# US 8,541,582 B2 · Phenyl bicyclic methyl amine derivatives as sphingosine-1 phosphate receptors modulators

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- Number: US 8,541,582 B2
- Document ID: US8541582B2
- Status: Granted
- Kind: B2
- Application number: 13/446,352
- Filed: 2012-04-13
- Published: 2012-10-18
- Granted: 2013-09-24
- Earliest claimed: 2011-04-14
- Assignees: Allergan, Inc.
- Applicants: Janet A. Takeuchi; Ling Li; Wha Bin Im
- Inventors: Janet A. Takeuchi; Ling Li; Wha Bin Im
- Web page: https://patentgrep.com/patent/US8541582B2

## CPC

- A61K 31/665: having oxygen as a ring hetero atom, e.g. fosfomycin
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61K 31/662: Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 11/08: Bronchodilators
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- 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 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 27/14: Decongestants or antiallergics
- 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 35/04: specific for metastasis
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 39/00: General protective or antinoxious agents
- A61P 41/00: Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
- C07F 9/3808: {Acyclic saturated acids which can have further substituents on alkyl}
- C07F 9/65517: {condensed with carbocyclic rings or carbocyclic ring systems}
- C07D 215/12: with substituted hydrocarbon radicals attached to ring carbon atoms
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to novel phenyl bicyclic methyl amine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

## Claims

### Claim 1

A compound having Formula I, its individual enantiomers, its individual diastereoisomers, its individual isomers, its individual tautomers or a pharmaceutically acceptable salt thereof
wherein:
represents a single
or a double bond
A is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C5-8 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl, or hydrogen;
R2 is hydrogen, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R3 is hydrogen, halogen, substituted or unsubstituted C1-3 alkyl, C(O)R8 or hydroxyl;
R4 is OPO3H2, carboxylic acid, PO3H2, substituted or unsubstituted C1-6 alkyl, —S(O)2H, —P(O)MeOH, —P(O)(H)OH or OR11;
R5 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R6 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R7 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R8 is H, OR11 or substituted or unsubstituted C1-3 alkyl;
R9 is H or substituted or unsubstituted C1-3 alkyl;
R10 is H or substituted or unsubstituted C1-3 alkyl;
R11 is H or substituted or unsubstituted C1-3 alkyl;
L1 is O, S, NH or CHR12;
L2 is O, S, NH or CHR13;
R12 is H or substituted or unsubstituted C1-3 alkyl;
R13 is H or substituted or unsubstituted C1-3 alkyl;
a is 1;
b is 0, 1, 2 or 3;
c is 0, 1, 2, 3 or 4;
d is 1, 2, 3 or 4;
represents

### Claim 2 (depends on 1)

A compound according to claim 1, wherein:
represents a double bond
A is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 5-8 cycloalkyl, substituted or unsubstituted C 5-8 cycloalkenyl, or hydrogen;
R2 is hydrogen, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R3 is hydrogen, halogen, substituted or unsubstituted C1-3 alkyl, C(O)R8 or hydroxyl;
R4 is OPO3H2, carboxylic acid, PO3H2, substituted or unsubstituted C1-6 alkyl, —S(O)2H, —P(O)MeOH, —P(O)(H)OH or OR11;
R5 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R6 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R7 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R8 is H, OR11 or substituted or unsubstituted C1-3 alkyl;
R9 is H or substituted or unsubstituted C1-3 alkyl;
R10 is H or substituted or unsubstituted C1-3 alkyl;
R11 is H or substituted or unsubstituted C1-3 alkyl;
L1 is O, S, NH or CHR12;
L2 is O, S, NH or CHR13;
R12 is H or substituted or unsubstituted C1-3 alkyl;
R13 is H or substituted or unsubstituted C1-3 alkyl;
a is 1;
b is 0, 1, 2 or 3;
c is 0, 1, 2, 3 or 4;
d is 1, 2, 3 or 4;
represents

### Claim 3 (depends on 1)

A compound according to claim 1, wherein:
represents a double bond
A is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C5-8 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl, or hydrogen;
R2 is hydrogen, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R3 is hydrogen, halogen, substituted or unsubstituted C1-3 alkyl, C(O)R8 or hydroxyl;
R4 is OPO3H2, carboxylic acid, PO3H2, substituted or unsubstituted C1-6 alkyl, —S(O)2H, —P(O)MeOH, —P(O)(H)OH or OR11;
R5 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R6 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R7 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R8 is H, OR11 or substituted or unsubstituted C1-3 alkyl;
R9 is H or substituted or unsubstituted C1-3 alkyl;
R10 is H or substituted or unsubstituted C1-3 alkyl;
R11 is H or substituted or unsubstituted C1-3 alkyl;
L1 is O, S, NH or CHR12;
L2 is O, S, NH or CHR13;
R12 is H or substituted or unsubstituted C1-3 alkyl;
R13 is H or substituted or unsubstituted C1-3 alkyl;
a is 1;
b is 0, 1, 2 or 3;
c is 0, 1, 2, 3 or 4;
d is 1, 2, 3 or 4; and
represents

