Cyclosporin A analogs

Patent metadata

Field	Value
Publication number	US-9266927-B2
Application number	US-201313905491-A
Country	US
Kind code	B2
Filing date	May 30, 2013
Priority date	Jun 1, 2012
Publication date	Feb 23, 2016
Grant date	Feb 23, 2016

Abstract

The present invention relates to novel cyclosporin analogs, processes for preparing them, pharmaceutical compositions containing them, and methods for using these analogs and the compositions containing them for the treatment of medical conditions, including but not limited to ocular conditions such as dry eye.

First claim

What is claimed is:

1. A compound having Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is —H, —C 1-6 alkyl, —OC 1-6 alkyl, —CH 2 F, —CH 2 OCH 3 , —SC 1-6 alkyl, —R 13 R 14 ,

R 2 is —CH 3 , —CH 2 CH 3 or —CH 2 CH 2 CH 3 ;
R 3 is —CH 2 CH(CH 3 ) 2 , —CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 2 (OH), —CH(CH 3 )(CH 2 CH 3 ) or —CH 2 CH(R 7 )(CH 2 CH 3 );
R 4 is —CH 3 or —CH 2 OH;
R 5 is —R 8 (CH 2 ) n (C═O) m —;
R 6 is —CH 2 CH 3 , —CH(CH 3 )(OH), —CH(CH 3 ) 2 or —CH 2 CH 2 CH 3 ;
R 7 is OC 1-5 alkyl;
R 8 is O, S, CH 2 O, CH 2 S or CH 2 ;
R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached, together form a monocyclic or polycyclic non-aromatic heterocycle, wherein said heterocycle is optionally interrupted by a C═O, and the S and N atoms are optionally oxidized, and wherein said heterocycle is optionally substituted with halogen, nitro, cyano, —OC 1-6 alkyl, —SC 1-6 alkyl, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, carboxylic acid, ester, ketone, aldehyde, amide, amine, sulfonamide, C 3-8 cycloalkyl, hydroxyl or haloalkyl;
R 13 is O, S, CH 2 O, CH 2 S, CH 2 SO or CH 2 SO 2 ;
R 14 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, CH 2 CH 2 N(CH 2 CH 3 ) 2 , CH 2 CH 2 NH(CH 2 CH 3 ), heterocycle or aryl;
n is 0, 1, 2, 3 or 4;
m is 0 or 1; and
p is 1;
wherein R 14 is optionally substituted with one or more groups independently selected from the group consisting of H, C 1-6 alkyl, halogen, hydroxyl, ester, sulfonamide, ketone, aldehyde, cycloalkyl, heterocycle, aryl, amine, heterocycle, amide and guanidinyl; and
wherein “- - - - - -” is a single bond.

2. A compound according to claim 1 , wherein m is 0 and R 1 is not —H.

3. A compound according to claim 1 , wherein m is 0.

4. A compound according to claim 1 , wherein n is 0 or 3, and m is 0.

5. A compound according to claim 1 , wherein R 1 is not —H.

6. A compound according to claim 1 , wherein R 2 is —CH 3 , R 3 is —CH 2 CH(CH 3 ) 2 , R 4 is —CH 3 , R 6 is —CH 2 CH 3 and R 8 is CH 2 .

7. A compound according to claim 1 , wherein R 1 is —CH 3 , R 6 is —CH 2 CH 3 or —CH(CH 3 ) 2 , R 8 is CH 2 , R 11 is O, and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form a morpholinyl.

8. A compound according to claim 1 , wherein R 1 is —CH 3 , R 2 is —CH 3 , R 3 is —CH 2 CH(CH 3 ) 2 , R 4 is —CH 3 , R 6 is —CH 2 CH 3 , R 8 is CH 2 , R 11 is O, n is 0 or 3, m is 0, and R 9 , R 10 , R 11 , the N to which R 9 and R 10 are attached taken together form:

wherein “*” represents the point of attachment to R 5 .

9. A compound according to claim 1 , wherein the heterocycle formed from R 9 , R 10 , R 11 and the N to which R 9 and R 10 are attached is selected from the group consisting of morpholinyl, piperazinonyl, N-methylpiperazinyl,

wherein “*” represents the point of attachment to R 5 .

