SMALL MOLECULE ANTIVIRAL DRUG TREATMENT FOR HUMAN PAPILLOMAVIRUS INFECTIONS
Compositions and methods are provided for treating HPV infections including pre-malignant and cancers. Compounds that specifically bind to the HPV E6 protein and inactivate the protein are disclosed.
1 . An HPV binding compound having the general structure of Formula I:
wherein Y is C or N;
X 4 is N or C;
W is —(CH 2 ) n — or —CH═CR 32 —;
R 32 is H or —(CH 2 ) n —
n is an integer selected from the range of 0-4;
R 31 is selected from the group consisting of —CH═CH 2 , —CR 51 =CH 2 , —CH═CHCH 2 N(CH 3 ) 2 , —CH═CHCH 3 , CH 2 (halo) and CH 3 wherein R 51 is H or halo, optionally where R 51 is H or F, optionally wherein R 31 is —CH═CH 2 ;
R 33 and R 34 together with the atoms to which they are attached form a ring structure selected from the group consisting of
X 3 is C or N;
R 38 is selected from the group consisting of H, —OCH 3 , —OCF 3 , —OCH 2 CH 3 , and —OCH 2 CH 2 OCH 3 ;
R 39 is H, halo or CH 3 ;
R 35 is selected from the group consisting of H and halo:
R 36 is selected from the group consisting of H, halo, —OCH 3 , —OCH 2 CH 3 and CONHCH 3 ;
R 41 is H or C 1 -C 4 alkyl;
R 42 is H, —CN, C 1 -C 4 alkyl, or R 41 and R 42 together with the atoms to which they are attached form a 4-6 membered ring; with the proviso that when R 41 and R 42 are both H, either R 36 is —OCH 2 CH 3 , or R 38 is other than H.
2 . The compound of claim 1 wherein
Y is C or N:
X 4 is N or C;
W is —(CH 2 ) n or —CH═CH—;
n is an integer selected from the range of 2-4;
R 31 is selected from the group consisting of —CH═CH 2 , —CH═CHCH 2 N(CH 3 ) 2 , —CH═CHCH 3 , CH 2 (halo) and CH 3 , optionally wherein R 31 is —CH═CH 2 ;
R 33 and R 34 together with the atoms to which they are attached form a ring structure selected from the group consisting of
X 3 is C or N;
X 4 is N;
R 38 is selected from the group consisting of H, —OCH 3 , —OCF 3 , —OCH 2 CH 3 , and —OCH 2 CH 2 OCH 3 ;
R 39 is H, halo or CH 3 ;
R 35 is selected from the group consisting of H and halo:
R 36 is selected from the group consisting of H, halo, —OCH 3 , —OCH 2 CH 3 and CONHCH 3 ;
R 41 is H or C 1 -C 4 alkyl;
R 42 is H, —CN, C 1 -C 4 alkyl, or R 41 and R 42 together with the atoms to which they are attached form a 4-6 membered ring; optionally with the proviso that when R 41 and R 42 are both H, either R 36 is —OCH 2 CH 3 , or R 38 is other than H.
3 . The compound of claim 1 , wherein
X 4 is N;
W is a bond (i.e., n=0);
R 31 is selected from the group consisting of —CH═CH 2 , —CH═CHCH 2 N(CH 3 ) 2 , —CH═CHCH 3 , CH 2 (halo) and CH 3 , optionally wherein R 31 is —CH═CH 2 ;
R 33 and R 34 together with the atoms to which they are attached form a ring structure of
R 38 is selected from the group consisting of H, —OCH 3 , —OCH 2 CH 3 , and —OCH 2 CH 2 OCH 3 ;
R 39 is H;
R 35 is selected from the group consisting of H and halo:
R 36 is selected from the group consisting of H, halo, —OCH 3 , and —OCH 2 CH 3 ;
R 41 is H;
R 42 is H, —CN, or C 1 -C 4 alkyl, optionally with the proviso that when R 41 and R 42 are both H, either R 36 is —OCH 2 CH 3 , or R 38 is other than H.
4 . The compound of claim 1 having the general structure of Formula II:
wherein
Y is C or N;
W is —(CH 2 ) n ;
n is 2;
R 31 is selected from the group consisting of —CH═CH 2 , —CH═CHCH 2 N(CH 3 ) 2 , —CH═CHCH 3 , CH 2 (halo) and CH 3 , optionally wherein R 31 is —CH═CH 2 ;
R 37 and R 38 are each H or R 37 and R 38 together with the atoms to which they are attached form a ring structure of
R 38 is H, halo or CH 3 , optionally wherein R 38 is H;
R 35 is halo:
R 36 is selected from the group consisting of halo, —OCH 3 , and —OCH 2 CH 3 and
R 41 is H or C 1 -C 4 alkyl.
