2-Thiopyrimidinones

Patent metadata

Field	Value
Publication number	US-2016304469-A1
Application number	US-201615191943-A
Country	US
Kind code	A1
Filing date	Jun 24, 2016
Priority date	Nov 11, 2011
Publication date	Oct 20, 2016
Grant date	—

Abstract

Myeloperoxidase inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat, for example, cardiovascular conditions.

First claim

1 . A compound having Formula I

or a pharmaceutically acceptable salt or prodrug thereof
wherein
R 1 is a five to six membered aromatic ring optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and
said R 1 is optionally mono-, di-, or tri-substituted independently with cyano, halo, hydroxyl, amino, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, hydroxy(C 2 -C 4 )alkoxy, carbamoyl(C 1 -C 4 )alkoxy, amino(C 2 -C 4 )alkoxy, cyano(C 1 -C 4 )alkyl, mono-N— or di-N,N—(C 1 -C 4 )alkylamino, aminocarbonyl, mono-N— or di-N,N(C 1 -C 4 )alkylaminocarbonyl, (C 1 -C 4 )alkylthio, aminosulfonyl, (C 1 -C 4 )alkylsulfinyl, (C 1 -C 4 )alkylsulfonyl, or mono-N— or di-N,N(C 1 -C 4 )alkylaminosulfonyl, wherein any of the (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy may be optionally mono-, di- or tri-substituted with fluoro; or wherein R 1 is optionally substituted with a five to six membered aromatic ring optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen;
R 2 is a fully saturated, partially unsaturated or fully unsaturated one to fourteen membered straight carbon chain wherein the carbons, other than the connecting carbon,
a. may be branched
b. may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said sulfur is optionally mono- or di-substituted with oxo,
c. may optionally be mono-, di- or tri-substituted independently with halo,
d. may optionally be mono-substituted with hydroxy, and
e. may optionally be mono-substituted with oxo,
and wherein the carbon chain is optionally mono-substituted with Z;
wherein Z is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
wherein said Z is optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, aminothioxo, amino(C 1 -C 6 )alkylcarbonyl, hydroxyl, diaminomethylene, carbamoyl or (C 1 -C 6 )alkoxy and wherein said (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy substituent is also optionally substituted with one to three halo, and wherein said (C 1 -C 6 )alkyl or (C 2 -C 6 )alkoxy substituent is also optionally substituted with one to three hydroxy;

with the proviso that R 1 is not phenyl, and R 2 is not (C 1 -C 6 )alkyl; and
with the proviso that when
R 1 is phenyl and said R 1 is mono-, di-, or tri-substituted independently with hydroxyethoxy, methyl, methoxy, fluoro or chloro; and
R 2 is diaminomethleneamino(C 2 -C 4 )alkyl, carbamoyl(C 1 -C 4 )alkyl, hydroxy(C 2 -C 4 )alkyl, amino(C 2 -C 4 )alkylcarbamoyl(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylcarbonylamino(C 2 -C 4 )alkyl, amino(C 1 -C 4 )alkylcarbonylamino(C 2 -C 4 )alkyl, amino(C 3 -C 4 )hydroxyalkyl or amino(C 2 -C 4 )alkyl, said compounds are not included; and

with the proviso that 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide and N-(2-aminoethyl)-2-[6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide or a pharmaceutically acceptable salt of said proviso's compounds are not included.

2 . The compound of claim 1 wherein R 1 is phenyl, naphthyl, furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolinyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl, benzo[b]thiophenyl, benzothiazolyl, benzo[b]furanyl or thiophenyl; and wherein said R 1 is mono-, di-, or tri-substituted independently with cyano, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy(C 2 -C 4 )alkoxy, trifluoro(C 1 -C 4 )alkyl, trifluoro(C 1 -C 4 )alkoxy or halo.

