1,9-diazaspiro undecane compounds having multimodal activity against pain

1. A compound of Formula (I)

wherein

n is 1,2, 3,4, 5 or 6

W is —CR w R w′ — or —O—;

X is a bond, —C(O)— or —CR 6 R 6′ —;

Y is a bond or —C(O)—;

R 1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl or substituted or unsubstituted alkylcycloalkyl;

R 2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl;

R w and R w′ are independently selected from hydrogen, halogen, —OR 10 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, haloalkyl, haloalkoxy, —C(O)OR 10 , —C(O)NR 10 R 10′ , —NR 10 C(O)R 10′ , and —NR 10 R 10′″ ;

wherein R 10 , R 10′ and R 10″ are independently selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, and unsubstituted C 2-6 alkynyl;

and wherein R 10′″ is selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl and -Boc;

R 3 and R 3′ are independently selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, and substituted or unsubstituted C 2-6 alkynyl;

R 4 and R 4′ are independently selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, —C(O)OR 8 , and —C(O)NR 8 R 8′ ;

wherein R 8 and R 8′ are independently selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, and unsubstituted C 2-6 alkynyl;

alternatively, R 4 and R 4′ may form, together with the carbon to which they are attached, a substituted or unsubstituted C 3-8 cycloalkyl;

R 5 and R 5′ are independently selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, —C(O)OR 9 , and —C(O)NR 9 R 9′ ;

wherein R 9 and R 9′ are independently selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, and unsubstituted C 2-6 alkynyl;

R 6 and R 6′ are independently selected from hydrogen, halogen, —OR 7 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, —C(O)OR 7 , —C(O)NR 7 R 7′ , —NR 7 C(O) R 7′ , and —NR 7 R 7′″ ;

wherein R 7 , R 7′ and R 7″ are independently selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, and unsubstituted C 2-6 alkynyl;

and wherein R 7′″ , is selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl and -Boc;

with the proviso that:

-when Y—R 1 and —(CR 3 R 3′ ) n —X—R 2 are both unsubstituted benzyl, then none of R 4 and R 4′ may be hydrogen or substituted or unsubstituted methyl while the other is hydrogen,

optionally as a stereoisomer, including enantiomers and diastereomers, a racemate or a mixture of at least two stereoisomers, including enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

2. The compound according to claim 1 , wherein Y is a bond.

3. The compound according to claim 1 , wherein n is 2.

4. The compound according to claim 1 , wherein n is 2, X is a bond and R 2 is substituted or unsubstituted phenyl.

5. The compound according to claim 1 , wherein R 1 is substituted or unsubstituted phenyl.

6. The compound according to claim 1 , wherein R 5 and R 5′ are hydrogen.

7. The compound according to claim 1 , wherein R 3 and R 3′ are hydrogen.

8. The compound according to claim 1 , wherein R 4 and R 4′ are hydrogen.

9. The compound according to claim 1 , wherein R w and R w′ are hydrogen.

10. The compound according to claim 1 , which is selected from the group consisting of

9-benzyl-1-phenyl-1,9-diazaspiro[5.5]undecane,

3-(9-benzyl-1,9-diazaspiro[5.5]undecan-1-yl)phenol,

9-phenethyl-1-phenyl-1,9-diazaspiro[5.5]undecane,

9-benzyl-1-(3-methoxyphenyl)-1,9-diazaspiro[5.5]undecane,

9-benzyl-1-phenyl-4-oxa-1,9-diazaspiro[5.5]undecane,

1-benzyl-9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecane,

9-phenethyl-1-phenyl-4-oxa-1,9-diazaspiro[5.5]undecane,

cyclopropyl(9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)methanone,

(9-benzyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)(phenyl)methanone,

(9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)(phenyl)methanone,

(9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)(pyridin-2-yl)methanone,

(9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)(thiazol-2-yl)methanone,

(9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)(pyridin-4-yl)methanone,

(9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)(pyridin-3-yl)methanone,

(2-fluorophenyl)(9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)methanone,

(9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)(thiazol-4-yl)methanone,

1-(9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)-2-(pyridin-2-yl)ethanone,

2-cyclopropyl-1-(9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)ethanone,

1-(9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)-2-(pyridin-4-yl)ethanone,

(9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)(thiazol-5-yl)methanone,

1-(9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)-2-phenylethanone,

1-(9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)-2-(pyridin-3-yl)ethanone,

N-(3-(2-(1-phenyl-4-oxa-1,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenyl)acetamide,