10. The compound according to claim 1 selected from the group consisting of:
[(3R,4R,5S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-(morpholin-4-yl) hexanoic acid] 1 [(R)-Me-Sar] 3 cyclosporin A (Compound F);
[(3R,4R,5S)-4-hydroxy-3-methyl-5-(methylamino)-1-(4-methylpiperazino)-hexanoic acid] 1 [(R)-Me-Sar] 3 cyclosporin A (Compound L);
[(3R,4R,5S)-4-hydroxy-3-methyl-5-(methylamino)-1-(N-3-piperazinone)-hexanoic acid] 1 [(R)-Me-Sar] 3 cyclosporin A (Compound N);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(N-(3 aR*,6aS*)-2-methyloctahydropyrrolo[3,4-c]pyrrolo)-hexanoic acid] 1 [(R)-methyl-Sar] 3 cyclosporin A (Compound O);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(thiomorpholino)-hexanoic acid] 1 [(R)-Me-Sar] 3 cyclosporin A (Compound J);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(1,1-dioxo-thiomorpholino)-hexanoic acid] 1 [(R)-Me-Sar] 3 cyclosporin A (Compound P);
[[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-homomorpholino-hexanoic acid] 1 [(R)-methyl-Sar] 3 cyclosporin A (Compound X);
[(6R,7R,8S)-7-hydroxy-6-methyl-8-(methylamino)-1-N-morpholino-nonanoic acid] 1 [(R)-methyl-Sar] 3 cyclosporin A (Compound G);
[(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-N-morpholino-1-oxo-octanoic acid] 1 [(R)-methyl-Sar] 3 cyclosporin A (Compound H);
[(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-(4-methylpiperazin-1-yl)-1-oxo-octanoic acid] 1 [(R)-methyl-Sar] 3 cyclosporin A (Compound T);
[(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-({1,1-dioxo}thiomorpholin-4-yl)-1-oxo-octanoic acid] 1 [(R)-methyl-Sar] 3 cyclosporin A (Compound Z);
[(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-(N-(3 aR*,6aS*)-2-methyloctahydropyrrolo[3,4-c]pyrrolo)-1-oxo-octanoic acid]1[(R)-methyl-Sar]3 cyclosporin A (Compound ZZ);
[(5R,6R,7S)-6-Hydroxy-5-methyl-7-(methylamino)-1-piperidino-1-oxo-octanoic acid] 1 [(R)-methyl-Sar] 3 cyclosporin A (Compound Q);
[(3R,4R,5S)-4-hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(R)-ethyl-Sar] 3 cyclosporin A (Compound AB);
[(3R,4R,5S)-4-hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(S)-thiomethyl-Sar] 3 cyclosporin A (Compound K);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(S)-thio-isopropyl-Sar] 3 cyclosporin A (Compound I);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(S)-methoxy-Sar] 3 cyclosporin A (Compound B);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(R)-methoxymethylene-Sar] 3 cyclosporin A (Compound D);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(R)-hydroxymethyl-Sar] 3 cyclosporin A (Compound V);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(R)2-diethylamino ethyl oxymethyl-Sar] 3 cyclosporin A (Compound S);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-homomorpholino-hexanoic acid] 1 [(R)2 diethylamino ethyl oxymethyl-Sar] 3 cyclosporin A (Compound AD);
[(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-(N-morpholino)-octanoic acid] 1 [(R)-methyl-Sar] 3 cyclosporin A (Compound KG);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(S)-2-diethylaminoethylthiomethyl-Sar] 3 cyclosporin A (Compound AC);
[(3R,4R,5S)-1-(3,3-Dimethyl-morpholin-4-yl)-4-hydroxy-3-methyl-5-(methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3 cyclosporin A (Compound DS);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-methylamino((R)-3-methyl-morpholin-4-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3 cyclosporin A (Compound DT);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3 cyclosporin A (Compound DV);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(S)-3-methyl-morpholin-4-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3 cyclosporin A (Compound DW);
[(3R,4R,5S)-1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-Hydroxy-3-methyl-5-(methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3 cyclosporin A (Compound DY);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(piperidin-1-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3 cyclosporin A (Compound EA);
[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(2-trifluoromethyl-piperidin-1-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3 cyc

Assignees

• Allergan Inc

Inventors

• Pettit Simon N
• Jones Andrew D
• Frydrych Catherine Simone V
• Carling William R
• Garst Michael E

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K7/645 Primary

  Cyclosporins; Related peptides · CPC title