# US 9,040,566 B2 · Adenosine A1 agonists for the treatment of glaucoma and ocular hypertension

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- Number: US 9,040,566 B2
- Document ID: US9040566B2
- Status: Granted
- Kind: B2
- Application number: 13/819,790
- Filed: 2011-08-29
- Published: 2013-08-15
- Granted: 2015-05-26
- Earliest claimed: 2010-09-02
- Assignees: Bayer Intellectual Property GmbH
- Applicants: Jürgen Klar; Georges Von Degenfeld; Hans-Georg Lerchen; Barbara Albrecht-Küpper; Andreas Knorr; Peter Sandner; Daniel Meibom
- Inventors: Jürgen Klar; Georges Von Degenfeld; Hans-Georg Lerchen; Barbara Albrecht-Küpper; Andreas Knorr; Peter Sandner; Daniel Meibom
- Web page: https://patentgrep.com/patent/US9040566B2

## CPC

- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 38/05: Dipeptides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/02: for peripheral neuropathies
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to the use of selective adenosine A1 agonists, in particular the dicyanopyridines of formula (I), for the treatment and/or prophylaxis of glaucoma and ocular hypertension as well as the their use for the production of a medicament for the treatment and/or prophylaxis of glaucoma and ocular hypertension.

## Claims

### Claim 1

A method of treatment of glaucoma, normotensive glaucoma, ocular hypertension and/or combinations thereof comprising administering a therapeutically effective amount of a compound of formula (I) to a human or animal in need thereof, wherein the compound of formula (I) is:
in which
A is oxygen or sulfur,
R1 is hydrogen or a group of the formula
in which
# is the attachment to the oxygen-atom,
L1 is linear (C2-C4)-alkanediyl,
L2 is linear (C1-C3)-alkanediyl,
R5 and R8 are identical or different and independently selected from the group consisting of hydrogen or a side group of a natural α-amino acid or its homologues or isomers,
R6 and R9 are independently selected from hydrogen or methyl,
R7 is hydrogen or (C1-C4)-alkyl,
or
R7 and R5 form together with the atoms which they are attached to a pyrrolidine- or piperidine-ring,
R10 and R11 are identical or different and are independently selected from hydrogen or (C1-C4)-alkyl,
wherein (C1-C4)-alkyl may be substituted with one group selected from hydroxy, (C1-C4)-alkoxy, amino, mono-(C1-C4)-alkylamino or di-(C1-C4)-alkylamino,
or
R10 and R8 form together with the atoms which they are attached to a pyrrolidine- or piperidine-ring,
and
R12 is hydrogen or hydroxycarbonyl,
R2 is hydrogen or a group of the formula —CH2OR1,
wherein R1 is defined as above,
R3 is hydrogen, methyl or ethyl,
R4 is hydrogen, methyl or ethyl,
or
R3 and R4 form together with the nitrogen-atom, which they are bound to, a azetidine-, pyrrolidine- or piperidine-ring,
wherein the azetidine-, pyrrolidine- or piperidine-ring may be substituted with one or 2 substituents independently selected from the group fluoro, trifluoromethyl, methyl, ethyl, methoxy and ethoxy,
or a salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein in the compound of formula (I)
A is sulfur,
R1 is a group of the formula
in which
# is the attachment to the oxygen-atom,
L1 is ethane-1,2-diyl,
R5 is hydrogen, methyl, propane-2-yl, 1-methylpropane-1-yl, 2-methylpropane-1-yl, hydroxymethyl or 1-hydroxymethyl,
R6 is hydrogen,
R7 is hydrogen,
R8 is hydrogen, methyl, propan-2-yl, 1-methylpropan-1-yl, 2-methylpropan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, hydroxyethyl, 2-carboxyethyl, 4-aminobutan-1-yl or 2-aminoethyl,
R9 is hydrogen,
R10 is hydrogen,
R11 is hydrogen,
or
R10 and R8 form together with the atoms which they are attached to a pyrrolidine-ring,
R2 is hydrogen
R3 is hydrogen,
R4 is hydrogen,
or
R3 and R4 form together with the nitrogen-atom, which they are bound to, a azetidine-pyrrolidine- or piperidine-ring,
or a salt thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein in the compound of formula (I)
A is sulfur,
R1 is a group of the formula
in which
# is the attachment to the oxygen-atom,
R5 is hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl, benzyl, hydroxymethyl or 1-hydroxyethyl,
R6 is hydrogen,
R7 is hydrogen,
R8 is hydrogen, methyl, propan-2-yl, 1-methylpropan-1-yl, 2-methylpropan-1-yl, imidazol-4-ylmethyl, 4-aminobutan-1-yl, 2-aminoethyl, 3-aminopropan-1-yl, aminomethyl or 3-guanidinopropan-1-yl,
R9 is hydrogen,
R10 is hydrogen,
R11 is hydrogen,
R2 is hydrogen,
R3 is hydrogen,
R4 is hydrogen,
or a salt thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound of formula (I) is selected from:
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-D-alaninate-Dihydrochloride,
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-arginyl-D-alaninate-Dihydrochloride,
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-D-valinate-Dihydrochloride,
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-arginyl-D-valinate-Trihydrochloride,
2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-D-phenylalaninate-Dihydrochloride,
2-{4-[2-(Azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-beta-alaninate-Trifluoroacetate,
2-{4-[2-(Azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-ornithinate-Bis(trifluoroacetate),
2-{4-[2-(Azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-L-alaninate-Bis(trifluoroacetate),
2-{4-[2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl-L-alanyl-L-alaninate-Hydrochloride,
2-{4-[2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl-L-isoleucyl-L-alaninate-Hydrochloride,
2-{4-[2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl-glycyl-L-leucinate-Hydrochloride,
(2S)-3-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}propan-1,2-diyl-(2S,2′S)-bis(2-{[(2S)-2-aminopropanoyl]amino}propanoate)-Dihydrochloride
or a salt thereof.

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound is administered topically to the eye.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound of formula (I) is administered in the form of an ophthalmic composition comprising the compound of formula (I) and a pharmaceutically acceptable vehicle or excipient.

### Claim 7 (depends on 6)

The method of claim 6, wherein the ophthalmic composition further comprises at least one active compound selected from the group consisting of an alpha adrenergic agonist, a beta blocker, and a carbonic anhydrase inhibitors.

### Claim 8 (depends on 1)

The method of claim 1, wherein the treatment is done without effecting hemodynamics.

### Claim 9 (depends on 8)

The method of claim 8, wherein the treatment is done without effecting the blood pressure.

### Claim 10 (depends on 8)

The method of claim 8, wherein the treatment is done without effecting heart rate.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound of formula (I) is
in which
R1 is
R3 is hydrogen,
R4 is hydrogen and
HA is 2 HCl.