U.S. patent application number 10/282726 was filed with the patent office on 2003-06-19 for non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents.
Invention is credited to Andrews, Steven W., Burk, Robert M., Garst, Michael E., Woodward, David F..
Application Number | 20030114528 10/282726 |
Document ID | / |
Family ID | 27538472 |
Filed Date | 2003-06-19 |
United States Patent
Application |
20030114528 |
Kind Code |
A1 |
Woodward, David F. ; et
al. |
June 19, 2003 |
Non-acidic 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.
Inventors: |
Woodward, David F.; (El
Toro, CA) ; Andrews, Steven W.; (Rancho Santa
Marguerita, CA) ; Burk, Robert M.; (Irvine, CA)
; Garst, Michael E.; (Newport Beach, CA) |
Correspondence
Address: |
ROBERT J. BARAN (T2-7H)
ALLERGAN, INC.
2525 Dupont Drive
Irvine
CA
92612
US
|
Family ID: |
27538472 |
Appl. No.: |
10/282726 |
Filed: |
October 28, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10282726 |
Oct 28, 2002 |
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08876937 |
Jun 16, 1997 |
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08876937 |
Jun 16, 1997 |
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08605567 |
Feb 22, 1996 |
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5688819 |
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08605567 |
Feb 22, 1996 |
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08371339 |
Jan 11, 1995 |
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5607978 |
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08371339 |
Jan 11, 1995 |
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08154244 |
Nov 18, 1993 |
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08154244 |
Nov 18, 1993 |
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07948056 |
Sep 21, 1992 |
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5352708 |
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Current U.S.
Class: |
514/568 ;
514/555 |
Current CPC
Class: |
A61K 31/559 20130101;
A61P 27/02 20180101; C07C 255/36 20130101; C07C 405/00 20130101;
A61K 31/5585 20130101; C07C 215/42 20130101; Y10S 514/913 20130101;
A61K 31/381 20130101; A61K 31/557 20130101; A61K 31/5575 20130101;
C07C 35/21 20130101; A61P 27/06 20180101; C07C 247/10 20130101;
C07C 235/34 20130101; C07C 2601/08 20170501 |
Class at
Publication: |
514/568 ;
514/555 |
International
Class: |
A61K 031/557 |
Claims
26. A method of treating glaucoma and ocular hypertension which
comprises topically administering to the affected eye a
therapeutically effective amount of a compound of formula:
14wherein R.sup.1=hydrogen, a cationic salt moiety, a
pharmaceutically acceptable amine moiety or C.sub.1-C.sub.12 alkyl
cycloalkyl or aryl; and R.sup.2=Cl or CF.sub.3.
27. The method of claim 26, wherein R.sup.1 is selected from the
group consisting of H, CH.sub.3, CH(CH.sub.3).sub.2 and
C(CH.sub.3).sub.3.
28. The method of claim 26, wherein R.sup.1 is selected from the
group consisting of Na.sup.+ and CH.sub.3
N.sup.+(CH.sub.2OH).sub.3.
29. The method of claim 26, wherein R.sup.2 is Cl.
30. The method of claim 27, wherein R.sup.2 is CF.sub.3.
31. The method of claim 26, wherein between about 0.001 and about
1000 .mu.g/eye of a compound of formula (I) is administered.
32. The method of claim 31, wherein between about 0.01 and about
100 .mu.g/eye of a compound of formula (I) is administered.
33. The method of claim 31, wherein between about 0.05 and about 10
.mu.g/eye of a compound of formula (I) is administered.
34. A topical ophthalmic composition for the treatment of glaucoma
and ocular hypertension in primates, comprising topically a
therapeutically effective amount of a compound of formula:
15wherein R.sup.1=hydrogen, a cationic salt moiety, a
pharmaceutically acceptable amine moiety or C.sub.1-C.sub.12 alkyl
cycloalkyl or aryl; and R.sup.2=Cl or CF.sub.3.
35. The composition of claim 34, wherein R.sup.1 is selected from
the group consisting of H, CH.sub.3, CH(CH.sub.3).sub.2 and
C(CH.sub.3).sub.3.
36. The composition of claim 34, wherein R.sup.1 is selected from
the group consisting of Na.sup.+ and
CH.sub.3N.sup.+(CH.sub.2OH).sub.3.
