Amide derivatives having multimodal activity against pain

1. A compound of Formula (I):

wherein

m is 1 or 2;

n is 0, 1 or 2;

p is 0, 1 or 2;

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

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

R x′ is selected from the group consisting of hydrogen, halogen, 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;

W is nitrogen or carbon;

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;

wherein the cycloalkyl, aryl or heterocyclyl in R 1 , if substituted, is substituted with one or more substituents 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′ , —NR 11 S(O) 2 NR 11′ R 11″ and —C(CH 3 ) 2 OR 11 ;

and wherein the cycloalkyl or non-aromatic heterocyclyl in R 1 , if substituted, may also be substituted with

 or ═O;

wherein the alkyl, alkenyl or alkynyl in R 1 , if substituted, is substituted with one or more substituent/s selected from the group consisting of —OR 11 , halogen, —CN, haloalkyl, haloalkoxy, —SR 11 , —S(O)R 11 , and —S(O) 2 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 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,

wherein said cycloalkyl, aryl or heterocyclyl in R 2 , if substituted, is substituted with one or more substituent/s selected from 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′ , —NR 12 S(O) 2 NR 12′ R 12″ and C(CH 3 ) 2 OR 12 ;

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

 or ═O;

wherein the alkyl, alkenyl or alkynyl in R 2 , if substituted, is substituted with one or more substituent/s selected from —OR 12 , halogen, —CN, haloalkyl, haloalkoxy, —SR 12 , —S(O)R 12 , and —S(O) 2 R 12 ;

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

and wherein R 12′″ is selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl and -Boc;

R 3 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, substituted or unsubstituted heterocyclyl, —NR 7 R 7′ and —CH 2 OR 7 ;

wherein R 7 and R 7′ are independently 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 4 and R 4′ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-5 alkenyl and substituted or unsubstituted C 2-6 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 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 and substituted or unsubstituted C 2-6 alkynyl;

and wherein

is selected from the group consisting of

wherein Rn is selected from the group consisting of unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl and unsubstituted C 2-6 alkynyl;

wherein

the alkyl, alkenyl or alkynyl, other than those defined in R 1 or R 2 , if substituted, is substituted with one or more substituent/s selected from the group consisting of —OR 13 , halogen, —CN, haloalkyl, haloalkoxy, —SR 13 , —S(O)R 13 , and —S(O) 2 R 13 ;

wherein R 13 is selected from the group consisting of hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, and unsubstituted C 2-6 alkynyl;

wherein the aryl, heterocyclyl or cycloalkyl other than those defined in R 1 or R 2 , if substituted, is substituted with one or more substituent/s selected from halogen, —R 14 , —OR 14 , —NO 2 , —NR 14 R 14′″ , NR 14 C(O)R 14′ , —NR 14 S(O) 2 R 14′ , —S(O) 2 NR 14 R 14′ , —NR 14 C(O)NR 14′ R 14″ , —SR 14 , —S(O)R 14 , S(O) 2 R 14 , —CN, haloalkyl, haloalkoxy, —C(O)OR 14 , —C(O)NR 14 R 14′ , —OCH 2 CH 2 OH, —NR 14 S(O) 2 NR 14′ R 14″ and C(CH 2 ) 2 OR 14 ;

and wherein the cycloalkyl or non-aromatic heterocyclyl, other than those defined in R 1 or R 2 , if substituted, may also be substituted with

 or ═O;

wherein R 14 , R 14″ and R 14″ are independently selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 , alkenyl, unsubstituted C 2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl;

and wherein R 14′″ is selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl and -Boc:

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.

2. The compound according to claim 1 , wherein

W is nitrogen or carbon; and Rn is selected from unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl and unsubstituted C 2-6 alkynyl.

3. The compound according to claim 2 , wherein W is nitrogen and Rn is unsubstituted C 1-6 alkyl.

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

5. The compound according to claim 1 , wherein

X is a bond or —O.

