JP2008521853A - Novel compounds for the treatment of neurological diseases - Google Patents

Abstract

The present invention relates to novel inhibitors of prolyl endopeptidase of Formula 1.
W-KCONH-X-CON-Y-CO-Z (1)
(Wherein K, W, X, Y, and Z are as defined herein).
The compounds are useful for the treatment of diseases such as mild cognitive impairment (MCI), Alzheimer's disease, Down's syndrome, Parkinson's disease, and Huntington's disease.
[Selection figure] None

Description

(Field of the Invention)
The present invention relates to prolyl endopeptidases (PEP, EC 3.4.21.26) and heteroaryl-carbonyl compounds as inhibitors of PEP-like enzymes.

(Background of the present invention)
Prolyl endopeptidase (PEP; EC 3.4.21.26; also called prolyl oligopeptidase) is a serine peptidase characterized by oligopeptidase activity. This is the name given to the SC family enzyme family S9A, prolyl oligopeptidase (* 1 (* means reference)). Enzymes belonging to the SC family differ from trypsin- or subtilisin-type serine peptidases in primary sequence, by structure, and by the order of three catalytic residues (* 2; * 3). It has recently been reported that the three-dimensional structure of PEP represents two domain structures (* 4). The catalytic domain exhibits an α / β hydrolase fold in which a catalytic triad (Ser554, His680, Asp641) is covered by a so-called β-propeller domain. Presumably, the propeller domain controls the possible substrate access to the active component of the enzyme and eliminates peptides with more than 30 amino acids.

Despite profound knowledge of the enzymatic and structural properties of PEP, the biological function of this enzyme is not known at all (* 5; * 6). In mammals, highly conserved PEP is ubiquitously distributed and occurs at high concentrations in the brain (* 7). In recent years, it has been reported that cognitive enhancement was induced by treatment with specific PEP inhibitors, and thus the enzyme has attracted attention as a pharmaceutical subject. In rats showing scopolamine-induced amnesia, PEP inhibitors caused acetylcholine release in the frontal lobe and hippocampus (* 8). Furthermore, in middle cerebral artery closed rats, administration of PEP inhibitors prolonged passive avoidance latency and decreased long escape latency in Morris water maze task (* 9). The potential of PEP inhibitors as anti-dementia drugs was further confirmed by reports of neuroprotective effects. In the presence of PEP inhibitors, induction of neurodegeneration in cerebellar granule cells increases neuronal survival and enhances neurite outgrowth (* 10). Furthermore, it was discovered that the level of m ₃ -muscarinic acetylcholine receptor is increased after PEP inhibitors. This occurred in phosphoinositide turnover stimulation.

These effects are postulated to be due to modulation of neuropeptide biological activity by PEP (* 11). In vitro, PEP can rapidly inactivate several neuropeptides, including substrate P and arginine-vasopressin (AVP) by limited protein hydrolysis (* 12; * 13). Neuropeptides such as substrate P or AVP are known to affect learning and memory (* 14; * 15). Substrate P administration can induce long-term potentiation (LTP), a well-established parameter of learning and recording (* 16). Binding of substrate P to neurokinin 1 receptor stimulates G-protein mediated increase in IP ₃ concentration and release of Ca ²⁺ from intracellular stores in the endoplasmic reticulum (ER) (* 17; * 18). Ca ²⁺ release from these stores is well established to be involved in the induction of LTP, as well as learning and memory, but has not been tested against substrate P (* 19). In post-synaptic cells, LTP is suppressed by inhibitors of IP ₃ receptors, indicating an essential role for IP ₃ formation and Ca ²⁺ release in this learning and memory model (* 20). However, it should be noted that PEP is mainly localized in the cytosol (* 21), while the neuropeptides and their receptors interact on the cell surface. Recently, Hasebe et al. Discovered that cytoplasmic prolyl endopeptidase is involved in the degradation of p40-phox splice variant protein in myeloid cells (* 22).

EP 0 172 458 discloses N-phenylalkanoylpyrrolidine derivatives useful as anti-amnesic drugs.
EP 0 359 547 discloses pyridine compounds that inhibit prolyl endopeptidase activity and are useful in the treatment of amnesia.
US 5,340,832 discloses N-substituted carbamoyl-alkanoyl-prolinal derivatives useful as inhibitors of prolyl endopeptidase for the treatment of 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 various inflammatory conditions such as tissue damage and herpes, and the treatment of neurodegenerative agents such as ischemia, stroke, and Alzheimer's disease. Further, the compound is an inhibitor of blood coagulation enzyme and a useful anticoagulant for treating thrombosis.

  WO 91/18891 discloses aromatic pyrrolidines and thiazolidine amides as prolyl endopeptidase inhibitors. This is useful in the treatment of CNS disorders such as various memory or learning dysfunctions associated with disorders of disorders caused by, for example, Alzheimer's disease; amnesia; dementia; anxiety; ischemia;

  WO 94/12474 discloses cyclic ketone compounds as prolyl endopeptidase inhibitors. The compound contains two nitrogen-containing heterocycles attached to a carbonyl group. These compounds inhibit the degradation and inactivation of TRH, substrate P, neurotensin, and vasopressin. They are useful for the treatment and suppression of dementia including amnesia and Alzheimer's disease.

WO 95/03277 discloses N-substituted pyrrolidinyl-oxo-acetamide compounds as protease (especially PEP) inhibitors useful for the treatment of, for example, memory impairment of Alzheimer's disease and autoimmune diseases.
WO 95/15310 discloses prolyl peptide derivatives as prolyl endopeptidase inhibitors. These compounds can be used as memory enhancers to improve intelligence, ability to recognitive events, and learning motor activity. Thus, the compounds of WO 95/15310 can be used in patients with aphasia, apraxia, agnosia, or some type of amnesia, benign amnesia, and Korsakov syndrome. The compounds can also be used to suppress or delay memory impairment.

WO 97/07116 discloses PEP inhibitors for use in the treatment of acute events (such as ischemia and hypoxia) and the treatment of progressive neurodegenerative disorders including Alzheimer's disease, AIDS dementia, and Huntington's chorea. is doing.
WO 98/35960 is a memory promoting and anti-anemic effect useful for treating cognitive impairment associated with aging, as well as acute events (ischemia / hypoxia), Alzheimer's disease, AIDS-related dementia, and Huntington's choreography Disclosed are PEP inhibitors as nootropics that have neuroprotective effects useful in the treatment of progressive neurodegenerative disorders such as diseases.

  WO 00/09542 discloses alpha-keto heterocycles that inhibit the enzymatic activity of serine proteases. The compound inhibits microbial growth, reduces intraoperative blood loss, preserves transplanted tissue or organ, inhibits cancer cell growth or tumor progression or tumor metastasis or invasion, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchi It can be used to treat pulmonary dysplasia, myocardial necrosis or post-heart transplant coronary artery disease, atherosclerosis, reperfusion injury, Alzheimer's disease, hypoxia, ischemia, and blood coagulation disorders.

US 5,547,978 discloses PEP inhibitors based on pyrrolidin-2-ylcarbonyl heterocycles. They can be used to inhibit PEP in the mammalian brain for pharmaceutical action.
US 2005/0171112 discloses the PEP inhibitor ZW215.

(References)
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* 3. Barrett, AJ and Rawlings, ND (1992) Biol. Chem. Hoppe Seyler 373, 353-360
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* 24. Tietze, LF and Eicher, Th. (1981) Reaktionen und Synthesen im organisch-chemisches Grundpraktikum; Georg Thieme Verlag Stuttgart
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(Definition)
The term "PEP-inhibitor" or "prolyl endopeptidase inhibitor" is generally known to those skilled in the art and is an enzyme inhibitor that inhibits the catalytic activity of prolyl endopeptidase (PEP, prolyl oligopeptidase, POP) Means an agent.
“PEP activity” is defined as the catalytic activity of an endoprotease capable of hydrolyzing the post-proline bond of a peptide or protein. The proline is present at amino acid position 3 or more, counting from the N-terminus of the peptide or protein substrate.

A “PEP-like enzyme” is an enzymatically active protein or peptide that has PEP activity and is therefore inhibited by a PEP inhibitor.
The term “pharmaceutically acceptable” as used herein includes human and veterinary use: for example, the term “pharmaceutically acceptable” refers to a veterinarily acceptable compound, or human medicine And medically acceptable compounds.
Throughout this specification and claims, the expression “acyl”, unless specifically limited, is a C _1-12 acyl residue, preferably a C _1-8 acyl residue, particularly preferably a C _1-4 acyl residue. Indicates. Examples of acyl include the following alkanoyl groups and benzoyl.

Throughout this specification and the claims, the expression “alkyl”, unless specifically limited, denotes a C _1-12 alkyl group, preferably a C _1-6 alkyl group. The alkyl group may be linear or branched. Suitable alkyl groups are, for example, methyl, ethyl, propyl (e.g. n-propyl and isopropyl), butyl (e.g. n-butyl, tert-butyl and sec-butyl), pentyl, hexyl, heptyl (e.g. n-heptyl). ), And octyl (eg, n-octyl). For example, the expression “alk” in the expression “alkoxy” and the expression “alkan” in, for example, “alkanoyl” are to be interpreted in accordance with the provisions of “alkyl”. Typical alkoxy groups include methoxy, ethoxy, butoxy (eg n-butoxy), heptyloxy (eg n-heptyloxy), and octyloxy (eg n-octyloxy). Typical alkanoyl (ie acyl groups) include ethanoyl (ie acetyl), propionyl, and butyryl.

The expression “alkenyl”, unless specifically limited, denotes a C _2-12 alkenyl group, preferably a C _2-6 alkenyl group, containing at least one double bond at any desired position. The alkenyl group may be linear or branched. Typical alkenyl groups include ethenyl, propenyl, and butenyl.

The expression “alkynyl”, unless specifically limited, denotes a C _2-12 alkynyl group, preferably a C _2-6 alkynyl group, containing at least one triple bond at any desired position. The alkynyl group may be linear or branched. Typical alkynyl groups include ethynyl, propynyl, and butynyl.

The expression “cycloalkyl” refers to a C _3-12 cycloalkyl group, generally a C _3-8 cycloalkyl group, unless otherwise specified. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl group may be branched when the number of carbon atoms represents the total number of carbon atoms in the component. In addition, a group such as cyclopentylmethyl (including a cycloalkyl group bonded to alkylene) is included by the definition of “cycloalkyl” when the carbon number indicates the total number of carbons in the component.

In addition to alkenyl, alkynyl, and cycloalkyl groups, alkyl groups, including derivatives such as alkoxy, may optionally be halogen substituted, such as, for example, fluoro substitution. For example, halo substituted alkyl groups include trifluoromethyl and halo substituted alkoxy groups include trifluoromethoxy.
The term “halogen” includes fluorine (—F), chlorine (—Cl), bromine (—Br), and iodine (—I).

  The expression “carbocyclic”, or “carbocycle”, unless specified otherwise, denotes a carbocyclic group containing 3 to 12 carbon atoms, generally 3 to 8 carbon atoms, It may be optionally branched. As used herein, a carbocyclic group means a group other than aryl or cycloalkyl containing at least one carbon atom ring that does not contain heteroatoms. Examples of carbocyclic groups include bridged ring systems (eg, bicyclo [2.2.1] heptenyl) and partially unsaturated ring systems (eg, cyclohexenyl). Said group may optionally be substituted, for example with alkyl, halo, oxo, or hydroxyl.

  The expression “heterocyclic” or “heterocycle” is not specifically limited, and one or more (eg, 1, 2, or 3) ring atoms are selected from N, S, or O A cycloalkyl residue or a carbocyclic residue substituted with a substituted heteroatom. Typical heterocyclic groups containing one heteroatom include pyrrolidine, tetrahydrofuran, and piperidine. Typical heterocyclic groups containing two heteroatoms include morpholine and piperazine. The group may optionally be substituted with alkyl (eg methyl), halo, oxo, or hydroxyl.

  Further examples of heterocyclic groups include oxirane (oxacyclopropane), aziridine (azacyclopropane), thiirane, oxetane, azetidine, thietane, thiolane, 1,3-dioxolane, thiazolidine, imidazolidine, oxazolidine, pyrazolidine, tetrahydro There are pyran and piperazine. Another example of a heterocycle is urotropin. Other heterocyclic groups include lactams, lactones, cyclic imides, and cyclic anhydrides. Examples of 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.

The expression “aryl”, unless specifically limited, denotes a C _6-12 aryl group, preferably a C _6-8 aryl group. Aryl groups will contain at least one aromatic ring (eg, 1, 2, or 3 rings). However, it may contain a partially unsaturated ring or a fully unsaturated ring. An example of an aryl group having one aromatic ring is phenyl. An example of an aromatic group having two aromatic rings is naphthyl (eg 1-naphthyl-, or 2-naphthyl-). Other aryl groups include 1-anthracenyl-, 2-anthracenyl-, and 3-anthracenyl-. Examples of aryl groups that contain partially or fully unsaturated rings include tetralin and indene. The most typical aryl group is phenyl.

  The expression “heteroaryl”, unless otherwise limited, is one or more (eg 1, 2, 3, or 4, preferably 1, 2, or 3) ring atoms selected from N, S, and O Aryl residues substituted with selected heteroatoms, or one or more selected from N, S, and O (e.g. 1, 2, 3, or 4, preferably 1, 2, or 3) A 5-membered aromatic ring containing As shown below, the heteroaryl group may be optionally substituted. Typical heteroaryl groups include: pyridine (eg, 2-, 3-, or 4-pyridine), pyrimidine, quinoline, pyrrole, furan, thiophene, oxazole, pyrazole, benzodioxolane (benzodioxole) ), Benzodioxane, benzothiophene, benzodioxepin, and thiazole, imidazole (e.g., 1-, 2-, or 4-imidazole), isoxazole, isothiazole, 3-pyrazole, 1,2,3-triazole, 1 2,4-triazole, tetrazole, pyridazine, pyrazine, indazole, indole (eg 6-indole), benzimidazole, isoquinoline, purine, carbazole, and acridine groups. The most common heteroaryl group is pyridine.

The aryl and heteroaryl groups may be optionally substituted with one or more (eg 1, 2, or 3, usually 1, or 2) monovalent or polyvalent functional groups where appropriate. Suitable substituents include: alkyl, cycloalkyl, phenyl, pyridyl, furyl, carbocycle, heterocycle, alkoxy, cycloalkoxy, phenyloxy, carbocycleoxy, heterocycleoxy, alkenyloxy, alkynyloxy , alkenyl, alkynyl, alkanoyl, alkoxycarbonyl alkanoyl, alkoxyalkyl, nitro, -S- alkyl (e.g. methylthio), halo (e.g. fluoro, chloro, bromo, and iodo), cyano, hydroxyl, -SO ₂ alkyl, -SO ₂ cycloalkyl Alkyl, —SO ₂ heterocycle, —CO ₂ H, —CO ₂ alkyl, —NH ₂ , —NH alkyl, —N (alkyl) ₂ (eg, dimethylamino), —CO—N (alkyl) ₂ , and —CO -NH (alkyl). The most common substituents are those selected from alkyl, alkoxy, halo, nitro, and hydroxyl.