9-phenethyl-1-(pyridin-4-ylmethyl)-4-oxa-1,9-diazaspiro[5.5]undecane,

1-(3-methoxybenzyl)-9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecane,

9-phenethyl-1-(pyridin-2-ylmethyl)-4-oxa-1,9-diazaspiro[5.5]undecane,

9-phenethyl-1-(pyridin-3-ylmethyl)-4-oxa-1,9-diazaspiro[5.5]undecane,

2-((9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)methyl)phenol,

1,9-diphenethyl-4-oxa-1,9-diazaspiro[5.5]undecane,

1-(4-methoxybenzyl)-9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecane,

1-((3-fluoropyridin-4-yl)methyl)-9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecane,

N-(3-((9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)methyl)phenyl)methanesulfonamide,

N-(4-((9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)methyl)phenyl)acetamide,

1-benzyl-9-(2-(pyridin-2-yl)ethyl)-4-oxa-1,9-diazaspiro[5.5]undecane,

1-benzyl-9-(2-methoxyphenethyl)-4-oxa-1,9-diazaspiro[5.5]undecane,

1-benzyl-9-(3-methoxyphenethyl)-4-oxa-1,9-diazaspiro[5.5]undecane,

1-benzyl-9-(4-methoxyphenethyl)-4-oxa-1,9-diazaspiro[5.5]undecane,

1-benzyl-9-(2-(pyridin-3-yl)ethyl)-4-oxa-1,9-diazaspiro[5.5]undecane,

1-benzyl-9-(2-(pyridin-4-yl)ethyl)-4-oxa-1,9-diazaspiro[5.5]undecane,

1-phenyl-9-(2-(pyridin-2-yl)ethyl)-4-oxa-1,9-diazaspiro[5.5]undecane,

9-(3-nitrophenethyl)-1-phenyl-4-oxa-1,9-diazaspiro[5.5]undecane,

1-phenyl-9-(2-(pyridin-3-yl)ethyl)-4-oxa-1,9-diazaspiro[5.5]undecane,

1-phenyl-9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4-oxa-1,9-diazaspiro[5.5]undecane,

1-phenyl-9-(2-(pyridin-4-yl)ethyl)-4-oxa-1,9-diazaspiro[5.5]undecane,

2-(1-benzoyl-4-oxa-1,9-diazaspiro[5.5]undecan-9-yl)-1-phenylethanone,

3-(2-(1-benzyl-4-oxa-1,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenol,

3-((9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)methyl)phenol,

4-(2-(1-benzyl-4-oxa-1,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenol,

2-(2-(1-benzyl-4-oxa-1,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenol,

3-(2-(1-phenyl-4-oxa-1,9-diazaspiro[5.5]undecan-9-yl)ethyl)aniline,

(9-(2-hydroxy-2-phenylethyl)-4-oxa-1,9-diazaspiro[5.5]undecan-1-yl)(phenyl)methanone, and

1-(cyclopropylmethyl)-9-phenethyl-4-oxa-1,9-diazaspiro[5.5]undecane.

11. A process for preparing a compound of formula I according to claim 1 ,

comprising

a) reacting a compound of formula IVH

with a compound of formula V, VI or VII,

wherein p represents 0, 1 or 2, and LG represents a leaving group such as halogen, mesylate, tosylate or triflate,

b) reacting a compound of formula II

with a compound of formula (III)

R 1 Z  (III)

wherein Z represents a leaving group, including halogen, mesylate, tosylate and triflate, or an aldehyde (CHO), or alternatively it represents COOH or COV wherein V represents halogen,

or

c) when R 5 and R 5′ are both hydrogen,

by a reduction reaction of a compound of formula IX″

12. A method for the preparation of a compound of Formula (I) according to claim 1 , employing a compound of formulae (X″), (XII′), (XIV′), (XVI′), (IXa′), XXII′), (XXIII′), IXb″), (XVIIa′), (XVIII′), (XIX′), (VIIIa′), (IIa′), (IIb′), (V), (VI) or (VII)

wherein A represents —(CR 3 R 3′ ) n XR 2 , hydrogen or P, wherein R 1 , R 2 , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , n, W, X and Y have the meanings as defined in claim 1 , for the compound of formula (I), p represents 0, 1 or 2, LG and Z independently represent a leaving group, including halogen, mesylate, tosylate and triflate, and P represents a suitable protecting group, including Boc.

13. A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

14. A method of treating pain in a subject in need thereof, comprising administration of an effective amount of the compound according to claim 1 .

15. The method according to claim 14 , wherein the pain is selected from medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain, neuropathic pain, allodynia, and hyperalgesia.