IP Library › Granted Patent US 8,084,451

Granted Patent B2

US 8,084,451 · App. 11/813,546 · Granted Dec 27, 2011

Heteropyrrole analogs acting on cannabinoid receptors

Assignee: University of Connecticut

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Quick Facts

Patent No.: US 8,084,451
App. No.: 11/813,546
Granted: Dec 27, 2011
Kind: B2

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Abstract

Disclosed are biologically active hetero pyrrole analogs such as imidazoles, thiazoles, oxazoles and pyrazoles capable of interacting with the CB1 and/or the CB2 cannabinoid receptors. One aspect discloses hetero pyrrole analogs acting as antagonists for the CB1 and/or the CB2 receptors. Another aspect discloses hetero pyrrole analogs having selectivity for the CB1 or CB2 cannabinoid receptor. Also disclosed are pharmaceutical preparations employing the disclosed analogs and methods of administering therapeutically effective amounts of the disclosed analogs to provide a physiological effect.

Claims (330)

1. A compound represented by the following structural formula

and physiologically acceptable salts thereof, wherein:

A is a direct bond;

B is N(R5),

R5 is selected from hydrogen, alkyl and substituted alkyl;

R2 is —(CH 2 ) n —Z,

n is 0, and

Z is selected from an aromatic ring having 5 to 7 ring members or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH 2 ) n — group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

Z is selected from a 6 member aromatic ring or a substituted 6 member aromatic ring; and wherein the connecting point between the —(CH 2 ) n — group and the Z group can be any available ring carbon atom; or

Z is selected from

wherein X and Y are each independently selected from H, halogen, N 3 , NCS, CN, NO 2 , NX 1 X 2 , OX 3 , OAc, O-acyl, O-aroyl, O(CH 2 ) j OX 3 , O(CH 2 ) j NX 1 X 2 , NH-acyl, NH-aroyl, CHO, C(halogen) 3 , COOX 3 , SO 3 H, SO 2 NX 1 X 2 , CONX 1 X 2 , alkyl, alcohol, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl and methylene dioxy when Z comprises a structure having two adjacent carbon atoms,

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ; or

Z is selected from an aromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms; or

R2 is -T-(CH 2 ) n —Z,

n is an integer from 0 to 7,

T is selected from an aromatic ring having 5 to 8 carbon atoms as ring members, and

Z is selected from H, halogen, N 3 , NCS, CN, NO 2 , NX 1 X 2 , OX 3 , OAc, O-acyl, O-aroyl, O(CH 2 ) j OH, O(CH 2 ) j OX 3 , O(CH 2 ) j NX 1 X 2 , NH-acyl, NH-aroyl, CHO, C(halogen) 3 , COOX 3 , SO 3 H, SO 2 NX 1 X 2 , CONX 1 X 2 , alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl and alkylsulfonyl,

X 1 and X 2 each independently is selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and or alkyl-NX 1 X 2 ,

j is an integer from 0 to 6; or

Z is selected from a carbocyclic ring having 4 to 7 ring members, a heterocyclic ring having 4 to 7 ring members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH 2 ) n — group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

Z is selected from 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH 2 ) n — group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

Z is selected from

wherein X and Y are each independently selected from H, halogen, N 3 , NCS, CN, NO 2 , NX 1 X 2 , OX 3 , OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, CHO, C(halogen) 3 , COOX 3 , SO 3 H, SO 2 NX 1 X 2 , CONX 1 X 2 , alkyl, alcohol, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl and methylene dioxy when Z comprises a structure having two adjacent carbon atoms,

X 1 and X 2 are each independently is selected from H or alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ; or

Z is selected from an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members and an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; or