### Claim 4 (depends on 1)

A compound according to claim 1, wherein:
represents a double bond
A is substituted or unsubstituted aryl;
R2 is hydrogen, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R3 is hydrogen, halogen, substituted or unsubstituted C1-3 alkyl, C(O)R8 or hydroxyl;
R4 is OPO3H2, carboxylic acid, PO3H2, substituted or unsubstituted C1-6 alkyl, —S(O)2H, —P(O)MeOH, —P(O)(H)OH or OR11;
R5 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R6 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R7 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R8 is H, OR11 or substituted or unsubstituted C1-3 alkyl;
R9 is H or substituted or unsubstituted C1-3 alkyl;
R10 is H or substituted or unsubstituted C1-3 alkyl;
R11 is H or substituted or unsubstituted C1-3 alkyl;
L1 is O, S, NH or CHR12;
L2 is O, S, NH or CHR13;
R12 is H or substituted or unsubstituted C1-3 alkyl;
R13 is H or substituted or unsubstituted C1-3 alkyl;
a is 1;
b is 0, 1, 2 or 3;
c is 0, 1, 2, 3 or 4;
d is 1, 2, 3 or 4;
represents

### Claim 5 (depends on 1)

A compound according to claim 1, wherein:
represents a double bond
A is hydrogen;
R2 is hydrogen, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R3 is hydrogen, halogen, substituted or unsubstituted C1-3 alkyl, C(O)R8 or hydroxyl;
R4 is OPO3H2, carboxylic acid, PO3H2, substituted or unsubstituted C1-6 alkyl, —S(O)2H, —P(O)MeOH, —P(O)(H)OH or OR11;
R5 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R6 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R7 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R8 is H, OR11 or substituted or unsubstituted C1-3 alkyl;
R9 is H or substituted or unsubstituted C1-3 alkyl;
R10 is H or substituted or unsubstituted C1-3 alkyl;
R11 is H or substituted or unsubstituted C1-3 alkyl;
L1 is O, S, NH or CHR12;
L2 is O, S, NH or CHR13;
R12 is H or substituted or unsubstituted C1-3 alkyl;
R13 is H or substituted or unsubstituted C1-3 alkyl;
a is 1;
b is 0, 1, 2 or 3;
c is 0, 1, 2, 3 or 4;
d is 1, 2, 3 or 4;
represents

### Claim 6 (depends on 1)

A compound according to claim 1, wherein:
represents a double bond
A is hydrogen;
R2 is hydrogen, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R3 is hydrogen, halogen, substituted or unsubstituted C1-3 alkyl, C(O)R8 or hydroxyl;
R4 is OPO3H2, carboxylic acid, PO3H2, substituted or unsubstituted C1-6 alkyl, —S(O)2H, —P(O)MeOH, —P(O)(H)OH or OR11;
R5 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R6 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R7 is H, halogen, —OC1-3 alkyl, substituted or unsubstituted C1-3 alkyl, CN, C(O)R8, NR9R10 or hydroxyl;
R8 is H, OR11 or substituted or unsubstituted C1-3 alkyl;
R9 is H or substituted or unsubstituted C1-3 alkyl;
R10 is H or substituted or unsubstituted C1-3 alkyl;
R11 is H or substituted or unsubstituted C1-3 alkyl;
L1 is O, S, NH or CHR12;
L2 is O, S, NH or CHR13;
R12 is H or substituted or unsubstituted C1-3 alkyl;
R13 is H or substituted or unsubstituted C1-3 alkyl;
a is 1;
b is 0, 1, 2 or 3;
c is 0, 1, 2, 3 or 4;
d is 1, 2, 3 or 4;
represents