5 . The compound of claim 1 having the general structure of Formula III:
wherein
Y is C or N;
X 3 is C or N;
W is —(CH 2 ) n or —CH═CH—;
n is an integer selected from the range of 0-4;
R 31 is selected from the group consisting of —CH═CH 2 , —CR 51 =CH 2 , —CH═CHCH 2 N(CH 3 ) 2 , —CH═CHCH 3 , CH 2 (halo) and CH 3 wherein R 51 is H or halo, optionally where R 51 is H or F, optionally wherein R 31 is —CH═CH 2 ;
R 35 is selected from the group consisting of H and halo:
R 36 is selected from the group consisting of H, halo, —OCH 3 , —OCH 2 CH 3 and CONHCH 3 ;
R 40 is selected from the group consisting of H, —OCH 3 , —OCH 2 CH 3 , and —OCH 2 CH 2 OCH 3 ;
R 41 is H or C 1 -C 4 alkyl;
R 42 is H, —CN, C 1 -C 4 alkyl, or R 41 and R 42 together with the atoms to which they are attached form a 4-6 membered ring; optionally with the proviso that when R 41 and R 42 are both H, either R 36 is —OCH 2 CH 3 , or R 40 is other than H.
6 . The compound of claim 1 having the general structure of Formula VI:
wherein
X 3 is C or N;
R 40 is H, halo of CH 3 ;
R 41 is H or Halo;
R 42 is CH 3 or
R 43 is CH 3 , CH 2 OCH 3 , or C 1 -C 3 cycloalkyl;
R 44 and R 45 are independently H or —(CH 2 ) n or R 44 and R 45 together with the atoms to which they are attached form a bridged bicyclic ring; and
R 46 is CH 3 , CH 2 NCH 3 CH 3 , N-methyl pyrrolidine or CH 2 R 47 , wherein R 47 is an N-linked morpholine or piperidine ring and
n is an integer selected from the range of 2-4.
7 . The compound of claim 5 , wherein
X 3 is N.
8 . The compound of claim 7 , wherein
R 35 is halo; and
R 36 is selected from the group consisting of H, halo, —OCH 3 , —OCH 2 CH 3 and CONHCH 3 , optionally wherein R 36 is —OCH 3 , —OCH 2 CH 3 , optionally wherein R 36 is halo.
9 . The compound of claim 8 , wherein
R 41 is H; and
R 42 is —CN, or C 1 -C 4 alkyl.
10 . The compound of claim 5 , wherein R 41 and R 42 together with the atoms to which they are attached form a 4-5 membered cycloalkyl ring.
11 . The compound of claim 1 having the general structure of Formula V:
wherein
Y is C or N;
W is —(CH 2 ) n ;
n is 2;
R 31 is selected from the group consisting of —CH═CH 2 , —CH═CHCH 2 N(CH 3 ) 2 , —CH═CHCH 3 , CH 2 (halo) and CH 3 , optionally wherein R 31 is —CH═CH 2 ;
R 37 and R 38 are each H or R 37 and R 38 together with the atoms to which they are attached form a ring structure of
R 38 is H, halo or CH 3 , optionally wherein R 38 is H;
R 35 is halo:
R 36 is selected from the group consisting of halo, —OCH 3 , and —OCH 2 CH.
12 . A compound having the general structure of Formula I:
wherein Y is C or N;
X 4 is N;
W is —(CH 2 ) 2 or —CH═CH—;
R 31 is selected from the group consisting of —CH═CH 2 , or —CH═CHCH 3 ;
R 33 and R 34 together with the atoms to which they are attached form a ring structure of
X 3 is C or N;
R 38 is selected from the group consisting of H, —OCH 3 , —OCH 2 CH 3 , and —OCH 2 CH 2 OCH 3 ;
R 39 is H;
R 35 is selected from the group consisting of H and halo:
R 36 is selected from the group consisting of H, halo, —OCH 3 , and —OCH 2 CH 3 ;
R 41 is H;
R 42 is H, —CN, or C 1 -C 4 alkyl, optionally with the proviso that when R 41 and R 42 are both H, either R 36 is —OCH 2 CH 3 , or R 38 is other than H.
13 . The compound of claim 12 wherein W is —CH═CH—.
14 . The compound of claim 12 wherein X 3 is C and R 38 is selected from the group consisting of —OCH 3 , —OCH 2 CH 3 , and —OCH 2 CH 2 OCH 3 .
15 . The compound of claim 12 wherein X 3 is N and R 38 is selected from the group consisting of —OCH 3 , —OCH 2 CH 3 , and —OCH 2 CH 2 OCH 3 .
16 . An HPV E6 binding compound having the general structure of
17 . A pharmaceutical composition comprising an HPV E6 binding compound of claim 1 and an acceptable carrier, optionally wherein the pharmaceutical composition is formulated for topical application, including for example as a cream.
18 . A formulation comprising an HPV E6 binding compound of claim 1 and a pharmaceutically-acceptable adjuvant, diluent or carrier.
19 . A method for treating an HPV infection, wherein the method comprises the step of delivering a pharmaceutical composition of claim 17 to a patient in need of treatment.
20 . A method for treating an HPV infection, wherein the method comprises the step of delivering a formulation of claim 18 to a patient in need of treatment.