises oxidising a precursor compound characterised as alcohol of formula H.
  • Compounds of formula H are accessible from compounds of formula J (Z-component with free ⁇ /-terminus) via a coupling reaction.
  • Compounds of formula J are typically obtained by deprotection of protected derivatives of formula K.
  • intermediate compounds of formula E may be converted directly to a compound of formula (I) by arylation with a Grignard reagent (see Scheme 4).
  • a process for preparing a compound of formula (1) which comprises:
  • Compounds of formula Q may be prepared by reacting the heteroaryl compound Z with a suitable alkyl magnesium halide compound such as MeMgBr.
  • Table 1 References disclosing the synthetic routes and synthesis schemes of compounds of formula M (or close analogue) when Y represents formula 2a, 2c, 2e, 2f, 2g, 2h, 2i, 2j and 2k
  • the present invention provides the compounds of formula 1 for use as a medicament.
  • the compounds of formula 1 are inhibitors of PEP and PEP-like enzymes.
  • the present invention provides the use of inhibitors of PEP and PEP- like enzymes of the formula 1 for the preparation of a medicament for the treatment of a disease selected from the group consisting of Alzheimer's disease, Down Syndrome, Parkinson disease, Chorea Huntington, pathogenic psychotic conditions, schizophrenia, impaired food intake, sleep-wakefulness, impaired homeostatic regulation of energy metabolism, impaired autonomic function, impaired hormonal balance, impaired regulation, body fluids, hypertension, fever, sleep dysregulation, anorexia, anxiety related disorders including depression, seizures including epilepsy, drug withdrawal and alcoholism, neurodegenerative disorders including cognitive dysfunction, dementia, aphasia, apraxia, agnosia, or any type of amnesias, mild cognitive impairment (MCI), benign forgetfulness and Korsakoff's syndrome, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or post-cardiac transplant coronary arteriopathy, atherosclerosis, reperfusion
  • the present invention also provides inhibitors of PEP and PEP-like enzymes of the formula 1 for use in the treatment of a disease selected from the group consisting of Alzheimer's disease, Down Syndrome, Parkinson disease, Chorea Huntington, pathogenic psychotic conditions, schizophrenia, impaired food intake, sleep- wakefulness, impaired homeostatic regulation of energy metabolism, impaired autonomic function, impaired hormonal balance, impaired regulation, body fluids, hypertension, fever, sleep dysregulation, anorexia, anxiety related disorders including depression, seizures including epilepsy, drug withdrawal and alcoholism, neurodegenerative disorders including cognitive dysfunction, dementia, aphasia, apraxia, agnosia, or any type of amnesias, mild cognitive impairment (MCI), benign forgetfulness and Korsakoff's syndrome, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or post-cardiac transplant coronary arteriopathy, atherosclerosis, reperfusion injury, hypoxia, ischemia and
  • the present invention also provides a method of treatment for a disease selected from the group consisting of Alzheimer's disease, Down Syndrome, Parkinson disease, Chorea Huntington, pathogenic psychotic conditions, schizophrenia, impaired food intake, sleep-wakefulness, impaired homeostatic regulation of energy metabolism, impaired autonomic function, impaired hormonal balance, impaired regulation, body fluids, hypertension, fever, sleep dysregulation, anorexia, anxiety related disorders including depression, seizures including epilepsy, drug withdrawal and alcoholism, neurodegenerative disorders including cognitive dysfunction, dementia, aphasia, apraxia, agnosia, or any type of amnesias, mild cognitive impairment (MCI), benign forgetfulness and Korsakoff's syndrome, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or post-cardiac transplant coronary arteriopathy, atherosclerosis, reperfusion injury, hypoxia, ischemia and blood coagulation disorders, comprising the administration of a therapeutically
