Spiro-cyclic amine derivatives as S1P modulators

Patent metadata

Field	Value
Publication number	US-10179791-B2
Application number	US-201113808903-A
Country	US
Kind code	B2
Filing date	Jul 8, 2011
Priority date	Jul 9, 2010
Publication date	Jan 15, 2019
Grant date	Jan 15, 2019

Abstract

The compounds of the invention have affinity to S1P receptors and may be used in the treatment, alleviation or prevention of diseases and conditions in which (a) S1P receptor(s) is (are) involved.

First claim

The invention claimed is:

1. A compound of the formula (I)

or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or an N-oxide of any of the foregoing,
wherein
R1 is
a (3-6C)cycloalkyl group, a (4-6C)cycloalkenyl group, or a (8-10C)bicyclic group,
wherein the group is optionally substituted with at least one substituent independently selected from the group consisting of a halogen atom and (1-4C)alkyl;

a phenyl group or a naphthyl group,
wherein the group is optionally substituted with at least one substituent independently selected from the group consisting of
a halogen atom,
cyano,
(1-6C)alkyl optionally substituted with at least one fluoro atom,
(1-6C)alkoxy optionally substituted with at least one fluoro atom,
amino,
di(1-4C)alkylamino, and
(3-6C)cycloalkyl optionally substituted with a phenyl group, wherein the phenyl group is optionally substituted with a substituent selected from the group consisting of (1-4C)alkyl and a halogen atom; or
wherein the phenyl group is optionally substituted with phenoxy, benzyl, benzyloxy, phenylethyl or monocyclic heterocycle,
wherein the phenoxy, benzyl, benzyloxy, phenylethyl or monocyclic heterocycle is optionally substituted with (1-4C)alkyl optionally substituted with at least one fluoro atom;

a monocyclic heterocycle optionally substituted with a substituent selected from the group consisting of
a halogen atom,
(1-6C)alkyl optionally substituted with at least one fluoro atom,
(3-6C)cycloalkyl, and
phenyl optionally substituted with a substituent selected from the group consisting of (1-4C)alkyl and a halogen atom; or

a bicyclic heterocycle optionally substituted with a halogen atom or (1-4C)alkyl optionally substituted with at least one fluoro atom;

—Y—(C n -alkylene)-X— is a linking group wherein
Y is attached to R1 and is selected from the group consisting of a bond, —O—, —CO—, —S—, —SO—, —SO 2 —, —CH═CH—, —C(CF 3 )═CH—, —C≡C—, CH 2 —O—, —O—CO—, —CO—O—, —CO—NH—, —NH—CO—, and a trans-cyclopropylene;
n is an integer from 0 to 10; and
X is attached to the phenylene/pyridyl moiety and is selected from the group consisting of a bond, —O—, —S—, —SO—, —SO 2 —, —NH—, —CO—, —CH═CH—, and a trans-cyclopropylene;

R2 is H, a halogen atom,(1-4C)alkoxy, or (1-4C)alkyl optionally substituted with at least one fluoro atom;
R3 is
(1-4C)alkylene-R4 wherein
the alkylene group is onally substituted with at least one halogen atom

or
the alkylene group is optionally substituted with a (CH 2 ) 2 to form a cyclopropyl moiety, or

(3-6C)cycloalkylene-R4, —CH 2 -(3-6C)cycloalkylene-R4, (3-6C)cycloalkylene-CH2-R4, or—CO—CH 2 -R4,
wherein R4 is selected from the group consisting of —PO 3 H 2 , —OPO 3 H 2 , —COOH, —COO(1-4C)alkyl, and tetrazol-5-yl;

Q is a bond;
—W-T- is —O—CH 2 —;
R5is H or a halogen atom;
Z is CH or CR2; and
A is a morpholine ring structure or piperidinyl.

2. The compound of claim 1 , wherein R3 is selected from the group consisting of —CH 2 —COOH, —(CH 2 ) 2 —COOH, —(CH 2 ) 3 —COOH, —CH 2 —CHCH 3 —COOH, —CH 2 -C(CH 3 ) 2 —COOH, —CHCH 3 —CH 2 —COOH, —CH 2 —CF 2 —COOH, —CO—CH 2 —COOH, 1,3-cyclobutylene-COOH, —(CH 2 ) 2 —PO 3 H 2 , —(CH 2 ) 3 —PO 3 H 2 , —(CH 2 ) 2 —OPO 3 H 2 , —(CH 2 ) 3 —OPO 3 H 2 , —CH 2 -tetrazol-5-yl, —(CH 2 ) 2 -tetrazol-5-yl, and —(CH 2 ) 3 tetrazol-5-yl.