7. The method of claim 6, wherein between about 0.01 and about 100
.mu.g/eye of a compound of formula (I) is administered.
8. The method of claim 6, wherein between about 0.05 and about 10
.mu.g/eye of a compound of formula (I) is administered.
9. A topical ophthalmic composition for the treatment of glaucoma
and ocular hypertension in primates, comprising topically a
therapeutically effective amount of a compound of formula:
16wherein R.sup.1=hydrogen, a cationic salt moiety, a
pharmaceutically acceptable amine moiety or C.sub.1-C.sub.12 alkyl
cycloalkyl or aryl; and R.sup.2=Cl or CF.sub.3.
10. The composition of claim 9, wherein R.sup.1 is selected from
the group consisting of H, CH.sub.3, CH(CH.sub.3).sub.2 and
C(CH.sub.3).sub.3.
11. The composition of claim 9, wherein R.sup.1 is selected from
the group consisting of Na.sup.+ and
CH.sub.3N.sup.+(CH.sub.2OH).sub.3.
12. The composition of claim 9, wherein R.sup.2 is Cl.
13. The composition of claim 9, wherein R.sup.2 is CF.sub.3.
14. The composition of claim 9, wherein between about 0.001 and
about 100 .mu.g/eye of a compound of formula (I) is
administered.
15. The composition of claim 14, wherein between about 0.01 and
about 100 .mu.g/eye of a compound of formula (I) is
administered.
16. The composition of claim 15, wherein between about 0.05 and
about 10 .mu.g/eye of a compound of formula (I) is
administered.
17. A method of treating glaucoma and ocular hypertension, which
comprises topically administering to the affected eye a
therapeutically effective amount of a compound of formula:
17wherein R.sup.1=a pharmaceutically acceptable ester moiety; and
R.sup.2=Cl or CF.sub.3.
18. The method of claim 17, wherein R.sup.2 is Cl.
19. The method of claim 17, wherein R.sup.2 is CF.sub.3.
20. The method of claim 17, wherein between about 0.001 and about
1000 .mu.g/eye of a compound of formula (I) is administered.
21. A method of treating glaucoma and ocular hypertension which
comprises topically administering to the affected eye a
therapeutically effective amount of cyclopentane heptenoic acid,
5-cis-2-(3-.alpha.-hydroxy-4-m-chl-
orophenoxy-1-trans-butenyl)-3,5-dihydroxy
1.sub..alpha.,2.sub..beta.,3.sub- ..alpha.,5.sub..alpha.].
22. A method of treating glaucoma and ocular hypertension which
comprises topically administering to the affected eye a
therapeutically effective amount of fluprostenol.
23. A topical ophthalmic composition for the treatment of glaucoma
and ocular hypertension in humans, comprising a therapeutically
effective amount of fluprostenol.
37. The composition of claim 34, wherein R.sup.2 is Cl.
38. The composition of claim 34, wherein R.sup.2 is CF.sub.3.
39. The composition of claim 34, wherein between about 0.001 and
about 100 .mu.g/eye of a compound of formula (I) is
administered.
40. The composition of claim 39, wherein between about 0.01 and
about 100 .mu.g/eye of a compound of formula (I) is
administered.
41. The composition of claim 40, wherein between about 0.05 and
about 10 .mu.g/eye of a compound of formula (I) is
administered.
42. A method of treating glaucoma and ocular hypertension, which
comprises topically administering to the affected eye a
therapeutically effective amount of a compound of formula:
18wherein R.sup.1=a pharmaceutically acceptable ester moiety; and
R.sup.2=C.sub.1 or CF.sub.3.
43. The method of claim 42, wherein R.sup.2 is Cl.
44. The method of claim 42, wherein R.sup.2 is CF.sub.3.
45. The method of claim 42, wherein between about 0.001 and about
1000 .mu.g/eye of a compound of formula (I) is administered.
46. A method of treating glaucoma and ocular hypertension which
comprises topically administering to the affected eye a
therapeutically effective amount of cyclopentane heptenoic acid,
5-cis-2-(3-a-hydroxy-4-m-chlorophe-
noxy-1-trans-butenyl)-3,5-dihydroxy
1.sub..alpha.,2.sub..beta.,3.sub..alph- a.,5.sub..alpha.].