  • the present invention provides a method of treatment and corresponding uses for a disease selected from the group consisting of mild cognitive impairment (MCI), Alzheimer's disease, Down Syndrome, Parkinson disease and Chorea Huntington, comprising the administration of a therapeutically active amount of at least one compound of formula 1 to a mammal, preferably a human.
  • MCI mild cognitive impairment
  • Alzheimer's disease Down Syndrome
  • Parkinson disease Chorea Huntington
  • the compounds of formula 1 are useful to inhibit microbial growth, reduce perioperative blood loss, preserve transplantation tissues or organs, inhibit cancer cell growth or tumor progression or tumor metastasis or invasion.
  • the present invention provides a composition, preferably a pharmaceutical composition comprising at least one compound of formula 1 optionally in combination with at least one compound selected from the group consisting of inhibitors of glutaminyl cyclase (QC), LiCI, inhibitors of dipeptidyl aminopeptidases, preferably inhibitors of DP IV or DP IV-like enzymes, NPY-receptor ligands, NPY agonists, acetylcholinesterase (AChE) inhibitors, protein isoaspartate carboxymethyl transferase (PIMT) enhancers, inhibitors of beta secretases, inhibitors of gamma secretases, inhibitors of neutral endopeptidase, inhibitors of Phosphodiesterase-4 (PDE-4), monoamine oxidase (MAO) inhibitors, TNFalpha inhibitors, amyloid protein or amyloid peptide deposition inhibitors, sigma-1 receptor inhibitors and histamine H3 antagonists.
  • QC glutaminyl cycl
  • Down Syndrome Parkinson disease, Chorea Huntington, pathogenic psychotic conditions, schizophrenia, impaired food intake, sleep-wakefulness, impaired homeostatic regulation of energy metabolism, impaired autonomic function, impaired hormonal balance, impaired regulation, body fluids, hypertension, fever, sleep dysregulation, anorexia, anxiety related disorders including depression, seizures including epilepsy, drug withdrawal and alcoholism, neurodegenerative disorders including cognitive dysfunction, dementia, aphasia, apraxia, agnosia, or any type of amnesias, mild cognitive impairment (MCI), benign forgetfulness and Korsakoff's syndrome, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or post-cardiac transplant coronary arteriopathy, atherosclerosis, reperfusion injury, hypoxia, ischemia and blood coagulation disorders.
  • MCI mild cognitive impairment
  • the combinations of the present invention are further useful to inhibit microbial growth, reduce perioperative blood loss, preserve transplantation tissues or organs, inhibit cancer cell growth or tumor progression or tumor metastasis or invasion.
  • the invention provides pharmaceutical compositions containing at least one compound of formula 1 optionally in combination with at least one agent as mentioned for the combinations above, together with one or more therapeutically acceptable diluents or carriers.
  • the active ingredient(s) is intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques, which diluent or carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • Soluble polymers as targetable drug carriers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamide- phenol, or polyethyleneoxidepolyllysine substituted with palmitoyl residue.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Injectable suspensions may also prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient(s) necessary to deliver an effective dose as described above.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, from about 0.03 mg to 100 mg/kg (preferred 0.1 - 30 mg/kg) and may be given at a dosage of from about 0.1 - 300 mg/kg per day (preferred 1 -
  • each active ingredient or combination thereof 50 mg/kg per day) of each active ingredient or combination thereof.
  • the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
  • compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of each active ingredient or combinations thereof of the present invention.
  • the tablets or pills of the compositions of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
  • the processes for the preparation of the compounds of the present invention give rise to mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • liquid forms in suitable flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • suitable suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • tragacanth for example, tragacanth, acacia, methyl-cellulose and the like.
