3-piperidyl-4-oxoquinazoline derivatives and pharmaceutical compositions comprising the same

• US 6,235,730 B1
• Filed: 10/26/1999
• Issued: 05/22/2001
• Est. Priority Date: 12/12/1997
• Status: Expired due to Fees

• Current Assignee: Japan Tobacco Inc.
• Original Assignee: Japan Tobacco Inc.
• Inventors: Sato, Motohide, Kinoshita, Hajime, Katsushima, Takeo
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Liu, Hong
• Application Number:
  US09/367,242
• Time in Patent Office: 574 Days
• Field of Search: 544/286, 544/47, 544/102, 514/259, 514/217, 514/220, 514/211.11, 514/228.2, 514/229.8, 540/586, 540/522, 540/547
• US Class Current: 514/211.11
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

3-piperidyl-4-oxoquinazoline derivatives are provided, which is represented by the formula (I):

wherein R represents an amino group or a cyclic amino group such as dibenzoazepine, each of which is substituted with a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or the like, n is an integer of 1 to 3, R₃ and R₄ independently represents a hydrogen atom, a lower alkyl group, or the like, or a pharmaceutically acceptable salt thereof. Compounds (I) of the present invention have excellent MTP-inhibitory activity. Thus, these compounds not only inhibit formation of LDL that is a cause of arteriosclerotic diseases but also regulate TG, cholesterol, and lipoproteins such as LDL in the blood and regulate cellular lipids through regulation of MTP activity. They can also be used as a new type of preventive or therapeutic agents for hyperlipemia or arteriosclerotic diseases. Furthermore, they can be used as therapeutic or preventive agents for pancreatitis, obesity, hypercholesterolemia, and hypertriglyceridemia.

Claims

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

wherein R represents the formula (i);

wherein each of R₁ and R₂, which may be the same or different, represents a cycloalkyl group with 3 to 7 carbon atoms;

an aryl group;

or a heteroaryl group with 1 to 3 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen atoms, where each of the cycloalkyl, aryl, and heteroaryl group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group with 1 to 4 carbon atoms, a lower haloalkyl group with 1 to 4 carbon atoms, a nitro group, a lower alkoxy group with 1 to 4 carbon atoms, an amino group, an amino group substituted with a lower alkyl group with 1 to 4 carbon atoms, a hydroxyl group, a phenoxy group, and a sulfo group, or the formula (ii);

wherein each of A and B, which may be the same or different, represents an aromatic hydrocarbon ring;

a cycloalkane ring with 3 to 7 carbon atoms;

or a cycloalkene ring with 5 to 7 carbon atoms, where each of the aromatic hydrocarbon, cycloalkane, and cycloalkene ring may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group with 1 to 4 carbon atoms, a lower haloalkyl group with 1 to 4 carbon atoms, a hydroxyl group, a nitro group, a lower alkoxy group with 1 to 4 carbon atoms, an amino group, an amino group substituted with a lower alkyl group having 1 to 4 carbon atoms, and a sulfo group, X represents a single bond, a straight chain or branched lower alkylene group with 1 to 4 carbon atoms, a straight chain or branched lower alkenylene group with 2 to 4 carbon atoms, an oxygen atom, a sulfur atom, an imino group which may be substituted with a lower alkyl group with 1 to 4 carbon atoms, a carbonyl group, —

O—

Z—

, —

Z—

O, —

S—

Z—

, —

Z—

S—

, —

NH—

Z—

, —

NR₅Z—

, —

Z—

NH—

, or —

Z—

NR₅—

, where the lower alkylene or lower alkenylene group may have substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, a lower alkoxy group with 1 to 4 carbon atoms, an amino group, and a sulfo group, and where Z represents a lower alkylene group with 1 to 4 carbon atoms or a carbonyl group, and R₅ represents a lower alkyl group with 1 to 4 carbon atoms; and