R2 is -T-(CH 2 ) n -Q 1 -(CH 2 ) n —Z,

each n is independently an integer from 0 to 7,

T is selected from an aromatic ring having 5 to 8 carbon atoms as ring members,

Q 1 is selected from N, O, S, CH═CH, C≡C CO, SO 2 and OSO 2 , and

Z is selected from H, halogen, N 3 , NCS, CN, NO 2 , NX 1 X 2 , OX 3 , OAc, O-acyl, O-aroyl, O(CH 2 ) j OX 3 , O(CH 2 ) j NX 1 X 2 , NH-acyl, NH-aroyl, CHO, C(halogen) 3 , COOX 3 , SO 3 H, SO 2 NX 1 X 2 , CONX 1 X 2 , alkyl, alcohol, alkoxy, alkylmercapto, alkylamino or di-alkylamino, alkylsulfinyl and alkylsulfonyl,

X 1 and X 2 each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

j is an integer from 0 to 6; or

Z is selected from a carbocyclic ring having 4 to 7 ring members, a heterocyclic ring having 4 to 7 ring members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 ring members, a bicyclic ring, a heterobicyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH 2 ) n — group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

Z is selected from

wherein X and Y are each independently is selected from H, halogen, N 3 , NCS, CN, NO 2 , NX 1 X 2 , OX 3 , OAc, O-acyl, O-aroyl, O(CH 2 ) j OX 3 , O(CH 2 ) j NX 1 X 2 , NH-acyl, NH-aroyl, CHO, C(halogen) 3 , COOX 3 , SO 3 H, SO 2 NX 1 X 2 , CONX 1 X 2 , alkyl, alcohol, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl and methylene dioxy when Z comprises a structure having two adjacent carbon atoms,

X 1 and X 2 are each independently is selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ; or

Z is selected from an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; or

Z is selected from

wherein E is selected from a C1 to C4 linear or branched alkyl group, a phenyl group, a substituted phenyl group, a benzyl group and a substituted benzyl group; or

Z is selected from

wherein k is an integer from 1 to 5, A 1 and A 2 are each independently selected from a C1 to C4 alkyl group, a phenyl group and a substituted phenyl group;

is selected from a carbocyclic ring having 4 to 7 members, a heterocyclic ring having 4 to 7 members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring; or

R3 is

wherein G is selected from CH and N, and L and J each independently selected from (CH 2 ) n , O, NH and S, n is an integer from 0 to 7; or

R3 is

wherein G, L and J are each independently selected from CH and N; or

R3 is selected from

wherein X and Y are independently selected from H, halogen, N 3 , NCS, phenyl, CN, NO 2 , NX 1 X 2 , OX 3 , OAc, O-acyl, O-aroyl, O(CH 2 ) j OX 3 , O(CH 2 ) j NX 1 X 2 , NH-acyl, NH-aroyl, CHO, C(halogen) 3 , COOX 3 , SO 3 H, SO 2 NX 1 X 2 , CONX 1 X 2 , alkyl, alcohol, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl and alkylsulfonyl,

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members),

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

j is an integer from 0 to 6; or

R3 is selected from a carbocyclic ring having 4 to 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, a carbocyclic ring having 4 to 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heterocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, a heterocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heteroaromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, and a heteroaromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms;

R4 is selected from H, halogen, N 3 , NCS, phenyl, CN, NO 2 , NX 1 X 2 , OX 3 , OAc, O-acyl, O-aroyl, O(CH 2 ) j OX 3 , O(CH 2 ) j NX 1 X 2 , NH-acyl, NH-aroyl, CHO, C(halogen) 3 , COOX 3 , SO 3 H, SO 2 NX 1 X 2 , CONX 1 X 2 , alkyl, alcohol, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl and alkylsulfonyl,

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members),

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

j is an integer from 0 to 6; or

R4 is selected from a carbocyclic ring having 4 to 7 ring members, a heterocyclic ring having 4 to 7 ring members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring; or

