Methyl-1H-pyrazole alkylamine compounds having multimodal activity against pain

1. A compound of Formula (I):

wherein

n is 1;

m is 1;

W is —O—, —NR w —, —S— or —S(O)—;

X is a bond;

R 1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl;

wherein said cycloalkyl, aryl or heterocyclyl in R 1 , if substituted, is substituted with one or more substituent/s selected from halogen, —R 8 , —OR 8 , —NO 2 , —NR 8 R 8′″ , NR 8 C(O)R 8′ , —NR 8 S(O) 2 R 8′ , —S(O) 2 NR 8 R 8′ , —NR 8 C(O)NR 8′ R 8″ , —SR 8 , —S(O)R 8 , S(O) 2 R 8 , —CN, haloalkyl, haloalkoxy, —C(O)OR 8 , —C(O)NR 8 R 8′ , —OCH 2 CH 2 OH, —NR 8 S(O) 2 NR 8′ R 8″ , and C(CH 3 ) 2 OR 8 ;

wherein R 8 , R 8′ and R 8″ are independently selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, unsubstituted aryl, unsubstituted alkylaryl, unsubstituted cycloalkyl, unsubstituted alkylcycloalkyl, unsubstituted heterocyclyl, and unsubstituted alkyheterocylcyl;

and wherein R 8′″ is selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, and -Boc;

R 2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or 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 9 , —OR 9 , —NO 2 , —NR 9 R 9′″ , NR 9 C(O)R 9′ , —NR 9 S(O) 2 R 9′ , —S(O) 2 NR 9 R 9′ , —NR 9 C(O)NR 9′ R 9″ , —SR 9 , —S(O)R 9 , S(O) 2 R 9 , —CN, haloalkyl, haloalkoxy, —C(O)NR 9 R 9′ , —OCH 2 CH 2 OH, —NR 9 S(O) 2 NR 9′ R 9″ , and C(CH 3 ) 2 OR 9 ;

wherein R 9 , 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;

and wherein R 9′″ is selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, and -Boc;

R 3 is hydrogen, or substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, or substituted or unsubstituted C 2-6 alkynyl;

R 4 and R 4′ are independently selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, and unsubstituted C 2-6 alkynyl;

R 5 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 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 10 , and —C(O)NR 10 R 10′ ;

wherein 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;

R w 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, —C(O)R 12 , —C(O)OR 12 , and —C(O)NR 12 R 12′ ;

wherein 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/or

wherein the alkyl, alkylene or alkynyl, other than those defined in R 1 or R 2 , if substituted, is substituted with one or more substituents selected from —OR 13 , halogen, —CN, haloalkyl, haloalkoxy, —NR 13 R 13′″ , —SR 13 , —S(O)R 13 , and —S(O) 2 R 13 ;

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

and wherein R 13′″ is selected from hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, and -Boc;

and/or

wherein the aryl, heterocyclyl or cycloalkyl, also in alkylaryl, alkylcycloalkyl and alkylheterocyclyl, other than those defined in R 1 or R 2 , if substituted, is substituted with one or more substituents 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 3 ) 2 OR 14 ;

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 alkylaryl, unsubstituted cycloalkyl, unsubstituted alkylcycloalkyl, unsubstituted heterocyclyl, and unsubstituted alkyheterocylcyl;

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, or a corresponding solvate thereof.

2. The compound according to claim 1 , wherein W is —O—.

3. The compound according to claim 1 , wherein R 2 is substituted or unsubstituted phenyl.

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

5. The compound according to claim 1 , wherein R 1 is substituted or unsubstituted thiophene and R 2 is substituted or unsubstituted phenyl.

6. The compound according to claim 1 , which is selected from:

N-benzyl-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(thiophen-2-yl)methoxy)ethanamine,

N-((6-methoxypyridin-3-yl)methyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)ethanamine,

N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)ethanamine,

N-(4-fluorobenzyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(thiophen-2-yl)methoxy)ethanamine,

N-benzyl-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)ethanamine,

N-(4-fluorobenzyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)ethanamine,

(R)-N-benzyl-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)ethanamine,

(R)-N-(4-fluorobenzyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)ethanamine,

N-(4-chloro-2-fluorobenzyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(thiophen-2-yl)methoxy)ethanamine,

N-(4-chloro-2-fluorobenzyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)ethanamine,

N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(thiophen-2-yl)methoxy)-N-(1-phenylethyl)ethanamine,

