Spiro-cyclic amine derivatives as S1P modulators

Patent metadata

Field	Value
Publication number	US-9951084-B2
Application number	US-201615230063-A
Country	US
Kind code	B2
Filing date	Aug 5, 2016
Priority date	Jul 9, 2010
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

The present invention relates spiro-cyclic amine derivatives of the formula (1) wherein R1; R2; R3; Q; —W-T-; R5; Z; and A have the definitions provided in the claims; or a pharmaceutically acceptable salt, a solvate or hydrate thereof or one or more N-oxides thereof. 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 (2-4C)alkenyl, (2-4C)alkynyl, or (1-4C)alkyl, wherein each of which is optionally substituted with CN or 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 —, —NH—, —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 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 selected from the group consisting of
(1-4C)alkylene-R4 wherein
the alkylene group is optionally substituted with at least one halogen atom or
the alkylene group is optionally substituted with a (CH 2 ) 2 to form a cyclopropyl moiety,

(3-6C)cycloalkylene-R4,
—CH2-(3-6C)cycloalkylene-R4,
(3-6C)cycloalkylene-CH2-R4, and
—CO—CH2-R4,
wherein R4 is selected from the group consisting of —OH, —PO3H2, —OPO3H2, COOH, —COO(1-4C)alkyl, and tetrazol-5-yl;

Q is a bond;
—W-T- is —O—CH 2 ;
R5 is H or a halogen atom;
Z is 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 ) 2 —OH, —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 trancyclopropylene; and n is an integer from 0 to 6.

6. The compound of claim 1 , wherein R1 is (1-4C)alkyl, optionally substituted with at least one halogen atom.

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

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

9. The compound of claim 1 , wherein the compound is selected from the group consisting of:
2-(6-(Hexyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)acetic acid,
2-(6-(Hexyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)propanoic acid,
2-(6-(Hexyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)butanoic acid,
2-(6-(Heptyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)acetic acid,
2-(6-(Heptyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)propanoic acid,
2-(6-(Heptyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)butanoic acid,
2-(6-(Octyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)acetic acid,
2-(6-(Octyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)propanoic acid,
2-(6-(Octyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)butanoic acid,
2-(5-(Hexyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)acetic acid,
2-(5-(Hexyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)propanoic acid,
2-(5-(Hexyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)butanoic acid,
2-(5-(Heptyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)acetic acid,
2-(5-(Heptyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)propanoic acid,
2-(5-(Heptyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)butanoic acid,
2-(5-(Octyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)acetic acid,
2-(5-(Octyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)propanoic acid,
2-(5-(Octyloxy)-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)butanoic acid,
3-{6-[(6-Cyanohexyl)oxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl} propanoic acid,
3-[6-(Hex-5-yn-1-yloxy)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl] propanoic acid,
3-{6-[(5-Oxohexyl)oxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl} propanoic acid,
3-{6-[(7-Methoxyheptyl)oxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl)} propanoic acid,
3-[7-fluoro-6-(hexyloxy)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl] propanoic acid,
3-[7-fluoro-6-(heptyloxy)-2H-spiro[1-benzofuran-3,4′-piperidine]-1-yl] propanoic acid,
3-[7-fluoro-6-(octyloxy)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl] propanoic acid,
3-[7-fluoro-6-(hex-5-en-1-yloxy)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl] propanoic acid,
3-[7-fluoro-6-(oct-7-en-1-yloxy)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl] propanoic acid,
3-[7-fluoro-6-(hept-6-en-1-yloxy)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl] propanoic acid,
3-{7-fluoro-6-[(5,6,6-trifluorohex-5-en-1-yl)oxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl} propanoic acid,
3-{7-fluoro-6-[(4,4,5,5,5-pentafluoropentyl)oxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl} propanoic acid,
3-{7-fluoro-6-[(5,5,6,6,6-pentafluorohexyl)oxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl} propanoic acid,
3-[7-fluoro-6-(4,4,4-trifluorobutoxy)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl] propanoic acid,
3-{6-[(2-Ethylhexyl)oxy]-7-fluoro-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-{7-Fluoro-6-[(3,5,5-trimethylhexyl)oxy]-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl}propanoic acid,
3-[7-Fluoro-6-(pentylsulfanyl)-2H-spiro[1-benzofuran-3,4′-piperidine]-1′-yl] propanoic acid,
3-[6-(Oct-7-en-1-yloxy)-2H-spiro[1-benzofuran-3,3′-piperidine]-1′-yl]propanoic acid,
3-[6-(Hept-6-en-1-yloxy)-2H-spiro[1-benzofuran-3,3′-piperidine]-1′-yl]propanoic acid,
3-[6-(Hex-5-en-1-yloxy)-2H-spiro[1-benzofuran-3,3′-piperidine]-1′-yl]propanoic acid,
3-{5-(Octyloxy)-2,3-dihydrospiro[indene-1,2′-morpholine]-4′-yl} propanoic acid, and
3-[5-Fluoro-6-(hexyloxy)-2H-spiro[1-benzofuran-3,4′-piperidine]-1-yl]propanoic acid,
or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or an N-oxide of any of the foregoing.

10. A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable auxiliary.

Assignees

• Abbvie Bv
• Abbvie Inc
• Abb Vie B V
• Abb Vie 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

• A61P43/00

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

• A61P37/00

  Drugs for immunological or allergic disorders · 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