Oxadiazaspiro compounds for the treatment of drug abuse and addiction

1. A compound of general Formula (I):

wherein

p is 0 or 1;

m is 1, 2 or 3;

n is 0, 1 or 2;

Y is —C(O)—;

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

wherein R x is selected from the group consisting of halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl substituted or unsubstituted C 2-6 alkynyl, and —OR 8 ;

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 8 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;

R 1 is selected from the group consisting of substituted or unsubstituted C 1-6 alkyl and substituted or unsubstituted cycloalkyl;

wherein the cycloalkyl in R 1 , if substituted, is substituted with one or more substituent/s selected from the group consisting of halogen, —R 11 , —OR 11 , —NO 2 , —NR 11 R 11′″ , NR 11 C(O)R 11′ , —NR 11 S(O) 2 R 11′ , —S(O) 2 NR 11 R 11′ , —NR 11 C(O)NR 11′ R 11″ , —SR 11 , —S(O)R 11 , S(O) 2 R 11 , —CN, haloalkyl, haloalkoxy, —C(O)OR 11 , —C(O)NR 11 R 11′ , —OCH 2 CH 2 OH, —NR 11 S(O) 2 NR 11′ R 11″ and C(CH 3 ) 2 OR 11 ;

additionally, the cycloalkyl in R 1 , if substituted, may also be substituted with

wherein the alkyl in R 1 , if substituted, is substituted with one or more substituent/s selected from the group consisting of halogen, —CN, haloalkyl, haloalkoxy and —NR 11 R 11′″ ;

wherein R 11 , R 11′ and R 11″ are independently selected from the group consisting of hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl and unsubstituted C 2-6 alkynyl;

and wherein R 11′″ is selected from the group consisting of hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl and -Boc;

R 2 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,

wherein the cycloalkyl, aryl or heterocyclyl in R 2 , if substituted, is substituted with one or more substituent/s selected from the group consisting of halogen, —R 12 , —OR 12 , —NO 2 , —NR 12 R 12′″ , NR 12 C(O)R 12′ , —NR 12 S(O) 2 R 12′ , —S(O) 2 NR 12 R 12′ , —NR 12 C(O)NR 12′ R 12″ , —SR 12 , —S(O)R 12 , S(O) 2 R 12 , —CN, haloalkyl, haloalkoxy, —C(O)OR 12 , —C(O)NR 12 R 12′ , —OCH 2 CH 2 OH, —NR 12 S(O) 2 NR 12′ R 12″ and C(CH 3 ) 2 OR 12 ;

additionally, the cycloalkyl or non-aromatic heterocyclyl in R 2 , if substituted, may also be substituted with

wherein the alkyl, alkenyl or alkynyl in R 2 , if substituted, is substituted with one or more substituent/s selected from the group consisting of —OR 12 , halogen, —CN, haloalkyl, haloalkoxy and —NR 12 R 12′″ ;

wherein R 12 , R 12′ and R 12″ are independently selected from the group consisting of hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl and unsubstituted C 2-6 alkynyl;

and wherein R 12′″ is selected from the group consisting of 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 the group consisting of hydrogen and substituted or unsubstituted C 1-6 alkyl;

alternatively, R 3 and R 3′ , together with the connecting C-atom, form a substituted or unsubstituted cycloalkyl;

R 4 and R 4′ are independently selected from the group consisting of hydrogen and substituted or unsubstituted C 1-9 alkyl;

R 5 and R 5′ are each hydrogen;

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, —OR 10 , —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;

optionally as a stereoisomer, including enantiomers and diastereomers, a racemate or in form of 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;

with the following proviso applying:

when R 2 is substituted or unsubstituted aryl or substituted or unsubstituted heterocyclyl, then m is 1, X is a bond, n is 0, and R 3 is not hydrogen.

2. The compound according to claim 1 , wherein p is 0 or 1.

3. The compound according to claim 1 , wherein

R 3 is substituted or unsubstituted C 1-6 alkyl and

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

alternatively, R 3 and R 3′ , taken together with the connecting C-atom form a substituted or unsubstituted cycloalkyl.