  Examples of substituted aryl groups include 4-fluoro-phenyl, 3-fluoro-phenyl, pentafluoro-phenyl, 4-hydroxyphenyl-, 3-nitro-phenyl-, 4- (trifluoromethyl) -phenyl-, There are 4-anilinyl-, 2-biphenylyl-, 3-biphenylyl-, and 4-biphenylyl-. Examples of 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- (ie benzyl) and phenylethyl, 2-phenyleth-1-yl, p-tolyl-methyl-, p-tolyl-ethyl-, 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-dimethyl-phenyl-ethyl-, 2,5-dimethyl- Phenyl-ethyl-, 2,6-dimethyl-phenyl-ethyl-, 3,4-dimethyl-phenyl-ethyl-, 3,5-dimethyl-phenyl-ethyl-, 2,4,6-trimethyl-phenyl-ethyl- The Zhydryl (ie diphenyl-methyl), diphenyl-ethyl, trityl (ie triphenyl-methyl), triphenyl-ethyl, cumyl (ie 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-, 1H-indenyl-methyl-, 2H-indenyl-methyl-, 1H-indenyl-ethyl-, 2H-indenyl-ethyl-, indanyl-methyl-, Indan-1-one-2-yl-methyl-, indan-1-one-2-yl-ethyl-, tetralinyl-methyl -, Tetralinyl-ethyl-, fluorenyl-methyl-, fluorenyl-ethyl-, dihydronaphthalinyl-methyl-, dihydronaphthalinyl-ethyl-, or (4-cyclohexyl) -phenyl-methyl-, (4-cyclohexyl)- Phenyl-ethyl-. The most common -alkylaryl group is phenylmethyl-.

  Examples of -alkylheteroaryl include: pyridinylmethyl- (eg 2-pyridinylmethyl), N-methyl-pyrrol-2-methyl-N-methyl-pyrrol-2-ethyl-, N-methyl- Pyrrole-3-methyl-, N-methyl-pyrrole-3-ethyl-, 2-methyl-pyrrole-1-methyl-, 2-methyl-pyrrole-1-ethyl-, 3-methyl-pyrrole-1-methyl- 3-methyl-pyrrol-1-ethyl-, 4-pyridino-methyl-, 4-pyridino-ethyl-, 2- (thiazol-2-yl) -ethyl-, tetrahydroisocinolinyl-methyl-, tetrahydroisocinolin Nyl-ethyl-, 2-ethyl-indole-1-methyl-, 2-ethyl-indole-1-ethyl-, 3-ethyl-indole-1-methyl-, 3-ethyl-indole-1-ethyl-, 4 -Methyl-pyridin-2-methyl-, 4-methyl-pyridin-2-yl-ethyl-, 4-methyl-pyridine-3-methyl, 4-methyl-pyridin-3- Is Le. The most common -alkylheteroaryl group is pyridinylmethyl-.

(amino acid)
The amino acids that can be used in the present invention can be, for example, α-, β-, or ω-amino acids (preferably α-amino acids), L and D-amino acids, N-alkylated amino acids, N-methyl-amino acids, allo -And threo-type Ile and Thr.

Examples of amino acids are:
Aspartic acid (Asp), glutamic acid (Glu), arginine (Arg), lysine (Lys), histidine (His), glycine (Gly), serine (Ser), cysteine (Cys), threonine (Thr), asparagine (Asn) , Glutamine (Gln), tyrosine (Tyr), alanine (Ala), proline (Pro), valine (Val), isoleucine (Ile), leucine (Leu), methionine (Met), phenylalanine (Phe), tryptophan (Trp) Hydroxyproline (Hyp), beta-alanine (beta-Ala), 2-aminooctanoic acid (Aoa), acetylidine- (2) -carboxylic acid (Ace), pipecolic acid (Pip), 3-aminopropionic acid, and 4-aminobutyric acid, alpha-aminoisobutyric acid (Aib), sarcosine (Sar), ornithine (Orn), citrulline (Cit), homoarginine (Har), t-butylalanine (t-butyl-Ala), t-butyl Glycine (t-butyl-Gly), N-methylisoleucine (N-MeIle), Phenylglycine (Phg), cyclohexylalanine (Cha), norleucine (Nle), cysteic acid (Cya), and methionine sulfoxide (MSO), acetyl-Lys, phosphoryl-serine (Ser (P)), benzyl-serine (Ser ( Bzl)), and modified amino acids such as phosphoryl-tyrosine (Tyr (P)), 2-aminobutyric acid (Abu), aminoethylcysteine (AECys), carboxymethylcysteine (Cmc), dehydroalanine (Dha), dehydroamino- 2-butyric acid (Dhb), carboxyglutamic acid (Gla), homoserine (Hse), hydroxylysine (Hyl), cis-hydroxyproline (cisHyp), trans-hydroxyproline (transHyp), isovaline (Iva), pyroglutamic acid ( Pyr), norvaline (Nva), 2-aminobenzoic acid (2-Abz), 3-aminobenzoic acid (3-Abz), 4-aminobenzoic acid (4-Abz), 4- (aminomethyl) benzoic acid ( Amb), 4- (aminomethyl) cyclohexa Carboxylic acid (4-Amc), penicillamine (Pen), 2-amino-4-cyano-butyric acid (Cba), cycloalkane - carboxylic acid. Examples of omega-amino acids are, for example: 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-ad (aminododecanoic acid). Further amino acids are: indanylglycine (Igl), indoline-2-carboxylic acid (Idc), octahydroindole-2-carboxylic acid (Oic), diaminopropionic acid (Dpr), diaminobutyric acid (Dbu ), Naphthylalanine (1-Nal) and (2-Nal), 4-aminophenylalanine (Phe (4-NH ₂ )), 4-benzoylphenylalanine (Bpa), diphenylalanine (Dip), 4-bromophenylalanine (Phe (4-Br)), 2-chlorophenylalanine (Phe (2-Cl)), 3-chlorophenylalanine (Phe (3-Cl)), 4-chlorophenylalanine (Phe (4-Cl)), 3,4- Chlorophenylalanine (Phe (3,4-Cl ₂ )), 3-fluorophenylalanine (Phe (3-F)), 4-fluorophenylalanine (Phe (4-F)), 3,4-fluorophenylalanine (Phe (3 , 4-F _2)), pentafluorophenylalanine _{(Phe (F 5)),} 4- guanidino phenylalanine (Phe (4-guanidino)), Mophenylalanine (hPhe), 3-Jodophenylalanine (Phe (3-J)), 4-Jodophenylalanine (Phe (4-J)), 4-Methylphenylalanine (Phe (4-Me)), 4-Nitrophenylalanine ( Phe-4-NO ₂ )), biphenylalanine (Bip), 4-phosphonomethylphenylalanine (Pmp), cyclohexylglycine (Ghg), 3-pyridinylalanine (3-Pal), 4-pyridinylalanine ( 4-Pal), 3,4-dehydroproline (A-Pro), 4-ketoproline (Pro (4-keto)), thioproline (Thz), isonipecotic acid (Inp), 1,2,3,4, -tetrahydro Isoquinoline-3-carboxylic acid (Tic), propargylglycine (Pra), 6-hydroxynorleucine (NU (6-OH)), homotyrosine (hTyr), 3-jodotyrosine (Tyr (3-J)), 3, 5-Diodotyrosine (Tyr (3,5-J ₂ )), Methyltyrosine (Tyr (Me)), 2 ', 6-Dimethyltyrosine (Dmt), 3-NO ₂ -Tyrosine (Tyr (3-NO ₂ )), Phosphotylo Down _{(Tyr (PO 3 H 2)} ), alkylglycine, 1-aminoindane-1-carboxylic acid, 2-aminoindane-2-carboxylic acid (Aic), 4-amino - methyl pyrrole-2-carboxylic acid (Py ), 4-amino-pyrrolidine-2-carboxylic acid (Abpc), 2-aminotetralin-2-carboxylic acid (Atc), diaminoacetic acid (Gly (NH ₂ )), diaminobutyric acid (Dab), 1,3-dihydro -2H-isoinol-carboxylic acid (Disc), homocyclohexylalanine (hCha), homophenylalanine (hPhe or Hof), trans-3-phenyl-azetidine-2-carboxylic acid, 4-phenyl-pyrrolidine-2-carboxylic acid, 5-Phenyl-pyrrolidine-2-carboxylic acid, 3-pyridylalanine (3-Pya), 4-pyridylalanine (4-Pya), styrylalanine, tetrahydroisoquinoline-1-carboxylic acid (Tiq), 1,2,3 , 4-tetrahydronorharman-3-carboxylic acid (Tpi), β- (2-thienyl) -alanine (Tha).

“Aza-amino acid” is defined as an amino acid in which the chiral α-CH group has been replaced by a nitrogen atom.
Also, other amino acid substituents encoded by the genetic code can include peptide compounds within the scope of the present invention and can be classified within this general scheme. Protein constituent amino acids are naturally occurring protein-derived α-amino acids (eg 20 common natural L-amino acids, ie: L-Asp (aspartic acid), L-Glu (glutamic acid), L-Arg (arginine), L-Lys). (Lysine), L-His (histidine), Gly (glycine), L-Ser (serine), L-Cys (cysteine), L-Thr (threonine), L-Asn (asparagine), L-Gln (glutamine) , L-Tyr (tyrosine), L-Ala (alanine), L-Pro (proline), L-Val (valine), L-Ile (isoleucine), L-Leu (leucine), L-Met (methionine), L-Phe (phenylalanine), L-Trp (tryptophan)). Non-proteinogenic amino acids are defined as all other amino acids that are not the basic unit of a common natural protein.

  Acyclic amino acids exclude cyclic amino acids such as Pro and its various derivatives (e.g., 3,4-dehydroproline (A-Pro), 4-ketoproline (Pro (4-keto)), and thioproline (Thz)), Contains the above amino acids. Acyclic azaamino acids include aza derivatives of Pro and various derivatives thereof (e.g., 3,4-dehydroproline (A-Pro), 4-ketoproline (Pro (4-keto)), and thioproline (Thz) aza derivatives) Aza derivatives of said amino acids, excluding cyclic azaamino acids such as

(Stereoisomers)
All possible stereoisomers of the claimed compounds are included within the invention. If the compounds according to the invention have at least one chiral center, they may accordingly exist as enantiomers. If the compounds have more than one chiral center, they can additionally exist as diastereomers. It is understood that all such isomers, and mixtures thereof are included within the scope of the present invention.

(Pharmaceutically acceptable salt)
In view of the close relationship between the free compound and these salt forms of the compound, if a compound is referred to in this context, the corresponding salt form is possible or appropriate under conditions Always the corresponding salt is also contemplated.

  Pharmaceutically acceptable salts can take the form in which the basic side chain is protonated with an inorganic or organic acid. Typical organic or inorganic acids are hydrochloric acid, hydrobromic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, Tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, pamonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid, saccharic acid Or trifluoroacetic acid. Alternatively, the pharmaceutically acceptable salt may take the form in which the acidic side chain is salted with a metal ion (such as sodium ion and potassium ion) or other cation such as ammonium. All pharmaceutically acceptable acid addition salt forms of the compounds are intended to be included within the scope of the present invention.

(Polymorph crystal form and solvate)
Moreover, some crystalline forms of the compound may exist in more than one polymorphic form. As such, all features are intended to be included in the present invention. In addition, some of the compounds can form solvates of water (ie hydrates) or solvates of common organic solvents. Such solvates are also intended to be included in the present invention. Also, the compounds including these salts can be obtained in their hydrate form or can include other solvents used for their crystallization.

(Prodrug)
Furthermore, the present invention includes within its scope prodrugs of the compounds of this invention. In general, the prodrug will be a functional derivative of the compound that is readily converted into the desired therapeutically effective compound in vivo. Thus, in the case of the therapeutic methods of the invention, the term “administering” includes treating various diseases as described using prodrug species of one or more of the claimed compounds. The prodrug species is converted to the specific compound in vivo after administration to a subject. Conventional procedures for selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985, and patent applications DE 198 28 113, DE 198 28 114. , WO 99/67228, and WO 99/67279, all of which are incorporated herein by reference.
As used herein, the term “composition” refers to a product containing a therapeutically effective amount of the claimed compound, as well as any product that results directly or indirectly from a combination of the claimed compounds. It is intended to include.

（式中、Wは、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、カルボシクリル、アリール、-アルキルアリール、又は-アルキルヘテロアリールを表し；
Kは、O、NH、又はCH₂を表し；
又はKは存在せず、かつW-COは、アミノ酸、又はアザ-アミノ酸の成分を表し；
NH-X-COは、非環状アミノ酸、又は非環状アザ-アミノ酸の成分を表し、ここで、NH-X-COがAsp、又はGluの成分を表す場合、前記Asp、又はGluの酸側鎖は、ペプチド結合を介して、他のアミノ酸、又はアザ-アミノ酸に任意に結合することができ；
N-Y-CO-は、式2a、2b、2c、2d、2e、2f、及び2gの成分から選択され：