47. A method of treating glaucoma and ocular hypertension which
comprises topically administering to the affected eye a
therapeutically effective amount of fluprostenol.
48. A topical ophthalmic composition for the treatment of glaucoma
and ocular hypertension in humans, comprising a therapeutically
effective amount of fluprostenol.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This patent application is a continuation of U.S. patent
application Ser. No. 08/876,937, filed on Jun. 16, 1997, which is a
continuation-in-part of U.S. patent application Ser. No.
08/371,339, filed on Jan. 11, 1995, now U.S. Pat. No. 5,607,978,
which is a continuation of U.S. patent application Ser. No.
08/154,244 which was filed on Nov. 18, 1993, now abandoned, which
is a divisional of U.S. patent application Ser. No. 07/948,056,
filed on Sep. 21, 1992, now U.S. Pat. No. 5,352,708 issued on Oct.
4, 1994, all of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] 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.
[0004] 2. Description of the Related Art
[0005] Ocular hypotensive agents are useful in the treatment of a
number of various ocular hypertensive conditions, such as
post-surgical and post-laser trabeculectomy ocular hypertensive
episodes, glaucoma, and as presurgical adjuncts.
[0006] Glaucoma is a disease of the eye characterized by increased
intraocular pressure. On the basis of its etiology, glaucoma has
been classified as primary or secondary. For example, primary
glaucoma in adults (congenital glaucoma) may be either open-angle
or acute or chronic angle-closure. Secondary glaucoma results from
pre-existing ocular diseases such as uveitis, intraocular tumor or
an enlarged cataract.
[0007] The underlying causes of primary glaucoma are not yet known.
The increased intraocular tension is due to the obstruction of
aqueous humor outflow. In chronic open-angle glaucoma, the anterior
chamber and its anatomic structures appear normal, but drainage of
the aqueous humor is impeded. In acute or chronic angle-closure
glaucoma, the anterior chamber is shallow, the filtration angle is
narrowed, and the iris may obstruct the trabecular meshwork at the
entrance of the canal of Schlemm. Dilation of the pupil may push
the root of the iris forward against the angle, and may produce
pupillary block and thus precipitate an acute attack. Eyes with
narrow anterior chamber angles are predisposed to acute
angle-closure glaucoma attacks of various degrees of severity.
[0008] Secondary glaucoma is caused by any interference with the
flow of aqueous humor from the posterior chamber into the anterior
chamber and subsequently, into the canal of Schlemm. Inflammatory
disease of the anterior segment may prevent aqueous escape by
causing complete posterior synechia in iris bombe and may plug the
drainage channel with exudates. Other common causes are intraocular
tumors, enlarged cataracts, central retinal vein occlusion, trauma
to the eye, operative procedures and intraocular hemorrhage.
[0009] Considering all types together, glaucoma occurs in about 2%
of all persons over the age of 40 and may be asymptotic for years
before progressing to rapid loss of vision. In cases where surgery
is not indicated, topical b-adrenoreceptor antagonists have
traditionally been the drugs of choice for treating glaucoma.
[0010] Prostaglandins were earlier regarded as potent ocular
hypertensives; however, evidence accumulated in the last two
decades shows that some prostaglandins are highly effective ocular
hypotensive agents and are ideally suited for the long-term medical
management of glaucoma. (See, for example, Starr, M. S. Exp. Eye
Res. 1971, 11, pp. 170-177; Bito, L. Z. Biological Protection with
Prostaglandins Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc.,
1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the
Medical Treatment of Glaucomas Drance, S. M. and Neufeld, A. H.
eds., New York, Grune & Stratton, 1984, pp. 477-505). Such
prostaglandins include PGF.sub.2a, PGF.sub.1a, PGE.sub.2, and
certain lipid-soluble esters, such as C.sub.1 to C.sub.5 alkyl
esters, e.g. 1-isopropyl ester, of such compounds.
[0011] In the U.S. Pat. No. 4,599,353 certain prostaglandins, in
particular PGE.sub.2 and PGF.sub.2a and the C.sub.1 to C.sub.5
alkyl esters of the latter compound, were reported to possess
ocular hypotensive activity and were recommended for use in
glaucoma management.
[0012] Although the precise mechanism is not yet known, recent
experimental results indicate that the prostaglandin-induced
reduction in intraocular pressure results from increased
uveoscleral outflow [Nilsson et al., Invest. Ophthalmol. Vis. Sci.
