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Claims for Patent: 5,688,819

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Claims for Patent: 5,688,819

Title: Cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents
Abstract:The present invention provides cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compounds, which may be substituted in the 1-position with amino, amido, ether or ester groups, e.g., a 1-OH cyclopentane heptanoic acid, 2-(cycloalkyl or arylalkyl) compound. The cyclopentane heptanoic acid, 2-(cycloalkyl or arylalkyl) compounds of the present invention are potent ocular hypotensives, and are particularly suitable for the management of glaucoma. Moreover, the cyclopentane heptanoic, 2-(cycloalkyl or arylalkyl) compounds of this invention are smooth muscle relaxants with broad application in systemic hypertensive and pulmonary diseases; smooth muscle relaxants with application in gastrointestinal disease, reproduction, fertility, incontinence, shock, etc.
Inventor(s): Woodward; David F. (El Toro, CA), Andrews; Steven W. (Rancho Santa Marguerita, CA), Burk; Robert M. (Irvine, CA), Garst; Michael E. (Newport Beach, CA)
Assignee: Allergan (Waco, TX)
Application Number:08/605,567
Patent Claims: 1. A method of treating ocular hypertension or glaucoma which comprises applying to the eye an amount sufficient to treat ocular hypertension or glaucoma of a compound represented by the formula V ##STR14## wherein X is a radical selected from the group consisting --OR.sup.4 and --N(R.sup.4).sub.2 wherein R.sup.4 is selected from the group consisting of hydrogen, a lower alkyl radical having from one to six carbon atoms, ##STR15## wherein R.sup.5 is a lower alkyl radical having from one to six carbon atoms; Z is .dbd.O or represents 2 hydrogen radicals; Y' is Cl or trifluoromethyl and the 9- and/or 11- and/or 15 esters, thereof.

2. The method of claim 1 wherein Z is .dbd.O and X is selected from the group consisting of NH.sub.2.

3. The method of claim 1 wherein Z is .dbd.O and X is selected from the group consisting of amido radicals.

4. The method of claim 1 wherein X is selected from the group consisting of NH.sub.2 and OCH.sub.3.

5. A method of treating ocular hypertension or glaucoma which comprises applying to the eye an amount sufficient to treat ocular hypertension or glaucoma of the formula ##STR16## wherein the dashed bonds represent a single or double bond which can be in the cis or trans configuration, X is a radical selected from the group consisting of --OR.sup.4 and --N(R.sup.4).sub.2 wherein R.sup.4 is selected from the group consisting or hydrogen, a lower alkyl radical having from one to six carbon atoms, ##STR17## wherein R.sup.5 is a lower alkyl radical having from one to six carbon atoms; Z is .dbd.O or represents 2 hydrogen radicals; R.sub.3 is .dbd.O, --OH or --O(CO)R.sub.6 ; one of R.sub.1 and R.sub.2 is .dbd.O, --OH or a --O(CO)R.sub.6 group, and the other one is --OH or --O(CO)R.sub.6, or R.sub.1 is .dbd.O and R.sub.2 is H, wherein R.sub.6 is a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms, or --(CH.sub.2).sub.m R.sub.7 wherein m is 0-10, and R.sub.7 is cycloalkyl radical, having from three to seven carbon atoms, or a hydrocarbyl aryl or heteroaryl radical having from four to ten carbon atoms wherein the heteroatom is selected from the group consisting of nitrogen, oxygen and sulfur atoms; or a pharmaceutically-acceptable salt thereof, provided however that when Z is .dbd.O, then X is not --OR.sup.4.

6. The method of claim 5 wherein said compound is represented by the formula ##STR18## wherein hatched lines indicate the .alpha. configuration and solid triangles indicate the .beta. configuration.

7. The method of claim 6 wherein said compound is represented by the formula ##STR19##

8. The method of claim 7 wherein said compound is represented by the formula ##STR20## and the 9- and/or 11- and/or 15 esters, thereof.

9. The method of claim 8 wherein Z is .dbd.O and X is --N(R.sup.4).sub.2.

10. The method of claim 9 wherein said compound is selected from the group consisting of

cyclopentane heptenamide-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihyd roxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane N,N-dimethylheptenamide-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-trans-penteny l)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane N-isopropyl hepteneamide-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-trans-pentenyl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane N-ethyl heptenamide-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-trans-pentenyl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ]; and

cyclopentane N-methyl heptenamide-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-trans-pentenyl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ].

