NOVEL SEH INHIBITORS AND THEIR USE

• US 20100261743A1
• Filed: 12/04/2008
• Published: 10/14/2010
• Est. Priority Date: 12/06/2007
• Status: Abandoned Application

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Inventors: Londregan, Allyn T., Marino, Joseph Paul JR., McAtee, John Jeffrey
• Application Number:
  US12/745,018
• Publication Number:
  US 20100261743A1
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 9/08 Vasodilators for multiple indications
• 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: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond

Abstract

The invention is directed to novel sEH inhibitors and their use in the treatment of diseases mediated by the sEH enzyme. Specifically, the invention is directed to compounds according to Formula I:

wherein R1, R2a, R2b, Rya, R6a, A, B, K, L, M, Y, Z, l, and m are defined herein, and to pharmaceutically-acceptable salts thereof. The compounds of the invention are sEH inhibitors and can be used in the treatment of diseases mediated by the sEH enzyme, such as hypertension. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting sEH and treatment of conditions associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

Claims

1. A compound according to Formula I:

2. A compound of claim 1 wherein:

A is phenyl, thiophenyl, or pyridyl;

R1 is CF₃, halo, OCF₃, CN, OC₁-C₆ alkyl, morpholino, CO₂H, or N(CH₃)₂;

l is 1, 2, or 3;

B is B1, B2, B6, and B7;

R2a and R2b and hydrogen;

n is 0;

m is 1;

Z is O;

Y is C1-C3 alkyl, phenyl, thiophenyl, or pyridyl;

wherein the phenyl, thiophenyl or pyridyl may be substituted by −

CO₂H, SO₂Me, CF₃, halo, or CN;

R5a is hydrogen or C1-C6 alkyl; and

R6a is hydrogen or C1-C6 alkyl;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 wherein:

A is phenyl;

R1 is CF₃, halo, OCF₃, CN, OC₁-C₆ alkyl, or N(CH₃)₂, or morpholino;

l is 1, or 2;

B is B2;

R2a and R2b and hydrogen;

L and M are N;

n is 0;

m is 1;

Z is O;

Y is methyl or phenyl;

R5a is hydrogen; and

R6a is hydrogen;

or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 chosen from:

2-[4-(dimethylamino)-6-methyl-2-pyrimidinyl]-N-{[2-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydro-6-isoquinolinecarboxamide;

1-[2-methyl-6-(methylamino)-4-pyrimidinyl]-N-({2-[(trifluoromethyl)oxy]phenyl}methyl)-2,3-dihydro-1H-indole-5-carboxamide;

N-[(2,4-dichlorophenyl)methyl]-1-[6-(methylamino)-2-phenyl-4-pyrimidinyl]-2,3-dihydro-1H-indole-5-carboxamide;

N-[(2,4-dichlorophenyl)methyl]-1-[2-methyl-6-(methylamino)-4-pyrimidinyl]-2,3-dihydro-1H-indole-5-carboxamide;

1-[2-methyl-6-(methylamino)-4-pyrimidinyl]-N-{[2-(trifluoromethyl)phenyl]methyl}-2,3-dihydro-1H-indole-5-carboxamide;

1-[6-(methylamino)-2-phenyl-4-pyrimidinyl]-N-({2-[(trifluoromethyl)oxy]phenyl}methyl)-2,3-dihydro-1H-indole-5-carboxamide;

1-[6-(methylamino)-2-phenyl-4-pyrimidinyl]-N-{[2-(trifluoromethyl)phenyl]methyl}-2,3-dihydro-1H-indole-5-carboxamide;

N-[(2,4-dichlorophenyl)methyl]-2-[2-methyl-6-(methylamino)-4-pyrimidinyl]-2,3-dihydro-1H-isoindole-5-carboxamide;

2-[2-methyl-6-(methylamino)-4-pyrimidinyl]-N-{[2-(trifluoromethyl)phenyl]methyl}-2,3-dihydro-1H-isoindole-5-carboxamide;

2-[2-methyl-6-(methylamino)-4-pyrimidinyl]-N-({2-[(trifluoromethyl)oxy]phenyl}methyl)-2,3-dihydro-1H-isoindole-5-carboxamide;

N-[(2,4-dichlorophenyl)methyl]-2-[6-(methylamino)-2-phenyl-4-pyrimidinyl]-2,3-dihydro-1H-isoindole-5-carboxamide;

2-[6-(methylamino)-2-phenyl-4-pyrimidinyl]-N-{[2-(trifluoromethyl)phenyl]methyl}-2,3-dihydro-1H-isoindole-5-carboxamide;

2-[6-(methylamino)-2-phenyl-4-pyrimidinyl]-N-{2-[(trifluoromethyl)oxy]phenyl}methyl)-2,3-dihydro-1H-isoindole-5-carboxamide;

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound or salt according to claim 1 and one or more pharmaceutically-acceptable excipient.

6. A method of treating hypertension, heart failure, renal failure, liver failure, peripheral vascular disease, coronary artery disease, myocardial ischemia, angina, hyperlipidemia, diabetes, hypergylcemia, metabolic syndrome, obesity, myocardial infarction, diabetic nephropathy, diabetic heart failure, dyslipidemia, and stroke which comprises administering to a human in need thereof, a compound of Formula I according to claim 1.

7. A method according to claim 6 wherein the compound of Formula I is administered orally.