28(suppl), 284 (1987)].
[0013] The isopropyl ester of PGF.sub.2a has been shown to have
significantly greater hypotensive potency than the parent compound,
which was attributed to its more effective penetration through the
cornea. In 1987 this compound was described as "the most potent
ocular hypotensive agent ever reported." [See, for example, Bito,
L. Z., Arch. Ophthalmol. 105, 1036 (1987), and Siebold et al.,
Prodrug 5, 3 (1989)].
[0014] Whereas prostaglandins appear to be devoid of significant
intraocular side effects, ocular surface (conjunctival) hyperemia
and foreign-body sensation have been consistently associated with
the topical ocular use of such compounds, in particular PGF.sub.2a
and its prodrugs, e.g. its 1-isopropyl ester, in humans. The
clinical potential of prostaglandins in the management of
conditions associated with increased ocular pressure, e.g.
glaucoma, is greatly limited by these side effects.
[0015] Certain phenyl and phenoxy mono, tri and tetra nor
prostaglandins and their 1-esters are disclosed in European Patent
Application 0,364,417 as useful in the treatment of glaucoma or
ocular hypertension.
[0016] In a series of co-pending United States patent applications
assigned to Allergan, Inc. prostaglandin esters with increased
ocular hypotensive activity accompanied with no or substantially
reduced side-effects are disclosed. The co-pending U.S. Ser. No.
386,835 (filed Jul. 27, 1989), relates to certain
11-acyl-prostaglandins, such as 11-pivaloyl, 11-acetyl,
11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF.sub.2a.
Intraocular pressure reducing 15-acyl prostaglandins are disclosed
in the co-pending application U.S. Ser. No. 357,394 (filed May 25,
1989). Similarly, 11,15-9,15- and 9,11-diesters of prostaglandins,
for example 11,15-dipivaloyl PGF.sub.2a are known to have ocular
hypotensive activity. See the co-pending patent applications U.S.
Ser. No. 385,645 filed Jul. 27, 1990, now U.S. Pat. No. 4,494,274;
Ser. No. 584,370 which is a continuation of U.S. Ser. Nos. 386,312,
and 585,284, now U.S. Pat. No. 5,034,413 which is a continuation of
U.S. Ser. No. 386,834, where the parent applications were filed on
Jul. 27, 1989. The disclosures of these patent applications are
hereby expressly incorporated by reference.
SUMMARY OF THE INVENTION
[0017] We have found that certain cyclopentane heptanoic acid,
2-cycloalkyl or arylalkyl compounds and derivatives thereof wherein
the carboxylic acid group is replaced by a non-acidic substituent
have pronounced effects on smooth muscle and are potent ocular
hypotensive agents. We have further found that such compounds, in
certain instances, may be significantly more potent than their
respective parent compounds and, in the case of glaucoma
surprisingly, cause no or significantly lower ocular surface
hyperemia than the parent compounds.
[0018] The present invention relates to methods of treating
cardiovascular, pulmonary-respiratory, gastrointestinal,
reproductive, allergic disease, shock and ocular hypertension which
comprises administering an effective amount of a cyclopentane
heptanoic acid, 2-cycloalkyl or arylalkyl compound represented by
the formula I 1
[0019] wherein the dashed bonds represent a single or double bond
which can be in the cis or trans configuration, A is an 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 akylcarboxy
groups wherein said alkyl radical comprises from one to six carbon
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 of hydrogen, a lower alkyl radical having from one to
six carbon atoms, 2
[0020] 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 --(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.mR.sub.- 7 wherein m is 0 or an
integer of from 1 to 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. (That is, the
cycloalkyl or hydrocarbyl aryl or heteroaryl radical is not
substituted with a pendant radical having an atom other than carbon
or hydrogen.)
[0021] More preferably the method of the present invention
comprises administering a cyclopentane heptanoic acid, 2-(phenyl
alkyl or phenyloxyalkyl) represented by the formula II 3
[0022] wherein y is 0 or 1, x is 0 or 1 and x and y are not both 1,
Y is a radical selected from the group consisting of alkyl, halo,
e.g. fluoro, chloro, etc., nitro, amino, thiol, hydroxy, alkyloxy,
alkylcarboxy, halo substituted alkyl wherein said alkyl radical
comprises from one to six carbon atoms, etc. and n is 0 or an
integer of from 1 to about 3 and R.sub.3 is .dbd.O, --OH or
--O(CO)R.sub.6 wherein R.sub.6 is as defined above. Preferably, n
is 1 or 2.
