Cyclosporins modified on the MeBmt sidechain by heterocyclic rings

Patent metadata

Field	Value
Publication number	US-10077289-B2
Application number	US-201615072738-A
Country	US
Kind code	B2
Filing date	Mar 17, 2016
Priority date	Mar 31, 2015
Publication date	Sep 18, 2018
Grant date	Sep 18, 2018

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 the following structure:

wherein:
Het 1 is a monocyclic or polycyclic aromatic heterocyclyl optionally substituted with 1 or more R a ; wherein each R a is independently selected from the group consisting of halogen, —C 1-6 alkyl, —OC 1-6 alkyl and —(CH 2 ) n R b ;
wherein each R b is independently Het 2 , —C 1-6 haloalkyl, —OH, —NH 2 , —NH(C 1-6 alkyl) or —N(C 1-6 alkyl) 2 , wherein each C 1-6 alkyl is the same or different; and
wherein each Het 2 is independently a heterocyclyl optionally substituted with one or more halogen, —C 1-6 alkyl, —C 1-6 haloalkyl, —OC 1-6 alkyl, —(CH 2 ) 1-6 OH, —(CH 2 ) 1-6 NH 2 , —(CH 2 ) 1-6 NH(C 1-6 alkyl) or —(CH 2 ) 1-6 N(C 1-6 alkyl) 2 , wherein each C 1-6 alkyl is the same or different;

R 2 is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 3 or —CH(CH) 3 (OH);
R 3 is —H, —C 1-6 alkyl, —OC 1-6 alkyl, —SC 1-6 alkyl, —CH 2 OH, —CH 2 OCH 3 ,

R 4 is —CH 3 or —CH 2 CH 3 ;
R 5 is —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 2 (OH), —CH(CH 3 )(CH 2 CH 3 ) or —CH 2 CH(R c )(CH 2 CH 3 ), wherein R c is OC 1-6 alkyl;
R 6 is —CH 3 or —CH 2 OH;
m is 1; and
n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein Het 1 is a bicyclic aromatic heterocyclyl, said compound having the following structure:

wherein q is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein Het 1 is a monocyclic aromatic heterocyclyl, said compound having the following structure:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

6. A method of treating a medical condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, thereby treating the condition;
wherein the medical condition is dry eye, dry eye disease, ocular surface inflammation, blepharitis, meibomian gland disease, allergic conjunctivitis, pterygium, ocular symptoms of graft versus host disease, ocular allergy, atopic keratoconjunctivitis, vernal keratoconjunctivitis, uveitis, anterior uveitis, Behcet's disease, Steven Johnson syndrome, ocular cicatricial pemphigoid, chronic ocular surface inflammation caused by viral infection, herpes simplex keratitis, adenoviral keratoconjunctivitis, ocular rosacea, pinguecula, corneal transplant rejection, inflammation in an eye caused by an ocular surgery or suppressed tear production due to ocular inflammation associated with keratoconjunctivitis sicca.

7. The method of claim 6 , wherein the subject is a human.

Assignees

• Allergan Inc

Inventors

• Pettit Simon N
• Jones Andrew D
• Frydrych Catherine Simone V
• Thomas Alex J
• Garst Michael E

Classifications

• C07K7/645 Primary

  Cyclosporins; Related peptides · 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

• A61P27/02

  Ophthalmic agents · CPC title