  • methyl-cellulose methyl-cellulose and the like.
  • suitable suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • the compounds or combinations of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds or combinations of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamid-ephenol, or polyethyl eneoxidepolyllysine substituted with palmitoyl residue.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross- linked or amphipathic block copolymers of hydrogels.
  • Compounds or combinations of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of the addressed disorders is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1.000 mg per mammal per day.
  • the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of each active ingredient or combinations thereof for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 300 mg/kg of body weight per day.
  • the range is from about 1 to about 50 mg/kg of body weight per day.
  • the compounds or combinations may be administered on a regimen of 1 to 4 times per day.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • the particularly beneficial effect provided by the treatment of the invention is an improved therapeutic ratio for the combination of the invention relative to the therapeutic ratio for one compound of the combination when used alone and at a dose providing an equivalent efficacy to the combination of the invention.
  • the particularly beneficial effect provided by the treatment of the invention is indicated to be a synergistic effect relative to the control expected from the effects of the individual active agents.
  • combining doses of at least one compound of formula 1 with at least one agent as defined for the combinations herein will preferably produce a greater beneficial effect than can be achieved for either agent alone at a dose twice that used for that agent in the combination.
  • the dosage level of each of the active agents when used in accordance with the treatment of the invention will be less than would have been required from a purely additive effect upon the neuronal condition.
  • the treatment of the invention will effect an improvement, relative to the individual agents, in decreasing the intracellular deposition of pGlu-amyloid-beta-peptides and thereby dramatically slowing down the plaque formation in the brain of a mammal, preferably in human brain.
  • the invention also provides a process for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising at least one at least one compound of formula 1 optionally in combination with at least one agent as defined for the combinations herein and a pharmaceutically acceptable carrier therefor, which process comprises admixing the compound of formula 1 and said optional agent(s) and a pharmaceutically acceptable diluent or carrier.
  • the compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.
  • Preferred compounds of formula 1 are those having an IC 5O value or a K 1 value, and preferably an IC 50 value and a Kj value, of less than 1x10 "6 , in particular less than 1x1 CT 7 and especially less than 1x10 8 M.
  • Preferred compounds of formula 1 have a molecular weight of less than 2000 Da especially less than 1000 Da particularly less than 600Da, e.g. less than 500 Da.
  • Compounds and combinations of the invention may have the advantage that they are, for example, more potent, more selective, have fewer side-effects, have better formulation and stability properties, have better pharmacokinetic properties, be more bioavailable, be able to cross blood brain barrier and are more effective in the brain of mammals, are more compatible or effective in combination with other drugs or be more readily synthesized than other compounds of the prior art.
  • the invention embraces all combinations of preferred and more preferred groups and embodiments of groups recited above. Examples
  • the chromogenic substrate Cbz-Gly-L-Pro-pNA was used in HEPES buffer pH 7.6 containing 50 mM HEPES, 200 mM NaCI, 1 mM EDTA, 1 mM DTT, 0.006 % Brij35. Measurements were carried out at 30 0 C. Release of pNA were monitored continuously at 405 nm.