[0023] Preferably the compound used in the above method of
treatment is a compound of formula (III). 4
[0024] wherein hatched lines indicate a configuration, solid
triangles are used to indicate .beta. configuration
[0025] In another aspect, the present invention relates to a method
of treating cardiovascular, pulmonary-respiratory,
gastrointestinal, reproductive and allergic diseases, shock and
ocular hypertension which comprises administering to a subject a
pharmaceutical composition comprising a therapeutically effective
amount of a compound of formula (IV) 5
[0026] wherein Y.sup.1 is Cl or trifluoromethyl and the other
symbols and substituents are as defined above, in combination with
a pharmaceutical carrier.
[0027] Finally, the method of the present invention relates to a
method of treating cardiovascular, pulmonary-respiratory,
gastrointestinal, reproductive and allergic diseases, shock and
ocular hypertension which comprises administering to a subject a
pharmaceutical composition comprising a therapeutically effective
amount of a compound of Formula V 6
[0028] and the 9-and/or 11- and/or 15 esters thereof.
[0029] In a further aspect, the present invention relates to
pharmaceutical compositions comprising a therapeutically effective
amount of a compound of formulae (I), (II), (m), (IV) or (V)
wherein the symbols have the above meanings, or a pharmaceutically
acceptable salt thereof in admixture with a non-toxic,
pharmaceutically acceptable liquid vehicle.
[0030] In a still further aspect, the present invention relates to
cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compounds of
the above formulae, wherein the substituents and symbols are as
defined hereinabove, or a pharmaceutically acceptable salt of such
compounds.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The present invention relates to the use of cyclopentane
heptanoic acid, 2-cycloalkyl or arylalkyl compounds as therapeutic
agents, e.g. as ocular hypotensives. These therapeutic agents are
represented by compounds having the formula I, 7
[0032] as defined above. The preferred nonacidic cyclopentane
heptanoic acid, 2-(phenyl alkyl or phenyloxyalkyl) compounds used
in accordance with the present invention are encompassed by the
following structural formula (II) 8
[0033] wherein the substituents and symbols are as hereinabove
defined. More preferably the compounds are represented by formula
(III). 9
[0034] wherein the substituents and symbols are as defined above.
More preferably, the compounds utilized in the present invention
are compounds represented by the formula (IV) 10
[0035] wherein the substituents and the symbols are as defined
above.
[0036] Most preferably the present invention utilizes the novel
compounds of the formula (V) 11
[0037] and their 9- and/or 11- and/or 15 esters.
[0038] In all of the above formulae, as well as in those provided
hereinafter, the dotted lines on bonds between carbons 5 and 6
(C-5), between carbons 13 and 14 (C-13), between carbons 8 and 12
(C-8), and between carbons 10 and 11 (C-10) indicate a single or a
double bond which can be in the cis or trans configuration. If two
solid lines are used that indicates a specific configuration for
that double bond.
[0039] Hatched lines at positions C-9, C-11 and C-15 indicate the a
configuration. If one were to draw the .beta. configuration, a
solid triangular line would be used.
[0040] In the compounds used in accordance with the present
invention, compounds having the C-9 or C-11 or C-15 substituents in
the .alpha. or .beta. configuration are contemplated. As
hereinabove mentioned, in all formulas provided herein broken line
attachments to the cyclopentane ring indicate substituents in the a
configuration. Thickened solid line attachments to the cyclopentane
ring indicate substituents in the .beta. configuration. Also, the
broken line attachment of the hydroxyl group or other substituent
to the C-11 and C-15 carbon atoms signifies the .alpha.
configuration.
[0041] For the purpose of this invention, unless further limited,
the term "alkyl" refers to alkyl groups having from one to ten
carbon atoms, the term "cycloalkyl" refers to cycloalkyl groups
having from three to seven carbon atoms, the term "aryl" refers to
aryl groups having from four to ten carbon atoms. The term
"saturated or unsaturated acyclic hydrocarbon group" is used to
refer to straight or branched chain, saturated or unsaturated
hydrocarbon groups having from one to about 6, preferably one to
about 4 carbon atoms. Such groups include alkyl, alkenyl and
alkynyl groups of appropriate lengths, and preferably are alkyl,
e.g. methyl, ethyl, propyl, butyl, pentyl, or hexyl, or an isomeric
form thereof.