4. The compound according to claim 3 , wherein R 3 is substituted or unsubstituted C 1-6 alkyl.

5. The compound according to claim 3 , wherein R 3′ is hydrogen.

6. The compound according to claim 1 , wherein the compound of Formula (I) is a compound of Formula (I′), (I a ′), (I b ′) or (I c ′)

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

8. The compound according to claim 1 , wherein the compound of Formula (I) is a compound of Formula (I 3′ )

9. The compound according to claim 1 , wherein X is a bond or —O—.

10. The compound according to claim 1 , wherein the compound of Formula (I) is a compound of Formula (I 4′ )

11. The compound according to claim 1 , wherein R 1 is substituted or unsubstituted C 1-6 alkyl.

12. The compound according to claim 11 , wherein R 1 is a substituted or unsubstituted group selected from the group consisting of methyl, ethyl and propyl.

13. The compound according to claim 11 , wherein R 1 is an unsubstituted group selected from the group consisting of methyl, ethyl and propyl.

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

15. The compound according to claim 14 , wherein R 2 is a substituted or unsubstituted group selected from the group consisting of methyl, ethyl, propyl, isopropyl, isobutyl, phenyl and pyridine.

16. The compound claim 14 , wherein R 2 is an unsubstituted group selected from the group consisting of methyl, ethyl, propyl, isopropyl, isobutyl, phenyl and pyridine.

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

12-ethyl-8-isopentyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

4-ethyl-9-isopentyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

8-isopentyl-12-methyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

(R)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

8-isopentyl-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

12-ethyl-8-isobutyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

(S)-4-ethyl-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

12-ethyl-8-(2-isopropoxyethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

8-isopentyl-12-propyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

12-isobutyl-8-isopentyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

8-butyl-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

8-(2-ethoxyethyl)-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

4-ethyl-9-isopentyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

12-ethyl-8-(4-fluorobenzyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

8-benzyl-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

8-benzyl-12-methyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

(R)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

8-benzyl-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

8,12-diethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

(S)-9-benzyl-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

12-ethyl-8-(3-fluorobenzyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

8-(3,4-difluorobenzyl)-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

12-ethyl-8-(pyridin-3-ylmethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

8-benzyl-12-propyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

8-benzyl-12-isobutyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

12-ethyl-8-(pyridin-4-ylmethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

12-ethyl-8-(pyridin-2-ylmethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

12-ethyl-8-propyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

12-ethyl-8-(2-fluorobenzyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

9-benzyl-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

and/or

(S)-9-isopentyl-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

9-isopentyl-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

9-(3,3-dimethylbutyl)-4-propyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

9-isopentyl-4-propyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

9-(3,3-dimethylbutyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

9-(3,3-dimethylbutyl)-4-ethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-9-(3,3-dimethylbutyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

9-isopentyl-4-isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

9-isopentyl-2,2-dimethyl-4-propyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-9-isopentyl-2-methyl-4-propyl-1-oxa-4,9-diazaspiro[5.5]u ndecan-3-one,

4-cyclopropyl-9-isopentyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-9-(2-isopropoxyethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-4-cyclopropyl-9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

4-cyclopropyl-9-(2-isopropoxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-4-ethyl-9-(2-isopropoxyethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

9-(2-isopropoxyethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-4-cyclopropyl-9-(2-isopropoxyethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-9-(2-cyclopropylethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

9-(2-cyclopropylethyl)-4-ethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-9-(2-cyclopropylethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-9-(2-isopropoxyethyl)-2-methyl-4-propyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

8-(4-fluorobenzyl)-12-methyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

4-ethyl-9-(4-fluorobenzyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-9-(4-fluorobenzyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(R)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-4-ethyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-9-(4-chlorobenzyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(R)-9-(4-chlorobenzyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(R)-4-((4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)benzonitrile,