11. A method of treating cardiovascular pulmonary-respiratory, gastrointestinal, reproductive and allergic diseases and shock in a human which comprises administering to said human an effective amount of a compound of formula I ##STR21## wherein the dashed bonds represent a single or double bond which can be in the cis or trans configuration, A is alkylene or alkenylene radical having from two to six carbon atoms, which radical may be interrupted by one or more oxide radicals and substituted with one or more hydroxy, oxo, alkyloxy or alkylcarboxy groups wherein said alkyl radical comprises from one to six carbon atoms, or an aryl radical selected from the group consisting of hydrocarbyl aryl and heteroaryl radicals having from four to ten carbon atoms wherein the heteroatom is selected from the group consisting of nitrogen, oxygen and sulfur atoms; B is a cycloalkyl radical having from three to seven carbon atoms, or an aryl radical, selected from the group consisting of hydrocarbyl aryl and heteroaryl radicals having from four to ten carbon atoms wherein the heteroatom is selected from the group consisting of nitrogen, oxygen and sulfur atoms; X is a radical selected from the group consisting of --OR.sup.4 and --N(R.sup.4).sub.2 wherein R.sup.4 is selected from the group consisting or hydrogen, a lower alkyl radical having from one to six carbon atoms, ##STR22## wherein R.sup.5 is a lower alkyl radical having from one to six carbon atoms; Z is .dbd.O or represents 2 hydrogen radicals; one of R.sub.1 and R.sub.2 is .dbd.O, --OH or a --O(CO)R.sub.6 group, and the other one is --OH or --O(CO)R.sub.6, or R.sub.1 is .dbd.O and R.sub.2 is H, wherein R.sub.6 is a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms, or --(CH.sub.2).sub.m R.sub.7 wherein m is 0-10, and R.sub.7 is cycloalkyl radical, having from three to seven carbon atoms, or a hydrocarbyl aryl or heteroaryl radical, as defined above, or a pharmaceutically-acceptable salt thereof, provided however that when B is not substituted with a pendant heteroatom-containing radical and Z is .dbd.O, then X is not --OR.sup.4.

12. The method of claim 11 wherein said compound represented by the formula (II) ##STR23## wherein y is 0 or 1, x is 0 or 1 and x+y are not both 1, Y is a radical selected from the group consisting of alkyl, halo, nitro, amino, thiol, hydroxy,. alkyloxy, alkylcarboxy and halosubstituted alkyl, wherein said alkyl radical comprises from one to six carbon atoms, n is 0 or an integer of from 1 to 3 and R.sub.3 is .dbd.O, --OH or --O(CO)R.sub.6.

13. The method of claim 12 wherein said compound is represented by formula III. ##STR24## wherein hatched lines indicate the .alpha. configuration and solid triangles indicate the .beta. configuration.

14. The method of claim 13 wherein said compound is represented by the formula IV. ##STR25## wherein Y.sup.1 is Cl or trifluoromethyl.

15. The method of claim 14 wherein said compound is a represented by the formula V ##STR26## and the 9- and/or 11- and/or 15 esters, thereof.

16. The method of claim 15 wherein Z is .dbd.O and X is selected from the group consisting of NH.sub.2 or OCH.sub.3.

17. The method of claim 15 wherein Y.sup.1 is Cl or trifluoromethyl, Z is .dbd.O and X is selected from the group consisting of alkoxy and amido radicals.

18. The method of claim 11 wherein said compound is selected from the group consisting of:

cyclopentane heptenol-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-trans-pentenyl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane heptenamide-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-trans-pentenyl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane N,N-dimethylheptenamide-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-trans-penteny l)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane heptenyl methoxide-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-trans-pentenyl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane heptenyl ethoxide-5-cis-2-(3.alpha.-hydroxy-4-meta-chloro-phenoxy-1-trans-butenyl)- 3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane heptenylamide-5-cis-2-(3.alpha.-hydroxy-4-meta-chloro-phenoxy-1-trans-bute nyl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane heptenylamide-5-cis-2-(3.alpha.-hydroxy-4-meta-trifluoromethyl-phenoxy-1-t rans-butenyl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane N-isopropyl heptenamide-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-trans-pentenyl)-3, 5-dihydroxy, [1.sub.a,2.sub.b,3.sub.a,5.sub.a ];

cyclopentane N-ethyl heptenamide-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-trans-pentenyl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane N-methyl heptenamide-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-trans-pentenyl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane N-methyl heptenamide-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-trans-pentenyl-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane heptenol-5-cis-2-(3.alpha.-hydroxy-4-m-chlorophenoxy-1-trans-butenyl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane heptenamide-5-cis-2-(3.alpha.-hydroxy-4-m-chlorophenoxy-1-trans-butenyl)-3 , 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ] and

cyclopentane heptenol-5-cis-2-(3.alpha.-hydroxy-5-phenylpentyl)3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ].

19. The method of claim 17 wherein X is selected from the group consisting of NH.sub.2 and OCH.sub.3.

20. The method of claim 11 wherein said compound is selected from the group consisting of:

cyclopentane heptenoic acid-5-cis-2-(3.alpha.-hydroxy-4-meta-chloro-phenoxy-1-trans-butenyl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane heptenylamide-5-cis-2-(3.alpha.-hydroxy-4-meta-chloro-phenoxy-1-trans-bute nyl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ];

cyclopentane heptenylamide-5-cis-2-(3.alpha.-hydroxy-4-meta-trifluoromethyl-phenoxy-1-t rans-butenyl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ]; and

cyclopentane heptenonic acid-5-cis-2-(3.alpha.-hydroxy-4-meta-trifluoromethylphenoxy-1-trans-buten yl)-3, 5-dihydroxy, [1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub..alpha. ].
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