3 . The compound of claim 2 wherein R 2 is a fully saturated, partially unsaturated or fully unsaturated one to fourteen membered straight carbon chain wherein the carbons, other than the connecting carbon,
a. may be branched
b. may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said sulfur is optionally mono- or di-substituted with oxo,
c. may optionally be mono-, di- or tri-substituted independently with halo,
d. may optionally be mono-substituted with hydroxy, and
e. may optionally be mono-substituted with oxo; or
R 2 is furanyl(C 1 -C 4 )alkyl, triazolyl(C 1 -C 4 )alkyl, pyridinyl(C 1 -C 4 )alkyl, pyrizinyl(C 1 -C 4 )alkyl, pyridazinyl(C 1 -C 4 )alkyl, pyrimidinyl(C 1 -C 4 )alkyl, imidazolyl(C 1 -C 4 )alkyl or pyrrolidinyl(C 1 -C 4 )alkyl, said R 2 rings optionally mono-, di- or tri-substituted independently with (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or halo.

4 . The compound of claim 3 wherein
R 1 is phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolinyl, furanyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl, benzo[b]thiophenyl, benzothiazolyl, benzo[b]furanyl or thiophenyl; wherein said R 1 is mono-, di-, or tri-substituted independently with (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy(C 2 -C 4 )alkoxy, cyano, trifluoromethyl, trifluoromethoxy or halo; and
R 2 is (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, carboxy(C 1 -C 4 )alkyl, mono- or di-hydroxy(C 2 -C 6 )alkyl, amino(C 2 -C 4 )alkyl, diaminomethyleneamino(C 2 -C 4 )alkyl, mono-N— or di-N,N(C 1 -C 4 )alkylamino(C 2 -C 4 )alkyl, (C 1 -C 4 )alkylcarbonyloxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxycarbonyl(C 1 -C 4 )alkyl, carbamoyl(C 1 -C 4 )alkyl, carbamoylamino(C 2 -C 4 )alkyl, mono-N— or di-N,N(C 1 -C 4 )alkylcarbamoyl(C 1 -C 4 )alkyl, amino(C 2 -C 4 )alkylcarbamoyl(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylcarbonylamino(C 2 -C 4 )alkyl, amino(C 1 -C 4 )alkylcarbonylamino(C 2 -C 4 )alkyl, (C r C 4 )alkoxycarbonylamino(C 2 -C 4 )alkyl, (C 1 -C 4 )alkylsulfonylamino(C 2 -C 4 )alkyl, (C 1 -C 4 )alkylaminosulfonyl(C 1 -C 4 )alkyl, aminosulfonyl(C 1 -C 4 )alkyl, amino(C 3 -C 4 )hydroxyalkyl or (C 1 -C 4 )alkylthioalkyl(C 1 -C 4 ).

5 . (canceled)

6 . The compound of claim 3 wherein
R 1 is phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolinyl, furanyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl, benzo[b]thiophenyl, benzothiazolyl, benzo[b]furanyl or thiophenyl; wherein said R 1 is mono-, di-, or tri-substituted independently with (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy(C 2 -C 4 )alkoxy, cyano, trifluoromethyl, trifluoromethoxy or halo; and
R 2 is triazolyl(C 1 -C 4 )alkyl, pyridinyl(C 1 -C 4 )alkyl, pyrizinyl(C 1 -C 4 )alkyl, pyridazinyl(C 1 -C 4 )alkyl, pyrimidinyl(C 1 -C 4 )alkyl, imidazolyl(C 1 -C 4 )alkyl or pyrrolidinyl(C 1 -C 4 )alkyl, said R 2 rings optionally mono-, di- or tri-substituted independently with (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or halo.

7 . The compound of claim 1 wherein R 1 is phenyl and said R 1 is mono-, di-, tri-substituted independently with hydroxyethoxy, methyl, methoxy, fluoro or chloro.

8 . The compound of claim 1 wherein R 2 is hydroxy(C 2 -C 4 )alkyl, diaminomethyleneamino(C 2 -C 4 )alkyl, carbamoyl(C 1 -C 4 )alkyl, amino(C 3 -C 4 )hydroxyalkyl, amino(C 2 -C 4 )alkylcar

Assignees

• Pfizer

Inventors

• Carpino Philip A
• Conn Edward L
• Dow Robert L
• Dowling Matthew S
• Hepworth David
• Kung Daniel Wei-Shung
• Orr Suvi
• Rocke Benjamin N
• Ruggeri Roger B
• Sammons Matthew F
• Warmus Joseph S
• Zhang Yan

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P13/12

  of the kidneys · CPC title