  • IC 50 values were determined using one substrate concentration (0.15 mM) and 11 - 15 serial dilutions of inhibitor starting with 0.1 mM. IC 50 values were calculated using non-linear regression to a 4-parameter equation (Prism 4.0, GraphPad).
  • the human glioma cell line, U-343 and the human neuroblastoma cell line, SH-SY5Y were maintained in Dulbecco ' s modified Eagle ' s medium (DMEM) containing 10% fetal bovine serum (Gibco BRL, Düsseldorf, Germany) and incubated at 37°C in a 5% CO 2 atmosphere.
  • Culture media contained in general 60 ⁇ g/ml gentamycin (Gibco BRL, Düsseldorf, Germany).
  • the radiolabeled proteins in the chase medium were precipitated with 8%(w/v) TCA-solution and centrifuged at 15500 x g for 10 min. After washing, the protein pellets were resuspended in 1 ml of distilled water and the radioactivity was measured in a Tri- carb2100TR-scintillation counter (Packard, Dreieich, Germany). All measurements were carried out at least in quadruplicate, and the experiment was repeated four times.
  • ⁇ -Amyloid ELISA To quantify intracellular and extracellular concentrations of ⁇ -amyloid peptides, 1-40 and 1-42, U-343 and SH-SY5Y cells were cultured in 6 well plates (1.5x10 6 cells/well) and treated with specific PEP inhibitors (20 ⁇ M each) for 24 hours. For quantitation of secreted ⁇ -amyloid peptides the conditioned medium was collected and concentrated by lyophylisation. Likewise , after determination of the cell numbers/well (easy cell counter I, Scharfe System, Reutlingen, Germany), cells were lyzed with cell extraction buffer (Biosource, Solingen, Germany) according to the manufacturer ' s protocol. The protein concentration was determined by the method of Bradford (1976).
  • the preferred PEP inhibitors of the present invention show a significant reduction of the IL-6 level and an increased ⁇ -amyloid secretion, especially of ⁇ -amyloid peptides 1-40 and 1-42. (see results shown in Fig. 1 and Fig. 2).
  • the peptide humanin is used as substrate.
  • the peptide humanin comprises 24 amino acids of the following sequence:
  • rhPEP is able to cleave humanin at two positions in the peptide sequence: after the proline residue in position 3 and after the cysteine residue at position 8.
  • the cleavage of humanin by PEP can be inhibited with specific PEP inhibitors of formula (I).
  • the inhibitors of formula (I) prevent both the post proline and the subsequent post cysteine cleavage in the humanin sequence.
  • All inhibitors are solved in 100% DMSO.
  • the final concentration of the inhibitors in the stock solution is 2 mM.
  • the DMSO stock solutions are stored at -20 0 C.
  • the Humanin peptide is solved in 100% DMSO first and then is diluted with PEP buffer until a final concentration of 1mg/ml, taking care that the final concentration of DMSO doesn't exceed 10% of this solution.
  • the Humanin stock solution is stored at -20 0 C.
  • PEP buffer which consists of 270 mM HEPES (ROTH), 1080 mM NaCI (ROTH), 5,4 mM EDTA (MP Biomedicals), 0,03% 30-35 w/v BRIJ® Solution (Sigma Diagnostics), 7,96 mM DTT ( Sigma).
  • the enzyme is stored at -20 0 C in a 50% ethylene glycol stock solution.
  • the rhPEP stock solution is diluted 1 :20 in PEP buffer.
  • the inhibitor stock solutions are diluted 1 :10 to 1 :20 in water. Afterwards, the inhibitor solutions are mixed with an equal volume of 1mg/ml Humanin stock solution in PEP buffer.
  • inhibitor/substrate solution 90 ⁇ l of the inhibitor/substrate solution is then mixed with 10 ⁇ l of enzyme solution. This mixture is incubated at 37°C over the complete reaction time. The final inhibitor and substrate concentration is 80 ⁇ M (inhibitor) and 0,45 mg/ml (humanin) respectively. The reaction is stopped at the following time points: 10, 30, 60, 120, 240, 480, 1440 minutes) by mixing 10 ⁇ l of the reaction mixture with 10 ⁇ l 0,1% TFA in water.
  • Figure 3 shows the production of humanin cleavage product HN 9-24 in the presence of PEP.
  • Figures 4 and 5 show that HN 9-24 is not produced in the presence of PEP when PEP inhibitors are present.
  • LiAIH 4 Lithium aluminium hydride
  • NMR spectra were performed on Bruker AM 400 and Varian Unity 500 spectrometers. The following abbreviations are used: s (singlet), d (doublet), dd (doublet of doublets), t (triplet), and m (multiplet).
