IP Library Granted Patent US 9,688,693
Granted Patent B2
US 9,688,693 · App. 14/341,097 · Granted Jun 27, 2017

NK

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Quick Facts
Patent No.
US 9,688,693
App. No.
14/341,097
Granted
Jun 27, 2017
Kind
B2
Abstract

A NK 1 antagonist having the formula (I), wherein Ar 1 and Ar 2 are optionally substituted phenyl or heteroaryl, X 1 is an ether, thio or imino linkage, R 4 and R 5 are not both H or alkyl, and the remaining variables are as defined in the specification, useful for treating a number of disorders, including emesis, depression, anxiety and cough. Pharmaceutical compositions. Methods of treatment and combinations with other agents are also disclosed.

Claims (52)

1. A method for treating a physiological disorder, symptom or disease in a patient, comprising administering to the patient an effective amount of at least one compound according to structural formula (I):

or a pharmaceutically-acceptable salt thereof, wherein

Ar 1 is phenyl, wherein said phenyl can be unsubstituted or substituted with 1 to 3 fluoro;

Ar 2 is bis(trifluoromethyl)phenyl;

X 1 is —O—;

R 1 and R 2 are each independently selected from the group consisting of H, C 1 -C 6 alkyl and hydroxyl(C 1 -C 3 alkyl), providing that at least one of R 1 and R 2 is H;

R 3 is H;

R 4 and R 5 are each independently selected from the group consisting of —(CR 28 R 29 ) n1 -G, wherein,

n 1 is an integer between 0 to 5;

G is —H, —NR 13 R 14 , —NR 12 C(O)R 14 , —C(O)NR 13 R 14 , —OC(O)NR 13 R 14 , —NR 12 C(O)OR 13 , —NR 12 (C(O)NR 13 R 14 ), —NR 12 SO 2 R 13 , —OH, —O(C 1-6 alkyl), —C(OR 12 )(R 13 )(R 14 ), —OC(O)R 14 , —C(O)R 13 , R 19 -heteroaryl, R 19 -phenyl, or heterocycloalkenyl,

wherein heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, benzofuranyl, thienyl, benzothienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazoyl, tetrazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl, oxazolyl, pyrrolyl, isoxazolyl, 1,3,5-triazinyl, and indolyl; and

wherein hetereocycloalkenyl is optionally substituted with 1 substituent independently selected from R 30 and R 31 ;

provided that R 4 and R 5 are not both selected from the group consisting of H, alkyl and cycloalkyl; and when one of R 4 and R 5 is —OH, then the other one of R 4 and R 5 is not alkyl or R 19 -phenyl;

R 6 and R 7 are each H;

n 2 is 2;

R 12 is H, C 1 -C 6 alkyl or C 3 -C 5 cycloalkyl;

R 13 and R 14 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, —CH 2 CF 3 , C 3 -C 6 cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, benzofuranyl, thienyl, benzothienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazoyl, tetrazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl, oxazolyl, pyrrolyl, isoxazolyl, 1,3,5-triazinyl and indolyl; or

R 13 and R 14 , together with the nitrogen atom to which they are both attached, form a 5- to 6-membered saturated or unsaturated ring that is optionally substituted with —OR 12 , where one of the carbon atoms in the ring is optionally replaced by a heteroatom selected from —O—;

n 6 is 0, 1 or 2;

R 18 is H;

each R 19 is a substituent on the phenyl or heteroaryl ring to which it is attached, and is independently selected from the group consisting of H and C 1 -C 6 alkyl;

R 23 and R 24 are each independently selected from the group consisting of H and C 1 -C 6 alkyl; or

R 23 and R 24 , together with the carbon atom to which they are both attached, form a C═O or cyclopropyl group;

R 27 is H, —OH or C 1 -C 6 alkyl;

R 28 and R 29 are each independently selected from the group consisting of H and C 1 -C 2 alkyl;

