Heterocyclic compounds useful as pharmaceutical agents

• US 6,313,127 B1
• Filed: 07/31/1998
• Issued: 11/06/2001
• Est. Priority Date: 02/02/1996
• Status: Expired due to Fees

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC)
• Inventors: Watkins, William John, Newcombe, Nicholas John, Stokes, Elaine Sophie Elizabeth, Waterson, David, Cumming, John Graham, Brown, George Robert, Wood, Robin
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US09/117,523
• Time in Patent Office: 1,194 Days
• Field of Search: 514/219, 514/318, 514/332, 514/333, 544/354, 546/193, 546/194, 546/255, 546/256
• US Class Current: 514/253.01
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Compounds of formula (I)

in which all variables are defined in the description and their salts inhibit the enzyme oxido squalene cyclase and are useful in treating hypercholesterolemia and also as anti-fungal agents. Processes for their preparation are also described together with their use in medicine.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof,

wherein

G¹ is CH;

G² is CH;

n is 1 or 2;

R is hydrogen, halogeno, trifluoromethyl, trifluoromethoxy, cyano, amino, hydroxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di(1-4C)alkylamino or phenyl(1-4C)alkyl;

A is methylene or ethylene;

B is ethylene; and

wherein A and B may independently optionally bear a substituent selected from (1-6C)alkyl, (1-6C)alkoxy, phenyl(1-4C)alkyl, halogeno and (1-6C)alkoxycarbonyl;

T is N;

X¹ is selected from SO₂, SO, CO and CR³R⁴O;

wherein R³ and R⁴ are independently selected from hydrogen and (1-4C)alkyl;

Y¹ represents CR⁶R⁷, wherein R⁶ and R⁷ are independently selected from hydrogen and (1-4C)alkyl;

Ar¹ is a phenylene, naphthylene, a 5- or 6-membered monocyclic heteroaryl ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulphur, or a 9- or 10-membered bicyclic heteroaryl ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulphur;

Q is a group of formula L¹X²L²Z in which L¹ is a bond, (1-4C)alkylene or (2-4C)alkenylene, L² is a bond or (1-4C)alkylene, X² is a bond, O, S, SO, SO₂, CR⁸R⁹, CO, OSO₂, OCR⁸R⁹, OCO, SO₂O, CR⁸R⁹O, COO, NR¹⁰SO₂, SO₂NR¹¹, NR¹²CO, CONR¹², NR¹³CONR¹⁴ and NR¹⁴ in which R⁸ and R⁹ are independently selected from hydrogen, hydroxy and (1-4C)alkyl; and

R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are independently selected from hydrogen and (1-4C)alkyl;

Z is hydrogen, (1-4C)alkyl, phenyl, naphthyl, phenyl(2-4C)alkenyl, phenyl(2-4C)alkynyl or a heterocyclic moiety containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulphur;

and wherein the phenyl, naphthyl or heteroaryl moiety in Ar¹ and the alkyl, phenyl, naphthyl, or heterocyclic moiety in Z may optionally bear one or more substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, (1-4C)alkylenedioxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, di-N[(1-6C)alkyl]carbamoyl, (1-6C)alkanoylamino, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, halogeno(1-6C)alkoxy, (1-6C)alkanoyl, tetrazoyl, phenyl, phenoxy, phenylsulphonylpiperidinocarbonyl, morpholinocarbonyl, hydroxy(1-6C)alkyl and amino(1-6C)alkyl;

wherein any phenyl containing substituents may optionally bear one or more substituents selected from halogeno, trifluoromethyl, trifluoromethoxy, cyano, amino, hydroxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di(1-4C)alkylamino;

provided that the compound is not N-[4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]phenyl]-(E)-4-chlorostyrenesulphonamide or N-[4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]phenyl]-4′

-bromo-4-biphenylesulphonamide;

and pharmaceutically acceptable salts thereof.

2. A compound as claimed in claim 1 wherein there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein

G¹ is CH;

G² is CH;

n is 1 or 2;

R is hydrogen, halogeno, trifluoromethyl, trifluoromethoxy, cyano, amino, hydroxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino or di(1-4C)alkylamino;

A is methylene or ethylene;

B is ethylene; and

wherein A and B may independently optionally bear a substituent selected from (1-6C)alkyl, (1-6C)alkoxy, phenyl (1-4C)alkyl, halogeno and (1-6C)alkoxycarbonyl;

T is N;

X¹ is selected from SO₂, SO, CO and CR³R⁴O, wherein R³ and R⁴ are independently selected from hydrogen and (1-4C)alkyl;

Y¹ represents CR⁶R⁷, wherein R⁶ and R⁷ are independently selected from hydrogen and (1-4C)alkyl;

Ar¹ is a phenylene ring or a 5- or 6-membered monocyclic heteroaryl ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulphur;

Q is a group of formula L¹X²L²Z in which L¹ is a bond or (1-4C)alkylene, L² is a bond or (1-4C)alkylene, X² is a bond, S, SO, SO₂, CR⁸R⁹, CO, NR¹⁰SO₂, SO₂NR¹¹, NR¹²CO, CONR¹² and NR¹³CONR¹⁴ in which R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are independently selected from hydrogen and (1-4C)alkyl;

Z is selected from phenyl, naphthyl, phenyl(2-4C)alkenyl, phenyl(2-4C)alkynyl and a heterocyclic moiety containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulphur;

and wherein the phenyl or heteroaryl moiety in Ar¹ and the phenyl, naphthyl, or heterocyclic moiety in Z may optionally bear one or more substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, (1-4C)alkylenedioxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, di-N[(1-6C)alkyl]carbamoyl, (1-6C)alkanoylamino, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, halogeno(1-6C)alkoxy, (1-6C)alkanoyl and tetrazoyl;

provided that the compound is not N-[4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]phenyl]-(E)-4-chlorostyrenesulphonamide,

and pharmaceutically acceptable salts thereof.