N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(thiophen-2-yl)methoxy)-N-(3-methylbenzyl)ethanamine,

N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)-N-(1-phenylethyl)ethanamine,

N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)-N-(3-methylbenzyl)ethanamine,

(R)-N-benzyl-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(thiophen-2-yl)methoxy)ethanamine,

(S)-N-benzyl-N-methyl-2-(1-methyl(1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)ethanamine,

(S)-N-(4-fluorobenzyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)ethanamine,

(N-(3-fluorobenzyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)ethanamine,

N-(3-chlorobenzyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)ethanamine,

(N-(3-fluorobenzyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)ethanamine,

(S)-N-(3-fluorobenzyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)ethanamine,

N-benzyl-N-(2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)ethyl)propan-2-amine,

N-(3-fluorobenzyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(thiophen-2-yl)methoxy)ethanamine,

N-(3-fluorobenzyl)-N-(2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy)ethyl)propan-2-amine,

(S)-N-benzyl-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(3-methylthiophen-2-yl)methoxy)ethanamine,

(R)-N-benzyl-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(3-methylthiophen-2-yl)methoxy)ethanamine,

N-benzyl-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methylthio)ethanamine,

N-benzyl-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methylsulfinyl)ethanamine,

N-benzyl-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(3-methylthiophen-2-yl)methoxy)ethanamine,

N-benzyl-2-((2-fluorophenyl)(1-methyl-1H-pyrazol-5-yl)methoxy)-N-methylethanamine,

N-benzyl-2-((2-methoxyphenyl)(1-methyl-1H-pyrazol-5-yl)methoxy)-N-methylethanamine,

N-benzyl-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(pyridin-2-yl)methoxy)ethanamine,

N-benzyl-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(thiazol-5-yl)methoxy)ethanamine,

N-(3-fluorobenzyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(3-methylthiophen-2-yl)methoxy)ethanamine,

N-benzyl-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(pyridin-3-yl)methoxy)ethanamine,

N-(3-fluorobenzyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(pyridin-3-yl)methoxy)ethanamine,

N-(3-fluorobenzyl)-2-((2-fluorophenyl)(1-methyl-1H-pyrazol-5-yl)methoxy)-N-methylethanamine,

N-(3-fluorobenzyl)-2-((2-methoxyphenyl)(1-methyl-1H-pyrazol-5-yl)methoxy)-N-methylethanamine,

N-(3-fluorobenzyl)-N-methyl-2-((1-methyl-1H-pyrazol-5-yl)(thiazol-5-yl)methoxy)ethanamine,

N1-benzyl-N1,N2-dimethyl-N2-((1-methyl-1H-pyrazol-5-yl)(phenyl)methyl)ethane-1,2-diamine,

4-((2-(benzyl(methyl)amino)ethoxy)(1-methyl-1H-pyrazol-5-yl)methyl)phenol,

2-((2-(benzyl(methyl)amino)ethoxy)(1-methyl-1H-pyrazol-5-yl)methyl)phenol, and

2-((2-((3-fluorobenzyl)(methyl)amino)ethoxy)(1-methyl-1H-pyrazol-5-yl)methyl)phenol,

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

7. A process for preparing a compound of Formula (I) according to claim 1 ,

which process comprises:

a) alkylating a compound of Formula (XIII)

with a compound of Formula (XIV)

Or

b) reacting a carbinol of Formula (IIa)

with a compound of general Formula (XV)

Or

c) reacting a compound of general Formula (V)

with a suitable reagent of Formula (VIa) or (VIb)

Or

d) the reduction of a compound of Formula (VIII)

wherein m, n, R 1 , R 2 , R 3 , R 4 , R 4′ , R 5 , R 6 , R 6′ and X have the meanings as defined in claim 1 for the compound of formula (I), W is —O—, and Y is a hydroxyl group or a leaving group, including chloro, bromo, mesylate and tosylate.

8. A process for the preparation of the compound of formula (I) according to claim 1 employing a compound of Formula (IIa), (III), (IV), (V), (VIa), (VIb), (VII), VIII), (IX), (X), (XI), (XII), (XIII), (XIV) or (XV)

wherein m, n, R 2 , R 4 , R 4′ , R 5 , R 6 , R 6′ and X have the meanings as defined in claim 1 for the compound of formula (I), and wherein Y is a hydroxyl group or a leaving group, including chloro, bromo, mesylate and tosylate.

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

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

11. The method according to claim 10 , 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.