# US 8,541,397 B2 · Alkyne and alkene derivatives as sphingosine 1-phosphate-1 receptor modulators

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- Number: US 8,541,397 B2
- Document ID: US8541397B2
- Status: Granted
- Kind: B2
- Application number: 13/759,505
- Filed: 2013-02-05
- Published: 2013-06-13
- Granted: 2013-09-24
- Earliest claimed: 2010-12-03
- Assignees: Allergan, Inc.
- Applicants: Allergan, Inc.
- Inventors: Santosh C. Sinha; Smita Bhat; Evelyn Corpuz; Ken Chow; Wenkui K. Fang; Wha-Bin Im
- Web page: https://patentgrep.com/patent/US8541397B2

## CPC

- C07C 229/14: to carbon atoms of carbon skeletons containing rings
- 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 7/10: Antioedematous agents; Diuretics
- 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 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/04: for throat disorders
- A61P 11/06: Antiasthmatics
- 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 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 17/16: Emollients or protectives, e.g. against radiation
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- 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 27/00: Drugs for disorders of the senses
- 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 31/04: Antibacterial agents
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/04: Immunostimulants
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 43/23: containing hydroxy or O-metal groups
- C07F 9/3808: {Acyclic saturated acids which can have further substituents on alkyl}
- C07F 9/3834: {Aromatic acids (P-C aromatic linkage)}
- C07F 9/65515: {the oxygen atom being part of a five-membered ring}
- C07F 9/655345: {the sulfur atom being part of a five-membered ring}
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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)

## Abstract

The present invention relates to novel alkyne and alkene 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 enantiomers, diastereoisomers, or a pharmaceutically acceptable salt thereof,
wherein:
represents a double bond “—CR14═CR15—”;
A is C6-10 aryl, heterocycle, C3-8 cycloakyl or C3-8 cycloalkenyl;
B is C6-10 aryl, heterocycle, C3-8 cycloakyl or C3-8 cycloalkenyl;
R1 is H, halogen, —OC1-8 alkyl, C1-8 alkyl, CN, C(O)R11, NR12R13 or hydroxyl;
R2 is H, halogen, —OC1-8 alkyl, C1-8 alkyl, CN, C(O)R11, NR12R13 or hydroxyl;
R3 is H, halogen, —OC1-8 alkyl, C1-8 alkyl, CN, C(O)R11, NR12R13 or hydroxyl;
R4 is H, halogen, —OC1-8 alkyl, C1-8 alkyl, CN, C(O)R11, NR12R13 or hydroxyl;
R5 is H, halogen, —OC1-8 alkyl, C1-8 alkyl, CN, C(O)R11, NR12R13 or hydroxyl;
R6 is H, halogen, —OC1-8 alkyl, C1-8 alkyl, CN, C(O)R11, NR12R13 or hydroxyl;
R7 is H, halogen, —OC1-8 alkyl, C1-8 alkyl, CN, C(O)R11, C6-10 aryl, heterocycle, C3-8 cycloakyl, C3-8 cycloalkenyl, NR12R13 or hydroxyl;
R8 is the same or independently halogen, —OC1-8 alkyl, C1-8 alkyl, CN, C(O)R11, NR12R13 or hydroxyl;
L1 is O, S, NH or CH2;
R9 is H or C1-6 alkyl;
L2 is CHR14 or O;
R10 is H, OPO3H2, carboxylic acid, hydroxyl, PO3H2, —S(O)2H, —P(O)MeOH or —P(O)(H)OH;
R11 is H or C1-8 alkyl;
a is 0, 1, 2 or 3;
b is 0 or 1;
R12 is H or C1-8 alkyl;
R13 is H or C1-8 alkyl;
R14 is H, hydroxyl or C1-8 alkyl;
R15 is H or C1-8 alkyl;
R16 is O, S, C(O) or CH2; and
c is 0 or 1;
with the proviso that the compound of Formula I is not of structure

### Claim 2 (depends on 1)

A compound according to claim 1, wherein:
L1 is CH2.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein:
L1 is O, S or NH.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein:

### Claim 5 (depends on 1)

A compound according to claim 1, wherein:
represents a double bond “—CR14═CR15—”;
R1 is H, halogen, —OC1-6 alkyl or C1-6 alkyl;
R2 is H, halogen, —OC1-6 alkyl or C1-6 alkyl;
R3 is H, halogen, —OC1-6 alkyl or C1-6 alkyl;
R4 is H, halogen, —OC1-6 alkyl or C1-6 alkyl;
R5 is H, halogen, —OC1-6 alkyl or C1-6 alkyl;
R6 is H, halogen, —OC1-6 alkyl or C1-6 alkyl;
R7 is H, halogen, —OC1-6 alkyl, C1-6 alkyl, C6 aryl, heterocycle, C3-8 cycloakyl or C3-8 cycloalkenyl;
R8 is halogen, —OC1-6 alkyl, C1-6 alkyl, CN, C(O)R11, NR12R13 or hydroxyl;
L1 is CH2;
R9 is H or C1-6 alkyl;
L2 is CHR14;
R10 is carboxylic acid or PO3H2;
R11 is H or C1-6 alkyl;
a is 0 or 1;
b is 1;
R12 is H or C1-6 alkyl;
R13 is H or C1-6 alkyl;
R14 is H or C1-6 alkyl;
R15 is H or C1-6 alkyl;
R16 is CH2; and
c is 0 or 1.

### Claim 6 (depends on 1)

A compound according to claim 1, selected from:
[3-({4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]benzyl}amino)propyl]phosphonic acid; and
3-({4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]benzyl}amino)propanoic acid.

### Claim 7 (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 8 (depends on 7)

A pharmaceutical composition according to claim 7, wherein the compound is selected from:
[3-({4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]benzyl}amino)propyl]phosphonic acid; and
3-({4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]benzyl}amino)propanoic acid.