### Claim 7 (depends on 1)

A compound according to claim 1 selected from:
[3-({[5-(4-hexylphenyl)quinolin-8-yl]methyl}amino)propyl]phosphonic acid;
[3-({[4-(4-hexylphenyI)-1-naphthyl]methyl}amino)propyl]phosphonic acid;
2-({[5-(4-hexylphenyl)quinolin-8-yl]methyl}amino)ethyl dihydrogen phosphate;
3-({[5-(4-hexylphenyl)quinolin-8-yl]methyl}amino)propanoic acid;
{3-[({5-[4-(3-phenylpropyl)phenyl]quinolin-8-yl}methyl)amino]propyl}phosphonic acid;
(3-{[(5-{4-[3-(2-methylphenyl)propyl]phenyl}quinolin-8-yl) methyl]amino}propyl)phosphonic acid;
[3-({[5-(4-hexylphenyl)quinolin-8-yl]methyl}amino)butyl]phosphonic acid;
{3-[({5-[3-fluoro-4-(3-phenylpropyl)phenyl]quinolin-8-yl}methyl)amino]propyl}phosphonic acid; [3-({[5-(2-fluoro-4-heptylphenyl)quinolin-8-yl]methyl}amino)propyl]phosphonic acid;
[3-({[5-(3-fluoro-4-heptylphenyl)quinolin-8-yl]methyl}amino)propyl]phosphonic acid;
{3-[({5-[4-(3-ethylheptyl)phenyl]quinolin-8-yl}methyl)amino]propyl}phosphonic acid;
[3-({[5-(4-octylphenyl)quinolin-8-yl]methyl}amino)propyl]phosphonic acid;
[3-({[5-(3-fluoro-4-hexylphenyl)quinolin-8-yl]methyl}amino)propyl]phosphonic acid;
{3-[({5-[4-(2-cyclohexylethyl)phenyl]quinolin-8-yl}methyl)amino]propyl}phosphonic acid;
2-({[5-(4-hexylphenyl)quinolin-8-yl]methyl}amino)ethanol;
(3-{[(5-{3-fluoro-4-[3-(2-methylphenyl)propyl]phenyl}quinolin-8-yl) methyl]amino}propyl)phosphonic acid;
(3-{[(5-{3-fluoro-4-[3-(3-methylphenyl)propyl]phenyl}quinolin-8-yl) methyl]amino}propyl)phosphonic acid;
(3-{[(5-{3-fluoro-4-[3-(4-methylphenyl)propyl]phenyl}quinolin-8-yl) methyl]amino}propyl)phosphonic acid;
{3-[({5-[4-(3-ethylheptyl)-3-fluorophenyl]quinolin-8-yl}methyl)amino]propyl}phosphonic acid;
{3-[({5-[4-(2-cyclohexylethyl)-3-fluorophenyl]quinolin-8-yl}methyl)amino] propyl}phosphonic acid;
2-[({5-[4-(3-ethylheptyl)-3-fluorophenyl]quinolin-8-yl}methyl)amino]ethanol; and
2-[({5-[4-(3-ethylheptyl)-3-fluorophenyl]quinolin-8-yl}methyl)amino]ethyl dihydrogen phosphate.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable adjuvant, diluents or carrier.

### Claim 9 (depends on 8)

A pharmaceutical composition according to claim 8 wherein the compound is selected from:
[3-({[5-(4-hexylphenyl)quinolin-8-yl]methyl}amino)propyl]phosphonic acid;
[3-({[4-(4-hexylphenyl)-1-naphthyl]methyl}amino)propyl]phosphonic acid;
2-({[5-(4-hexylphenyl)quinolin-8-yl]methyl}amino)ethyl dihydrogen phosphate;
3-({[5-(4-hexylphenyl)quinolin-8-yl]methyl}amino)propanoic acid;
{3-[({5-[4-(3-phenylpropyl)phenyl]quinolin-8-yl}methyl)amino]propyl}phosphonic acid;
(3-{[(5-{4-[3-(2-methylphenyl)propyl]phenyl}quinolin-8-yl) methyl]amino}propyl)phosphonic acid;
[3-({[5-(4-hexylphenyl)quinolin-8-yl]methyl}amino)butyl]phosphonic acid;
{3-[({5-[3-fluoro-4-(3-phenylpropyl)phenyl]quinolin-8-yl}methyl)amino]propyl}phosphonic acid;
[3-({[5-(2-fluoro-4-heptylphenyl)quinolin-8-yl]methyl}amino)propyl]phosphonic acid;
[3-({[5-(3-fluoro-4-heptylphenyl)quinolin-8-yl]methyl}amino)propyl]phosphonic acid;
{3-[({5-[4-(3-ethylheptyl)phenyl]quinolin-8-yl}methyl)amino]propyl}phosphonic acid;
[3-({[5-(4-octylphenyl)quinolin-8-yl]methyl}amino)propyl]phosphonic acid;
[3-({[5-(3-fluoro-4-hexylphenyl)quinolin-8-yl]methyl}amino)propyl]phosphonic acid;
{3-[({5-[4-(2-cyclohexylethyl)phenyl]quinolin-8-yl}methyl)amino]propyl}phosphonic acid;
2-({[5-(4-hexylphenyl)quinolin-8-yl]methyl}amino)ethanol;
(3-{[(5-{3-fluoro-4-[3-(2-methylphenyl)propyl]phenyl}quinolin-8-yl) methyl]amino}propyl)phosphonic acid;
(3-{[(5-{3-fluoro-4-[3-(3-methylphenyl)propyl]phenyl}quinolin-8-yl) methyl]amino}propyl)phosphonic acid;
(3-{[(5-{3-fluoro-4-[3-(4-methylphenyl)propyl]phenyl}quinolin-8-yl) methyl]amino}propyl)phosphonic acid;
{3-[({5-[4-(3-ethylheptyl)-3-fluorophenyl]quinolin-8-yl}methyl)amino]propyl}phosphonic acid;
{3-[({5-[4-(2-cyclohexylethyl)-3-fluorophenyl]quinolin-8-yl}methyl)amino] propyl}phosphonic acid;
2-[({5-[4-(3-ethylheptyl)-3-fluorophenyl]quinolin-8-yl}methyl)amino]ethanol; and
2-[({5-[4-(3-ethylheptyl)-3-fluorophenyl]quinolin-8-yl}methyl)amino]ethyl dihydrogen phosphate.