（式中、R¹〜R¹⁵、及びR¹⁷〜R¹⁹は、独立に、H、又はアルキル鎖、アルケニル鎖、アルキニル鎖, シクロアルキル、炭素環、アリール、ヘテロアリール、複素環、又はハロゲン、アミノ、-CONH₂、CONH(アルキル)、-CON(アルキル)₂、ニトロ、ヒドロキシル、-CN、及びSCNから選択された基であり；
又はその他に、R²/R³、R⁴/R⁵、R⁶/R⁷、R⁹/R¹⁰、R¹¹/R¹²は、結合している炭素原子とともに、独立にオキソを表し；
又はその他に、R³とR⁵とが結合し、アゼチジン環に縮合したベンゼン環を形成する(この場合、R²、及びR⁴は存在せず)か、又はR¹⁰とR¹¹とが結合し、ピペリジン環に縮合したベンゼン環を形成し(この場合、R⁹、及びR¹²は存在せず)；
R¹⁶は、アミノ酸成分の側鎖であり；
X¹は、CR²⁰R²¹、O、S、SO、SO₂、又はNR²²であり；
X²は、CR²³R²⁴、O、S、SO、SO₂、又はNR²⁵であり；
X³は、CR²⁶R²⁷、O、S、SO、SO₂、又はNR²⁸であり；
R²²、R²⁵、及びR²⁸は、互いに独立に、H、アルキル、アルケニル、アルキニル、シクロアルキル、炭素環、複素環、アリール、ヘテロアリール、アリール-アルキル、又はヘテロアリール-アルキル基であり；
R²⁰、R²¹、R²³、R²⁴、R²⁶、及びR²⁷は、互いに独立に、H、アルキル、アルケニル、アルキニル、シクロアルキル、炭素環、複素環、アリール、ヘテロアリール、アリール-アルキル、ヘテロアリール-アルキル基、又はカルバルデヒド(-CHO)、ケトン基(-CO-R²⁹)、ボロン酸基(-B(OH)₂)、シアノ基(-C≡N)、カルボン酸基(-COOH)、カルボン酸エステル基(-COOR³⁰)、カルボン酸無水物基(-CO-O-CO-R³¹)、ヒドロキサム酸基(-CO-NH(OH))、N-置換ヒドロキサム酸基(-CO-NR³²(OH))、O-置換ヒドロキサム酸基(-CO-NH(OR³³))、カルボキサミド基(-CO-NH₂)、N-置換もしくはN,N-二置換カルボン酸アミド基(-CO-NHR³⁴；-CO-NR³⁵R³⁶)、アミド基(-HN-CO-R³⁷)、スルホン酸基(-SO₃H)、スルホンアミド基(-SO₂-NH₂)、N-置換もしくはN,N-二置換スルホンアミド基(-SO₂-NHR³⁸；-SO₂-NR³⁹R⁴⁰)、アミドスルホン基(-NH-SO₂-R⁴¹)、スルホン基(-SO₂-R⁴²)、リン酸基(-OP(=O)(OH)₂)、リン酸エステル基(-OP(=O)(OR⁴³)(OR⁴⁴))、ホスホン酸基(-P(=O)(OH)₂)、ホスホン酸エステル基(-P(=O)(OR⁴⁵)(OR⁴⁶))、ハロゲノ基、トリフルオロメチル基(-CF₃)、チオール基(-SH)；チオエーテル基(-S-R⁴⁷)、ヒドロキシ基(-OH)；アルコキシ基(-O-R⁴⁸)、テトラゾール基、アミノ基(-NH₂)、又はN-置換もしくはN,N-二置換アミノ基(-NHR⁴⁹；-NR⁵⁰R⁵¹)であり；又は
X¹がCR²⁰R²¹である場合、R⁶、及びR²⁰が結合し、ピロリジン環に縮合したベンゼン環を形成することができ(この場合、R⁷、及びR²¹は存在せず)、又はX²がCR²²R²³である場合、R²⁰、及びR²²が結合し、ピロリジン環に縮合したベンゼン環を形成することができ(この場合、R²¹、及びR²³は存在せず)；又は
X³がCR²⁶R²⁷である場合、R¹¹、及びR²⁶が結合し、ピペリジン環に縮合したベンゼン環を形成することができ(この場合、R¹²、及びR²⁷は存在せず)、又はR²⁷、及びR¹³が結合し、ピペリジン環に縮合したベンゼン環を形成することができ(この場合、R²⁶、及びR¹⁴は存在せず)；
置換基R²⁹、R³⁰、R³¹、R³²、R³³、R³⁴、R³⁵、R³⁶、R³⁷、R³⁸、R³⁹、R⁴⁰、R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁴⁵、R⁴⁶、R⁴⁷、R⁴⁸、R⁴⁹、R⁵⁰、及びR⁵¹は、互いに独立に、H、アルキル、アルケニル、アルキニル、シクロアルキル、炭素環、複素環、アリール、ヘテロアリール、アリール-アルキル-、又はヘテロアリール-アルキル-であり；あるいは、組合せR³⁵R³⁶、R³⁹R⁴⁰、及びR⁵⁰R⁵¹は、互いに独立に、結合している窒素とともに、複素環の一部を形成することができ(例えばピロリジン、ピペリジン、又はモルフォリン)；又は組合せR⁴³/R⁴⁴、R⁴⁵/R⁴⁶は、C_1-4アルキレン鎖を形成するように結合することができ；
X⁴は、CR⁵²、又はNであり；
X⁵は、CR⁵³、又はNであり；
R⁵²、及びR⁵³は、互いに独立に、H、アルキル、アルケニル、アルキニル、シクロアルキル、炭素環、複素環、アリール、ヘテロアリール、アリール-アルキル、ヘテロアリール-アルキル、アリール-ヘテロアルキル、ヘテロアリール-ヘテロアルキル基、又はカルバルデヒド(-CHO)、ケトン基(-CO-R⁵⁴)、ボロン酸基(-B(OH)₂)、シアノ基(-C≡N)、カルボン酸基(-COOH)、カルボン酸エステル基(-COOR⁵⁵)、カルボン酸無水物基(-CO-O-CO-R⁵⁶)、ヒドロキサム酸基(-CO-NH(OH))、N-置換ヒドロキサム酸基(-CO-NR⁵⁷(OH))、O-置換ヒドロキサム酸基(-CO-NH(OR⁵⁸))、カルボキサミド基(-CO-NH₂)、N-置換もしくはN,N-二置換カルボン酸アミド基(-CO-NHR⁵⁹；-CO-NR⁶⁰R⁶¹)、アミド基(-HN-CO-R⁶²)、スルホン酸基(-SO₃H)、スルホンアミド基(-SO₂-NH₂)、N-置換もしくはN,N-二置換スルホンアミド基(-SO₂-NHR⁶³；-SO₂-NR⁶⁴R⁶⁵)、アミドスルホン基(-NH-SO₂-R⁶⁶)、スルホン基(-SO₂-R⁶⁷)、リン酸基(-OP(=O)(OH)₂)、リン酸エステル基(-OP(=O)(OR⁶⁸)(OR⁶⁹))、ホスホン酸基(-P(=O)(OH)₂)、ホスホン酸エステル基(-P(=O)(OR⁷⁰)(OR⁷¹))、ハロゲノ基、トリフルオロメチル基(-CF₃)、チオール基(-SH)；チオエーテル基(-S-R⁷²)、ヒドロキシ基(-OH)；アルコキシ基(-O-R⁷³)、テトラゾール基、アミノ基(-NH₂)、又はN-置換もしくはN,N-二置換アミノ基(-NHR⁷⁴；-NR⁷⁵R⁷⁶)であり；
置換基R⁵⁴、R⁵⁵、R⁵⁶、R⁵⁷、R⁵⁸、R⁵⁹、R⁶⁰、R⁶¹、R⁶²、R⁶³、R⁶⁴、R⁶⁵、R⁶⁶、R⁶⁷、R⁶⁸、R⁶⁹、R⁷⁰、R⁷¹、R⁷²、R⁷³、R⁷⁴、R⁷⁵、及びR⁷⁶は、互いに独立に、H、又はアルキル、アルケニル、アルキニル、シクロアルキル、炭素環、複素環、アリール、ヘテロアリール、アリール-アルキル、ヘテロアリール-アルキル基であり；かつ
あるいは、組合せR⁵²/R⁵³は、存在する場合、結合している炭素原子とともに、複素環、又は炭素環の一部を形成することができ；又は組合せR⁶⁰R⁶¹、R⁶⁴R⁶⁵、及びR⁷⁵R⁷⁶は、互いに独立に、結合している窒素とともに、複素環の一部を形成することができ(例えばピロリジン、ピペリジン、又はモルフォリン)；又は組合せR⁶⁸/R⁶⁹、及びR⁷⁰/R⁷¹は、C_1-4アルキレン鎖を形成するように結合することができ；
mは、整数0〜2を表し；
nは、整数0〜2を表す。）；
Zは、ヘテロアリールであり、
但し、下記化合物は、式１から除かれる。）。

(Summary of the present invention)
The present invention provides prolyl endopeptidase (PEP, EC 3.4.21.26) and compounds that act as inhibitors of PEP-like enzymes. These compounds are represented by the general formula 1 together with their pharmaceutically acceptable salts and stereoisomers thereof.

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 an amino acid or aza-amino acid component;
NH-X-CO represents a non-cyclic amino acid or a non-cyclic aza-amino acid component, and when NH-X-CO represents a component of Asp or Glu, the acid side chain of Asp or Glu Can be optionally linked to other amino acids or aza-amino acids via peptide bonds;
NY-CO- is selected from the components of formulas 2a, 2b, 2c, 2d, 2e, 2f, and 2g:

Wherein R ^{1 to} R ¹⁵ and R ^{17 to} R ¹⁹ are independently H, or alkyl chain, alkenyl chain, alkynyl chain, cycloalkyl, carbocycle, aryl, heteroaryl, heterocycle, or halogen; A group selected from amino, —CONH ₂ , CONH (alkyl), —CON (alkyl) ₂ , nitro, hydroxyl, —CN, and SCN;
Or, in addition, R ² / R ³ , R ⁴ / R ⁵ , R ⁶ / R ⁷ , R ⁹ / R ¹⁰ , R ¹¹ / R ¹² independently represent oxo together with the carbon atoms to which they are attached;
Alternatively, R ³ and R ⁵ are combined to form a benzene ring condensed with the azetidine ring (in this case, R ² and R ⁴ are not present), or R ¹⁰ and R ¹¹ are combined. Forming a benzene ring fused to the piperidine ring (in which case R ⁹ and R ¹² are not present);
R ¹⁶ is the side chain of the amino acid component;
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 are independently of each other H, alkyl, alkenyl, alkynyl, cycloalkyl, carbocycle, heterocycle, aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl group;
R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁶ , and R ²⁷ are independently of each other H, alkyl, alkenyl, alkynyl, cycloalkyl, carbocycle, heterocycle, aryl, heteroaryl, aryl-alkyl, Heteroaryl-alkyl group, or carbaldehyde (-CHO), ketone group (-CO-R ²⁹ ), boronic acid group (-B (OH) ₂ ), cyano group (-C≡N), carboxylic acid group (- COOH), carboxylic acid ester group (-COOR ³⁰ ), carboxylic anhydride group (-CO-O-CO-R ³¹ ), hydroxamic acid group (-CO-NH (OH)), N-substituted hydroxamic acid group ( -CO-NR ³² (OH)), O-substituted hydroxamic acid group (-CO-NH (OR ³³ )), carboxamide group (-CO-NH ₂ ), N-substituted or N, N-disubstituted carboxylic acid amide Group (—CO—NHR ³⁴ ; —CO—NR ³⁵ R ³⁶ ), amide group (—HN—CO—R ³⁷ ), sulfonic acid group (—SO ₃ H), sulfonamide group (—SO ₂ —NH ₂ ) , N- substituted or N, N- disubstituted sulfonamide group _{^{(-SO 2 -NHR 38; -SO 2}} -NR 39 R 40), amides Sulfone group ^{_{(-NH-SO 2 -R 41)}} , sulfone group (-SO ₂ -R ^42), a phosphoric acid group (-OP (= O) (OH ) 2), phosphoric acid ester group (-OP (= O ) (OR ⁴³ ) (OR ⁴⁴ )), phosphonic acid group (-P (= O) (OH) ₂ ), phosphonic acid ester group (-P (= O) (OR ⁴⁵ ) (OR ⁴⁶ )), halogeno group , Trifluoromethyl group (—CF ₃ ), thiol group (—SH); thioether group (—SR ⁴⁷ ), hydroxy group (—OH); alkoxy group (—OR ⁴⁸ ), tetrazole group, amino group (—NH ₂₎ Or an N-substituted or N, N-disubstituted amino group (—NHR ⁴⁹ ; —NR ⁵⁰ R ⁵¹ ); or
When X ¹ is CR ²⁰ R ²¹ , R ⁶ and R ²⁰ can be bonded to form a benzene ring fused to the pyrrolidine ring (in this case, R ⁷ and R ²¹ are not present), Or when X ² is CR ²² R ²³ , R ²⁰ and R ²² can be bonded to form a benzene ring fused to the pyrrolidine ring (in this case, R ²¹ and R ²³ are not present) Or
When X ³ is CR ²⁶ R ²⁷ , R ¹¹ and R ²⁶ can be bonded to form a benzene ring fused to the piperidine ring (in this case, R ¹² and R ²⁷ are not present), Or R ²⁷ and R ¹³ can be joined to form a benzene ring fused to a piperidine ring (in this case, R ²⁶ and R ¹⁴ are not present);
Substituents R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ⁴⁸ , R ⁴⁹ , R ⁵⁰ , and R ⁵¹ are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, carbocycle, heterocycle, aryl, heteroaryl, aryl -Alkyl-, or heteroaryl-alkyl-; or alternatively, the combination R ³⁵ R ³⁶ , R ³⁹ R ⁴⁰ , and R ⁵⁰ R ⁵¹ , independently of one another, together with the nitrogen to which it is attached, part of the heterocycle Can be formed (eg, pyrrolidine, piperidine, or morpholine); or the combination R ⁴³ / R ⁴⁴ , R ⁴⁵ / R ⁴⁶ can be joined to form a C _1-4 alkylene chain;
X ⁴ is CR ⁵² or N;
X ⁵ is CR ⁵³ or N;
R ⁵² and R ⁵³ are independently of each other H, alkyl, alkenyl, alkynyl, cycloalkyl, carbocycle, heterocycle, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl, aryl-heteroalkyl, heteroaryl. -Heteroalkyl group, or carbaldehyde (-CHO), ketone group (-CO-R ⁵⁴ ), boronic acid group (-B (OH) ₂ ), cyano group (-C≡N), carboxylic acid group (-COOH ), Carboxylic acid ester group (-COOR ⁵⁵ ), carboxylic acid anhydride group (-CO-O-CO-R ⁵⁶ ), hydroxamic acid group (-CO-NH (OH)), N-substituted hydroxamic acid group (- CO-NR ⁵⁷ (OH)), O-substituted hydroxamic acid group (-CO-NH (OR ⁵⁸ )), carboxamide group (-CO-NH ₂ ), N-substituted or N, N-disubstituted carboxylic acid amide group (-CO-NHR ⁵⁹ ; -CO-NR ⁶⁰ R ⁶¹ ), amide group (-HN-CO-R ⁶² ), sulfonic acid group (-SO ₃ H), sulfonamide group (-SO ₂ -NH ₂ ), N-substituted or N, N-disubstituted sulfonamide groups (-SO ₂ -NHR ⁶³ ; -SO ₂ -NR ⁶⁴ R ⁶⁵ ), amide sulfone group (-NH-SO ₂ -R ⁶⁶ ), sulfone group (-SO ₂ -R ⁶⁷ ), phosphate group (-OP ( = O) (OH) ₂ ), phosphate ester group (-OP (= O) (OR ⁶⁸ ) (OR ⁶⁹ )), phosphonic acid group (-P (= O) (OH) ₂ ), phosphonic acid ester group (-P (= O) (OR ⁷⁰ ) (OR ⁷¹ )), halogeno group, trifluoromethyl group (-CF ₃ ), thiol group (-SH); thioether group (-SR ⁷² ), hydroxy group (-OH An alkoxy group (—OR ⁷³ ), a tetrazole group, an amino group (—NH ₂ ), or an N-substituted or N, N-disubstituted amino group (—NHR ⁷⁴ ; —NR ⁷⁵ R ⁷⁶ );
Substituents R ⁵⁴ , R ⁵⁵ , R ⁵⁶ , R ⁵⁷ , R ⁵⁸ , R ⁵⁹ , R ⁶⁰ , R ⁶¹ , R ⁶² , R ⁶³ , R ⁶⁴ , R ⁶⁵ , R ⁶⁶ , R ⁶⁷ , R ⁶⁸ , R ⁶⁹ , R ⁷⁰ , R ⁷¹ , R ⁷² , R ⁷³ , R ⁷⁴ , R ⁷⁵ , and R ⁷⁶ are each independently H, or alkyl, alkenyl, alkynyl, cycloalkyl, carbocycle, heterocycle, aryl, heteroaryl, Aryl-alkyl, heteroaryl-alkyl groups; and alternatively, the combination R ⁵² / R ⁵³ , when present, can form a heterocycle or part of a carbocycle with the carbon atoms to which it is attached. Or the combinations R ⁶⁰ R ⁶¹ , R ⁶⁴ R ⁶⁵ , and R ⁷⁵ R ⁷⁶ , independently of one another, can form part of a heterocyclic ring with the attached nitrogen (eg, pyrrolidine, piperidine, or morpho Phosphorus); or the combinations R ⁶⁸ / R ⁶⁹ and R ⁷⁰ / R ⁷¹ can be linked to form a C _1-4 alkylene chain;
m represents an integer 0-2;
n represents an integer 0-2. );
Z is heteroaryl,
However, the following compounds are excluded from Formula 1. ).

(Detailed Description of the Invention)
Preferably 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). To express. In the W group, aryl can represent, for example, optionally alkyl and / or halo substituted phenyl. In the W group, heteroaryl may represent, for example, optionally alkyl and / or halo substituted pyridyl.

When K is not present and W-CO represents an amino acid or an azaamino acid component, W-CO is, for example, L-Phe (i.e., W is -CH (NH ₂ ) (CH ₂ Ph)), Alternatively, it can represent a component of L-Tyr (ie, W is CH (NH ₂ ) (CH ₂ PhOH)).
Preferably K represents O or CH ₂ , in particular O.
Most preferably WK-CO represents allyloxycarbonyl (Aloc), t-butyloxycarbonyl (Boc), or benzyloxycarbonyl (Cbz), in particular benzyloxycarbonyl.

NH-X-CO is preferably an acyclic amino acid, more preferably a protein-constituting amino acid, most preferably L-Ala (i.e., X is CH (Me)), L-Arg (i.e., X is CH (CH ₂ CH ₂ CH ₂ NHC (= NH ₂ ) NH ₂ ), L-Asp (i.e., X is CH (CH ₂ COOH)), or L-Phe (i.e., X is CH ₂ Ph), especially L-Ala, L-Arg, or L Represents a component of -Phe, a further example being L-Lys (ie X is (CH ₂ ) ₄ NH ₂ )).
Typically R ¹⁶ will represent the side chain of a proteinogenic amino acid. Examples of R ¹⁶ groups 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 _{There are 2} COOH, -CH ₂ CONH ₂ , and CH ₂ CH ₂ COOH.

