OXA-Diazaspiro compounds having activity against pain

1. A compound of general Formula (I):

wherein

R 1 is

m is 1, 2, 3, 4 or 5;

n is 0, 1, 2, 3, 4 or 5;

p is 0 or 1;

q is 0, 1 or 2;

r is 0 or 2;

X is a bond, —C(R x R x′ )—, —C(O)—, —O—, —C(O)NR 7 —, —NR 7 C(O)— or —C(O)O—;

wherein R x is selected from the group consisting of halogen or substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl substituted or unsubstituted C 2-6 alkynyl, and —OR 7 ;

R x′ is selected from the group consisting of hydrogen, halogen or substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl and substituted or unsubstituted C 2-6 alkynyl;

R 7 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl and substituted or unsubstituted C 2-6 alkynyl;

Y is —CH 2 — or —C(O)—;

R 1′ is selected from the group consisting of substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;

R 2 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl,

R 3 is selected from the group consisting of substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl and substituted or unsubstituted C 2-6 alkynyl;

R 3′ is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl and substituted or unsubstituted C 2-6 alkynyl; or

R 3 and R 3′ , together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl;

R 4 and R 4′ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, —CHOR 9 and —C(O)OR 9 ;

wherein R 9 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-9 alkyl, substituted or unsubstituted C 2-9 alkenyl and substituted or unsubstituted C 2-9 alkynyl;

R 5 and R 5′ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, —CHOR 8 and —C(O)OR 8 ;

wherein R 8 is 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 6 and R 6′ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, —CHOR 10 and —C(O)OR 10 ;

wherein R 10 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl and substituted or unsubstituted C 2-6 alkynyl;

or a stereoisomer, a racemate or a mixture of at least two stereoisomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof;

with the following proviso applying:

when Y is —C(O)—, then R 1 is not

2. The compound according to claim 1 , which is a compound of Formula (I′)

3. The compound according to claim 1 , which is a compound of Formula (I 2′ ), (I 2a′ ), (I 2b′ ) or (I 2c′ )

4. The compound according to claim 1 , which is a compound of Formula (I 3′ ), (I 3a′ ), (I 3b′ ) or (I 3c′ )

5. The compound according to claim 1 , which is a compound of Formula (I 4′ ), (I 4a′ ) (I 4b′ ) or (I 4c′ )

6. The compound according to claim 1 , wherein R 1′ is selected from the group consisting of substituted or unsubstituted C 1-6 alkyl and substituted or unsubstituted aryl.

7. The compound according to claim 6 , wherein R 1′ is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl or substituted or unsubstituted phenyl.

8. The compound according to claim 1 , wherein R 2 is selected from the group consisting of substituted or unsubstituted C 1-6 alkyl and substituted or unsubstituted aryl.

9. The compound according to claim 8 , wherein R 2 is selected from the group consisting of substituted or unsubstituted isopropyl, substituted or unsubstituted isobutyl or substituted or unsubstituted phenyl.

10. The compound according to claim 1 , wherein R 3 and R 3′ , together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl.

11. The compound according to claim 10 , wherein R 3 and R 3′ form a substituted or unsubstituted cyclopropyl.

12. The compound according to claim 1 which is selected from the group consisting of:

12-ethyl-7-isopentyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,

12-ethyl-7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,

13-ethyl-8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

13-ethyl-8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

7-benzyl-10-ethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one,

10-ethyl-7-isopentyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one,

7-phenethyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,

7-isopentyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,

8-phenethyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

8-isopentyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

7-benzyl-12-ethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,

8-benzyl-13-ethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

7-benzyl-10-ethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one,

8-benzyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

7-benzyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-13-one,

13-ethyl-8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane,

7-benzyl-12-ethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,

12-ethyl-7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,

7-phenethyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,

7-isopentyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,

8-benzyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane and

8-phenethyl-13-phenyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane.

