Cannabinergic nitrate esters and related analogs

Patent metadata

Field	Value
Publication number	US-9580400-B2
Application number	US-201414770331-A
Country	US
Kind code	B2
Filing date	Feb 26, 2014
Priority date	Feb 26, 2013
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

The present technology relates to novel cannabinergic nitrate esters and related analogs, process of preparation, pharmaceutical compositions and their methods of use as medicaments, pharmacological tools and/or biomarkers. The novel cannabinergic nitrate ester compounds provide medicaments useful in treating a variety of diseases and medical disorders.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
ring C has zero, one, two or three double bonds;
X is carbon, CH, N, NH, C(CH 2 ) 2 , S, O, SO, SO 2 , or CF 2 ;
R 1 is H, OH, alkyl-OH, ═O, halogen, alkyl, COOH, C(O)Oalkyl, O(CO)alkyl, nitro, ONO 2 , or optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, acyl, aryl, heterocyclyl, heteroaryl, alkoxy, aryloxy, heteroarylalkyl, heteroalkoxy, heteroaryloxy, alkenyl, amino, thio, cyano, thiocynato, isothiocynato, carboxyl, formyl, carbamyl, amino, acylamino, amido, imido, aminoalkyl, aminoaryl, heteroarylamino, heterocyclylamino, sulfonate, sufonamide, sulfonyl, thioalkyl, thioaryl, heteroarylthio, heterocyclylthio, phosphonate, phosphate, or acetate;
W is C(CH 3 ) 2 , CH(CH 3 ), C═O, CF 2 , C═S, C═CH 2 , spirocyclic ring, S, SO, SO 2 , or C[CH 3 (R 4 )];
R 4 is an optionally substituted alkyl, alkenyl, or alkynyl group;
Z is O, S, SO, SO 2 , NH, or N-alkyl;
R 2 is H, OH, SH, NH 2 , CF 3 , COOH, alkoxy, halogen, ONO 2 , alkyl-ONO 2 , or optionally substituted alkyl, haloalkyl, amine, amide, imide, alkoxy, alkoxy thio, phosphate, phosphonate, carboxyl, formyl, carbamyl, amino, acylamino, amido, imido, aminoalkyl, aminoaryl, heteroarylamino, heterocyclylamino, sulfonate, sufonamide, sulfonyl, thioalkyl, thioaryl, heteroarylthio, heterocyclylthio, phosphonate, phosphate, or acetate;
Y is a bond, C(CH 3 ) 2 , CF 2 , C═O, CH(alkyl), C(alkyl) 2 , C(O)O, NHCO, CONH, alkyl, C(O)Oalkyl, OC(O)alkyl, cycloalkyl, heterocyclyl, lactone, lactam, sultam, O, S, SO, SO 2 , OSO 2 , amine, diazine, alkenyl, or alkynyl group;
R 3 is absent, or is O, S, SO 2 , SO 2 NH, NHSO 2 , OSO 2 , OSO 2 alkyl, C(O)Oalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, a carbocyclic, a spirocyclic, heterocyclyl, aryl, heteroaryl, carboxyl, acetate, amine, amide, or imide;
V is V 1 or ONO 2 , wherein when any of rings A, B or C comprises a group comprising ONO 2 , V is V 1 , otherwise V is ONO 2 ; and
V 1 is H, F, Cl, Br, I, haloalkyl, N 3 , NCS, CN, NO 2 , OH, alkoxy, amino, alkylamino, dialkylamino, trialkylamino, aryl, cycloalkyl, alkyl, alkenyl, alkynyl, —C(O)aryl, —C(O)alkyl, C(O)Oalkyl, —C(O)heteroaryl, —C(O)amino, —C(O)(dialkylamino), C(O)(trialkylamino), C(O)(heterocyclyl), C(O)heteroaryl, —OC(O)alkyl, OSO 2 H, OSO 2 (alkyl), OSO 2 (aryl), OSO 2 NO 2 , OSO 2 (alkyl)CN, OSO 2 (alkyl)OH, OSO 2 alkylamino), —SC(O)alkyl, —SO 2 alkyl, —SO-alkyl, —SC(CH 3 ) 2 C(O)Oalkyl, —SC(CH 3 ) 2 C(O)Oaryl, —SC(CH 3 ) 2 C(O)Oheteroaryl, —SC(CH 3 ) 2 C(O)Oheterocyclyl, Si(alkyl) 3 , —OC(O)aryl, NHC(O)alkyl, NHC(O)aryl, —C(O)H, C(O)Oalkyl, SO 2 (amino), SO 2 (heterocyclyl), SO 2 (trialkylamino), SO 2 (dialkylamino), carbocyclic, a spirocyclic ring, heterocyclyl, heteroaryl, alkylthio, alkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, boronic acid, boronate ester, BF 3 K, or a biotin group tethered via an amide bond.