In one embodiment of the invention NY-CO represents a component of formula 2a, 2e, 2f, or 2g. In another embodiment of the invention NY-CO represents a component of formula 2b or 2c. In another embodiment of the invention NY—CO represents a component of formula 2d, in particular R ¹⁶ represents alkyl, for example methyl (ie a component of Ala, in particular L-Ala).

（式中、X¹、X²、及びX³は、上記で規定したものであり；かつ
R⁷⁷、及びR⁷⁸は、独立に、H、ハロゲン、CN、又はアルキル、例えば、H、CN、又はMeを表す。）。例えば、R⁷⁷、及びR⁷⁸は、独立にCNを表すことができる。あるいは、これらは、独立にMeを表すことができる。好ましくは、これらは、独立にHを表す。 Preferably, NY-CO represents a component of formula 2h, or 2i:

(Wherein X ¹ , X ² and X ³ are as defined above; and
R ⁷⁷ and R ⁷⁸ independently represent H, halogen, CN, or alkyl, such as H, CN, or Me. ). For example, R ⁷⁷ and R ⁷⁸ can independently represent CN. Alternatively, they can independently represent Me. Preferably they represent H independently.

（式中、R⁷⁷、及びX¹は、上記で規定したものであり、かつR⁸⁰、及びR⁸¹は、独立にH、又はフロオロである。）。 More preferably, NY-CO represents a component of formula 2j or 2k:

(Wherein R ⁷⁷ and X ¹ are as defined above, and R ⁸⁰ and R ⁸¹ are independently H or fluoro).

Most preferably, NY-CO is L-Pro in which the pyrrolidine ring is optionally substituted with methyl, for example R ⁷⁷ is H or methyl and X ¹ is CH ₂ and is a component of formula 2j, especially Unsubstituted L-Pro.
Preferably, R ¹ to R ^15, and R ¹⁷ to R ¹⁹ are independently, H, halogen (eg F), represents CN, or alkyl (e.g. Me), for example H, CN, or Me, especially H To express.

Most preferably, 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, particularly H.
Preferably, R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁶ , R ²⁷ , R ²⁸ , R ⁵² , and R ⁵³ are H.

Preferably, the R ^{29 to} R ⁵¹ groups represent H.
Preferably, the R ^{54 to} R ⁷⁶ group represents H.
Preferably X ¹ represents CH ₂ or CHMe, in particular CH ₂ .
Preferably X ² represents CH ₂ or CHMe, in particular CH ₂ .

Preferably X ³ represents CH ₂ or CHMe, in particular CH ₂ .
Preferably X ⁴ represents CH or CMe, in particular CH.
Preferably X ⁵ represents CH or CMe, in particular CH.
Preferably n represents 0 or 1, especially 0.
Preferably m represents 0 or 1, especially 0.

（式中、R⁸²、R⁸³、R⁸⁴、R⁸⁵、及びR⁸⁶は、独立に、H、又はアルキル鎖、アルケニル鎖、アルキニル鎖, シクロアルキル、炭素環、アリール、ヘテロアリール、複素環、或いは、ハロゲン、アミノ、-CONH₂、CONH(アルキル)、-CON(アルキル)₂、ニトロ、ヒドロキシル、オキソ、-CN、及び-SCNから選択された基である。）。 Preferably Z represents a 5-membered heteroaryl ring optionally fused to a benzene ring,
(Especially when bound to the rest of the molecule via a 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 a component of formula 3a, 3b, 3c, 3d, or 3e:

Wherein R ⁸² , R ⁸³ , R ⁸⁴ , R ⁸⁵ , and R ⁸⁶ are independently H, or an alkyl chain, alkenyl chain, alkynyl chain, cycloalkyl, carbocycle, aryl, heteroaryl, heterocycle, Or a group selected from halogen, amino, —CONH ₂ , CONH (alkyl), —CON (alkyl) ₂ , nitro, hydroxyl, oxo, —CN, and —SCN).

The R ⁸² , R ⁸³ , R ⁸⁴ , R ⁸⁵ , and R ⁸⁶ groups are typically H or alkyl (eg, methyl), and more typically H.
More preferably, Z is 2-imidazole, 2-thiazole, 4-thiazole, 5-thiazole, 2-thiophene, 3-thiophene, 2-oxazole, 4-oxazole, 5-oxazole, 3-pyrazole, 4-pyrazole. , 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, in particular 2-thiazole or 2-benzo [d] thiazole. Another group of particular interest is pyrrole, for example 2-pyrrole.

この化合物は、US 2005/0171112に開示されている。 According to one particular embodiment of the invention, we provide a compound of formula 1. However, the following compounds are excluded from Formula 1.

This compound is disclosed in US 2005/0171112.

  The PEP-inhibitors of the present invention have been surprisingly shown to be effective in regulating basal levels of interleukin-6 (IL-6) in human glial cells. These compounds show significant suppression of IL-6 secretion. This is not known for all PEP-inhibitors described in the prior art.

  IL6, a pleiotropic cytokine, contributes to many neuropathological and pathophysiological processes, particularly in inflammation, cancer, infection, and autoimmune diseases. Overexpression of IL-6 is caused by multiple myeloma, solid tumor, prostate cancer, bladder cancer, neuronal cancer, Castleman's disease, inflammation, myocardial infarction, Paget's disease, ischemia, asthma, rheumatoid arthritis, psoriasis, Alzheimer's disease, Associated with multiple sclerosis, meningitis, stroke, osteoporosis, insulin resistance, obesity, impaired glucose tolerance, type 2 diabetes, cancer-related eating disorders and cachexia, and multidrug resistance pathology . Accordingly, reduction of pathological IL-6 levels by the compounds described herein may be useful, for example, in the treatment of the above-mentioned IL-6 related diseases.

Furthermore, the PEP inhibitors of the present invention are surprisingly effective in regulating the basal levels of β-amyloid peptides, particularly Aβ _1-40 and Aβ _1-42 , in various human cell lines such as neurons. It is shown that there is. The compounds of the present invention show a significant increase in β-amyloid peptide secretion. This is not known for all PEP-inhibitors described in the prior art.

β-amyloid peptide is thought to be responsible for MCI (mild cognitive impairment), Alzheimer's disease (AD), and neurodegeneration in patients facing progression from MCI to AD, and neuronal cell death. Recently, it has been shown that β-amyloid species involved in the development of MCI and AD are formed in cells. Furthermore, not the full length of peptides Aβ _1-40 and Aβ _1-42 , but N-terminal truncated and N-terminal modified forms of β-amyloid peptide, such as Aβ _3-40 , Aβ _3-42 , pGlu- Aβ _3-40 , pGlu-Aβ _3-42 , Aβ _11-42 , and pGlu-Aβ _11-42 have been discussed as toxic forms (Piccini et al., J. Biol. Chem. 280 (40), 2005, pp. 34186-34192).

Accordingly, the compounds of the present invention are neurotoxic β-amyloid peptides such as Aβ _3-40 , Aβ _3-42 , by N-terminal truncation and enhanced secretion of full length Aβ _1-40 and Aβ _1-42 before modification. It is useful for suppressing the formation of pGlu-Aβ _3-40 , pGlu-Aβ _3-42 , Aβ _11-42 , and pGlu-Aβ _11-42 .

  We have shown for the first time that a protease can cleave a substrate after a cysteine residue in the peptide chain. In addition, the inventors have shown that the peptide humanin is a substrate for PEP. Specifically, the inventors have shown that prolyl endopeptidase can cleave the peptide humanin at two positions in the peptide sequence, after a proline residue at position 3 and after a cysteine residue at position 8. Is shown. This cleavage pattern can be completely inhibited by the use of specific PEP inhibitors.

  Humanin was originally discovered by unbiased functional screening methods for genes that suppress FAD (familial Alzheimer's disease) and Aβ-induced neuronal cell death (* 30, 32, respectively). The peptide is an abnormal 75 bp gene product of mitochondrial 16S ribosomal RNA (* 27, 30). Evidence for cellular expression of this gene product was obtained by Western blot using peptide antibodies (* 33). Detailed analysis of the bioactivity showed the presence of the humanin core region (residues 3-19) (* 34, * 35). In particular, it is necessary to conserve seven residues such as Pro (3); Cys (8); Leu (9); Leu (12); Thr (13); Ser (14), and Pro (19). (* 34, 35). Substitution of these residues with alanine or omission of the core sequence results in a loss of humanin's ability to rescue apoptosis.

  Recently, humanin has been highlighted for its ability to inhibit apoptosis by interacting with Bcl2-related X protein (Bax) (* 27). Further interaction with insulin-like growth factor binding protein-3 (IGFBP-3) inhibits the IGFBP-3-induced cell death of glioblasts and supports humanin's ability to promote cell survival (* 28). The 24-amino acid peptide protects cortical neurons from prion-peptide or amyloid-β-induced injury (* 28, * 39), improves metabolic activity abnormalities and prolongs the survival of serum-deficient human lymphocytes (* 31). )be able to.

  Accordingly, PEP-inhibitors are useful for inhibiting the degradation of peptide substrates that can be degraded by post-cysteine cleavage, such as peptide humanin. Furthermore, the present invention provides a method for inhibiting the degradation of peptide substrates that can be degraded by post-cysteine cleavage, such as peptide humanin. Compounds of formula (1) are particularly suitable for use in the present method.

The compounds of the present invention have several unique and surprising properties and are expected to be useful in the treatment of neurodegenerative diseases such as MCI, AD, Down syndrome, Parkinson's disease, and Huntington's disease .
Methods for preparing compounds of Formula 1 are presented in Scheme 1 and detailed in Scheme 2, Scheme 3, and Scheme 4, and “General Methods”. Thus, with reference to Route 1 of Scheme 1, the process for preparing the compound of formula 1 involves reacting the compound of formula A and the compound of formula B under metalation conditions. A dipeptide of formula A is an activating molecule (wine levamide) and can react with an organometallic (eg, organolithium) derivative of a compound of formula B. A dipeptide of formula A can be prepared by reaction of a dipeptide of formula C (usually activated, for example, as a mixed anhydride) with a compound of formula D (Wine Rev activating group). A compound of formula C (dipeptide without C-terminus) can be prepared by hydrolysis of a compound of formula E (ester). A compound of formula E can be prepared by reaction of a compound of formula F (N-protected amino acid derivative) (usually activated, for example, as a mixed anhydride) with a compound of formula G (C-protected amino acid derivative). Alternatively, with reference to Route 2 of Scheme 1, the process for preparing the compound of formula 1 involves the oxidation of a precursor compound characterized as an alcohol of formula H. A compound of formula H can be reached from a compound of formula J (Z-component without N-terminus) via a coupling reaction. Compounds of formula J are typically obtained by deprotection of protected derivatives of formula K. Compounds of formula K (N-protected Z component) can be reached starting from compounds of formula L via reduction of the alcohol (formula La) and subsequent oxidation to the corresponding aldehyde (formula Lb). This aldehyde compound can then be reacted with an organolithium derivative of component Z (eg, a compound of formula B). Finally, with reference to route 3 in Scheme 1, the process for the preparation of the compound of formula 1 involves arylation in which a Grignard reagent of formula Q is reacted with a compound of formula E. Compounds of formula Q can be readily prepared from the aryl compound HZ and the commercially available Grignard reagent MeMgBr.

スキーム１．式１を含む化合物の逆合成経路。R^x=ワインレブ活性化基、すなわちN(CH₃)OCH₃、R^y=アルコキシ、例えばOMe、R^Z=アミン保護基、例えばBoc。*は、基が、例えば混合無水物として活性化されるのに適し得る。式B、D、G、及びLの化合物は、市場で入手することが可能であり、又は公知の方法で製造され得る。
スキーム１において、式G、及びLの化合物は、式HN-Y-COOH（式M）の化合物から容易に製造され得る。

Scheme 1. A reverse synthetic route for compounds comprising Formula 1. R ^x = Wine rev activating group, ie N (CH ₃ ) OCH ₃ , R ^y = alkoxy, eg OMe, R ^Z = amine protecting group, eg Boc. * May be suitable for the group to be activated, for example as a mixed anhydride. Compounds of formula B, D, G, and L are commercially available or can be prepared by known methods.
In Scheme 1, compounds of formula G and L can be readily prepared from compounds of formula HN—Y—COOH (formula M).

Specific synthetic routes and synthetic schemes for the starting materials of compounds of formula M are well known to those skilled in the art. For example, reference 1 disclosing synthetic routes and synthetic schemes for these compounds (or analogs) when Y is 2a, 2c, 2e, 2f, 2g, 2h, 2i, 2j is shown in Table 1. Indicated. These references are incorporated by reference herein in their entirety and of compounds of formula M when Y is 2a, 2c, 2e, 2f, 2g, 2h, 2i, 2j, and 2k. With respect to synthesis, it is part of the present invention.
Other compounds of formula M, and compounds of formulas B, D, and F are known or can be prepared by conventional methods known per se.
The compound of formula 1 can also be prepared by deprotecting the protected compound of formula 1.

（式中、W、K、X、及びYは、上記で規定したのものであり、かつR^xは、ワインレブ活性化基を表す。）；

（式中、Zは、上記で規定したのものである。）；又は
（b）式Hの化合物又はその保護誘導体を酸化すること；

（式中、W、K、X、Y、及びZは、上記で規定したのものである。）；
及び必要に応じて、その生成物を脱保護して、式（１）の化合物を得ることである。
式（１）の化合物への別経路として、グリニャール試薬を用いたアリール化により、式Eの中間体化合物を、式（１）の化合物に直接変換することができる（スキーム４を参照）。 Accordingly, as an aspect of the present invention, the inventors provide a method for producing a compound of formula (1) comprising the following steps:
(A) reacting a compound of formula A or a protected derivative thereof with a compound of formula B or a protected derivative thereof:

Wherein W, K, X and Y are as defined above and R ^x represents a wine rev activating group;

(Wherein Z is as defined above); or (b) oxidizing a compound of formula H or a protected derivative thereof;

(W, K, X, Y and Z are as defined above);
And optionally deprotecting the product to obtain a compound of formula (1).
As an alternative route to compounds of formula (1), intermediate compounds of formula E can be directly converted to compounds of formula (1) by arylation with a Grignard reagent (see Scheme 4).

（式中、W、K、X、及びYは、上記で規定したものであり、かつR^yは、アルコキシ基、例えばOMeなどのOC_1-4アルキルを表す。）；

（式中、Zは、上記で規定したものであり、かつXは、Brなどのハロゲンを表す。）；続いて、水又は水性緩衝液で後処理することである。 Thus, as a further aspect of the present invention we provide a process for the preparation of the compound of formula (1) comprising the following steps:
(C) reacting a compound of formula E or a protected derivative thereof with a compound of formula Q or a protected derivative thereof:

Wherein W, K, X and Y are as defined above and R ^y represents an alkoxy group, for example an OC _1-4 alkyl such as OMe);

(Wherein Z is as defined above and X represents a halogen such as Br); followed by post-treatment with water or an aqueous buffer.

Compounds of formula Q can be prepared by reacting heteroaryl compound Z with a suitable alkylmagnesium halide compound such as MeMgBr.
Appropriate conditions for the reaction with the Grignard reagent (Q) are known to the person skilled in the art.

The present invention provides a compound of formula 1 for use as a medicament.
The compound of formula 1 is an inhibitor of PEP and PEP-like enzymes.
Furthermore, the present invention provides the use of an inhibitor of PEP and PEP-like enzymes of formula 1 for the manufacture of a medicament for the treatment of a disease selected from the group consisting of:
Alzheimer's disease, Down syndrome, Parkinson's disease, Huntington's disease, pathogenic psychosis, schizophrenia, food intake disorder, sleep awakening, homeostasis control disorder of energy metabolism, autonomic dysfunction, hormone balance disorder, control disorder, fluid, hypertension, fever , Sleep dysregulation, eating disorders, anxiety-related illnesses including depression, epilepsy, drug withdrawal symptoms, and seizures including alcoholism, cognitive impairment, dementia, aphasia, apraxia, agnosia, or some Types of amnesia, mild cognitive impairment (MCI), benign amnesia, and neurodegenerative disorders including Korsakov syndrome, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or heart transplantation Posterior coronary artery disease, atherosclerosis, reperfusion injury, hypoxia, ischemia, and blood clotting disorders.