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

7-benzyl-12-phenyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane,

(7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-yl)(phenyl)methanone,

(7-isopentyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-yl)(phenyl)methanone,

(7-isobutyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-yl)(phenyl)methanone,

(8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)methanone,

(8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)methanone,

(8-isobutyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)methanone,

4-ethyl-2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

4-ethyl-9-isopentyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

4-ethyl-9-isobutyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

10-benzyl-7-phenethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one,

(2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone,

10-ethyl-7-(2-isopropoxyethyl)-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-11-one,

(R)-8-ethyl-2-isopentyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(S)-8-ethyl-2-isopentyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(R)-8-ethyl-2-isobutyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(S)-8-ethyl-2-isobutyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(R)-2-isopentyl-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(S)-2-isopentyl-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(R)-2-isobutyl-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(S)-2-isobutyl-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(S)-2-(3,3-dimethylbutyl)-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(R)-2-(3,3-dimethylbutyl)-8-isopropyl-6-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(2R,6S)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2R,6R)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2S,6S)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2S,6R)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(9-(2-isopropoxyethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone,

(7-benzyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecan-12-yl)(phenyl)methanone,

(8-benzyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)methanone,

9-benzyl-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

4-((4-ethyl-2,2-dimethyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile,

(2R,6S)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2R,6R)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2S,6S)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2S,6R)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2R,6S)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2R,6R)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2S,6S)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

(2S,6R)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-3-one,

4-(((2R,6S)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile,

4-(((2R,6R)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile,

4-(((2S,6S)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile,

4-(((2S,6R)-4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.6]dodecan-9-yl)methyl)benzonitrile,

8-benzyl-13-methyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-4-one,

8-(4-fluorobenzyl)-13-methyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

4-((13-methyl-14-oxo-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-8-yl)methyl)benzonitrile,

(S)-8-ethyl-6-methyl-2-neopentyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(R)-8-ethyl-6-methyl-2-neopentyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(S)-8-isopropyl-6-methyl-2-neopentyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

(R)-8-isopropyl-6-methyl-2-neopentyl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one,

7,12-dibenzyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane(*),

12-benzyl-7-phenethyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane(*),

12-benzyl-7-isopentyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane(*),

12-benzyl-7-isobutyl-4-oxa-7,12-diazadispiro[2.1.5.3]tridecane(*),

8,13-dibenzyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane(*),

13-benzyl-8-phenethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane(*),

13-benzyl-8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane(*),

13-benzyl-8-isobutyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecane(*),

9-benzyl-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecane,

4-ethyl-2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecane,

4-ethyl-9-isopentyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecane,

4-ethyl-9-isobutyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.6]dodecane,

10-benzyl-7-phenethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecane,

(7-Phenethyl-4-oxa-7,10-diazadispiro[2.1.3.3]undecan-10-yl)(phenyl)methanone,

(R)-8-benzyl-3-ethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

(S)-8-benzyl-13-ethyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-14-one,

(R)-(2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone and

(S)-(2,2-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone.

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

((2S,6R)-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone,

((2S,6S)-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone,

((2R,6R)-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone,

((2R,6S)-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.6]dodecan-4-yl)(phenyl)methanone,

(R)-(8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)methanone and

(S)-(8-isopentyl-4-oxa-8,13-diazadispiro[2.1.6.3]tetradecan-13-yl)(phenyl)methanone.

15. A process for the preparation of the compound according to claim 1 , wherein R 1 is —(CR 4 R 4′ ) p R 1′ , which process comprises:

a) an intramolecular cyclization of a compound of formula VIIa

wherein LG represents a leaving group selected from the group consisting of halogen, mesylate, tosylate and triflate, with the proviso that when Y=CO, LG represents chloro or bromo,

or

b) the reaction of a compound of formula VIIIH

with a compound of formula IX, X or XI,

wherein LG represents a leaving group selected from the group consisting of halogen, mesylate, tosylate and triflate,

or

c1) when Y is CH 2 , by the alkylation of a compound of formula XIV

with a compound of formula XV

wherein the compound of formula XV is an alkylating agent and V is a leaving group, or alternatively by the reductive amination reaction of a compound of formula XIV with a compound of formula XV, wherein the compound of formula XV is an aldehyde and V is a C(O)H group;

or

c2) when Y is C(O), by the alkylation of a compound of formula XIV

with a compound of formula XV

wherein the compound of formula XV is an alkylating agent and V is a leaving group, and

wherein R 1′ , R 2 , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , R 7 , R 8 , R 9 , R 10 , R x , R x′ , X, Y, m, n, p, q and r have the meanings as defined in claim 1 for the compound of Formula (I).

