TETRAZOLE-SUBSTITUTED ARYLAMIDES AS P2X3 AND P2X2/3 ANTAGONISTS

• US 20150191487A1
• Filed: 01/09/2014
• Published: 07/09/2015
• Est. Priority Date: 06/29/2006
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Dillon, Michael Patrick, Hawley, Ronald Charles, Chen, Li, Feng, Lichun, Yang, Minmin
• Granted Patent: US 9,593,128 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 : without antiinflammatory effect
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 241/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 401/10 : linked by a carbon chain containing aromatic rings
• 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 403/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : 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 407/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/107 : with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07D 498/08 : Bridged systems

Abstract

Compounds of the formula I:

or a pharmaceutically acceptable salt thereof, wherein, R¹ is optionally substituted tetrazolyl, R² is optionally substituted phenyl, optionally substituted pyridinyl or optionally substituted thienyl, and R³, R⁴, R⁵ and R⁶ are as defined herein. Also provided are methods of using the compounds for treating diseases associated with the P2X₃ and/or a P2X_2/3 receptor antagonist and methods of making the compounds.

Claims

1-109. -109. (canceled)

110. A compound of formula IIc:

111. The compound of claim 110, wherein R¹¹ is halo or methyl.

112. The compound of claim 110, wherein R¹² is hydrogen, halo or methyl.

113. The compound of claim 110, wherein R¹¹ is methyl and R¹² is halo.

114. The compound of claim 110, wherein R¹³ is C_1-6alkyl or halo-C_1-6haloalkyl.

115. The compound of claim 110, wherein R¹³ is C_1-6alkyl.

116. The compound of claim 110, wherein R⁵ is:

hydroxymethyl;

methoxymethyl;

morpholin-4-ylmethyl;

piperidin-1-yl methyl optionally substituted at the 4-position with methyl, methanesulfonyl or acetyl;

1,1,-dioxo-thiomorpholin-1-yl;

piperidin-1-yl optionally substituted once or twice with a group or groups selected independently from methyl, methoxy or halo;

pyridinyl;

pyrimidinyl;

pyrazinyl;

pyridazinyl;

pyrazolyl;

or thiazolyl;

wherein the pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl and thiazolyl each may be optionally substituted once or twice with a group or groups selected independently from methyl, methylamino, dimethylamino and halo.

117. The compound of claim 110, wherein R⁵ is:

C_1-6alkyloxy-C_1-6alkyl;

hydroxy-C_1-6alkyl;

heteroaryl, or heterocyclyl-C_1-6alkyl.

118. The compound of claim 110, wherein R⁵ is pyridinyl, pyrimidinyl, or pyrazinyl, each of which may be substituted once or twice with a group or groups independently selected from methyl, fluoro, chloro, amino, methylamino or dimethylamino.

119. The compound of claim 110, wherein R⁵ is pyridinyl, pyrimidinyl, or pyrazinyl, each of which may be substituted once or twice with methyl.

117-1. The compound of claim 110, wherein R⁵ is:

methoxymethyl;

hydroxymethyl;

or pyridazin-2-yl.

120. A compound of formula IIIc:

121. The compound of claim 120, wherein R¹² is halo.

122. The compound of claim 120, wherein R¹² is fluoro.

123. The compound of claim 120, wherein R¹³ is C_1-6alkyl.

124. The compound of claim 120, wherein R¹³ is isopropyl.

125. The compound of claim 120, wherein R¹³ is trifluoromethyl.

126. The compound of claim 120, wherein R⁵ is methoxymethyl.

127. The compound of claim 120, wherein R⁵ is hydroxymethyl.

128. The compound of claim 120, wherein R⁵ is pyridazin-2-yl.

129. The compound of claim 120, wherein R⁵ is 5-methyl-pyrazin-2-yl.

130. The compound 2′

-fluoro-5-(5-isopropyl-tetrazol-1-yl)-4′

-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide, or a pharmaceutically acceptable salt thereof.

131. The compound 2′

-fluoro-5-(5-isopropyl-tetrazol-1-yl)-4′

-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide, or a pharmaceutically acceptable salt thereof.

132. The compound 2′

-fluoro-5-(5-isopropyl-tetrazol-1-yl)-4′

-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide, or a pharmaceutically acceptable salt thereof.

133. The compound 5-(5-isopropyl-tetrazol-1-yl)-4′

-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide, or a pharmaceutically acceptable salt thereof.

134. The compound 2′

-fluoro-5-(5-isopropyl-tetrazol-1-yl)-4′

-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide, or a pharmaceutically acceptable salt thereof.

135. A compound of formula IVc: