# US 7,465,798 B2 · Methods and compositions for selectin inhibition

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- Number: US 7,465,798 B2
- Document ID: US7465798B2
- Status: Granted
- Kind: B2
- Application number: 10/984,522
- Filed: 2004-11-09
- Published: 2005-05-12
- Granted: 2008-12-16
- Earliest claimed: 2003-11-10
- Assignees: Wyeth
- Inventors: Neelu Kaila; Silvano L. Debernardo; Kristin M. Jantz; Raymond T. Camphausen; Patricia W. Bedard; Adrian Huang
- Web page: https://patentgrep.com/patent/US7465798B2

## CPC

- C07D 221/10: Aza-phenanthrenes
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/06: Antianaemics
- A61P 7/08: Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock (artificial tears A61P27/04)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic agents
- A61P 33/14: Ectoparasiticides, e.g. scabicides
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to the field of anti-inflammatory substances, and more particularly to novel compounds that act as antagonists of the mammalian adhesion proteins known as selectins. In some embodiments, methods for treating selectin mediated disorders are provided which include administration of compound of Formula I: wherein the constituent variables are defined herein.

## Claims

### Claim 1

A compound having the Formula III:
or a pharmaceutically acceptable salt thereof,
wherein:
bond a and bond b are each a single bond;
k is 1;
Q1, Q2, Q3 and Q are each CHR2;
L is CO2H or an ester thereof;
Y is O, (CR3R4)por NR5;
n′ is 0 or 1;
p is 1 to 3;
X is OH, OR3, OC1-6 alkyl, OC(═O)-aryl, OC(═O)C1-6 alkyl OC(═O)OC1-6 alkyl, or NR3R3;
each R1, R3, R3, and R4 is independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 perhaloalkyl OC1-6 alkyl, OC1-6 perhaloalkyl, halogen, thioalkyl, CN, OH, SH, (CH2)nOSO3H, (CH2)nSO3H, (CH2)nCO2R6, OSO3R6, SO3R6, PO3R6R7;
each R12 is independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, OC1-6 alkyl, OC1-6 perhaloalkyl, thioalkyl, OH, (CH2)1OSO3H, (CH2)1SO3H, (CH2)1CO2R6,(CH2)1SO2NR8R9, (CH2)1C(═O)NR8R9, NR8R9, alkenyl, alkynyl, or NHCOR8, wherein any of said alkyl, Oalkyl, alkenyl or alkynyl can optionally be substituted with up to three substituents selected from the group consisting of halogen, C1-6 alkyl, OC1-6 alkyl and CN;
each n is an independently selected integer from 0 to 6;
each 1 is an independently selected integer from 1 to 6; and
Z is aryl, arylalkyl, heteroaryl or heterocyclo, wherein each of said aryl, arylalkyl, heteroaryl and heterocyclo is optionally substituted.

### Claim 2 (depends on 1)

The compound of claim 1 wherein n′ is 0.

### Claim 3 (depends on 1)

The compound of claim 1 wherein n′ is 1; and Y is CR3R4.

### Claim 4 (depends on 3)

The compound of claim 3 wherein Y is CH2 and X is OH.

### Claim 5 (depends on 1)

The compound of claim 1 wherein n′ is 0 and X is OH.

### Claim 6 (depends on 1)

The compound of claim 1 wherein Z is selected from:
(a) a five-membered heterocyclic ring containing one to three ring heteroatoms selected from N, S or O; wherein said five-membered heterocyclic ring is optionally substituted by from 1 to 3 substituents selected from halogen, C1-10 alkyl, OC1-10 alkyl, NO2, NH2, CN, CF3, and CO2H;
(b) a six-membcred heterocyclic ring containing one to three ring heteroatoms selected from N, S or O; wherein said six-membered heterocyclic ring is optionally substituted by from 1 to 3 substituents selected from halogen, C1-10 alkyl, OC1-10 alkyl, CHO, CO2H, C(═O)R20, SO2R20, NO2, NH2, CN, CF3 and OH;
(c) a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N or O; wherein said bicyclic ring moiety is optionally substituted by from 1 to 3 substituents selected from halogen, C1-6 alkyl, OC1-6 alkyl, CHO, NO2, NH2, CN, CE3, CO2H, C(═O)R20, SO2R20, and OH; and
(d) a benzyl, naphthyl, or phenyl ring, each of which is optionally substituted by from 1 to 3 substituents selected from halogen, C1-6 alkyl, phenyl, benzyl, Ophenyl, Obenzyl, SO2NH2, SO2NH(C1-6 alkyl), SO2N(C1-6 alkyl)2, CH2COOH, CO2H, CO2Me, CO2Et, CO2iPr, C(═O)NH2, C(═O)NH(C1-6 alkyl), C(═O)N(C1-6 alkyl)2, OH, SC1-6 alkyl, OC1-6 alkyl, NO2, NH2, CF3, and CN.

### Claim 7 (depends on 1)

The compound of claim 1 wherein R1 and each R2′ are independently hydrogen.

### Claim 8 (depends on 1)

The compound of claim 1 wherein Z is phenyl or phenyl substituted with 1 to 3 substituents selected from halogen, C1-6 alkyl, CO2H, CO2Me, CO2Et, CO2iPr, C(═O)NH2, C(═O)NH(C1-6 alkyl), C(═O)N(C1-6 alkyl)2, OH, OC1-6 alkyl, NH2, CF3, and CN.

### Claim 9 (depends on 1)

The compound of claim 1 having the Formula IV:
i) 3-Hydroxy-2-(thiophen-2--ylmethyl)-7,8,9,10-tetrahydrobenzo[h]quinoline-4-carboxylic acid;
j) 2-(Bcnzo[b]thiophen-3-ylmethyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h]quinoline-4-carboxylic acid;
k) 2-(2-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo [h]quinoline-4-carboxylic acid;
l) 2-(3-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo [h]quinoline-4-carboxylic acid;
m) 3-Hydroxy-2-[2-(3-methylbenzo [b]thiophen-2-ylmethyl)]-7,8,9,10-tetrahydrobenzo[h]quinoline-4-carboxylic acid;
n) 3-Hydroxy-2-(thiophen-3-ylmethyl)-7,8,9,10-tetrahydrobenzo [h]quinoline-4-carboxylic acid;
o) 3-Hydroxy-2-(indol-3-ylmethyl)-7,8,9,10-tetrahydrobenzo [h]quinoline-4-carboxylic acid;
p) 2-(5-Chlorobenzo[b]thiophen-3-ylmethyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h]quinoline-4-carboxylic acid;
q) 3-Hydroxy-2-phenyl-7,8,9,10-tetrahydro-benzo[h]quinoline-4-carboxylic acid;
r) 2-(4-Cyano-benzyl)-3-hydroxy-7,8,9,10-tetrahydro-benzo[h]quinoline-4-carboxylic acid;
s) 2-(4-Carboxy-benzyl)-3-hydroxy-7,8,9,10-tetrahydro-benzo[h]quinoline-4-carboxylic acid;
t) 2-(4-Carbamoyl-benzyl)-3-hydroxy-7,8,9,10-tetrahydro-benzo [h]quinoline-4-carboxylic acid;
u) 2-Benzyl-3-hydroxy-7,8,9,10-tetrahydro-benzo[h]quinoline-4-carboxylic acid;
v) 3-Hydroxy-2-phenethyl-7,8,9,10-tetrahydro-benzo[h]quinoline-4-carboxylic acid;
or a pharmaceutically acceptable salt thereof,
wherein:
n′ is 0 or 1;
R1 is H, halogen, OH, CN, SH, C1-6 alkyl, OC1-6 alkyl, C1-6 perhaloalkyl, C1-6 thioalkyl, aryl or heteroaryl;
wherein said aryl and said heteroaryl can each optionally be substituted with up to three substituents selected from the group consisting of halogen, OH, CN, SH, NH2, C1-6 alkyl, OC1-6 alkyl, C1-6 perhaloalkyl and C1-6 thioalkyl; and
wherein said C1-6 alkyl, OC1-6 alkyl and C1-6 thioalkyl can each optionally be substituted with up to three substituents selected from the group consisting of halogen, OH, CN, SH, NH2, OC1-6 alkyl, C1-6 perhaloalkyl and C1-6 thioalkyl;
R23 is aryl or heteroaryl, wherein said aryl and said heteroaryl can each optionally be substituted with up to three substituents selected from the group consisting of halogen, OH, CN, SH, NH2, C1-6 alkyl, OC1-6 alkyl, C1-6 perhaloalkyl and C1-6 thioalkyl; and
wherein R24 and R25 together form.

### Claim 10 (depends on 9)

The compound of claim 9 wherein R23 is optionally substituted aryl.

### Claim 11 (depends on 9)

The compound of claim 9 wherein R23 is optionally substituted phenyl.

### Claim 12 (depends on 9)

The compound of claim 9 wherein R23 is phenyl substituted at the 4-position thereof by a substituent selected from the group consisting of halogen, OH, CN, SH, NH2, CH3, OCH3, CF3 and OCF3.

### Claim 13 (depends on 9)

The compound of claim 9 wherein R23 is phenyl substituted at the 4-position thereof by a substituent selected from the group consisting of halogen and OCF3.

### Claim 14 (depends on 9)

The compound of claim 9 wherein R1 is H.

### Claim 15 (depends on 1)

The compound of claim 1 that is selected from the group consisting of:
b) 2-(4-Chloro-phenyl)-3-hydroxy-7,8,9,10-tetrahydro-benzo [h]quinoline-4-carboxylic acid;
c) 3-Hydroxy-2-(4-trifluoromethoxy-benzyl)-7,8,9,10-tetrahydro-benzo[h]quinoline-4-carboxylic acid;
f) 2-(4-Chloro-benzyl)-3-hydroxy-7,8,9,10-tetrahydro-benzo [h]quinoline-4-carboxylic acid;
g) Triethylammonium 7,8-benzo-2-(4-chlorophenyl)-3-hydroxyquinoline-4-carboxylate;
h) 2-(3,4-Dichlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h]quinoline-4-carboxylic acid;
ak) 2-( 1-acetyl-piperidin-4-yl)-3-hydroxy-7,8,9,10-tetrahydro-benzo[h]quinoline-4-carboxylic acid,
and pharmaceutically acceptable salts thereof.

### Claim 16 (depends on 1)

A composition comprising a pharmaceutically effective amount of a compound according to claim 1, and a pharmaceutically acceptable carrier or excipient.

### Claim 17 (depends on 9)

A composition comprising a pharmaceutically effective amount of a compound according to claim 9, and a pharmaceutically acceptable carrier or excipient.

### Claim 18 (depends on 1)

The compound of claim 1 wherein Z is heteroaryl optionally substituted with 1 to 3 substituents selected from halogen, C1-6 alkyl, CN, and CF3.

### Claim 19 (depends on 18)

The compound of claim 18, wherein Z is selected from pyrrole, furan, thiophene, indole, benzofuran and benzothiophene, each optionally substituted with 1 to 3 substituents selected from halogen, C1-6 alkyl, CN, and CF3.

### Claim 20 (depends on 19)

The compound of claim 19, wherein n′ is 1 and Y is CH2.

### Claim 21 (depends on 8)

The compound of claim 8, wherein n′ is 0.

### Claim 22 (depends on 8)

The compound of claim 8, wherein n′ is 1 and Y is CH2.

### Claim 23 (depends on 8)

The compound of claim 8, wherein Z is phenyl substituted with 1 to 3 halogens.

### Claim 24 (depends on 23)

The compound of claim 23, wherein Z is phenyl substituted with 1 to 3 chlorine atoms.

### Claim 25 (depends on 24)

The compound of claim 24, wherein Z is 4-chiorophenyl.

### Claim 26 (depends on 25)

The compound of claim 25, wherein n′ is 1 and Y is CH2.

### Claim 27 (depends on 9)

The compound of claim 9, wherein n′ is 0.

### Claim 28 (depends on 27)

The compound of claim 27, wherein n′ is 1.

### Claim 29 (depends on 9)

The compound of claim 9 wherein R23 is heteroaryl optionally substituted with 1 to 3 substituents selected from halogen, C1-6 alkyl, CN, and CF3.

### Claim 30 (depends on 29)

The compound of claim 29, wherein R23 is selected from pyrrole, furan, thiophene, indole, benzofuran and benzothiophene, each optionally substituted with 1 to 3 substituents selected from halogen, C1-6 alkyl, C1-6 perhaloalkyl, and CN.

### Claim 31 (depends on 30)

The compound of claim 30, wherein n′ is 1.

### Claim 32 (depends on 11)

The compound of claim 11, wherein n′ is 1.

### Claim 33 (depends on 13)

The compound of claim 13, wherein n′ is 1.

### Claim 34 (depends on 13)

The compound of claim 13, wherein R23 is 4-chlorophenyl.

### Claim 35 (depends on 34)

The compound of claim 34, wherein n′ is 1.