3. The compound of claim 1 , wherein R2 is selected from the group consisting of H, methyl, chloro, and fluoro.

4. The compound of claim 1 , wherein R5 is H.

5. The compound of claim 1 , wherein Y is selected from the group consisting of a bond, —O—, —CO—, —CH═CH—, —C(CF 3 )═CH—, —C≡C—, and a trans-cyclopropylene; and n is an integer from 0 to 6.

6. The compound of claim 1 , wherein
R1 is
cyclohexyl, cyclohexenyl, or biphenyl, each of which is optionally substituted with at least one halogen atom;
a phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of
halogen,
(1-4C)alkyl,
trifluoromethyl,
(1-4C)alkoxy,
trifluoromethoxy, and
cyclopropyl optionally substituted with phenyl, thienyl, pyridyl, or tetrahydropyranyl, wherein the phenyl, thienyl, pyridyl, or tetrahydropyranyl is optionally substituted with halogen, (1-4C)alkyl, cyclopropyl or phenyl optionally substituted with halogen; or

indolyl dihydrobenzofuranyl, or benzdioxanyl, each of which is optionally substituted with a halogen atom or (1-4C)alkyl.

7. The compound of claim 1 , wherein
R1 is phenyl, optionally substituted with at least one substituent independently selected from the group consisting of
a halogen atom,
(1-4C)alkyl,
a cyclopropyl, and
a trifluoromethyl; and

the group —Y—(C n -alkylene)-X— is selected from the group consisting of
—CH 2 O—,
—CH 2 -S—, and
—CH═CH—.

8. The compound of claim 1 , wherein A is piperidinyl.

9. The compound of claim 1 , having the formula (II):

10. The compound of claim 1 , wherein R1 is 2,6-dichlorophenyl and R3 is —(CH 2 ) 2 —COOH.

11. The compound of claim 1 , wherein the compound is selected from the group consisting of:
3-(5-{[2-(Trifluoromethyl)phenyl]methoxy}-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl)propanoic acid,
3-(5-(Cyclohexylmethoxy)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl]propanoic acid,
3-(5-{[3-(Trifluoromethyl)phenyl]methoxy}-2H-spiro[1-benzofuran-3,4′-piperdine]-1′-yl)propanoic acid,
3-{5-[(2,6-Dichlorophenyl)methoxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-{ 5 -[(3,5-Dichlorophenyl)methoxy]-2H-spiro[-1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-{ 5 -[(2,6-Difluorophenyl)methoxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-{5-[(2-Chlorophenyl)methoxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-{ 5 -[(2,4,6-Trichlorophenyl)methoxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-{ 5 -[(2-Chloro-6-methylphenyl)methoxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-[5(Phenylamino)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl]propanoic acid,
3-{6-[(2,6-Dichlorophenyl)methoxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-{6-[(4-Phenylpentyl)oxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-{6-[(3-Chlorophenyl)methoxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-[6-(Cyclohexylmethoxy)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl]propanoic acid,
3-[6-(Oxan-2ylmethoxy)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl]propanoic acid,
3-{6-[(2,5Dichlorophenyl)methoxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-(6-{[3-(Trifluoromethyl)phenyl]methoxy}-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl)propanoic acid,
3-(6{[2-(Trifluoromethyl)phenyl]methoxy}-2H-Spiro[1-benzofuran-3,4′-piperidine]-1′-yl)propanoic acid,
3-{ 6 -[2,3-Dichlorophenyl)methoxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-{ 6 -[(2-Chloro-6-fluorphenyl)methoxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-[6-(Benzyloxy)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl]-propanoic acid,
3-{6-[(2,4-Dichlorophenyl)methoxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-(6-{[2-Chloro-6-(trifluoromethyl)phenyl]methoxy}-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl)propanoic acid,
3-[6(Cyclohex-3-en-lylmethoxy)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl]propanoic acid,
3-{6-[(3,5-Dichloropyridin-4-yl)methoxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic

Assignees

• Stoit Axel
• Iwema Bakker Wouter I
• Coolen Hein K A C
• Van Dongen Maria J P
• Leflemme Nicolas J L D
• Hobson Adrian
• Abbvie Bv
• Abbvie Inc

Inventors

• Stoit Axel
• Iwema Bakker Wouter I
• Coolen Hein K A C
• Van Dongen Maria J P
• Leflemme Nicolas J -L D
• Hobson Adrian

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/28

  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 · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title