  • ESI-MS Mass spectra were taken with an MDS Sciex API 365 mass spectrometer equipped with an lonsprayTM interface (MDS Sciex; Thorn Hill, ON, Canada). The instrument settings, data acquisition and processing were controlled by the Applied Biosystems (Foster City, CA, USA) AnalystTM software for Windows NTTM. 50 - 100 scans were performed by the positive ionization Q1 scan mode to accumulate the peaks.
  • Sample solutions were diluted with 50% methanol in 0.5% formic acid to reach concentrations about 10 ⁇ g/ml.
  • Each sample solution was introduced directly by a microsyringe (1 ml) through an infusion pump (Havard Apperatus 22; Havard Instruments; Holliston, MA 1 USA) and fused silica capillary tubing at a rate of 20 ul/min.
  • Thin layer chromatography (TLC) was done using Macherey Nagel Polygram ® SIL G/UV 245 . Visualisation was accomplished by means of UV light at 254 nm, followed by dyeing with potassium permanganate or Cer-Molybdate-solution. Solvents were distilled prior to use.
  • Method B Ester hydrolysis: The ester (Intermediate E I, II; 1.0 equiv.) was dissolved in EtOH and 1 M NaOH was added (2.3 equiv.). The reaction mixture was stirred at room temperature and the conversion was checked by TLC. At the final end of conversion the pH of the mixture was adjusted to 2-3 with 1 N HCI. The organic material was extracted five times with EE. The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified by flash chromatography generating Intermediate C I, II.
  • Method C Metallation and Alkylation: A stirred solution of the heteroaryl compound (H-Z, 3.0 equiv.) in dry THF was cooled to -5O 0 C.
  • n-BuLi (3.0 equiv.) was added dropwise. After 10 minutes, a solution of (Intermediate A III, IV; 1.0 equiv.) in dry THF was added dropwise. The mixture was stirred for 30 minutes before the mixture was diluted with pH-7 buffer solution. The product was extracted with EE. The solvent was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude compound was purified by flash chromatography generating Examples 1 , 2, 4, 9, and 10.
  • Method D Reduction of carboxylic acid to alcohol: A mixed anhydride of a protected amino acid derivate (1.0 equiv.) was prepared according to Method A, filtered under an atmosphere of argon and cooled to -20 0 C. LiAIH 4 (1.5 equiv.) was added in portions in order to control the progress of the reaction. The mixture was stirred at - 20 0 C for 1 h and at room temperature for 2 h. The reaction mixture was hydrolysed with a 1 M KHSO 4 solution at 0 0 C. After warming to room temperature the crude product was extracted with EE, dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. Intermediate La I, Il were used without further purification. Method generates Intermediates La I 1 II.
  • Method E (Swern oxidation of alcohol to aldehyde): A stirred solution of oxalyl chloride (1.2 equiv.) in dry CH 2 CI 2 was cooled to -70°C. DMSO (2.6 equiv.) was added dropwise and the mixture was stirred for 30 minutes. A solution of the alcohol (Intermediate La I, II) in dry CH 2 CI 2 was added dropwise and the mixture was stirred for 2 h. NEt ⁇ (5.0 equiv.) was added and the mixture was allowed to warm to room temperature. The reaction mixture was diluted with water. After separation of the layers the organic phase was washed with water and brine and dried over Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure. The crude compound was purified by flash chromatography generating the Intermediate Lb I, II, N and Examples 3, 5, 6, 7.
  • Method F Metallation and Arylation: A stirred solution of the heteroaryl compound (H-Z) (1.1 equiv.) in dry THF was cooled to -78 0 C. ⁇ -BuLi (1.15 equiv.) was added dropwise. After 10 minutes, a solution of Intermediate Lb I, Il (1.0 equiv.) in dry THF was added dropwise. The mixture was stirred for 30 minutes before the mixture was diluted with pH-7 buffer solution. The product was extracted with EE. The solvent was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude compound was purified by flash chromatography generating the Intermediate K I, II.