The present invention also provides an inhibitor of the PEP and PEP-like enzymes of formula 1 for use in the treatment of a disease selected from the group consisting of:
Alzheimer's disease, Down syndrome, Parkinson's disease, Huntington's disease, pathogenic psychosis, schizophrenia, food intake disorder, sleep awakening, homeostasis control disorder of energy metabolism, autonomic dysfunction, hormone balance disorder, control disorder, fluid, hypertension, fever , Sleep dysregulation, eating disorders, anxiety-related illnesses including depression, epilepsy, drug withdrawal symptoms, and seizures including alcoholism, cognitive impairment, dementia, aphasia, apraxia, agnosia, or some Types of amnesia, mild cognitive impairment (MCI), benign amnesia, and neurodegenerative disorders including Korsakov syndrome, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or heart transplantation Posterior coronary artery disease, atherosclerosis, reperfusion injury, hypoxia, ischemia, and blood clotting disorders.

The present invention also provides a method of treating a disease selected from the group consisting of: comprising administering to a mammal, preferably a human, a therapeutically effective amount of at least one compound of formula 1.
Alzheimer's disease, Down syndrome, Parkinson's disease, Huntington's disease, pathogenic psychosis, schizophrenia, food intake disorder, sleep awakening, homeostasis control disorder of energy metabolism, autonomic dysfunction, hormone balance disorder, control disorder, fluid, hypertension, fever , Sleep dysregulation, eating disorders, anxiety-related illnesses including depression, epilepsy, drug withdrawal symptoms, and seizures including alcoholism, cognitive impairment, dementia, aphasia, apraxia, agnosia, or some Types of amnesia, mild cognitive impairment (MCI), benign amnesia, and neurodegenerative disorders including Korsakov syndrome, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or heart transplantation Posterior coronary artery disease, atherosclerosis, reperfusion injury, hypoxia, ischemia, and blood clotting disorders.

Most preferably, the invention comprises mild cognitive impairment (MCI), Alzheimer's disease, Down's syndrome, Parkinson's disease, comprising administering to a mammal, preferably a human, a therapeutically effective amount of at least one compound of formula 1. Methods of treating a disease selected from the group consisting of Huntington's disease and corresponding uses are provided.
In further embodiments, the compounds of Formula 1 are useful for inhibiting microbial growth, reducing intraoperative blood loss, preserving transplanted tissue or organs, inhibiting cancer cell growth or tumor progression or tumor metastasis or invasion.

(combination)
In a further embodiment, 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:
Glutaminyl cyclase (QC) inhibitor, LiCl, dipeptidyl aminopeptidase inhibitor, preferably DP IV or DP IV-like enzyme inhibitor, NPY-receptor ligand, NPY agonist, acetylcholinesterase (AChE) inhibitor Protein isoaspartate carboxymethyltransferase (PIMT) enhancer, beta secretase inhibitor, gamma secretase inhibitor, neutral endopeptidase inhibitor, phosphodiesterase-4 (PDE-4) inhibitor, monoamine oxidase (MAO) Inhibitors, TNF alpha inhibitors, amyloid protein or amyloid peptide deposition inhibitors, sigma-1 receptor inhibitors, and histamine H3 antagonists.

These combinations provide a particularly beneficial effect on the behavioral state, thus said combinations are shown to be effective and useful for the treatment of diseases selected from the group consisting of:
Alzheimer's disease, Down syndrome, Parkinson's disease, Huntington's disease, pathogenic psychosis, schizophrenia, food intake disorder, sleep awakening, homeostasis control disorder of energy metabolism, autonomic dysfunction, hormone balance disorder, control disorder, fluid, hypertension, fever , Sleep dysregulation, eating disorders, anxiety-related illnesses including depression, epilepsy, drug withdrawal symptoms, and seizures including alcoholism, cognitive impairment, dementia, aphasia, apraxia, agnosia, or some Types of amnesia, mild cognitive impairment (MCI), benign amnesia, and neurodegenerative disorders including Korsakov syndrome, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or heart transplantation Posterior coronary artery disease, atherosclerosis, reperfusion injury, hypoxia, ischemia, and blood clotting disorders.
The combinations of the present invention are further useful for inhibiting microbial growth, reducing intraoperative blood loss, preserving transplanted tissues or organs, inhibiting cancer cell growth or tumor progression or tumor metastasis or invasion.

(Pharmaceutical composition)
The present invention provides a pharmaceutical composition comprising at least one compound of formula 1, optionally in combination with at least one agent of the above combination, together with one or more therapeutically acceptable diluents or carriers. . The active ingredient is thoroughly mixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques. The diluent or carrier may take a wide variety of forms depending on the form of preparation desired for administration, eg, oral or parenteral, such as intramuscular. In preparing the oral dosage form of the composition, all conventional pharmaceutical media can be used. Thus, for liquid oral formulations such as suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, fragrances, preservatives, colorants, and the like; For solid oral dosage forms such as powders, capsules, gelcaps, and tablets, suitable carriers and additives include starches, sugars, diluents, granules, lubricants, binders, disintegrants, and the like. Because of their ease in administration, tablets and capsules are the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets can be sugar-coated or enteric-coated by standard techniques. For parenteral administration, the carrier usually contains sterile water, but other ingredients may be included, eg, for solubility aids or storage.

  Soluble polymers as targetable drug carriers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspartamide-phenol, or polyethylene oxide polylysine substituted with palmitoyl residues be able to.

  Furthermore, the compounds of the present invention can be used to crosslink or parent polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels useful for achieving controlled drug release. It may be bound to a series of biodegradable polymers such as a damaging block copolymer.

Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, Examples include but are not limited to sodium acetate and sodium chloride.
Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum.

  Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents and the like can be employed. The pharmaceutical compositions herein will contain the amount of active ingredient necessary to carry the effective amount per dosage unit, such as tablets, capsules, powders, injections, and teaspoonfuls. The pharmaceutical composition herein contains about 0.03 mg to 100 mg / kg (preferably 0.1 to 30 mg / kg) per dosage unit such as tablets, capsules, powders, injections, suppositories, and a teaspoonful. And can be administered at a dosage of about 0.1 to 300 mg / kg of each active ingredient or combination thereof per day (preferably 1 to 50 mg / kg per day). However, the dosage may vary depending on the condition of the patient, the severity of the condition being treated, and the compound used. The use of daily administration or post-periodic dosing can be employed.

  Preferably these compositions are for tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions for oral, parenteral, nasal, sublingual or rectal administration or for inhalation or infusion. A unit dosage form such as a suspension, metered dose aerosol or liquid spray, drop, ampoule, auto-injector, or suppository. Alternatively, the composition may be present in a form suitable for once-weekly or monthly administration; for example, an insoluble salt of an active compound such as decanoate is adapted to provide a sustained formulation for intramuscular injection can do. For the production of solid compositions such as tablets, the main ingredients are the conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum, and water Other pharmaceutical diluents are mixed with a pharmaceutical carrier to form a solid preformulation composition comprising a homogeneous mixture of the compound of the invention or a pharmaceutically acceptable salt thereof. When these pre-formulated compositions are referred to as homogeneous, the active ingredient is evenly distributed throughout the composition so that the composition can be subdivided into equally effective dosage forms such as tablets, pills, and capsules. Means that they are distributed. As a result, this solid preformulation composition is subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of each active ingredient of the present invention or combinations thereof.

  Tablets or pills of the composition of the invention can be coated or formulated to provide a dosage form that provides the benefit of prolonged action. For example, the tablet or pill can include an inner dosage component and an outer dosage component, the latter being in a form that wraps around the former. The two components can be separated by an enteric layer that serves to resist degradation in the stomach and transfers the internal component intact into the duodenum or delays release. Various materials can be used for the enteric layer or coating. The materials include many polymeric acids along with materials such as shellac, cetyl alcohol, and cellulose acetate.

  Liquid forms in which the compositions of the invention may be taken orally or taken in by injection are aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and edibles such as cottonseed oil, sesame oil, coconut oil, or peanut oil Includes perfume emulsions with oils, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate or ester, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, or gelatin.

  When the process for producing the compounds of the present invention yields a mixture of stereoisomers, these isomers can be separated by conventional techniques such as separation chromatography. The compounds can be made in racemic form, or individual enantiomers can be made by enantiospecific synthesis, or resolution. For example, the compound may be converted to a diastereomer by salt formation using an optically active acid such as (−)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl-l-tartaric acid. These component enantiomers can be resolved by standard techniques such as pairing, subsequent fractional crystallization, and regeneration of the free base. The compounds can also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation, and removal of chiral auxiliary groups. Alternatively, the compound can be resolved using a chiral HPLC column.

  Advantageously, the compounds of the invention can be administered in a single daily dose, or the total daily dose is divided into 2, 3, 4 daily doses. be able to. Furthermore, the compounds of the present invention can be administered in nasal dosage forms via topical use of suitable nasal administration vehicles well known to those skilled in the art or via transdermal skin patches. To be administered in the form of a transdermal delivery system, the administration will, of course, be continuous rather than intermittent throughout the administration regimen.

  For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, and water. In addition, if desired or required, suitable binders; lubricants, disintegrants, and colorants can also be combined in the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, Examples include but are not limited to sodium acetate and sodium chloride. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum.

  Liquid forms in suitable perfume suspending or dispersing agents such as, for example, synthetic and natural gums such as tragacanth, acacia, and methylcellulose. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain sterile preservatives are employed when intravenous administration is desired.

  The compounds or combinations of the 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.

  Also, the compounds or combinations of the present invention can be transported through the use of monoclonal antibodies as individual carriers to which the compound molecules bind. The compounds of the present invention can also be coupled with soluble polymers as targetable drug carriers. The polymer may comprise polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspartamide-phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention can be used to crosslink or parent polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels useful for achieving controlled drug release. It may be bound to a series of biodegradable polymers such as a damaging block copolymer.

Where treatment of the disease is required, the compounds or combinations of the invention can be administered in any of the compositions according to art-established dosing regimens.
The daily dosage of the product can be varied over a wide range from 0.01 to 1.000 mg per day for mammals. For oral administration, the composition comprises 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, each active ingredient or combination thereof for symptomatic adjustment of the dosage to the patient being treated. Provided in the form of tablets containing 25.0, 50.0, 100, 150, 200, 250, and 500 milligrams. Usually, an effective amount of the drug is provided at a dosage of about 0.1 mg / kg to about 300 mg / kg body weight per day. Preferably, the range is about 1-50 mg / kg body weight per day. The compound or combination may be administered on a regimen of 1 to 4 times per day.

  The optimal dosage to be administered can be readily determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the effect of the formulation, the mode of administration, and the progression of the disease state . In addition, factors associated with the particular patient being treated, including patient age, weight, dietary restrictions, and time of administration, may necessitate dosage adjustments.

  Suitably, in the case of the combination of the present invention, the particularly beneficial effect provided by the treatment of the present invention is that the therapeutic ratio in the combination of the present invention is such that one compound of the combination alone or the present It is an improvement over the therapeutic ratio when used at a dosage that provides the same effect as the combination of the invention.

In a preferred embodiment, the particularly beneficial effects provided by the treatment of the present invention are shown to be synergistic as compared to the control predicted from the effects of the individual active agents.
In a further aspect of the invention, preferably a combination administration of at least one compound of formula 1 and at least one agent as defined in the combination herein is used for the agent in the combination It will produce a more beneficial effect than can be achieved with two doses alone.

In a preferred embodiment, the dose of each of the active agents when used in accordance with the treatment of the present invention will be less than would be required simply because of the additional effect during neurological symptoms.
Without being limited by theory, the treatment of the present invention also reduces the intracellular deposition of pGlu-amyloid-beta-peptide compared to individual drugs, resulting in mammalian brain, preferably human It will slow down plaque formation in the brain and bring about improvement.

In a further aspect, the present invention also relates to a medicament comprising at least one compound of formula 1 or a pharmaceutically acceptable carrier thereof, optionally in combination with at least one agent as defined in the combinations herein. A method for producing the composition is provided. The method comprises mixing the compound of Formula 1, the optional agent, and a pharmaceutically acceptable diluent or carrier.
The composition is preferably in a unit dosage form in an amount appropriate for the daily dosage.

  Suitable dosages for the following compounds, particularly including unit dosages, are described in the UK and US Pharmacopoeia, “Remington's Pharmaceutical Sciences” (Mack Publishing Co.), Martindale The Extra Pharmacopoeia ( London, The Pharmaceutical Press) (eg, page 341 of the 31st edition, and pages cited therein), or any known dosage, including unit dosages of compounds described or referenced in the above publications Formula 1, QC-inhibitor, LiCl, dipeptidylaminopeptidase inhibitor, preferably DP IV or DP IV-like enzyme inhibitor, NPY-receptor ligand, NPY agonist, acetylcholinesterase (AChE) inhibitor, PIMT enhancer, beta secretase inhibitor, gamma secretase inhibitor, neutral endopeptidase inhibitor, phosphodiesterase-4 (PDE-4) inhibitor, Noamine oxidase (MAO) inhibitors, TNF alpha inhibitors, amyloid protein or amyloid peptide deposition inhibitors, sigma-1 receptor inhibitors, and histamine H3 antagonists.

Preferred compounds of formula 1 are those having an IC ₅₀ value or K _i values, preferably, 1 × less than 10 ^-6, in particular less than 1 × 10 ^-7, especially 1 × 10 an IC ₅₀ value of less than ^-7, or It has a K _i value.
Preferred compounds of formula 1 have a molecular weight of less than 2000 Da, in particular less than 1000 Da, in particular less than 600 Da, for example less than 500 Da.

The compounds and combinations of the present invention are more effective, selective, have fewer side effects, have better formulation and stability, and are better than other compounds in the prior art, for example, in the mammalian brain Has pharmacokinetic properties, high bioavailability, can cross the blood brain barrier and is more effective, compatible or effective in combination with other drugs, or more It can have the advantage of being easily synthesized.
The present invention encompasses preferred groups, more preferred groups, and combinations of embodiments from the groups listed above.

(Biological evaluation, determination of IC _50- and K _i -values of PEP-inhibitors)
Recombinant human prolyl oligopeptidase was used for the measurement. Recombinant expression was performed in E. coli under standard conditions as described elsewhere in the state of the art. For activity measurements, the chromogenic substrate Cbz-Gly-L-Pro-pNA in HEPES buffer pH 7.6 containing 50 mM HEPES, 200 mM NaCl, 1 mM EDTA, 1 mM DTT, 0.006% Brij35 was used. The measurement was performed at 30 ° C. The release of pNA was continuously monitored at 405 nm.

IC ₅₀ values were determined using a single substrate concentration (0.15 mM) and 11-15 serial dilutions of inhibitor starting from 0.1 mM. IC ₅₀ values were calculated using non-linear regression to a 4-parameter equation (Prism 4.0, GraphPad).
For the K _i measurement, four concentrations of substrate (0.15 mM, 0.08 mM, 0.04 mM, 0.02 mM) and an appropriate range of seven concentrations of inhibitor were used. Calculations were performed by multiple nonlinear regression analysis on the equations for competitive inhibitors using GraFit 5.0 software (Erithacus Software).

