US2011207654A1PendingUtilityA1
Peptide analogues
Est. expiryFeb 25, 2030(~3.6 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 29/00C07K 5/06078A61P 25/04
42
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Claims
Abstract
The present invention relates to compounds of Formula (I) and their pharmaceutically acceptable salts, wherein the substituents are as described herein, and their use in medicine, in particular as opioid agonists.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I)
wherein
Ar 1 is phenyl optionally substituted by one or more substituents independently selected from OH, C 1-3 alkyl and halogen,
or Ar 1 is phenyl fused to a 5- or 6-membered heterocycle optionally substituted by one or more substituents independently selected from halogen, OH, and ═O,
Ar 2 is phenyl optionally substituted by one or more substituents independently selected from OH, C 1-3 alkyl and halogen,
or Ar 2 is phenyl fused to a 5- or 6-membered heterocycle optionally substituted by one or more substituents independently selected from halogen, OH, and ═O,
Gu is guanidinyl (or a tautomeric form thereof) optionally substituted by up to 4 substituents independently selected from C 1-3 alkyl,
R 1 is independently H or C 1-5 alkyl optionally substituted by Y,
where Y is halogen, S(O) m —(C 1-3 alkyl), CO 2 —R 5 or Gu,
where R 5 is H or C 1-6 alkyl,
and m is 0, 1 or 2,
R 2 is independently H or C 1-3 alkyl,
or R 1 and R 2 together with the carbon atom to which they are attached can be a cyclopropyl group,
one of R 3 and R 4 is H and the other is Q where Q is H, NH 2 , NHC(O)(C 1-6 alkyl), Gu, NHC(O)(CH 2 ) n NH2, NHC(O)(CH 2 ) n Gu, or (CH 2 ) n Gu,
where n is 1, 2, 3, 4 or 5,
or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
2 . A compound or salt according to claim 1 wherein Ar 1 is 4-hydroxyphenyl, 2,6-dimethyl-4-hydroxyphenyl or benzoxazol-2-one-6-yl.
3 . A compound or salt according to claim 2 wherein Ar 1 is 2,6-dimethyl-4-hydroxyphenyl.
4 . A compound or salt according to claim 3 wherein Ar 2 is 2,6-dimethyl-4-hydroxyphenyl or phenyl.
5 . A compound or salt according to claim 4 wherein Ar 2 is phenyl.
6 . A compound or salt according to claim 5 wherein Gu is guanidinyl or tetramethylguanidinyl or a tautomer thereof.
7 . A compound or salt according to claim 6 wherein Gu is guanidinyl or a tautomer thereof.
8 . A compound or salt according to claim 7 wherein R 1 is C 1-5 alkyl optionally substituted by S(O)CH 3 or CO 2 H.
9 . A compound or salt according to claim 8 wherein R 1 is methyl, (CH 2 ) 5 CO 2 H or (CH 2 ) 2 S(O)CH 3 .
10 . A compound or salt according to claim 9 wherein R 1 is methyl.
11 . A compound or salt according to claim 10 wherein R 2 is H.
12 . A compound or salt according to claim 11 wherein one of R 3 and R 4 is H and the other is Q where Q is H, NH 2 , NHC(O)CH 3 , guanidinyl, NHC(O)CH 2 NH 2 , NHC(O)CH 2 -guanidine, NHC(O)CH 2 CH 2 NH 2 , NHC(O)CH 2 CH 2 -guanidine or CH 2 -guanidine.
13 . A compound or salt according to claim 12 wherein R 3 is Q and R 4 is H.
14 . A compound or salt according to claim 13 wherein R 3 and R 4 are as follows:
R 3 is guanidinyl and R 4 is H;
R 3 is H and R 4 is H;
R 3 is NHC(O)CH 3 and R 4 is H; or
R 3 is NH 2 and R 4 is H.
15 . A compound or salt according to claim 14 wherein R 3 is guanidinyl and R 4 is H.
16 . A compound or salt according to claim 15 wherein the stereochemistry of the R 3 group is as shown in formula Ia below.
17 . A compound of formula I according to claim 1 or pharmaceutically acceptable salt thereof wherein:
Ar 1 is 4-hydroxyphenyl, 2,6-dimethyl-4-hydroxyphenyl or benzoxazol-2-one-6-yl;
Ar 2 is 2,6-dimethyl-4-hydroxyphenyl or phenyl;
Gu is guanidinyl or tetramethylguanidinyl;
R 1 is methyl, (CH 2 ) 5 CO 2 H or (CH 2 ) 2 S(O)CH 3 ;
R 2 is H,
and R 3 and R 4 are as follows:
R 3 is guanidinyl and R 4 is H;
R 3 is H and R 4 is H;
R 3 is NHC(O)CH 3 and R 4 is H; or
R 3 is NH 2 and R 4 is H.
18 . A compound of formula I according to claim 1 which is selected from any one of the compounds below,
or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
19 . A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 , and a pharmaceutically acceptable carrier.
20 .- 22 . (canceled)
23 . A method of treatment of a mammal, to treat a disease for which an opioid receptor agonist is indicated, comprising treating said mammal with an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 .
24 . A method of treatment of pain in a mammal, comprising treating said mammal with an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 .
25 . A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 , and a pharmaceutically acceptable carrier further comprising a further drug susbtance.
26 . A compound of formula INT2
whereby Ar 1 , Ar 2 , R 1 , R 2 R 3 and R 4 are as defined in claim 1 regarding formula (I), and PG is a Nitrogen-protecting group.Join the waitlist — get patent alerts
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