R 30 and R 31 are each independently selected from the group consisting of H, —OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl and —C(O)NR 13 R 14 ; or

R 30 and R 31 , together with the carbon atom to which they are both attached, form ═O, ═S, a cyclopropyl ring or ═NR 36 ;

R 32 and R 33 are each independently H or C 1 -C 6 alkyl;

R 34 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl or hydroxy(C 2 -C 6 )alkyl;

R 35 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, —P(O)(OH) 2 , allyl, hydroxy(C 2 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —SO 2 R 15 or —(CH 2 ) 2 —N(R 12 )—SO 2 —R 15 ;

R 36 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, —NO 2 , —CN or OR 12 ;

R 37 is 1 to 3 substituents independently selected from the group consisting of H, C 1 -C 6 alkyl, —OH, C 1 -C 6 alkoxy and halogen;

r is 1 to 3;

X 2 is —NR 35 —, —O—, —S—, —S(O)—, —SO 2 —, —CH 2 —, —CF 2 — or —CR 12 F—;

X 3 is —NR 34 —, —N(CONR 13 R 14 )—, —N(CO 2 R 15 )—, —N(COR 12 )—, —N(SO 2 NHR 13 )—, —O—, —S—, —S(O)—, —SO 2 —, —CH 2 —, —CF 2 — or —CR 12 F—;

n 3 is 1 to 5; and

n 5 is 1 to 3;

or a diastereomer, enantiomer, stereoisomer, regiostereomer, rotomer, or tautomer thereof;

wherein the physiological disorder, symptom or disease is emesis and/or nausea.

2. The method of claim 1 , wherein R 4 is —NR 13 R 14 , —NR 12 C(O)R 14 , —NR 12 C(O)OR 13 , —NR 12 (C(O)NR 13 R 14 ), —OH, —O—(C 1 -C 6 )alkyl, —O—(C 3 -C 8 )cycloalky, —OC(O)R 14 , —OC(O)NR 13 R 14 , —NR 12 SO 2 R 13 , —SO 2 NR 13 R 14 , R 19 -heteroaryl,

wherein X 2 is —O—, —S—, —CH 2 — or —NR 35 —; and

R 5 is —C(O)OR 13 or —C(O)NR 13 R 14 .

3. The method of claim 1 , wherein R 12 and R 27 are independently selected from the group consisting of H and —CH 3 ; n 3 is 2 or 3; and n 5 is 1 or 2.

4. The method of claim 1 , wherein the compound is selected from the group consisting of:

5. The method of claim 1 , wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 , wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

Assignments (5)
RELEASE OF INTELLECTUAL PROPERTY SECURITY AGREEMENTS AT R/F 41939/0487, 46591/0544 AND 53940/0001 Recorded Apr 15, 2026
From: MIDCAP FINANCIAL TRUST
To: TERSERA THERAPEUTICS LLC,
Reel/Frame 075420/0453 →
RELEASE OF SECURITY INTEREST Recorded Apr 4, 2023
From: MIDCAP FINANCIAL TRUST, AS AGENT
To: TERSERA THERAPEUTICS LLC
Reel/Frame 063253/0942 →
FIRST LIEN PATENT SECURITY AGREEMENT Recorded Jul 19, 2018
From: TERSERA THERAPEUTICS LLC
To: MIDCAP FINANCIAL TRUST, AS AGENT
Reel/Frame 046591/0544 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 18, 2017
From: PALIWAL, SUNIL; REICHARD, GREGORY A.; WANG, CHENG; XIAO, DONG; TSUI, HON-CHUNG; SHIH, NENG-YANG; ARREDONDO, JUAN D.; WROBLESKI, MICHELLE LACI; PALANI, ANANDAN
To: SCHERING CORPORATION
Reel/Frame 042431/0652 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 18, 2017
From: SCHERING CORPORATION
To: OPKO HEALTH, INC.
Reel/Frame 042431/0670 →