  • Method G Deprotecting a protecting group: TFA (7.5 ml) was added to a mixture of the protected compound (Intermediate K I, II; 1.0 equiv.) and TIPS (2.5 equiv.) in dry CH 2 CI 2 (10 ml). This solution was stirred for 2 h at room temperature before it was diluted with toluol. The solvents were removed under reduced pressure and the obtained residue was used due to instability without further purification generating the Intermediate J I, II. This method was used to generate Example 8.
  • Method H Coupling reaction: The protected amino acid derivate (W-KCONH-X-COOH), 1.0 equiv.) was dissolved in dry DMF.
  • Method J (Arylation with Grignard reagent): A solution of methylmagnesium bromide (3.0 M in Et 2 O, 8.0 equiv.) in toluene (15 ml) was cooled to -30 0 C and treated with Z- H (pyrrole) (12 equiv.). After stirring for 10 minutes at -30 0 C, the solution was warmed up to 0 0 C and stirred for 30 minutes and was then cooled to -60 0 C. This prepared Grignard-solution was added to a solution of Intermediate E I in toluene (3 ml), which was cooled to -60 0 C. The mixture was stirred overnight and was allowed to warm to room temperature.
  • Example 11 The mixture was diluted with pH-7 buffer solution, diluted with EE and filtered. After separation of the layers, the water phase was extracted with EE (2 x), dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography generating Example 11.
  • a mixed anhydride was prepared according to Method A (W-KCONH-X-CON-Y- COOH: Cbz-L-Phe-L-Pro-OH). After stirring for 15 minutes, 1.0 equiv. of HCI * HN(CH 3 )OCH 3 in dry THF and NMM (1.0 equiv.) were added. The mixture was stirred overnight, during which time it was allowed to warm to room temperature. The solvent was evaporated in vacuo and the obtained residue was dissolved in EE, washed with 1 N HCI, water, aqueous NaHCO 3 , water and brine and dried over Na 2 SO 4 . After filtration the solvent was evaporated under reduced pressure. The crude compound was purified by flash chromatography generating Intermediate A III, yield of the purified compound: 81%.
  • Example 1 was prepared according to Route 1 via Intermediate E I, Intermediate C I, Intermediate A III and Method C (H-Z: Benzothiazole, yield of the purified compound: 82%).
  • Example 2 was prepared according Route 1 via Intermediate E II, Intermediate C II, Intermediate A IV and Method C (H-Z: Benzothiazole, yield of the purified compound: 17%).
  • Example 3 2-[Cbz-L-Phe-L-Ala]Benzothiazole
  • Example 3 was prepared according to Route 2 via Intermediate La I, Intermediate Lb I, Intermediate K I, Intermediate J I, Intermediate H I, Method E (yield of the purified compound: 28%).
  • Example 4 2-[Cbz-L-Phe-L-Pro]Thiazole
  • Example 4 was prepared according to Route 1 via Intermediate E I, Intermediate C I, Intermediate A III and Method C (H-Z: Thiazole, yield of the purified compound: 19%).
  • Example 5 2-[Cbz-L-Arg-L-Pro]Benzothiazole Example 5 was prepared according to Route 2 via Intermediate La II, Intermediate Lb II, Intermediate K Ii, Intermediate J II, Intermediate H II, Method E (yield of the purified compound: 38%).
  • Example 6 was prepared according to Route 2 via Intermediate La II, Intermediate Lb II, Intermediate K II, Intermediate J II, Intermediate H III, Method E (yield of the purified compound: 24%).
  • Example 7 was prepared according to Route 2 via Intermediate La II, Intermediate Lb II, Intermediate K II, Intermediate J II, Intermediate H IV and Method E (yield of the purified compound: 20%).
  • Example 8 was prepared according to Route 2 via Intermediate La II, Intermediate Lb II, Intermediate K II, Intermediate J II, Intermediate H V, Intermediate N and Method G (yield of the purified compound for synthjesis step of Method G: 100%).
  • Example 9 2-[Boc-L-Phe-L-Pro]Benzothiazole
  • Example 9 was prepared according to Route 1 via the Dipeptide Intermediate A V and Method C (H-Z: Benzothiazole, yield of the purified compound: 24%).
  • Example 10 was prepared according to Route 1 via Intermediate E II, Intermediate C II, Intermediate A IV and Method C (H-Z: Thiazole, yield of the purified compound: 7%).
  • Example 11 was prepared according to Route 3 via Intermediate E I and Method J (yield of the purified compound: 35%).