[0042] The definition of R.sub.6 may include a cyclic component,
--(CH.sub.2).sub.mR.sub.7, wherein n is 0 or an integer of from 1
to 10, R.sub.7 is an aliphatic ring from about 3 to about 7 carbon
atoms, or an aromatic or heteroaromatic ring. The "aliphatic ring"
may be saturated or unsaturated, and preferably is a saturated ring
having 3-7 carbon atoms, inclusive. As an aromatic ring, R.sub.7
preferably is phenyl, and the heteroaromatic rings have oxygen,
nitrogen or sulfur as a heteroatom, i.e. R.sub.7 may be thienyl,
furanyl, pyridyl, etc. Preferably m is 0 or an integer of from 1 to
4.
[0043] Z is .dbd.O or represents two hydrogen atoms.
[0044] X may be selected from the group consisting of --OR.sup.4
and --N(R.sup.4)2 wherein R.sup.4 is selected from the group
consisting of hydrogen, a lower alkyl radical having from one to
six carbon atoms, 12
[0045] wherein R.sup.5 is a lower alkyl radical having from one to
six carbon atoms.
[0046] Preferred representatives of the compounds within the scope
of the present invention are the compounds of formula V wherein X
is --OH, i.e. cyclopentane heptenoic acid, 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 methylheptenoate-5-cis-2(3-.alpha.hydroxy-
-4-m-chlorophenoxy-1-trans-butenyl)-3,5 dihydroxy,
[1.sub..alpha.,2.sub..b- eta.,3.sub..alpha.,5.sub..alpha.] and the
9-and/or 11- and/or 15-esters of this compound. (The numbered
designations in brackets refer to the positions on the cyclopentane
ring.)
[0047] The following novel compounds may be used in the
pharmaceutical compositions and the methods of treatment of the
present invention.
[0048] (1) cyclopentane
heptenol-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-tran-
s-pentenyl)-3,5-dihydroxy,
[1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub- ..alpha.]
[0049] (2) cyclopentane
heptenamide-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-t-
rans-pentenyl)-3,5-dihydroxy,
[1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.- sub..alpha.]
[0050] (3) cyclopentane
N,N-dimethylheptenamide-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.]
[0051] (4) cyclopentane heptenyl
methoxide-5-cis-2-(3.alpha.-hydroxy-5-phe-
nyl-1-trans-pentenyl)-3,5-dihydroxy,
[1.sub..alpha.,2.sub..beta.,3.sub..al- pha.,5.sub..alpha.]
[0052] (5) cyclopentane heptenyl
ethoxide-5-cis-2-(3.alpha.-hydroxy-4-meta-
-chlorophenoxy-1-trans-pentenyl)-3,5-dihydroxy,
[1.sub..alpha.,2.sub..beta- .,3.sub..alpha.,5.sub..alpha.]
[0053] (6) cyclopentane
heptenylamide-5-cis-2-(3.alpha.-hydroxy-4-meta-chl-
orophenoxy-1-trans-pentenyl)-3,5-dihydroxy,
[1.sub..alpha.,2.sub..beta., 3.sub..alpha.,5.sub..alpha.]
[0054] (7) cyclopentane
heptenylamide-cis-2-(3.alpha.-hydroxy-4-trifluorom-
ethylphenoxy-1-trans-pentenyl)-3,5-dihydroxy,
[1.sub..alpha.,2.sub..beta.,- 3.sub..alpha.,5.sub..alpha.]
[0055] (8) cyclopentane N-isopropyl
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.]
[0056] (9) cyclopentane N-ethyl
heptenamide-5-cis-2-(3.alpha.-hydroxy-5-ph-
enyl-1-trans-pentenyl)-3,5 dihydroxy,
[1.sub..alpha.,2.sub..beta.,3.sub..a- lpha.,5.sub..alpha.]
[0057] (10) 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.]