(R)-4-ethyl-9-(4-methoxybenzyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

9-(4-chlorobenzyl)-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

4-((4-ethyl-2,2-dimethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)benzonitrile,

4-ethyl-9-(4-methoxybenzyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-4-ethyl-2-methyl-9-neopentyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-4-ethyl-9-(4-methoxybenzyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-4-((4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)benzonitrile,

(R)-4-((2,4-dimethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)benzonitrile,

(S)-4-((4-isopropyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)benzonitrile,

(R)-9-(4-fluorobenzyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-4-cyclopropyl-9-(4-fluorobenzyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-9-benzyl-4-cyclopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-4-((4-cyclopropyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)benzonitrile,

(S)-4-((2,4-dimethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)benzonitrile,

(S)-9-(4-fluorobenzyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-9-benzyl-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-2,4-dimethyl-9-(4-(trifluoromethoxy)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-3-((4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)benzonitrile,

(S)-4-((4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)-2-fluorobenzonitrile,

(S)-5-((4-ethyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)-2-fluorobenzonitrile,

(S)-9-(2,4-difluorobenzyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(S)-3-((4-isopropyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)benzonitrile,

(S)-9-benzyl-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(R)-9-benzyl-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,

(R)-9-(4-fluorobenzyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, and

(R)-4-((4-isopropyl-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)benzonitrile.

18. A process for the preparation of the compound of Formula (I) according to claim 1 , wherein said process comprises:

a) an intramolecular cyclization of a compound of formula Vila

or

b) the reaction of a compound of formula VIIIH

with a compound of formula IX, X or XI,

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, wherein R 1 , R 1′ , R 2 , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , m, n, p, X and Y have the meanings as defined in claim 16 for the compound of Formula (I) and LG represents a leaving group, including halogen, mesylate, tosylate and triflate, with the proviso that when Y═CO, LG represents chloro or bromo.

19. 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, Va, VaP, VI, Vila, VIIb, VIIb, VIIbP, VIIIP, VIIIH, IX, X, XI, XII, XIIP, XIII, XIIIP, XIV, XIVP, XIVH, XV, XVI, XVIP, XVIH, Ia, XVIIP, XVIIH, Ib, XVIIIP, Ic, XIXP, XIXH, Id, XXP, XXH, XXI, XXIP, XXIH, XXII, XXIIP, XXIIH, XXIII, XXIIIP, XXIIIH, XXIV, XXIVP, XXIVH, XXV, XXVP, XXVH, Ie, XXVIP, XXVIH, XXVIIa, XXVIIb, XXVIIc, If, XXVIIIP, XXVIIIH, Ig, XXIXP, XXIXH, Ih, XXXI, XXXIP, XXXIH, XXXII, XXXIIP, XXXIIH, XXXIII, XXXIIIP or XXXIIIH,

wherein R 1 , R 1′ , R 2 , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , m, n, p, X and Y have the meanings as defined in claim 16 for the compound of Formula (I), LG represents a leaving group, including halogen, mesylate, tosylate and triflate, with the proviso that when Y═CO, LG represents chloro or bromo, P represents a suitable protecting group, including Boc, P′ represents a suitable protecting group, including 4-methoxybenzyl and benzyl, s represents 1, 2, 3 or 4, R s and R s′ represent hydrogen or alkyl, Q represents methyl or benzyl, X′ and X″ independently represent a leaving group, including halogen, mesylate, tosylate and triflate, and V represents an aldehyde or another leaving group, including halogen, mesylate, tosylate or triflate.

20. 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.

21. A method of treating drug abuse or addiction in a subject in need thereof, comprising administration of an effective amount of the compound according to claim 1 .

22. A compound selected from the group consisting of:

8-cyclopentyl-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

8-cyclobutyl-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,

8-cyclohexyl-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one, and

optionally as a stereoisomer, including enantiomers and diastereomers, a racemate or in form of 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.