(IL-6 ELISA)
To analyze basal secretion of IL-6, human glial U-343 cells were cultured in 6-well plates (1.5 × 10 ⁶ cells / well, Greiner) and specific PEP inhibitors as indicated (each 20 μM) for 24 hours in serum-free D-MEM medium (invitrogen). A 40 μl aliquot of the culture supernatant was used to quantify the amount of secreted IL-6 by a human specific IL-6 ELISA (Biosource) following the manufacturer's instructions. All data was obtained in 4 sets. For the calculation of the IL-6 concentration in the cell culture medium after treatment with the PEP-inhibitor, the basal IL-6 concentration in the cell culture medium of the untreated cell sample was taken as 100%. The measurement results of IL-6 concentration using PEP inhibitor-treated cells are shown as% of untreated cell samples.

(Β-amyloid ELISA)
(Cell culture)
Human glioma cell line U-343 and human neuroblastoma cell line SH-SY5Y were maintained in Dulbecco's modified Eagle medium (DMEM) containing fetal bovine serum and incubated at 37 ° C. in a 5% CO ₂ atmosphere. . In general, the medium contained 60 μg / ml gentamycin (Gibco BRL, Karlsruhe, Germany).

(Metabolic labeling)
For the metabolic labeling approach, 5 × 10 ⁵ cells were seeded in 35 mm culture dishes and grown for 40 hours in the appropriate medium. After washing, the cells are incubated with [ ³⁵ S] methionine (1 μCi / ml, ICN Biomedicals, Eschwege, Germany) for 2 hours in DMEM (ICN Biochemicals) without L-methionine, L-cysteine, and L-cystine. Keep warm. The presence or absence of the PEP inhibitor Fmoc-Ala-Pyrr-CN (5 μM) was followed for 24 hours at 37 ° C. in serum-free medium. Radiolabeled protein in the chase medium was precipitated with 8% (w / v) TCA-solution and centrifuged at 15500 × g for 10 minutes. After washing, the protein pellet was resuspended in 1 ml distilled water and radioactivity was measured with a Tri-carb2100TR-scintillation counter (Packard, Dreieich, Germany). All measurements were performed in at least 4 sets and the experiment was repeated 4 times.

(Β-amyloid ELISA)
To quantify intracellular and extracellular concentrations of β-amyloid peptides 1-40 and 1-42, U-343 and SH-SY5Y cells were cultured in 6-well plates (1.5 × 10 ⁶ cells / well). And a specific PEP inhibitor (20 μM each) for 24 hours. Culture supernatants were collected and concentrated by lyophilization for quantification of secreted β-amyloid peptide. Similarly, after cell number / well measurement (casy cell counter I, Schrfe System, Reutlingen, Germany), cells were lysed with cell extraction buffer (Biosource, Solingen, Germany) according to the manufacturer's protocol. The protein concentration was measured by the Bradford method (1976). Using 100 μl aliquots, β-amyloid peptides 1-40 and 1-42 were quantified in quadruplicate by ELISA (IBL, Hamburg, Germany) following manufacturer's instructions. All obtained intracellular and extracellular concentrations were normalized to cell number and protein concentration, respectively.

Basal concentrations of β-amyloid peptides 1-40 and 1-42 in the medium of untreated cell samples for calculation of the concentration of β-amyloid peptides 1-40 and 1-42 in the cell medium after treatment with PEP inhibitors Was 100%. The results of measuring the concentrations of β-amyloid peptides 1-40 and 1-42 using PEP inhibitor-treated cells are shown as% of untreated cell samples.
Preferred PEP inhibitors of the present invention exhibit a significant decrease in IL-6 concentration and increased β-amyloid secretion, particularly increased secretion of β-amyloid 1-40 and 1-42 (shown in FIGS. 1 and 2). See results).

(Inhibition of post-cysteine cleavage of peptide humanin by recombinant human prolyl endopeptidase)
Degradation experiments were performed using recombinant human prolyl endopeptidase (rhPEP). Peptide humanin was used as a substrate. Peptide humanin contains 24 amino acids of the following sequence:
MAPRGFSCLLLLTSEIDLPVKRRA
rhPEP is capable of cleaving humanin at two positions in the peptide sequence: after the proline residue at position 3 and after the cysteine residue at position 8.
Humanin cleavage by PEP can be inhibited with a specific PEP inhibitor of formula (1). The inhibitor of formula (1) suppresses cleavage after proline in the humanin sequence and subsequent cysteine.

(Experiment contents)
All inhibitors are dissolved in 100% DMSO. The final concentration of the inhibitor in stock solution is 2 mM. The DMSO stock solution is stored at −20 ° C. The humanin peptide is first dissolved in 100% DMSO and then with PEP buffer until the final concentration is 1 mg / ml, taking care that the DMSO concentration does not exceed 10% of this solution. Diluted. The humanin stock solution is stored at -20 ° C. Enzyme reaction consists of 270 mM HEPES (ROTH), 1080 mM NaCl (ROTH), 5.4 mM EDTA (MP Biomedicals), 0.03% 30-35 w / v BRIJ (registered trademark), 7.96 mM DTT (Sigma) Perform in PEP buffer. The enzyme is stored at −20 ° C. in a 50% ethylene glycol stock solution.

(Reaction mixture)
The rhPEP stock solution is diluted 1:20 with PEP buffer.
The inhibitor stock solution is diluted 1:10 to 1:20 with water. The inhibitor solution is then mixed with an equal volume of 1 mg / ml humanin stock solution (in PEP buffer).

Next, 90 μl of the inhibitor / substrate solution is mixed with 10 μl of enzyme solution. The mixture is kept at 37 ° C. until the end of reaction time is exceeded. The final concentrations of the inhibitor and substrate are 80 μM (inhibitor) and 0.45 mg / ml (humanin), respectively.
The reaction is stopped by mixing 10 μl of the reaction mixture with 10 μl of 0.1% TFA aqueous solution at the following reaction time points: 10, 30, 60, 120, 240, 480, 1440 minutes.

  The identity and amount of different products resulting from enzymatic hydrolysis were evaluated by matrix-assisted laser desorption mass spectrometry. FIG. 3 shows the production of the humanin cleavage product HN 9-24 in the presence of PEP. 4 and 5 show that HN 9-24 does not form in the presence of PEP in the presence of PEP inhibitor.

(Example compounds)

(General synthesis method of starting materials and compounds of Examples)
Example compounds were prepared via Route 1, Route 2, or Route 3.
Of starting material path 1: protected amino acid derivative (. W-KCONH-X- COOH, HN-Y-COR y, R y is representative of the normal OMe) and were purchased from Bachem. The dipeptide (W-KCONH-X-CON-Y-COOH) was prepared via Method A and Method B (Intermediates EI, II, and CI, II) according to the procedure of Ref. The starting material for Intermediate A IV was purchased from Bachem. The N-methoxy-N-methyl derivative (* 25) (Intermediates A III, IV, and V) was prepared via Method A. Examples: Intermediates A III, IV and V (weinlevamide) were treated with n-BuLi solution to compounds of Examples 1, 2, 4, 9, 10 and via Method C. Conversion into each aromatic heterocyclic compound (* 26). The aromatic heterocyclic compound was purchased from FLUKA or ALDRICH. A diagram is provided in Scheme 2.

スキーム２．中間体E I, II (C-保護ジペプチド)、中間体C I, II (ジペプチド)、中間体 A III, IV, 及びV (ワインレブアミド)、及び実施例１、２、４、９、１０の化合物の合成。方法A：混合無水物；方法B：けん化；方法C：n-BuLi, H-Z：ヘテロアリール化合物。

Scheme 2. Intermediate EI, II (C-protected dipeptide), Intermediate CI, II (dipeptide), Intermediate A III, IV, and V (Wine Revamide) and the compounds of Examples 1, 2, 4, 9, 10 Synthesis of. Method A: Mixed anhydride; Method B: Saponification; Method C: n-BuLi, HZ: Heteroaryl compound.

  Route 2 starting material: The protected amino acid derivative (Boc-NY-COOH) was purchased from Bachem and reduced via Method D to give intermediates La I and II (* 24). Intermediates La I and II were oxidized to the corresponding intermediates Lb I and II (aldehyde) by swarnidation via Method E (* 24). Intermediates K I and II were prepared via Method F (US 5,547,978). Intermediates K I and II were deprotected via Method G (* 23). Intermediates JI and II were coupled with W-KCO-NH-X-COOH via Method H. Examples: Intermediate H I-V was converted to the compounds of Examples 3, 5, 6, 7 by swarnidation via Method E (Scheme 3). After oxidation, the compound of Example 8 was obtained by deprotection via Method G.

スキーム３．中間体La I, II (アルコール)、中間体Lb I, II (アルデヒド)、中間体 K I, II(保護ヘテロアリール化合物成分)、中間体J I, II (脱保護ヘテロアリール化合物成分)、中間体H I-V (ヘテロアリール-アルコール)、及び実施例３、５、６、７、及び８の化合物の合成。方法D：1.)無水物を混合、2.)LiAlH₄；方法E：スワーン酸化；方法F：n-BuLi, H-Z：ヘテロアリール化合物；方法G：TFA, TIPS；方法H：カップリング反応、アミノ酸リシン成分に対してR = Boc。経路３の出発物質：中間体E Iを、スキーム２に記載するように製造した。

Scheme 3. Intermediate La I, II (alcohol), intermediate Lb I, II (aldehyde), intermediate KI, II (protected heteroaryl compound component), intermediate JI, II (deprotected heteroaryl compound component), intermediate H Synthesis of IV (heteroaryl-alcohol) and the compounds of Examples 3, 5, 6, 7, and 8. Method D: 1.) Mixed with anhydride, 2.) LiAlH ₄ ; Method E: Swarnidation; Method F: n-BuLi, HZ: Heteroaryl compound; Method G: TFA, TIPS; Method H: Coupling reaction, R = Boc for the amino acid lysine component. Route 3 starting material: Intermediate EI was prepared as described in Scheme 2.

スキーム４．実施例１１の化合物の合成。方法J：Et_２O中のMeMgBr、ピロール；ZMgBrを、その場（in situ）で形成した。 Example: Intermediate EI was converted to the compound of Example 11 by arylation with Grignard reagent via Method J (* 36) (Scheme 4).

Scheme 4. Synthesis of the compound of Example 11. Method J: MeMgBr, pyrrole; ZMgBr in Et ₂ O were formed in situ.

(Abbreviation)
Aloc allyloxycarbonyl
Boc tert.-Butyloxycarbonyl
n-BuLi n-Butyllithium
Cbz benzyloxycarbonyl
EE ethyl acetate
EtOH ethanol
Et ₂ O diethyl ether
LiAlH ₄ Lithium aluminum hydride
NEt ₃ triethylamine
NMM 4-methylmorpholine
pNA 4-nitroanilide
TFA trifluoroacetic acid
TIPS Triisopropylsilane
TLC thin layer chromatography

(Analysis method)
NMR spectra were performed on a Bruker AM 400 and a Varian Unity 500 spectrometer. The following abbreviations were used: s (single line), d (double line), dd (double line double line), t (triple line), and m (multiple line). ESI-MS: Mass spectra were taken on an MDS Sciex API 365 mass spectrometer with an Ionspray ™ interface (MDS Sciex; Thorn Hill, ON, Canada). Instrument setup, data collection, and processing were controlled by Applied Biosystems (Foster City, CA, USA) Analyst ™ software for Windows NT ™. 50-100 scans were performed in positive ionization Q1 scan mode to accumulate peaks. The sample solution was diluted with 50% methanol in 0.5% formic acid to a concentration of about 10 μg / ml. Each sample solution was introduced directly by microsyringe (1 mL) through an infusion pump (Havard Apperatus 22; Havard Instruments; Holliston, MA, USA) and fused silica capillary tubes at a rate of 20 μl / min. Thin layer chromatography (TLC) was performed using Macherey Nagel Polygram® SIL G / UV245. Visualized by means of UV light at 254 nm and stained with potassium permanganate or Cer-Molybdate-solution. The solvent was diluted before use. All commercially available reagents were used without further purification. Aloc-L-Phe-OMe and other amino acid derivatives were purchased from Bachem. A pH 7 buffer solution used in the work-up procedure was prepared by dissolving potassium dihydrogen phosphate (85.0 g) and sodium hydroxide (14.5 g) in water (1 L). Analytical HPLC uses a Merck-Hitachi apparatus (acetonitrile-water (flow rate: 1 ml min ^-1 ), column: LiChrosphere 5um RP18e, 125 x 4.0 mm (Merck), pump: L-7100 Merck-Hitachi is used) I went. Gradient A was used to detect the purified compounds of the examples. Gradient A characteristics: starting from acetonitrile-water (5/95) at t = 0 min, acetonitrile-water (60/40) within 20 min, acetonitrile-water (95/5) after another 10 min. Gradient B characteristics: starting from acetonitrile-water (20/80) at t = 0 min, acetonitrile-water (95/5) within 30 min.

(Specific synthesis and analysis information of starting materials and specific compounds)
(General law)
Method A (Conversion of carboxylic acid to mixed anhydride): N-protected amino acid (W-KCONH-X-COOH or W-KCONH-X-CON-Y-COOH, 1.0 eq) is dissolved in dry THF, Cooled to -15 ° C. NMM (1.0 eq) was added. Isobutyl chloroformate (1.0 eq) was added dropwise. The method produces intermediates EI, II, and A III, IV, V.

Method B (ester hydrolysis): The ester (intermediate EI, II; 1.0 eq) was dissolved in EtOH and 1 M NaOH (2.3 eq) was added. The reaction mixture was stirred at room temperature and conversion was confirmed by TLC. At the end of conversion, the pH of the mixture was adjusted to 2-3 with 1 N HCl. The organic material was extracted 5 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 to yield intermediate CI, II.

Method C (metalation and alkylation): A stirred solution of the heteroaryl compound (H-Z, 3.0 eq) in dry THF solution was cooled to -50 <0> C. n-BuLi (3.0 eq) was added dropwise. After 10 minutes, a solution of (Intermediate A III, IV; 1.0 eq) in dry THF was added dropwise. The mixture was stirred for 30 minutes, after which the mixture was diluted with a 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 to give the compounds of Examples 1, 2, 4, 9, and 10.

Method D (Reduction of carboxylic acid to alcohol): A mixed anhydride of protected amino acid derivative (1.0 eq) was prepared according to Method A, filtered under an argon atmosphere and cooled to -20 <0> C. LiAlH ₄ (1.5 eq) was added in portions for reaction promotion control. The mixture was stirred at −20 ° C. for 1 hour and at room temperature for 2 hours. The reaction mixture was hydrolyzed with 1 M KHSO ₄ solution at 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. The intermediate La I, II was used without further purification. The method produces intermediate La I, II.

METHOD E (Swern oxidation of alcohol to aldehyde): A stirred solution of oxalyl chloride in dry CH ₂ Cl ₂ (1.2 equiv) and cooled to -70 ° C.. DMSO (2.6 eq) was added dropwise and the mixture was stirred for 30 minutes. A solution of the alcohol (intermediate La I, II) in dry CH ₂ Cl _{2 was} added dropwise and the mixture was stirred for 2 hours. NEt ₃ (5.0 eq) was added and the mixture was warmed to room temperature. The reaction mixture was diluted with water. After layer separation, the organic layer 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 to give intermediates Lb I, II, N and the compounds of Examples 3, 5, 6, 7.

Method F (metalation and arylation): A stirred solution of the heteroaryl compound (H-Z) (1.1 eq) in dry THF solution was cooled to -78 ° C. n-BuLi (1.15 eq) was added dropwise. After 10 minutes, a solution of intermediate Lb I, II (1.0 eq) in dry THF was added dropwise. The mixture was stirred for 30 minutes, after which the mixture was diluted with a 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 to give intermediate KI, II.

Method G (protection group deprotection): mixture of TFA (7.5 ml) with the protected compound (intermediate KI, II; 1.0 eq) and TIPS (2.5 eq) in dry CH ₂ Cl ₂ (10 ml). Added to. The solution was stirred at room temperature for 2 hours and then diluted with toluene. The solvent was removed under reduced pressure and the resulting residue was used without further purification due to its instability to give intermediates JI, II. This method was used to produce the compound of Example 8. Method H (coupling reaction): The protected amino acid derivative (W-KCONH-X-COOH) (1.0 eq) was dissolved in dry DMF. To this mixture was added HATU (1.0 eq), HOAt (1.0 eq), Intermediate JI, II (1.0 eq), and N-ethyldiisopropylamine (2.0 eq) and the whole mixture was stirred overnight. The solvent was evaporated under reduced pressure using an oil pump. The resulting crude compound was dissolved in EE, washed with 1 N HCl, water, aqueous NaHCO ₃ solution, 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 to yield intermediates HI, II, III, IV, and V.

Method J (Arylation with Grignard reagent): Methylmagnesium bromide (3.0 M in Et ₂ O, 8.0 equiv) in toluene (15 ml) was cooled to −30 ° C. and ZH (pyrrole) (12 equiv) Treated with. After stirring at −30 ° C. for 10 minutes, the solution was warmed to 0 ° C. and stirred for 30 minutes and then cooled to −60 ° C. This prepared Grignard solution was added to a solution of intermediate EI in toluene (3 ml) cooled to −60 ° C. The mixture was stirred overnight and warmed to room temperature. The mixture was diluted with a pH 7 buffer solution, diluted with EE and filtered. After layer separation, the aqueous layer was extracted with EE (2 ×), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography to give the compound of Example 11.

(Intermediate)
Intermediate EI: Cbz-L-Phe-L-Pro-OMe
A mixed anhydride was prepared according to Method A (W-KCONH-X-COOH: Cbz-L-Phe-OH). After stirring for 15 minutes, 1.0 equivalent of HCl.HL-Pro-OMe in dry THF and NMM (1.0 equivalent) were added. The mixture was stirred overnight while warming to room temperature. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in EE, washed with 1 N HCl, 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 to yield intermediate EI. 72% yield of purified compound.

Intermediate E II: Cbz-L-Ala-L-Pro-OMe
Intermediate E II, the Intermediate EI:;: was prepared as described in (W-KCONH-X-COOH Cbz-L-Ala-OH HN-Y-COR y HCl · HL-Pro-OMe). 92% yield of purified compound.
Intermediate CI: Cbz-L-Phe-L-Pro-OH
Intermediate CI was prepared according to Method B. 94% yield of purified compound.
Intermediate C II: Cbz-L-Ala-L-Pro-OH
Intermediate C II was prepared according to Method B. Yield of purified compound: 91%.

Intermediate A III: Cbz-L-Phe-L-Pro-N (CH ₃ ) OCH ₃
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 equivalent of HCl.HN (CH ₃ ) OCH ₃ in dry THF and NMM (1.0 equivalent) were added. The mixture was stirred overnight while warming to room temperature. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in EE, washed with 1 N HCl, 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 to yield intermediate AIII. Yield 81% of purified compound.

Intermediate A IV: Cbz-L-Ala-L-Pro-N (CH ₃ ) OCH ₃
Intermediate A IV is converted to the above Intermediate A III (W-KCONH-X-CON-Y-COOH: Cbz-L-Ala-L-Pro-OH; HR ^x : HCl · HN (CH ₃ ) OCH ₃ ) Prepared as described. Yield of purified compound 98%.
Intermediate AV: Boc-L-Phe-L-Pro-N (CH ₃ ) OCH ₃
Intermediate AV was prepared as described in Intermediate A III above (W-KCONH-X-CON-Y-COOH: Boc-L-Phe-L-Pro-OH (purchased from Bachem). Yield 59%.

Intermediate La I: The Boc-L-alaninol intermediate La I was prepared according to Method D using the product alcohol without further purification. Yield 48% of purified compound.
Intermediate La II: Boc-L-Prolinol
Intermediate La II was prepared according to Method D using the product alcohol without further purification. 79% yield of purified compound.

Intermediate Lb I: Boc-L-Ala-aldehyde intermediate Lb I was prepared according to Method E and purified by flash chromatography. 60% yield of purified compound.
Intermediate Lb II: Boc-L-Pro-aldehyde intermediate Lb II was prepared according to Method E and purified by flash chromatography. Yield 58% of purified compound.

Intermediate KI: tert-butyl (2S) -1- (benzo [d] thiazol-2-yl) -1-hydroxypropan-2-ylcarbamate Intermediate KI was prepared according to Method F. Yield of purified compound 30%.
Intermediate K II: (S) -tert-butyl-2-((R)-(benzo [d] thiazol-2-yl) (hydroxy) methyl) -pyrrolidine-1-carboxylate intermediate K II Manufactured according to 49% yield of purified compound.

Intermediate JI: (2S) -2-Amino-1- (benzo [d] thiazol-2-yl) propan-1-ol Intermediate JI was prepared according to Method G. Because of instability, the compound was used without further purification.
Intermediate J II: (R)-(Benzo [d] thiazol-2-yl) ((S) -pyrrolidin-2-yl) methanol intermediate J II was prepared according to Method G. Because of instability, the compound was used without further purification.

Intermediate HI: benzyl (1S) -1-((2R) -1- (benzo [d] thiazol-2-yl) -1-hydroxypropan-2-ylcarbamoyl) -2-phenylethylcarbamate intermediate HI Was prepared according to Method H, which couples Cbz-L-Phe-OH (W-KCONH-X-COOH) and intermediate JI. Yield 29% of purified compound.
Intermediate H II: benzyl (1S) -1-((S) -2-((R)-(benzo [d] thiazol-2-yl) (hydroxy) -methyl) pyrrolidin-1-yl) -1- Oxohexylguanyl-2-ylcarbamate intermediate HII was prepared according to Method H, which couples Cbz-L-Arg-OH (W-KCONH-X-COOH) and intermediate JII. Yield of purified compound 50%.

Intermediate H III: benzyl (1S) -1-(((2R) -1- (benzo [d] thiazol-2-yl) (hydroxy) methyl) -pyrrolidin-1-yl) -2-carboxyethylcarbamate Intermediate H III is coupled to Cbz-L-Asp (OtBu) -OH (W-KCONH-X-COOH) and Intermediate J II. Method H (purified compound yield: 46%), followed by intermediate Prepared according to Method G (yield of purified compound: 35%) to produce Form HIII.
Intermediate H IV: allyl (1S) -1-(((2R) -1- (benzo [d] thiazol-2-yl) (hydroxy) methyl) -pyrrolidin-1-yl) -2-phenylethylcarbamate Intermediate H IV was prepared according to Method H coupling Aloc-L-Phe-OH (W-KCONH-X-COOH) and Intermediate JI. Yield 71% of purified intermediate H IV.

Intermediate HV: benzyl (1S) -1-(((2R) -1- (benzo [d] thiazol-2-yl) (hydroxy) methyl) -pyrrolidin-1-yl) -2- (4-tert- Butyloxycarbonylaminobutyl) -carbamate intermediate HV was prepared according to method H coupling ZL-Lys (Boc) -OH (W-KCONH-X-COOH) and intermediate JII. Yield of purified intermediate HV 33%.
Intermediate N: benzyl (1S) -1-(((2R) -1- (benzo [d] thiazol-2-yl) (oxymethyl) -pyrrolidin-1-yl) -2- (4-tert-butyl) Oxycarbonylaminobutyl) -carbamate intermediate N was prepared according to Method E. Yield of purified intermediate N 24%.

(Example)
Example 1: 2- [Cbz-L-Phe-L-Pro] benzothiazole The compound of Example 1 was prepared according to Route 1 via Intermediate EI, Intermediate CI, Intermediate A III, and Method C ( HZ: benzothiazole, yield of purified compound: 82%).
Example 2: 2- [Cbz-L-Ala-L-Pro] benzothiazole The compound of Example 2 is prepared according to Route 1 via Intermediate E II, Intermediate C II, Intermediate A IV, and Method C (HZ: benzothiazole, yield of purified compound: 17%).
Example 3: 2- [Cbz-L-Phe-L-Ala] benzothiazole The compound of Example 3 is intermediate La I, intermediate Lb I, intermediate KI, intermediate JI, intermediate HI, method E (Purified compound yield: 28%).

Example 4: 2- [Cbz-L-Phe-L-Pro] thiazole The compound of Example 4 was prepared according to Route 1 via Intermediate EI, Intermediate CI, Intermediate A III, and Method C (HZ : Thiazole, yield of purified compound: 19%).
Example 5: 2- [Cbz-L-Arg-L-Pro] benzothiazole The compound of Example 5 is intermediate La II, intermediate Lb II, intermediate K II, intermediate J II, intermediate H II , Prepared according to route 2 via method E (yield of purified compound: 38%).
Example 6: 2- [Cbz-L-Asp-L-Pro] benzothiazole The compound of Example 6 is intermediate La II, intermediate Lb II, intermediate K II, intermediate J II, intermediate H III. , Prepared according to route 2 via method E (yield of purified compound: 24%).

Example 7: 2- [Aloc-L-Phe-L-Pro] benzothiazole The compound of Example 7 is intermediate La II, intermediate Lb II, intermediate K II, intermediate J II, intermediate H IV And according to route 2 via method E (purified compound yield: 20%).
Example 8: 2- [Cbz-L-Lys-L-Pro] benzothiazole The compound of Example 8 comprises intermediate La II, intermediate Lb II, intermediate K II, intermediate J II, intermediate HV, Prepared according to Intermediate N, and route 2 via Method G (yield of purified compound relative to the synthetic step of Method G: 100%).
Example 9: 2- [Boc-L-Phe-L-Pro] benzothiazole The compound of Example 9 was prepared according to dipeptide intermediate AV and route 1 via Method C (HZ: benzothiazole, purified compound Yield: 24%).

Example 10: 2- [Cbz-L-Ala-L-Pro] thiazole The compound of Example 10 was prepared according to Route 1 via Intermediate E II, Intermediate C II, Intermediate A IV, and Method C. (HZ: thiazole, yield of purified compound: 7%).
Example 11: 2- [Cbz-L-Ala-L-Pro] pyrrole The compound of Example 11 was prepared according to Intermediate EI and Route 3 via Method J (purified compound yield: 35%).

Throughout this specification and the appended claims, unless the context requires otherwise, the term “includes” (
composition) "and variants such as" comprises "and" comprising "mean the inclusion of a specified integer, process, integer group, or process group, and other integers, processes, integer groups It will be understood that this does not mean the exclusion of process groups.
All of the above patents and patent applications are hereby incorporated by reference in their entirety.

Quantification of basal medium IL-6 in human glial U-343 cells treated with various PEP inhibitors. Culture supernatants of human glial U-343 cells treated with PEP inhibitors for 24 hours contain IL-6 levels that are only 15% to 60% of the IL-6 levels measured in untreated control samples. It was. Values are shown as the mean ± SD of 4 sets of wells and analyzed for statistical significance by unpaired t test ( ^*** p <0.001). Quantification of basal Aβ1-42 values of human neuroblastoma cell line SH-SY5Y cells treated with various PEP inhibitors. Culture supernatants of human glial U-343 cells treated with PEP inhibitors for 24 hours contained 87.5% to 546% Aβ1-42 levels measured in untreated control samples. . Values are shown as the mean ± SD of 4 sets of wells and analyzed for statistical significance by unpaired t test ( ^*** p <0.001). PEP-catalyzed degradation of humanin-a positive control without inhibitors. The cleavage product was measured with a matrix-assisted laser desorption mass spectrometer. HN 1-24 represents the full length of humanin. HN 9-24 represents post-cysteine truncated humanin 9-24. PEP-catalyzed degradation of humanin-PEP inhibitor as shown in Example 2. The cleavage product was measured with a matrix-assisted laser desorption mass spectrometer. HN 1-24 represents the full length of humanin. HN 9-24 represents post-cysteine truncated humanin 9-24. PEP-catalyzed degradation of humanin-PEP inhibitor as shown in Example 2. The cleavage product was measured with a matrix-assisted laser desorption mass spectrometer. HN 1-24 represents the full length of humanin. HN 9-24 represents post-cysteine truncated humanin 9-24.

Claims (52)

Compounds of general formula 1, or all pharmaceutically acceptable salts thereof, including all stereoisomers and polymorphs thereof:

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 an amino acid or an aza-amino acid component;
NH-X-CO represents a non-cyclic amino acid or a non-cyclic aza-amino acid component, and when NH-X-CO represents a component of Asp or Glu, the acid side chain of Asp or Glu Can be optionally linked to other amino acids or aza-amino acids via peptide bonds;
NY-CO- is selected from the components of formula 2a, 2b, 2c, 2d, 2e, 2f, or 2g:

Wherein R ^{1 to} R ¹⁵ and R ^{17 to} R ¹⁹ are independently H, or alkyl chain, alkenyl chain, alkynyl chain, cycloalkyl, carbocycle, aryl, heteroaryl, heterocycle, or halogen; A group selected from amino, —CONH ₂ , CONH (alkyl), —CON (alkyl) ₂ , nitro, hydroxyl, —CN, and SCN;
Or, in addition, R ² / R ³ , R ⁴ / R ⁵ , R ⁶ / R ⁷ , R ⁹ / R ¹⁰ , R ¹¹ / R ¹² independently represent oxo together with the carbon atoms to which they are attached;
Alternatively, R ³ and R ⁵ are combined to form a benzene ring condensed with the azetidine ring (in this case, R ² and R ⁴ are not present), or R ¹⁰ and R ¹¹ are combined. Forming a benzene ring fused to the piperidine ring (in this case, R ⁹ and R ¹² are not present);
R ¹⁶ is the side chain of the amino acid component;
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 are independently of each other H, alkyl, alkenyl, alkynyl, cycloalkyl, carbocycle, heterocycle, aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl group;
R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁷ , and R ²⁸ are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, carbocycle, heterocycle, aryl, heteroaryl, aryl-alkyl, Heteroaryl-alkyl group, or carbaldehyde (-CHO), ketone group (-CO-R ²⁹ ), boronic acid group (-B (OH) ₂ ), cyano group (-C≡N), carboxylic acid group (- COOH), carboxylic acid ester group (-COOR ³⁰ ), carboxylic anhydride group (-CO-O-CO-R ³¹ ), hydroxamic acid group (-CO-NH (OH)), N-substituted hydroxamic acid group ( -CO-NR ³² (OH)), O-substituted hydroxamic acid group (-CO-NH (OR ³³ )), carboxamide group (-CO-NH ₂ ), N-substituted or N, N-disubstituted carboxylic acid amide Group (—CO—NHR ³⁴ ; —CO—NR ³⁵ R ³⁶ ), amide group (—HN—CO—R ³⁷ ), sulfonic acid group (—SO ₃ H), sulfonamide group (—SO ₂ —NH ₂ ) , N- substituted or N, N- disubstituted sulfonamide group _{^{(-SO 2 -NHR 38; -SO 2}} -NR 39 R 40), amides Sulfone group ^{_{(-NH-SO 2 -R 41)}} , sulfone group (-SO ₂ -R ^42), a phosphoric acid group (-OP (= O) (OH ) 2), phosphoric acid ester group (-OP (= O ) (OR ⁴³ ) (OR ⁴⁴ )), phosphonic acid group (-P (= O) (OH) ₂ ), phosphonic acid ester group (-P (= O) (OR ⁴⁵ ) (OR ⁴⁶ )), halogeno group , Trifluoromethyl group (—CF ₃ ), thiol group (—SH); thioether group (—SR ⁴⁷ ), hydroxy group (—OH); alkoxy group (—OR ⁴⁸ ), tetrazole group, amino group (—NH ₂₎ Or an N-substituted or N, N-disubstituted amino group (—NHR ⁴⁹ ; —NR ⁵⁰ R ⁵¹ ); or
When X ¹ is CR ²⁰ R ²¹ , R ⁶ and R ²⁰ can be bonded to form a benzene ring fused to the pyrrolidine ring (in this case, R ⁷ and R ²¹ are not present), Or when X ² is CR ²² R ²³ , R ²⁰ and R ²² can be bonded to form a benzene ring fused to the pyrrolidine ring (in this case, R ²¹ and R ²³ are not present) Or
When X ³ is CR ²⁶ R ²⁷ , R ¹¹ and R ²⁶ can be bonded to form a benzene ring fused to the piperidine ring (in this case, R ¹² and R ²⁷ are not present), Or R ²⁷ and R ¹³ can be joined to form a benzene ring fused to a piperidine ring (in this case, R ²⁶ and R ¹⁴ are not present);
Substituents R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ⁴⁸ , R ⁴⁹ , R ⁵⁰ , and R ⁵¹ are each independently H, or alkyl, alkenyl, alkynyl, cycloalkyl, carbocycle, heterocycle, aryl, heteroaryl, Aryl-alkyl- or heteroaryl-alkyl-groups; and or alternatively, the combination R ³⁵ R ³⁶ , R ³⁹ R ⁴⁰ , and R ⁵⁰ R ⁵¹ , independently of one another, together with the nitrogen to which they are attached, Can form part (eg, pyrrolidine, piperidine, or morpholine); or the combinations R ⁴³ / R ⁴⁴ , R ⁴⁵ / R ⁴⁶ can be joined to form a C _1-4 alkylene chain. ;
X ⁴ is CR ⁵² or N;
X ⁵ is CR ⁵³ or N;
R ⁵² and R ⁵³ are independently of each other H, alkyl, alkenyl, alkynyl, cycloalkyl, carbocycle, heterocycle, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl, aryl-heteroalkyl, heteroaryl. -Heteroalkyl group, or carbaldehyde (-CHO), ketone group (-CO-R ⁵⁴ ), boronic acid group (-B (OH) ₂ ), cyano group (-C≡N), carboxylic acid group (-COOH ), Carboxylic acid ester group (-COOR ⁵⁵ ), carboxylic acid anhydride group (-CO-O-CO-R ⁵⁶ ), hydroxamic acid group (-CO-NH (OH)), N-substituted hydroxamic acid group (- CO-NR ⁵⁷ (OH)), O-substituted hydroxamic acid group (-CO-NH (OR ⁵⁸ )), carboxamide group (-CO-NH ₂ ), N-substituted or N, N-disubstituted carboxylic acid amide group (-CO-NHR ⁵⁹ ; -CO-NR ⁶⁰ R ⁶¹ ), amide group (-HN-CO-R ⁶² ), sulfonic acid group (-SO ₃ H), sulfonamide group (-SO ₂ -NH ₂ ), N-substituted or N, N-disubstituted sulfonamide groups (-SO ₂ -NHR ⁶³ ; -SO ₂ -NR ⁶⁴ R ⁶⁵ ), amide sulfone group (-NH-SO ₂ -R ⁶⁶ ), sulfone group (-SO ₂ -R ⁶⁷ ), phosphate group (-OP ( = O) (OH) ₂ ), phosphate ester group (-OP (= O) (OR ⁶⁸ ) (OR ⁶⁹ )), phosphonic acid group (-P (= O) (OH) ₂ ), phosphonic acid ester group (-P (= O) (OR ⁷⁰ ) (OR ⁷¹ )), halogeno group, trifluoromethyl group (-CF ₃ ), thiol group (-SH); thioether group (-SR ⁷² ), hydroxy group (-OH An alkoxy group (—OR ⁷³ ), a tetrazole group, an amino group (—NH ₂ ), or an N-substituted or N, N-disubstituted amino group (—NHR ⁷⁴ ; —NR ⁷⁵ R ⁷⁶ );
Substituents R ⁵⁴ , R ⁵⁵ , R ⁵⁶ , R ⁵⁷ , R ⁵⁸ , R ⁵⁹ , R ⁶⁰ , R ⁶¹ , R ⁶² , R ⁶³ , R ⁶⁴ , R ⁶⁵ , R ⁶⁶ , R ⁶⁷ , R ⁶⁸ , R ⁶⁹ , R ⁷⁰ , R ⁷¹ , R ⁷² , R ⁷³ , R ⁷⁴ , R ⁷⁵ , and R ⁷⁶ are each independently H, or alkyl, alkenyl, alkynyl, cycloalkyl, carbocycle, heterocycle, aryl, heteroaryl, Aryl-alkyl, heteroaryl-alkyl groups; and alternatively the combination R ⁵² / R ⁵³ , when present, can form a heterocycle, or part of a carbocycle, together with the carbon atoms to which it is attached. Or the combinations R ⁶⁰ R ⁶¹ , R ⁶⁴ R ⁶⁵ , and R ⁷⁵ R ⁷⁶ , independently of one another, can form part of a heterocyclic ring with the attached nitrogen (eg, pyrrolidine, piperidine, or morpho Phosphorus); or the combination R ⁶⁸ / R ⁶⁹ and R ⁷⁰ / R ⁷¹ can be joined to form a C _1-4 alkylene chain;
m represents an integer 0-2;
n represents an integer 0-2. );
Z is heteroaryl;
However, the following compounds are excluded from Formula 1. ):

. The compound according to claim 1, wherein R ^{1 to} R ¹⁵ and R ^{17 to} R ¹⁹ independently represent H, halogen, CN, or alkyl. The compound according to claim 1, wherein R ^{1 to} R ¹⁵ and R ^{17 to} R ¹⁹ are H. The compound according to any one of claims 1 to ³ , wherein X ¹ , X ² , and X ³ independently represent CH ₂ or CHMe. The compound according to any one of claims 1 to 3, wherein X ⁴ and X ⁵ independently represent CH or CMe. The compound according to any one of claims 1 to 5, wherein R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁶ , R ²⁷ , R ²⁸ , R ⁵² , and R ⁵³ are H.   The compound according to any one of claims 1 to 6, wherein m and n independently represent 0 or 1.   The compound according to claim 7, wherein m and n are 0.   9. A compound according to any one of claims 1 to 8, wherein W represents -alkylaryl, -alkylheteroaryl, alkyl, alkenyl, alkynyl or cycloalkyl.   10. A compound according to claim 9, wherein W represents alkenyl-, alkyl-, or arylalkyl-.   11. A compound according to claim 10, wherein W is arylalkyl-. 10. The compound of claim 9, wherein W is selected from the group consisting of -methylaryl, methylheteroaryl, _C2-6 alkenyl, and _C2-6 alkyl.   13. A compound according to any one of claims 9 to 12, wherein aryl represents alkyl and / or phenyl optionally substituted with halo.   13. A compound according to claim 9 or 12, wherein heteroaryl represents pyridyl optionally substituted with alkyl and / or halo.   The compound according to any one of claims 1 to 8, wherein W-K-CO represents allyloxycarbonyl (Aloc), t-butyloxycarbonyl (Boc), or benzyloxycarbonyl (Cbz).   16. A compound according to claim 15, wherein W-K-CO is benzyloxycarbonyl. K is, O, or CH _2, in particular represents a O, compounds of any one of claims 1 to 16.   18. A compound according to any one of claims 1 to 17, wherein NH-X-CO represents a component of an acyclic amino acid.   The compound according to any one of claims 1 to 18, wherein NH-X-CO represents a protein-constituting amino acid.   20. The compound of claim 19, wherein NH-X-CO is selected from the group consisting of L-Ala, L-Arg, L-Asp, and L-Phe.   21. A compound according to claims 1-20, wherein N-Y-CO represents a component of formula 2d. The compound according to claims 1 to ²¹ , wherein R ¹⁶ represents a side chain of a protein-constituting amino acid. R ¹⁶ is 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, or CH represents a ₂ CH ₂ COOH, according to claim 22 a compound according. R ¹⁶ is alkyl, 23. A compound according. R ¹⁶ is methyl, claim 24 A compound according.   21. A compound according to any one of claims 1 to 20, wherein N-Y-CO represents a component of formula 2a, 2e, 2f, or 2g.   21. A compound according to any one of claims 1 to 20, wherein N-Y-CO represents a component of formula 2b or 2c. 21. A compound according to any one of claims 1 to 20, wherein NY-CO represents a component of formula 2h or 2i:

(Wherein R ⁷⁷ and R ⁷⁸ independently represent H, halogen, CN, or alkyl). 21. A compound according to any one of claims 1 to 20, wherein NY-CO represents a component of formula 2j or 2k:

Wherein R ⁷⁷ represents H, halogen, CN, or alkyl, and
R ⁸⁰ and R ⁸¹ are independently H or fluoro. ). ^30. The compound according to claim 28 or 29, wherein ^R77 and ^R78 are independently methyl. R ^77, and R ⁷⁸ are, independently, a CN, according to claim 28, or 29 compound as described. ^30. The compound of claim 28 or 29, wherein ^R77 and ^R78 are independently H. X ¹ is, represents a CH _2, any one compound according to claim 1 to 32.   34. A compound according to claims 1 to 33, wherein Z represents a 5-membered heteroaryl optionally fused to a benzene ring. Z is 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 35. The compound of claim 34, selected from the group or selected from components of formula 3a, 3b, 3c, 3d, or 3e:

Wherein R ⁸² , R ⁸³ , R ⁸⁴ , R ⁸⁵ , and R ⁸⁶ are independently H, or an alkyl chain, alkenyl chain, alkynyl chain, cycloalkyl, carbocycle, aryl, heteroaryl, heterocycle, Or a group selected from halogen, amino, —CONH ₂ , CONH (alkyl), —CON (alkyl) ₂ , nitro, hydroxyl, oxo, —CN, and —SCN). ^{R 82, R 83, R 84} , R 85, and R ⁸⁶ is, H, or alkyl, claim 35 A compound according. ^{R 82, R 83, R 84} , R 85, and R ⁸⁶ is H, and claim 36 A compound according. The compound of claim 1, corresponding to Example 1, or a pharmaceutical salt, stereoisomer or polymorph thereof:

. The compound according to claim 1, which corresponds to any one of Examples 2 to 7, or a pharmaceutical salt, stereoisomer or polymorph thereof:

. The compound according to claim 1, which corresponds to any one of claims 8 to 11, or a pharmaceutical salt, stereoisomer or polymorph thereof:

.   41. A compound according to any one of claims 1 to 40 for use as a medicament.   41. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 40 together with one or more therapeutically acceptable diluents or carriers.   42. A pharmaceutical composition according to claim 41 for parenteral, enteral or oral administration.   QC-inhibitor, LiCl, dipeptidyl aminopeptidase inhibitor, preferably DP IV or DP IV-like enzyme inhibitor, NPY-receptor ligand, NPY agonist, ACE inhibitor, PIMT enhancer, beta secretase inhibitor , Inhibitors of gamma secretase, inhibitors of neutral endopeptidase, PDE-4 inhibitors, MAO inhibitors, TNF alpha inhibitors, amyloid protein or amyloid peptide deposition inhibitors, sigma-1 receptor inhibitors, and histamine H3 44. The pharmaceutical composition according to claim 42 or 43, further comprising at least one compound selected from the group consisting of antagonists. 45. Use of a compound according to any one of claims 1 to 40 or a pharmaceutical composition according to any one of claims 42 to 44 for the preparation of a medicament for the treatment of a disease selected from the group consisting of: Use of objects:
Alzheimer's disease, Down syndrome, Parkinson's disease, Huntington's disease, pathogenic psychosis, schizophrenia, food intake disorder, sleep awakening, homeostasis control disorder of energy metabolism, autonomic dysfunction, hormone balance disorder, control disorder, fluid, hypertension, fever , Sleep dysregulation, eating disorders, anxiety-related diseases including depression, epilepsy, drug withdrawal symptoms, and seizures including alcoholism, cognitive impairment, dementia, aphasia, apraxia, agnosia, or some Types of amnesia, mild cognitive impairment (MCI), benign amnesia, and neurodegenerative disorders including Korsakov syndrome, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or heart transplantation Posterior coronary artery disease, atherosclerosis, reperfusion injury, hypoxia, ischemia, and blood clotting disorders. 45. A method for the treatment of a disease selected from the group consisting of: an effective amount of a compound of formula 1 according to any one of claims 1 to 40 or according to any one of claims 42 to 44. Said method comprising administering the pharmaceutical composition to a mammal:
Alzheimer's disease, Down syndrome, Parkinson's disease, Huntington's disease, pathogenic psychosis, schizophrenia, food intake disorder, sleep awakening, homeostasis control disorder of energy metabolism, autonomic dysfunction, hormone balance disorder, control disorder, fluid, hypertension, fever , Sleep dysregulation, eating disorders, anxiety-related diseases including depression, epilepsy, drug withdrawal symptoms, and seizures including alcoholism, cognitive impairment, dementia, aphasia, apraxia, agnosia, or some Types of amnesia, mild cognitive impairment (MCI), benign amnesia, and neurodegenerative disorders including Korsakov syndrome, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or heart transplantation Posterior coronary artery disease, atherosclerosis, reperfusion injury, hypoxia, ischemia, and blood clotting disorders. 45. A compound according to any one of claims 1 to 40 or a pharmaceutical composition according to any one of claims 42 to 44 for use in the treatment of a disease selected from the group consisting of:
Alzheimer's disease, Down syndrome, Parkinson's disease, Huntington's disease, pathogenic psychosis, schizophrenia, food intake disorder, sleep awakening, homeostasis control disorder of energy metabolism, autonomic dysfunction, hormone balance disorder, control disorder, fluid, hypertension, fever , Sleep dysregulation, eating disorders, anxiety-related diseases including depression, epilepsy, drug withdrawal symptoms, and seizures including alcoholism, cognitive impairment, dementia, aphasia, apraxia, agnosia, or some Types of amnesia, mild cognitive impairment (MCI), benign amnesia, and neurodegenerative disorders including Korsakov syndrome, pulmonary vascular disease, restenosis or pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis or heart transplantation Posterior coronary artery disease, atherosclerosis, reperfusion injury, hypoxia, ischemia, and blood clotting disorders.   48. A compound, composition, or composition according to any one of claims 45 to 47, for the treatment of a neuronal disease selected from the group consisting of mild cognitive impairment (MCI), Alzheimer's disease, Down's syndrome, Parkinson's disease, and Huntington's disease. Use or method.   41. The preparation according to any one of claims 1 to 40 for the preparation of an inhibitor of microbial growth, reduction of blood loss during surgery, preservation of transplanted tissue or organ, inhibition of cancer cell growth or tumor progression or tumor metastasis or invasion. 45. Use of a compound, or use of a pharmaceutical composition according to any one of claims 42 to 44.   41. A compound according to any one of claims 1 to 40 for use in inhibiting microbial growth, reducing blood loss during surgery, preservation of transplanted tissue or organ, cancer cell proliferation or tumor progression or tumor metastasis or invasion. Or a pharmaceutical composition according to any one of claims 42 to 44.   41. A method for the inhibition of microbial growth, reduction of intraoperative blood loss, preservation of transplanted tissue or organ, inhibition of cancer cell growth or tumor progression or tumor metastasis or invasion, comprising an effective amount. 45. The method comprising administering to a mammal a compound of formula 1 according to any one of the above or a pharmaceutical composition according to any one of claims 42 to 44. 41. A process for the preparation of a compound of formula (1) according to any one of claims 1-40, comprising:
(A) reacting a compound of formula A or a protected derivative thereof with a compound of formula B or a protected derivative thereof;

(Wherein, W, K, X, and Y are as defined in any one of claims 1 to 40, and R ^x represents a wine rev activating group);

(Wherein Z is as defined in any one of claims 1 to 40);
(B) oxidizing the compound of formula H;

(Wherein, W, K, X, Y, and Z are those according to any one of claims 1 to 40);
And optionally deprotecting the product to obtain a compound of formula (1).

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