R4 is selected from

R4 is —(CH 2 ) d —Z,

d is an integer from 1 to 6, and

Z is selected from H, halogen, N 3 , NCS, phenyl, CN, NO 2 , NX 1 X 2 , OX 3 , OAc, O-acyl, O-aroyl, O(CH 2 ) j OH, O(CH 2 ) j OX 3 , O(CH 2 ) j NX 1 X 2 , NH-acyl, NH-aroyl, CHO, C(halogen) 3 , COOX 3 , SO 3 H, SO 2 NX 1 X 2 , CONX 1 X 2 , alkyl, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl and alkylsulfonyl,

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members),

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

j is an integer from 0 to 6; or

Z is selected from a carbocyclic ring having 4 to 7 ring members, a heterocyclic ring having 4 to 7 ring members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH 2 ) d - group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

Z is selected from 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH 2 ) d — group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

R4 is —(CH 2 ) m -Q 1 -(CH 2 ) n —Z,

Q 1 is selected from N, O, S, CH═CH, C≡C, CO, SO 2 and OSO 2 ,

m is an integer from 1 to 7,

n is an integer from 0 to 7, and

Z is selected from H, halogen, N 3 , NCS, phenyl, CN, NO 2 , NX 1 X 2 , OX 3 , OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, O(CH 2 ) j OX 3 , O(CH 2 ) j NX 1 X 2 , CHO, C(halogen) 3 , COOX 3 , SO 3 H, SO 2 NX 1 X 2 , CONX 1 X 2 , alkyl, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl and alkylsulfonyl,

X 1 and X 2 are each independently selected from H or alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

j is an integer from 0 to 6; or

Z is selected from a carbocyclic ring having 4 to 7 ring members, a heterocyclic ring having 4 to 7 ring members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 ring members; a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH 2 ) n — group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

Z is selected from 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH 2 ) n — group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

Z is selected from

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

J is an integer from 0 to 6;

R1 is -T-Q-(CH 2 ) n —Z,

n is an integer from 0 to 7,

T is selected from an aromatic ring having 5 to 8 carbon atoms as ring members, a heteroaromatic ring having 5 to 8 ring members,

Q is C≡C, and

Z is selected from H, halogen, N 3 , NCS, CN, NO 2 , NX 1 X 2 , OX 3 , OAc, O-acyl, O-aroyl, O(CH 2 ) j OX 3 , O(CH 2 ) j NX 1 X 2 , NH-acyl, NH-aroyl, NHC(O)—O—X 3 , CHO, C(halogen) 3 , COOX 3 , SO 3 H, SO 2 NX 1 X 2 , CONX 1 X 2 , SX 1 , Si(X 1 ) 3 , alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl,

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

each j is independently an integer from 0 to 6; or

Z is selected from

wherein X and Y are each independently selected from H, halogen, N 3 , NCS, CN, NO 2 , NX 1 X 2 , OX 3 , OAc, O-acyl, O-aroyl, O(CH 2 ) j OX 3 , O(CH 2 ) j NX 1 X 2 NH-acyl, NH-aroyl, CHO, C(halogen) 3 , COOX 3 , SO 3 H, SO 2 NX 1 X 2 , CONX 1 X 2 , alkyl, alcohol, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl and methylene dioxy when Z comprises a structure having two adjacent carbon atoms,

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

j is an integer from 0 to 6; or

Z is selected from an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; or

Z is selected from

E is selected from a C1 to C4 linear or branched alkyl group, a phenyl group, a substituted phenyl group, a benzyl group and a substituted benzyl group; or

Z is selected from

wherein k is an integer from 1 to 5, A 1 and A 2 are each independently selected from a C1 to C4 alkyl group, a phenyl group and a substituted phenyl group.

2. A pharmaceutical preparation comprising a therapeutically effective amount of a compound of claim 1 and at least one member selected from an excipient, a vehicle, an adjuvant, a flavoring, a colorant, or a preservative.