Y represents a single bond, a straight chain or branched lower alkylene group with 1 to 4 carbon atoms, or a carbonyl group;

n represents an integer of 1 to 4; and

each of R₃ and R₄, which may be the same or different, represents a hydrogen atom, a lower alkyl group with 1 to 4 carbon atoms, a halogen atom, a lower haloalkyl group with 1 to 4 carbon atoms, a hydroxyl group, an amino group or a nitro group,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein each of R₁ and R₂, which may be the same or different, represents a cycloalkyl group with 3 to 7 carbon atoms, an aryl group, or a heteroaryl group with 1 to 3 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen atoms, where each of the cycloalkyl, aryl, and heteroaryl group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group with 1 to 4 carbon atoms, a lower haloalkyl group with 1 to 4 carbon atoms, a nitro group, a lower alkoxy group with 1 to 4 carbon atoms, an amino group, an amino group substituted with a lower alkyl group having 1 to 4 carbon atoms, a hydroxyl group, and a sulfo group and wherein each of A and B, which may be the same or different, represents an aromatic hydrocarbon ring;

a cycloalkane ring with 3 to 7 carbon atoms;

or a cycloalkene ring with 5 to 7 carbon atoms, where each of the aromatic hydrocarbon, cycloalkane, and cycloalkene ring may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group with 1 to 4 carbon atoms, a lower haloalkyl group with 1 to 4 carbon atoms, a hydroxyl group, a nitro group, a lower alkoxy group with 1 to 4 carbon atoms, an amino group, an amino group substituted with a lower alkyl group having 1 to 4 carbon atoms, and a sulfo group, X represents a single bond, a straight chain or branched lower alkylene group with 1 to 4 carbon atoms, a straight chain or branched lower alkenylene group with 2 to 4 carbons, an oxygen atom, a sulfur atom, an imino group which may be substituted with a lower alkyl group having 1 to 4 carbon atoms, a carbonyl group, —

O—

Z—

, —

Z—

O, —

S—

Z—

, —

Z—

S—

, —

NH—

Z—

, —

NR₅—

Z—

, —

Z—

NH—

, or —

Z—

NR₅—

where the lower alkylene or lower alkenylene group may have substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, a lower alkoxy group with 1 to 4 carbon atoms, an amino group, and a sulfo group, and where Z represents a lower alkylene group with 1 to 4 carbon atoms or a carbonyl group, and R₅ represents a lower alkyl group with 1 to 4 carbon atoms, and Y represents a single bond, a straight chain or branched lower alkylene group with 1 to 4 carbon atoms, or a carbonyl group, and

each of R₃ and R₄, which may be the same or different, represents a hydrogen atom or a lower alkyl group with 1 to 4 carbon atoms,

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein each of R₁ and R₂, which may be the same or different, represents a cycloalkyl group with 3 to 7 carbon atoms, an aryl group, or a heteroaryl group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen atoms, where each of the cycloalkyl, aryl, and heteroaryl group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group with 1 to 4 carbon atoms, a lower haloalkyl group with 1 to 4 carbon atoms, a nitro group, a lower alkoxy group with 1 to 4 carbon atoms, and a hydroxyl group,

and wherein each of A and B, which may be the same or different, represents an aromatic hydrocarbon ring which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group with 1 to 4 carbon atoms, a lower haloalkyl group with 1 to 4 carbons atoms, a nitro group, a lower alkoxy group with 1 to 4 carbon atoms, and a hydroxyl group, X represents a single bond, a straight chain or branched lower alkylene group with 1 to 4 carbon atoms, a straight chain or branched lower alkenylene group with 2 to 4 carbon atoms, an oxygen atom, a sulfur atom, an imino group which may be substituted with a lower alkyl group having 1 to 4 carbon atoms, a carbonyl group, —

O—

Z—

, —

S—

Z—

, —

NH—

Z—

, or —

NR₅—

Z—

, where the lower alkylene or lower alkenylene group may have substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, and a lower alkoxy group with 1 to 4 carbon atoms, and where Z represents a lower alkylene group with 1 to 4 carbon atoms or a carbonyl group, and R₅ represents a lower alkyl group with 1 to 4 carbon atoms, Y represents a single bond, and

