Chemical compounds as inhibitors of amyloid beta protein production

• US 5,624,937 A
• Filed: 03/02/1995
• Issued: 04/29/1997
• Est. Priority Date: 03/02/1995
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Reel, Jon K., Simon, Richard L., Whitesitt, Celia A.
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): HUANG, EVELYN MEI
• Application Number:
  US08/397,466
• Time in Patent Office: 789 Days
• Field of Search: 546/153, 546/157, 546/300, 514/312, 514/351, 514/247, 514/367, 514/376, 514/395, 514/586, 564/27, 564/29, 544/239, 548/306.4, 548/221, 548/222
• US Class Current: 514/312
• CPC Class Codes: C07C 335/16 having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
• CPC Class Codes: C07D 213/52 Sulfur atoms
• CPC Class Codes: C07D 215/22 attached in position 2 or 4
• CPC Class Codes: C07D 215/36 Sulfur atoms C07D215/24 takes precedence
• CPC Class Codes: C07D 215/40 attached in position 8
• CPC Class Codes: C07D 235/28 Sulfur atoms
• CPC Class Codes: C07D 237/18 Sulfur atoms
• CPC Class Codes: C07D 263/58 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2

Abstract

A compound of the formula I in which ##STR1## Z is O or S; R¹¹ is a halogen atom;

R¹² is a halogen atom or a trifluoromethyl group; and

X is S, SO, SO₂, O or NH;

R⁴ is naphthyl, quinolinyl, benzimidazolyl, pyridyl, pyradazinyl, benzoxazolyl or benzothiazolyl, unsubstituted or substituted by one or two substituents selected from a halogen atom, (1-4C)alkyl, (1-4C)alkoxy, nitro, (1-4C)alkoxycarbonyl, halo(1-4C)alkyl, and phenyl;

or a pharmaceutically acceptable salt thereof.

The compounds are useful as inhibitors of amyloid beta-protein production.

Claims

1. A compound of the formula ##STR5## in which Z is O or S;

R¹¹ is a halogen atom;

R¹² is a halogen atom or a trifluoromethyl group;

X is S, SO, SO₂, O or NH; and

R⁴ is naphthyl, quinolinyl, benzimidazolyl, pyridyl, pyridazinyl, benzoxazolyl or benzothiazolyl, unsubstituted or substituted by one or two substituents selected from a halogen atom, (1-4C)alkyl, (1-4C)alkoxy, nitro, (1-4C)alkoxycarbonyl, halo(1-4C)alkyl, and phenyl;

with the proviso that when R⁴ is pyridyl or pyridazinyl X must be S, SO, SO₂ or NH;

or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1, in which R⁴ is unsubstituted or substituted naphth-1-yl, naphth-2-yl, quinolin-2-yl, quinolin-4-yl, quinolin-6-yl, benzimidazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl, pyridin-2-yl or pyridazin-3-yl.

3. A compound as claim in claim 1, in which R¹¹ is chlorine and R¹² is chlorine or trifluoromethyl.

4. A compound as claimed in claim 1, in which R⁴ is naphth-1-yl, naphth-2-yl, quinolin-2-yl, 6-chloroquinolin-2-yl, 6-methoxyquinolin-2-yl, 5-nitroquinolin-6-yl, 4-ethoxycarbonylquinolin-2-yl, 4-phenylquinolin-2-yl, 7-trifluoromethylquinolin-4-yl, quinolin-4-yl, benzimidazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl, 5-chloro-benzothiazol-2-yl, 6-phenylpyrazin-3-yl or pyridin-2-yl.

5. A compound as claimed in claim 1, in which X is S.

6. A compound as claim in claim 1, in which Z is S.

7. A compound as claimed in claim 1, in which

Z is O or S;

R¹¹ is a chlorine atom;

R¹² is a chlorine atom or a trifluoromethyl group;

X is S, SO₂, O or NH; and

R⁴ is naphth-1-yl, naphth-2-yl, quinolin-2-yl, 6-chloroquinolin-2-yl, 6-methoxyquinolin-2-yl, 5--nitroquinolin-6-yl, 4-ethoxycarbonylquinolin-2-yl, 4-phenylquinolin-2-yl, 7-trifluoromethylquinolin-4-yl, quinolin-4-yl, benzimidazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl, 5-chlorobenzothiazol-2-yl, 6-phenylpyrazin-3-yl or pyridin-2-yl.

8. A compound as claimed in claim 1, which is 1-[4-(2-quinolyl) thiophenyl]-3-(4-chloro-3-trifluoromethylphenyl)thiourea.

9. A pharmaceutical composition, which comprises a compound as defined in claim 1 and a pharmaceutically acceptable diluent or carrier.

10. A pharmaceutical composition which comprises a compound of the formula ##STR6## in which Z is O or S;

R¹¹ is a halogen atom;

R¹² is a halogen atom or a trifluoromethyl group;

X is S, SO, SO₂, O or NH; and

R⁴ is naphthyl, quinolinyl, benzimidazolyl, pyridyl, pyridazinyl, benzoxazolyl or benzothiazolyl, unsubstituted or substituted by one or two substituents selected from a halogen atom, (1-4C)alkyl, (1-4C)alkoxy, nitro, 1-4C)alkoxycarbonyl, halo(1-4C)alkyl, and phenyl;

or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

11. A method of inhibiting the production of Aβ

peptide in a biological system, which comprises administering an effective amount of a compound as defined in claim 10.

12. A method of inhibiting the accumulation of Aβ

peptide in senile plaques in a warm blooded mammal, which comprises administering an effective amount of a compound as defined in claim 10.