3. A compound of claim 1 , wherein

R1 is -T-Q-(CH 2 ) n —Z,

n is an integer from 0 to 7,

T is selected from an aromatic ring having 5 to 8 carbon atoms as ring members,

Q is C≡C, and

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

each j is independently an integer from 0 to 6; or

Z is selected from

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

j is an integer from 0 to 6; or

Z is selected from an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; or

Z is selected from

E is selected from a C1 to C4 linear or branched alkyl group, a phenyl group, a substituted phenyl group, a benzyl group and a substituted benzyl group; or

Z is selected from

wherein k is an integer from 1 to 5, A 1 and A 2 are each independently selected from a C1 to C4 alkyl group, a phenyl group and a substituted phenyl group.

4. A compound of claim 3 , wherein

R2 is —(CH 2 ) n —Z,

n is 0, and

Z is selected from an aromatic ring having 5 to 7 ring members,

Z is selected from

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 .

5. A compound of claim 1 , wherein

R1 is -T-Q-(CH 2 ) n —Z,

n is an integer from 0 to 7,

T is selected from a heteroaromatic ring having 5 to 8 carbon atoms as ring members,

Q is C≡C, and

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

each j is independently an integer from 0 to 6; or

Z is selected from

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

j is an integer from 0 to 6; or

Z is selected from an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; or

Z is selected from

E is selected from a C1 to C4 linear or branched alkyl group, a phenyl group, a substituted phenyl group, a benzyl group and a substituted benzyl group; or

Z is selected from

wherein k is an integer from 1 to 5, A 1 and A 2 are each independently selected from a C1 to C4 alkyl group, a phenyl group and a substituted phenyl group.

6. A compound of claim 5 , wherein

R2 is —(CH 2 ) n —Z,

n is 0, and

Z is selected from an aromatic ring having 5 to 7 ring members,

Z is selected from

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 .

7. A compound of claim 3 , wherein

A is a direct bond,

B is NH,

R1 is -T-Q-(CH 2 ) n —Z,

each n is independently an integer from 0 to 7,

T is selected from an aromatic ring having 5 to 8 ring members,

Q is C≡C, and

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

each j is independently an integer from 0 to 6; or

Z is selected from

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl- NX 1 X 2 ,

j is an integer from 0 to 6; or

Z is selected from an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; or

Z is selected from

E is selected from a C1 to C4 linear or branched alkyl group, a phenyl group, a substituted phenyl group, a benzyl group and a substituted benzyl group; or

Z is selected from

wherein k is an integer from 1 to 5, A 1 and A 2 are each independently selected from a C1 to C4 alkyl group, a phenyl group and a substituted phenyl group;

R2 is selected from

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 .

8. A compound of claim 5 , wherein

A is a direct bond,

B is NH,

R1 is -T-Q-(CH 2 ) n —Z,

each n is independently an integer from 0 to 7,

T is selected from a heteroaromatic ring having 5 to 8 ring members,

Q is C≡C, and

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

each j is independently an integer from 0 to 6; or

Z is selected from

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

j is an integer from 0 to 6; or

Z is selected from an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; or

Z is selected from

E is selected from a C1 to C4 linear or branched alkyl group, a phenyl group, a substituted phenyl group, a benzyl group and a substituted benzyl group; or

Z is selected from

wherein k is an integer from 1 to 5, A 1 and A 2 are each independently selected from a C1 to C4 alkyl group, a phenyl group and a substituted phenyl group;

R2 is selected from

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X2 together comprise part of an imide ring having 5 to 6 members,

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 .

9. A compound of claim 7 , wherein

R4 is selected from CN, OX 3 , O(CH 2 ) j OX 3 , C(halogen) 3 , alkyl, alcohol, alkoxy, alkylmercapto, alkylsulfinyl and alkylsulfonyl,

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members),

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

j is an integer from 0 to 6; or

R4 is —(CH 2 ) d —Z,

d is an integer from 1 to 6, and

Z is selected from H, CN, OX 3 , O(CH 2 ) j OX 3 , O(CH 2 ) j NX 1 X 2 , NH—C(halogen) 3 , alkyl, alkoxy, alkylmercapto, alkylsulfinyl and alkylsulfonyl,

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members),

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

j is an integer from 0 to 6.

10. A compound of claim 8 , wherein

R4 is selected from CN, OX 3 , O(CH 2 ) j OX 3 , C(halogen) 3 , alkyl, alcohol, alkoxy, alkylmercapto, alkylsulfinyl and alkylsulfonyl,

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members),

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

j is an integer from 0 to 6; or

R4 is —(CH 2 ) d —Z,

d is an integer from 1 to 6, and

Z is selected from H, CN, OX 3 , O(CH 2 ) j OX 3 , O(CH 2 ) j NX 1 X 2 , NH—C(halogen) 3 , alkyl, alkoxy, alkylmercapto, alkylsulfinyl and alkylsulfonyl,

X 1 and X 2 are each independently selected from H and alkyl, or

X 1 and X 2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from O, N or S, or

X 1 and X 2 together comprise part of an imide ring having 5 to 6 members),

X 3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX 1 X 2 ,

j is an integer from 0 to 6.

11. A compound of claim 7 , wherein

12. A compound of claim 8 , wherein

13. A compound of claim 7 , wherein

R3 is selected from a carbocyclic ring having 4 to 7 members, a heterocyclic ring having 4 to 7 members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring.

14. A compound of claim 8 , wherein

15. A compound of claim 1 , wherein R4 is selected from —CH 2 OH and —CH 2 Oalkyl.

16. A compound of claim 1 , wherein R1 is aryl- C≡C—(CH 2 ) n —Z.

17. A compound of claim 1 , wherein R1 is heteroaryl-C≡C—(CH 2 ) n —Z.

18. A compound of claim 1 , wherein A is a direct bond and B is N(R5).

19. A compound of claim 1 , and physiologically accepted salts thereof, selected from one of the following structures:

20. A compound of claim 1 , wherein R2 is T-(CH 2 ) n -Q 1 -(CH 2 ) n —Z.

21. A compound of claim 1 , wherein R2 is -T-(CH 2 ) n —Z.

22. A compound of claim 1 , wherein R2 is -T-(CH 2 ) n -Q 1 -(CH 2 ) n —Z.

23. A compound of claim 3 , wherein

R3 is selected from the list consisting of

R5 is H;

R2 is

R1 is —T-Q-(CH 2 ) n -Z,

Z is CN, OH, N 3 , NCS, NH 2 or N(CH 3 ) 2 , a substituted or unsubstituted carbocyclic, aromatic or heteroaromatic ring; and

R4 is CH 3 , CH 2 CH 3 or CN.

24. A compound of 5 , wherein

R3 is selected from the list consisting of

R5 is H;

R2 is

R1 is —T-Q-(CH 2 ) n -Z,

Z is selected from the list consisting of CN, OH, N 3 , NCS, NH 2 or N(CH 3 ) 2 , a substituted or unsubstituted carbocyclic, aromatic or heteroaromatic ring; and

R4 is CH 3 , CH 2 CH 3 or CN.

Assignments (3)

CONFIRMATORY LICENSE Recorded Feb 28, 2017

From: UNIVERSITY OF CONNECTICUT

To: NATIONAL INSTITUTES OF HEALTH - DIRECTOR DEITR

Reel/Frame 041392/0798 →

CONFIRMATORY LICENSE Recorded Sep 30, 2016

From: UNIVERSITY OF CONNECTICUT

To: NATIONAL INSTITUTES OF HEALTH - DIRECTOR DEITR

Reel/Frame 040193/0196 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 9, 2011

From: MAKRIYANNIS, ALEXANDROS; VEMURI, VENKATA KIRAN; OLSZEWSKA, TERESA

To: UNIVERSITY OF CONNECTICUT

Reel/Frame 027360/0521 →

Continuity (2)

Provisional Application 60642544 · Jan 10, 2005

Related Publication 20100063050A1 · Mar 11, 2010