16. A process for the preparation of the compound according to claim 1 , wherein R 1 is —(CR 4 R 4′ ) p R 1′ , Y represents CO and R 3 and R 3′ , together with the carbon atom to which they are attached, form a cyclopropyl (compounds of formula Id),

which process comprises

a) the treatment with a strong base of a compound of formula Ic wherein R s =R s′ =H and s=1

wherein LG represents a leaving group selected from the group consisting of halogen, mesylate, tosylate and triflate,

or

b) a cyclopropanation reaction on a compound of formula XXI

or

c) the alkylation of a compound of formula XXV

with a compound of formula XV

wherein the compound of formula XV is an alkylating agent and V is a leaving group;

or

d) the reaction of a compound of formula XIXH

with a compound of formula IX, X or XI,

wherein LG is a leaving group selected from the group consisting of halogen, mesylate, tosylate and triflate, and

wherein R 1′ , R 2 , R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , R 7 , R 8 , R 9 , R 10 , R x , R x′ , X, m, n, p, q and r have the meanings as defined in claim 1 for the compound of Formula (I).

17. A process for the preparation of the compound of Formula (I) according to claim 1 , employing a compound of Formula II, IIP, III, IIIP, IVa, IVb, Vb, VbP, XII, XIIP, Va, VaP, VI, VIIb, VIIbP, XIII, XIIIP, VIIa, VIIaP, XVI, XVIP, XVIH, XIV, XIVP, XIVH, Ia, VIIIP, VIIIH, XV, IX, X, XI, Ie, XXP, XXH, XXI, XXIP, XXIH, Ib, XVIIP, XVIIH, Ic, XVIIIP, Id, XIXP, XIXH, XXIII, XIIP XXIIIP, XXIIIH, XXV, XXVP, XXVH, XXII, XXIIP, XXIIH, XXIV, XXIVP, XXIVH, If, XXVIP, XXVIH, XXVIIa, Ig, XXVIIIP, XXVIIIH, XXVIIb, Ih, XXIXP, XXIXH, XXVIIIc, Ib, XVIIP, XVIIH, XXXII, XXXIIP, XXXIIH, XXXIV, XXXIVP, XXXIVH, XXXI, XXXIP, XXXIH, XXXIII, XXXIIIP, XXXIIIH, XXXV, Ij, XXXVIP, XXXVIH, Ih, XXIXP, XXIXH, Ii, XXXP or XXXH,

wherein R 1′ , R 2 , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , R 7 , R 8 , R 9 , R 10 , R x , R x′ , X, Y, m, n, p, q and r have the meanings as defined in claim 1 for the compound of Formula (I), LG represents a leaving group selected from the group consisting of halogen, mesylate, tosylate and triflate, V represents an aldehyde or a leaving group selected from the group consisting of halogen, mesylate, tosylate and triflate, P represents a suitable protecting group or Boc, P′ represents an orthogonal protecting group selected from the group consisting of 4-methoxybenzyl, benzyl and benzhydryl, X′ and X″ independently represent a leaving group selected from the group consisting of halogen, mesylate, tosylate and triflate, Q represents methyl or benzyl, Z represents OH or halogen, R s and R s′ represent hydrogen or alkyl and s represents 1, 2, 3 or 4.

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

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

20. The method according to claim 19 , wherein the pain, is selected from the group consisting of medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain, neuropathic pain, allodynia and hyperalgesia.