Combinations of prostaglandins and brimonidine or derivatives thereof

• US 6,294,563 B1
• Filed: 11/15/1999
• Issued: 09/25/2001
• Est. Priority Date: 10/27/1994
• Status: Expired due to Term

• Current Assignee: Allergan Incorporated (Abbvie Incorporated)
• Original Assignee: Allergan Sales LLC (Abbvie Incorporated)
• Inventors: Garst, Michael E.
• Primary Examiner(s): FAY, ZOHREH A
• Application Number:
  US09/440,379
• Time in Patent Office: 680 Days
• Field of Search: 514/530, 514/573, 514/912, 514/913, 514/393
• US Class Current: 514/392
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/557 Eicosanoids, e.g. leukotrienes or prostaglandins
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 31/5585 having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin

Abstract

The invention concerns combinations of alpha adrenergic agents such as brimonidine and its derivatives as represented by formula (I) below

wherein each Y is independently selected from the group consisting of N, N—CH3, O, S and C—R₁; R₁ is hydrogen, lower alkyl or oxo; R₂, R₃ and R₄ are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkenyl; n is an integer from 1 to 3; and a broken line beside a solid line indicates either a single or a double bond with the proviso that when n=1, both bonds from Y to C—R1 cannot be double bonds,

and prostaglandins known in the art to cause lowering of intraocular pressure

which are useful in compositions, methods of treatment and articles of manufacture for the treatment of glaucoma and alleviation of elevated intraocular pressure and providing neuroprotection.

Claims

1. A method of treating a mammal suffering from glaucoma or ocular hypertension, comprising administering to the mammal a therapeutically effective amount of a prostaglandin and a therapeutically effective amount of an alpha adrenergic agent of formula (I)

wherein each Y is independently selected from the group consisting of N, N—

CH3, O, S and C—

R₁;

R₁is hydrogen, lower alkyl or oxo;

R₂, R₃ and R₄ are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkenyl;

n is an integer from 1 to 3; and

a broken line beside a solid line indicates either a single or a double bond, provided that two double bonds are not on the same carbon in the case when n=1, and their pharmaceutically acceptable salts and esters as appropriate wherein said method provides neuroprotection.

2. The method of claim 1 wherein the prostaglandin is selected from the group consisting of PGF_2α

, PGE₂, PGE₁, prostacyclin, 15(S)-methyl-PGF_2α

, 16,16-dimethyl-PGF_2α

, 15(S)-methyl-PGE₂,16,16-dimethyl-PGE₂, 17,18,19,20-tetranor-16-phenoxy-PGE2, 17,18, 19,20-tetranor-16-phenoxy-PGF_2α

, 18,19,20-trinor-17-phenyl-PGE₂, 18,19,20-trinor-17-phenyl-PGF_2α

, the free acid and lower alkyl esters of PGF_2α

, wherein the omega chain has been replaced with phenylethylsulfonamidomethyl-, trimoprostil, RS-84-135, rioprostil, S-1033 (15-deshydroxy PGF_2α

, sodium salt), S-747260, nocloprost, CS-412, YPG-209, K-10134, cloprostenol, fluprostenol, luporstiol, etiproston, tiaprost, SQ 27986, ZK 138519, 13,14-dihydro-ZK 138519, ZK 118182, 13,14-dihydro-ZK 118182, ZK 110841, 13,14-dihydro-ZK 110841, PhXA41 (latanoprost), RO-221327, HR-466, HR-601, ONO-1206, UFO-21, 11-deoxy-PGE₂, 11-deoxy-PGF_2α

, 11-deoxy-16,16-dimethyl-PGE₂, 11-deoxy-15(S)-methyl-PGE₂, 11-deoxy-15(S)-methyl-PGF_2α

, misoprostol, enisoprost, MDL-646, CL-115,574, CL-115,347, TR-4161, TR-4752, TR-4367, CP-27987, sulprostone, gemeprost, alfaprostol, delprostenate, prostalene, fenprostalene, CL-116,069, ONO-995 and RO-229648, and their pharmaceutically acceptable esters and salts, as appropriate.

3. The method of claim 2 wherein the prostaglandin is selected from the group consisting of PGF_2α

-11-pivalyl ester, the 1-amido-15-methyl ether of PGF_2α

1-ethylamido-18,19,20-trinor-17-phenyl-PGF_2α

, PGF_2α

-1-ethyl ester, PGF_2α

-1-isopropyl ester, the acid and isopropyl ester derivatives of PGF_2α

wherein the omega chain has been replaced with phenylethylsulfonamidomethyl-, as represented by the structure below;

RO-229648, SQ 27986, ZK 138519, 13,14-dihydro-ZK 138519, ZK 110841, 13,14-dihydro-ZK 110841, PhXA41, and 18,19,20-trinor-17-phenyl-PGF_2α

-1-methyl ester.

4. The method of claim 1 wherein the alpha adrenergic agent is further selected from formula (I) to contain the groups of formula (II) wherein R2 is bromine or methyl and all other variables are defined as in claim 1.

5. The method of claim 3 wherein the alpha adrenergic agent is brimonidine (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine).

6. The method of claim 4 wherein the alpha adrenergic agent is brimonidine (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine).

7. The method of claim 1 wherein the prostaglandin is the 11-pivalyl ester of PGF_2α

and the alpha adrenergic agent is brimonidine.