6. The compound according to claim 5 , wherein

X is a bond; and/or

m is 1; and/or

n is 0; and/or

p is 0.

7. The compound according to claim 1 , wherein the compound

is a compound of Formula (I 2′ )

wherein

X is a bond, C═O or —O—;

m is 1 or 2; and

p is 0, 1 or 2.

8. The compound according to claim 7 , wherein

X is a bond;

m is 1; and

p is 0.

9. The compound according to claim 1 , wherein the compound

is a compound of Formula (I 3′ )

10. The compound according to claim 1 , wherein

R 1 is selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl.

11. The compound according to claim 10 , wherein R 1 is substituted or unsubstituted phenyl or substituted or unsubstituted pyridine.

12. The compound according to claim 1 , wherein

R 2 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, and substituted or unsubstituted aryl.

13. The compound according to claim 12 , wherein R 2 is substituted or unsubstituted phenyl.

14. The compound according claim 1 , wherein

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

15. The compound according to claim 14 , wherein R 3 is unsubstituted ethyl.

16. The compound according to claim 1 , wherein

R 4 and R 4′ are independently selected from hydrogen and substituted or unsubstituted C 1-6 alkyl.

17. The compound according to claim 1 , wherein

R 5 and R 5′ are independently selected from hydrogen and substituted or unsubstituted C 1-6 alkyl.

18. The compound according to claim 17 , wherein R 5 and R 5′ are both hydrogen.

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

N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(3-fluoropyridin-2-yl)propionamide

N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-phenylpropionamide

(S)—N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-phenylpropionamide

(R)—N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-phenylpropionamide

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.

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

N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(trifluoromethyl)pyridin-2-yl)propionamide

Enantiomer of N-(2-(3-(benzyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(trifluoromethyl)pyridin-2-yl)propionamide

N-(2-(3-(benzyl(methyl)amino)azetidin-1-yl)ethyl)-N-(6-(trifluoromethyl)pyridin-2-yl)propionamide

N-(2-(3-(isobutyl(methyl)amino)azetidin-1-yl)ethyl)-N-(6-(trifluoromethyl)pyridin-2-yl)propionamide

N-(2-(3-((2-methoxyethyl)(methyl)amino)azetidin-1-yl)ethyl)-N-(6-(trifluoromethyl)pyridin-2-yl)propionamide

N-(2-(3-(isobutyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(trifluoromethyl)pyridin-2-yl)propionamide

Enantiomer of N-(2-(3-(isobutyl(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(trifluoromethyl)pyridin-2-yl)propionamide

N-(2-(3-((2-ethoxyethyl)(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(trifluoromethyl)pyridin-2-yl)propionamide

Enantiomer of N-(2-(3-((2-ethoxyethyl)(methyl)amino)pyrrolidin-1-yl)ethyl)-N-(6-(trifluoromethyl)pyridin-2-yl)propionamide

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.

21. A process for the preparation of the compound of Formula (I) as defined in claim 1 , wherein the process comprises reacting a compound of Formula VII

with a compound of formula Villa through an alkylaton reaction or VIIIb through a reductive amination reaction

or

wherein the process comprises an acylation of a compound of Formula IVb

wherein Y is

with a compound of formula Va or Vb

wherein

is selected from the group consisting of

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

wherein Z is chloro, bromo, hydroxy, methoxy or ethoxy.

22. A process for the preparation of a compound of Formula (I) according to claim 1 , employing a compound of Formula IIa, IIb, III, IVa, IVb, Va, Vb, VI, VII, VIIIa or VIIIb

wherein

is selected from the group consisting of

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

wherein Z is chloro, bromo, hydroxy, methoxy or ethoxy;

wherein Y is

and

wherein PG is a protecting group selected from the group consisting of benzyl and tert-butoxycarbonyl.

23. 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.

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

25. The method according to claim 24 , 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.