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux inhibiteurs de propyl endopeptidase de formule (I), soit W-KCONH-X-CON-Y-CO-Z, dans laquelle K, W, X, Y et Z sont tels que définis dans la description. Ces composés sont utiles pour le traitement de maladies telles que la déficience cognitive bénigne (MCI), la maladie d'Alzheimer, le syndrome de Down, la maladie de Parkinson et la chorée de Huntington.
EP05826439A 2003-11-03 2005-11-30 Nouveaux composes pour le traitement de troubles neurologiques Withdrawn EP1824846A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US51671703P 2003-11-03 2003-11-03
US10/976,677 US20050137142A1 (en) 2003-11-03 2004-10-29 Combinations useful for the treatment of neuronal disorders
US11/002,169 US20050171112A1 (en) 2003-11-03 2004-12-02 Combinations useful for the treatment of neuronal disorders
US68413705P 2005-05-24 2005-05-24
PCT/EP2005/012765 WO2006058720A2 (fr) 2003-11-03 2005-11-30 Nouveaux composes pour le traitement de troubles neurologiques

Publications (1)

Publication Number Publication Date
EP1824846A2 true EP1824846A2 (fr) 2007-08-29

Family

ID=38331139

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05826439A Withdrawn EP1824846A2 (fr) 2003-11-03 2005-11-30 Nouveaux composes pour le traitement de troubles neurologiques

Country Status (2)

Country Link
EP (1) EP1824846A2 (fr)
WO (1) WO2006058720A2 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5379692B2 (ja) 2006-11-09 2013-12-25 プロビオドルグ エージー 潰瘍、癌及び他の疾患の治療のためのグルタミニルシクラーゼの阻害薬としての３−ヒドロキシ−１，５−ジヒドロ−ピロール−２−オン誘導体
SI2091948T1 (sl) 2006-11-30 2012-07-31 Probiodrug Ag Novi inhibitorji glutaminil ciklaze
NZ579310A (en) 2007-03-01 2012-03-30 Probiodrug Ag Use of glutaminyl cyclase inhibitors for the treatment of mild cognitive impairment and diagnostic purposes thereof
EP2142514B1 (fr) 2007-04-18 2014-12-24 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
MX2012002993A (es) 2009-09-11 2012-04-19 Probiodrug Ag Derivados heterociclicos como inhibidores de ciclasa glutaminilo.
US9181233B2 (en) 2010-03-03 2015-11-10 Probiodrug Ag Inhibitors of glutaminyl cyclase
SG183229A1 (en) 2010-03-10 2012-09-27 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
EP2560953B1 (fr) 2010-04-21 2016-01-06 Probiodrug AG Inhibiteurs de glutaminyl cyclase
DK2686313T3 (en) 2011-03-16 2016-05-02 Probiodrug Ag Benzimidazole derivatives as inhibitors of glutaminyl cyclase
EP3461819B1 (fr) 2017-09-29 2020-05-27 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60188317A (ja) * 1984-03-09 1985-09-25 Yakult Honsha Co Ltd 抗健忘症剤
JPS6137764A (ja) 1984-07-31 1986-02-22 Suntory Ltd 抗プロリルエンドペプチダ−ゼ活性を有する新規生理活性化合物
EP0201741B1 (fr) * 1985-04-16 1991-07-31 Suntory Limited Dérivés de dipeptides, procédé de préparation, compositions pharmaceutiques et utilisation
DE3786229T2 (de) 1986-11-20 1993-10-07 Ono Pharmaceutical Co Prolinalderivate.
CA1339423C (fr) 1988-09-14 1997-09-02 Yuji Ono Pyridines et leur emploi en pharmacie
WO1991018891A1 (fr) 1990-06-04 1991-12-12 Pfizer Inc. Amides de pyrrolidine et de thiazolidine aromatiques
EP0670309A1 (fr) 1992-11-20 1995-09-06 Japan Tobacco Inc. Compose inhibant la prolyle endopeptidase et utilisation pharmaceutique de ce dernier
JP3810097B2 (ja) * 1993-01-15 2006-08-16 明治製菓株式会社 ピロリジン−２−イルカルボニル複素環式化合物誘導体
EP0709373B1 (fr) 1993-07-23 2001-10-17 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Derive de pyrrolidine
CA2177821C (fr) 1993-12-02 2000-03-28 Norton P. Peet Inhibiteurs de la prolyle endopeptidase
HUT76640A (en) 1995-08-17 1997-10-28 Chinoin Gyogyszer Es Vegyeszet Compounds of pharmaceutical activity cyclic amide derivatives, pharmaceutical compositions containing them, process for producing them and their use
US5763576A (en) 1995-10-06 1998-06-09 Georgia Tech Research Corp. Tetrapeptide α-ketoamides
HUP9700442A1 (hu) 1997-02-14 1999-09-28 Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. Gyűrűs amidszármazékok, e vegyületeket tartalmazó gyógyászati készítmények, eljárás előállításukra és alkalmazásuk
DE19828113A1 (de) 1998-06-24 2000-01-05 Probiodrug Ges Fuer Arzneim Prodrugs von Inhibitoren der Dipeptidyl Peptidase IV
DE19828114A1 (de) 1998-06-24 2000-01-27 Probiodrug Ges Fuer Arzneim Produgs instabiler Inhibitoren der Dipeptidyl Peptidase IV
HUP0201967A3 (en) 1998-06-24 2010-01-28 Aventis Pharma Inc Fluorophenyl resin compounds
AU9031598A (en) 1998-08-17 2000-03-06 Cortech, Inc. Serine protease inhibitors comprising alpha-keto heterocycles
US20050171112A1 (en) * 2003-11-03 2005-08-04 Probiodrug Ag Combinations useful for the treatment of neuronal disorders
CA2554809C (fr) * 2004-02-05 2014-04-29 Probiodrug Ag Nouveaux inhibiteurs de la glutaminyl-cyclase comportant de la n thiouree alkyle et de l'imidazolyl substitue par thioamide
AU2005236063A1 (en) * 2004-04-20 2005-11-03 Merck & Co., Inc. 2, 4, 6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's disease

