Peptide derivatives having β-secretase inhibitory activity

• US 7,312,188 B2
• Filed: 02/27/2004
• Issued: 12/25/2007
• Est. Priority Date: 02/28/2003
• Status: Expired due to Fees

• Current Assignee: Yoshiaki Kiso
• Original Assignee: Yoshiaki Kiso
• Inventors: Kiso, Yoshiaki
• Primary Examiner(s): Gupta; Anish
• Assistant Examiner(s): Ha; Julie
• Application Number:
  US10/546,914
• Publication Number:
  US 20070004637A1
• Time in Patent Office: 1,397 Days
• Field of Search: None
• US Class Current: 514/17.8
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 5/0202 containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

Provided are excellent β-secretase inhibitors, that is, compounds represented by the general formula (1) or prodrugs thereof:

wherein A is amino or protected amino; B¹ and B² are each a single bond, alkylene of 1 to 3 carbon atoms, or the like; D is a single bond, —NHCO, or the like; E is —COOH, tetrazole ring, or the like; n is an integer of 1 to 3; m is an integer of 1 to 3; G is hydroxyl, a group represented by the general formula (2), or the like:

in which Z is —NH, -Asp-Ala-NH—, -Asp-Ala-, -Asp-NH—, or the like; L is a 5-to 10-membered ring optionally containing a heteroatom and/or unsaturated bond; X is —COOH, tetrazole ring, or the like; Y is hydrogen, —COOH, or the like; and k is an integer of 1 to 4; and R¹, R², and R³ are each alkyl of 1 to 6 carbon atoms, or the like.

Claims

1. A compound represented by the general formula (1):

2. The compound of claim 1, wherein in the general formula (1),

B¹ and B² are each a single bond, or alkylene of 1 to 3 carbon atoms optionally substituted with R⁴,

in which R⁴ is halogen atom;

alkyl of 1 to 6 carbon atoms;

alkenyl of 2 to 6 carbon atoms;

alkynyl of 2 to 6 carbon atoms;

cycloalkyl of 3 to 7 carbon atoms;

optionally substituted heterocycle;

optionally substituted aralkyl;

or optionally substituted aryl, and the substituent thereof is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or aryl,

D is a single bond, —

NHCO—

or —

NHCO—

R⁵—

,

in which R⁵ is alkylene of 1 to 6 carbon atoms;

alkenylene of 2 to 6 carbon atoms;

alkynylene of 2 to 6 carbon atoms;

cycloalkylene of 3 to 7 carbon atoms;

optionally substituted heterocycle;

optionally substituted aralkylene;

or optionally substituted arylene, and the substituent thereof is halogen atom, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or aryl,

E is —

COOH or a group equivalent to COOH, hydrogen atom, hydroxy group, amino group, halogen atom, or —

COOCH₃,

n is an integer of 1 to 3,

m is 1,

G is hydroxy group, or a group represented by the formula;

3. The compound of claim 1, wherein in the general formula (1),

B¹ is a single bond or methylene,

B² is a single bond or alkylene of 1 to 3 carbon atoms,

D is a single bond, —

NHCO—

, a group represented by the formula;

4. The compound of claim 1, wherein in the general formula (1),

B¹ is a single bond,

B² is alkylene of 1 to 2 carbon atoms,

D is a single bond, —

NHCO—

, or a group represented by the following formula;

5. The compound of claim 1, wherein in the general formula (1), a partial structure other than G is a group represented by the formula:

6. The compound of claim 1, which has a molecular weight of 1100 or lower.

7. A pharmaceutical composition comprising the compound of claim 1 as an active ingredient and a pharmaceutically acceptable carrier.

8. An agent for treating Alzheimer'"'"'s disease, comprising the compound of claim 1 as an active ingredient.

9. An agent for promoting secretion of sAPPα

, comprising the compound of claim 1 as an active ingredient.

10. A method for treating Alheimer'"'"'s disease, which comprises administering an effective amount of the compound of claim 1 to a mammal in need thereof.