R₃ and R₄ are both hydrogen atoms,

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3, wherein R represents formula (i),

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4, wherein each of R₁ and R₂, which may be the same or different, represents a cyclohexyl group, a phenyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, or a pyrrolyl group, where each of the above groups may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group with 1 to 4 carbon atoms, a lower haloalkyl group with 1 to 4 carbon atoms, a nitro group, a lower alkoxy group with 1 to 4 carbon atoms, and a hydroxyl group,

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5, wherein R represents a diphenylamino group, an N-phenyl-N-thienylamino group, an N-phenyl-N-pyridylamino group, a dipyridylamino group, or an N-phenyl-N-pyrimidylamino group, where each of the above groups may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group with 1 to 4 carbon atoms, a lower haloalkyl group with 1 to 4 atoms, a nitro group, a lower alkoxy group with 1 to 4 carbon atoms, and a hydroxyl group,

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 3, in which R represents formula (ii),

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 7, wherein each of A and B represents a benzene ring, which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group with 1 to 4 carbon atoms, a lower haloalkyl group with 1 to 4 carbon atoms, a nitro group, a lower alkoxy group with 1 to 4 carbon atoms, and a hydroxyl group,

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8, wherein R represents a carbazol-9-yl group, a phenoxazin-10-yl group, a phenothiazin-10-yl group, an acridon-10-yl group, a 9,9-dimethylacridan-10-yl group, a 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl group, a 10,11-dihydro-2-hydroxy-5H-dibenzo[b,f]azepin-5-yl group, a 10,11-dihydro-10-hydroxy-5H-dibenzo[b,f]azepin-5-yl group, a 5H-dibenzo[b,f]azepin-5-yl group, a 5,11-dihydrodibenzo[b,e][1,4]oxazepin-5-yl group, a 10,11-dihydro-11-oxo-5H-dibenzo[b,e][1,4]diazepine-5-yl group, or a 11-hydro-10-methyl-11-oxo-5H-dibenzo[b,e][1,4]diazepin-5-yl group,

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 3, where the compound is 3-[1-[2-[N-(2-methylphenyl)-N-phenylamino]ethyl]piperidin-4-yl]-3H-quinazolin-4-one, 3-[1-[2-(10,11-dihydro-5H-dibenzo[b,f]-azepin-5-yl)ethyl]piperidin-4-yl]-3H-quinazolin-4-one, 3-[1-[2-(10,11-dihydro-10-hydroxy-5H-dibenzo[b,f]azepin-5-yl)-ethyl]-piperidin-4-yl]-3H-quinazolin-4-one, 3-[1-[2-(10,11-dihydro-2-hydroxy-5H-dibenzo[b,f]azepin-5-yl)ethyl]piperidin-4-yl]-3H-quinazolin-4-one, or 3-[1-[2-(5,11-dihydrodibenzo[b,e][1,4]-oxazepin-5-yl)ethyl]piperidin-4-yl]-3H-quinazolin-4-one,

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmacologically acceptable carrier.

12. The compound of claim 1, wherein n is 2 or 3.

13. The compound of claim 12, wherein n is 2.

14. The compound of claim 5, wherein each of R₁ and R₂, which may be the same or different, is substituted at the ortho position with respect to the atom bonding to the amino nitrogen atom depicted in formula (i).

15. The compound of claim 5, wherein the ortho-substituted substituent is a lower alkyl with 1 to 4 carbon atoms.

16. A method of inhibiting a microsomal triglyceride transfer protein (MTP) by administering to a subject in need thereof an effective amount of a compound of claim 1 or a salt thereof.

17. A method of treating hyperlipemia or arteriosclerosis by administering to a subject in need thereof an effective amount of a compound of claim 1 or a salt thereof.