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006058720A2 *

Also Published As

Publication number Publication date
WO2006058720A3 (fr) 2006-07-27
WO2006058720A2 (fr) 2006-06-08

Similar Documents

Publication Publication Date Title
US7667044B2 (en) Compounds for the treatment of neurological disorders
JP4996926B2 (ja) グルタミニルシクラーゼの新規の阻害剤
US7625939B2 (en) Cyclopropyl-fused pyrrolidine derivatives as dipeptidyl peptidase IV inhibitors
JP3993651B2 (ja) シクロプロパクロメンカルボン酸誘導体
Popova et al. Synthesis and biological properties of amino acids and peptides containing a tetrazolyl moiety
JP2006525276A (ja) グルタミニルシクラーゼ阻害剤
US7592467B2 (en) Inhibitors of prolyl endopeptidase
EP1824846A2 (fr) Nouveaux composes pour le traitement de troubles neurologiques
US20100099721A1 (en) Novel compounds for the treatment of neurological disorders
Asoh et al. Synthesis and structure–activity relationships of novel benzofuran farnesyltransferase inhibitors
EP2382206B1 (fr) Composés et procédés pour le traitement de la douleur et d'autres maladies
JPH02256658A (ja) アミノ酸誘導体
JPWO2009001730A1 (ja) βセクレターゼ阻害活性を有する新規化合物
CN116139282A (zh) 用于治疗神经退行性疾病的组合物和方法
STATION et al. Niestroj et al.(43) Pub. Date: May 11, 2006
JP2008521853A (ja) 神経疾患治療用の新規化合物
Zhang et al. Optimization of physicochemical properties of pyridone-based EP3 receptor antagonists
US20100273835A1 (en) Novel compounds
US20060229254A1 (en) Compounds having prolyl oligopeptidase inhibitory activity
US20100286164A1 (en) Substituted aryl alkylamino-oxy-analogs and uses thereof
EP3043791A1 (fr) Agent anticancéreux comportant un composé d'aminoacétonitrile en tant que principe actif
JPH05222013A (ja) 巨環ラクタム誘導体
STATION et al. Niestroj et al.(43) Pub. Date: Oct. 12, 2006
EVANS Schilling et al.(43) Pub. Date: Sep. 29, 2005
WO2006009325A1 (fr) Inhibiteur de métalloprotéase

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20070615

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

RIN1 Information on inventor provided before grant (corrected)

Inventor name: RAHFELD, JENS-ULRICH

Inventor name: DEMUTH, HANS-ULRICH

Inventor name: NIESTROJ, ANDRE, JOHANNES

Inventor name: HEISER, ULRICH

Inventor name: SCHULZ, INGO

Inventor name: BAER, JOACHIM

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20090511

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20110628