3. A compound as claimed in claim 1 wherein X¹ is CO or SO₂.

4. A compound as claimed in claim 1 wherein R and n are as defined in claim 1 and X¹, A, B and Ar¹ are selected from:

(a) X¹ is SO₂ or CO;

A and B are both ethylene;

Ar¹ is a phenyl ring;

(b) X¹ is SO₂ or CO, A and B are ethylene, Ar¹ is a phenyl ring and;

(e) X¹ is SO₂ or CO, A and B are ethylene, Ar¹ is a pyridyl ring.

5. A compound as claimed in claim 1 wherein X¹ is CO or SO₂, A and B are ethylene, and Ar¹ is phenyl.

6. A compound as claimed in claim 1 wherein Q is a group of formula L¹X²L²Z.

7. A compound as claimed in claim 1 wherein R and n are as defined in claim 1 and A, B, X¹, Y¹, and Q are selected from:

(a) A is ethylene, or methylene, B is ethylene, Q is a group of formula L¹X²L²Ar² in which L¹ is (1-4C)alkylene or a bond, X² is selected from CONR¹², NR¹²CO, NR¹⁰SO₂, NR¹³CONR¹⁴ and SO₂, L is a (1-4C)alkylene or a bond, R¹⁰, R¹², R¹³ and R¹⁴ are independently selected from hydrogen and (1-4C)alkyl;

(b) A and B are ethylene, Q is a group of formula L¹X²L²Ar² in which L¹ is (1-4C)alkylene or a bond, X² is NHCO, NHSO₂, NHCONH or SO₂, L² is (1-4C)alkylene or a bond, and R and n are as hereinbefore defined;

(c) A and B are ethylene, Q is L¹X²L²Ar² in which L¹ is (1-4C)alkylene, L² is a bond, X² is NHCO, NHSO₂, NHCONH and SO₂;

or

(d) A and B are ethylene, Ar¹ is phenyl, Q is a group of formula L¹X²L²Ar² in which L¹ is (1-4C)alkylene or a bond, X² is NHCO, NHSO₂, NHCONH or SO₂, L² is (1-4C)alkylene or a bond.

8. A compound as claimed in claim 1 wherein A and B are ethylene, Ar¹ is phenyl, Q is of formula L¹X²L²Z in which L¹ is (1-4C)alkylene, X² is NR⁶SO₂ in which R⁶ is (1-4C)alkyl or hydrogen, and Z is phenyl, wherein the phenyl moiety of Ar¹ and Z may optionally be substituted as defined in claim 1 and R and n are as defined in claim 1.

9. A compound of the formula I as claimed in claim 1 wherein

Ar¹ is a phenylene ring, a pyridyl ring, or a fused heterocyclic system containing 1, 2 or 3 heteroatoms, and may optionally bear one or more substituents selected from halogeno, nitro, cyano, (1-6C) alkyl, (1-6C)alkylthio, halogeno(1-6C)alkyl, halogeno(1-6C)alkylthio, halogeno(1-6C)alkoxy, (1-6C)alkoxycarbonyl,

Q is a group of formula L¹X²L²Ar² in which L¹ is a bond or (1-4C)alkylene, L² is a bond or (1-4C)alkylene, X² is a bond, NR⁸, O or S, in which R⁸ is hydrogen or (1-4)C alkyl;

and

Ar² is selected from phenyl, and a monocyclic heterocyclic moiety containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulphur, and may optionally bear one or more substituents selected from halogeno, nitro, cyano, (1-6C)alkyl, (1-6C)alkylthio, halogeno(1-6C)alkyl, halogeno(1-6C)alkylthio, halogeno(1-6C)alkoxy, (1-6C)alkoxycarbonyl.

10. A compound as claimed in claim 1 wherein Ar¹ is a phenylene ring, a 2-pyridyl ring, a benzthiazol-2yl ring, a 2-quinoyloxy ring, a benzoxazolyl ring, a thiazolopyridin-2-yl or a quinoxalinyloxy ring.

11. A compound as claimed in claim 1 wherein R is hydrogen, halogeno or (1-4C)alkyl.

12. A compound as claimed in claim 1 wherein the substituent Q on Ar¹ is in the 4-position.

13. A compound as claimed in claim 1 wherein the substituent(s) on Ar¹ and/or Ar² are independently selected from methyl, methylthio, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorine, bromine, fluorine and methoxycarbonyl.

14. A process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 which process is selected from:

(a) for the production of those compounds of the formula I wherein T is N and X¹ is CO, the reaction, conveniently in the presence of a suitable base, of an amine of the formula II,

with an acid of the formula III,

15. A pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 13, together with a pharmaceutically acceptable carrier or diluent.

16. A method for treating diseases or medical conditions in which an inhibition of cholesterol biosynthesis is desirable comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13.

17. A method for the treatment of hypercholesterolemia or atherosclerosis comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8.