2. The compound of claim 1 , wherein V is ONO 2 .

3. The compound of claim 1 , wherein R 1 is ONO 2 , alkyl-ONO 2 , O-alkyl-ONO 2 , O—SO 2 -alkyl-ONO 2 , —C(O)O-alkyl-ONO 2 , alkyl-C(O)O-alkyl-ONO 2 , or alkyl-O-alkyl-ONO 2 .

4. The compound of claim 1 , wherein:
ring C has one, two or three double bonds, and at least one double bond is at the C8-C9 position, the C9-C10 position, or the C6a-C10a position;
W is C(CH 3 ) 2 , CH(CH 3 ), C═O, or CF 2 ;
Z is O or N; and
V is H when R 1 is a group comprising ONO 2 , or V is ONO 2 .

5. The compound of claim 1 , wherein Y—R 3 —V is ONO 2 , alkyl-ONO 2 , O-alkyl-ONO 2 , O—SO 2 -alkyl-ONO 2 , —C(O)O-alkyl-ONO 2 , alkyl-C(O)O-alkyl-ONO 2 , or alkyl-O-alkyl-ONO 2 .

6. The compound of claim 1 , wherein:
ring C is:

ring B is:

and V is ONO 2 .

7. The compound of claim 1 , wherein:
ring C has one double bond at the C8-C9 position or the C9-C10 position;
W is C(CH 3 ) 2 ;
X is carbon;
R 1 is H, alkyl, COOH, alkyl-OH;
R 2 is OH, O-alkyl, SH, O(CO)alkyl, OC(O)NH 2 , OC(O)NHalkyl, or OC(O)N(alkyl) 2 ;
Z is O;
Y is alkyl, C(CH 3 ) 2 , or CF 2 ; and
V is ONO 2 .

8. The compound of claim 1 , wherein:
ring C is saturated;
W is C(CH 3 ) 2 ;
X is CH, R 1 is OH, or X—R 1 is C═O;
R 2 is OH, O-alkyl, SH, O(CO)alkyl, O(CO)N—
Z is O
Y is alkyl, C(CH 3 ) 2 , or CF 2 ;
V is ONO 2 .

9. A compound that is:

10. The compound of claim 1 that is: 4-(nitrooxy)butyl 2-((1′S,2′S)-5′-(acetoxymethyl)-2,6-dihydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2-methylpropanoate; 5-(nitrooxy)pentyl 2-((1′S,2′S)-5′-(acetoxymethyl)-2,6-dihydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2-methylpropanoate; 6-(nitrooxy)hexyl 2-((1′S,2′S)-5′-(acetoxymethyl)-2,6-dihydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2-methylpropanoate; (E)-4-(((1′R,2′R)-6-hydroxy-5′-methyl-4-(2-methyl-1-(4-(nitrooxy)butoxy)-1-oxopropan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)-4-oxobut-2-enoic acid; (1′R,2′R)-6-hydroxy-5′-methyl-4-(2-methyl-1-(4-(nitrooxy)butoxy)-1-oxopropan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl 4-(nitrooxy)butanoate; (1′R,2′R)-6-hydroxy-5′-methyl-4-(2-methyl-1-(4-(nitrooxy)butoxy)-1-oxopropan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl 2,5,8,11,14,17,20-heptaoxadocosan-22-oate; (1′S,2′S)-5′-(acetoxymethyl)-6-hydroxy-4-(2-methyl-1-oxo-1-propoxypropan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl 4-(nitrooxy)butanoate; (1′S,2′S)-5′-(acetoxymethyl)-6-hydroxy-4-(2-methyl-1-(3-(nitrooxy)propoxy)-1-oxopropan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl 2-propylpentanoate; 4,4′-(((1′S,2′S)-5′-(acetoxymethyl)-4-(2-methyl-1-(4-(nitrooxy)butoxy)-1-oxopropan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diyl)bis(oxy))bis(4-oxobutanoic acid); (1′S,2′S)-5′-(acetoxymethyl)-4-(1-(hexyloxy)-2-methyl-1-oxopropan-2-yl)-6-hydroxy-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl 4-(nitrooxy)butanoate; 2-(((1′S,2′S)-5′-(acetoxymethyl)-6-hydroxy-4-(2-methyl-1-((6-(nitrooxy)hexyl)oxy)-1-oxopropan-2-yl)-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)-N,N,N-trimethyl-2-oxoethanaminium iodide; 2-(nitrooxy)ethyl 2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate; 3-(nitrooxy)propyl 2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate; 4-(nitrooxy)butyl 2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate; 5-(nitrooxy)pentyl 2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluoroacetate; 6-(nitrooxy)hexyl 2-((1′R,2′R)-2,6-dihydroxy-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-4-yl)-2,2-difluor

Assignees

• Univ Northeastern

Inventors

• Makriyannis Alexandros
• Vemuri Venkata Kiran

Classifications

• C07D209/12

  Radicals substituted by oxygen atoms · CPC title

• C07D221/06

  Ring systems of three rings · CPC title

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07C203/04

  having nitrate groups bound to acyclic carbon atoms · CPC title

• C07D311/80 Primary

  Dibenzopyrans; Hydrogenated dibenzopyrans · CPC title