[0058] (11) cyclopentane
heptenol-5-cis-2-(3.alpha.-hydroxy-4-meta-chlorop-
henoxy-1-trans-butenyl)-3,5-dihydroxy, [1.sub..alpha.,2.sub..beta.,
3.sub..alpha.,5.sub..alpha.]
[0059] (12) cyclopentane
heptenamide-5-cis-2-(3-hydroxy-4-meta-chloropheno-
xy-1-trans-butenyl)-3,5-dihydroxy, [1.sub..alpha.,2.sub..beta.,
3.sub..alpha.,5.sub..alpha.]
[0060] (13) cyclopentane
heptenol-5-cis-2-(3.alpha.-hydroxy-5-phenyl-1-tra-
ns-pentenyl)3,5-dihydroxy,
[1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub- ..alpha.]
[0061] A pharmaceutically acceptable salt is any salt which retains
the activity of the parent compound and does not impart any
deleterious or undesirable effect on the subject to whom it is
administered and in the context in which it is administered. Such
salts are those formed with pharmaceutically acceptable cations,
e.g., alkali metals, alkali earth metals, etc.
[0062] Pharmaceutical compositions may be prepared by combining a
therapeutically effective amount of at least one compound according
to the present invention, or a pharmaceutically acceptable salt
thereof, as an active ingredient, with conventional ophthalmically
acceptable pharmaceutical excipients, and by preparation of unit
dosage forms suitable for topical ocular use. The therapeutically
efficient amount typically is between about 0.0001 and about 5%
(w/v), preferably about 0.001 to about 1.0% (w/v) in liquid
formulations.
[0063] For ophthalmic application, preferably solutions are
prepared using a physiological saline solution as a major vehicle.
The pH of such ophthalmic solutions should preferably be maintained
between 4.5 and 8.0 with an appropriate buffer system, a neutral pH
being preferred but not essential. The formulations may also
contain conventional, pharmaceutically acceptable preservatives,
stabilizers and surfactants.
[0064] Preferred preservatives that may be used in the
pharmaceutical compositions of the present invention include, but
are not limited to, benzalkonium chloride, chlorobutanol,
thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A
preferred surfactant is, for example, Tween 80. Likewise, various
preferred vehicles may be used in the ophthalmic preparations of
the present invention. These vehicles include, but are not limited
to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose,
poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose
cyclodextrin and purified water.
[0065] Tonicity adjustors may be added as needed or convenient.
They include, but are not limited to, salts, particularly sodium
chloride, potassium chloride, mannitol and glycerin, or any other
suitable ophthalmically acceptable tonicity adjustor.
[0066] Various buffers and means for adjusting pH may be used so
long as the resulting preparation is ophthalmically acceptable.
Accordingly, buffers include acetate buffers, citrate buffers,
phosphate buffers and borate buffers. Acids or bases may be used to
adjust the pH of these formulations as needed.
[0067] In a similar vein, an ophthalmically acceptable antioxidant
for use in the present invention includes, but is not limited to,
sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated
hydroxyanisole and butylated hydroxytoluene.
[0068] Other excipient components which may be included in the
ophthalmic preparations are chelating agents. The preferred
chelating agent is edentate disodium, although other chelating
agents may also be used in place of or in conjunction with it.
[0069] The ingredients are usually used in the following
amounts:
1 Ingredient Amount (% w/v) active ingredient about 0.001-5
preservative 0-0.10 vehicle 0-40 tonicity adjustor 0-10 buffer
0.01-10 pH adjustor q.s. pH 4.5-7.5 antioxidant as needed
surfactant as needed purified water as needed to make 100%
[0070] The actual dose of the active compounds of the present
invention depends on the specific compound, and on the condition to
be treated; the selection of the appropriate dose is well within
the knowledge of the skilled artisan.
[0071] The ophthalmic formulations of the present invention are
conveniently packaged in forms suitable for metered application,
such as in containers equipped with a dropper, to facilitate
application to the eye. Containers suitable for dropwise
application are usually made of suitable inert, non-toxic plastic
material, and generally contain between about 0.5 and about 15 ml
solution. One package may contain one or more unit doses.
[0072] Especially preservative-free solutions are often formulated
in non-resealable containers containing up to about ten, preferably
up to about five units doses, where a typical unit dose is from one
to about 8 drops, preferably one to about 3 drops. The volume of
one drop usually is about 20-35 ml.
[0073] The invention is further illustrated by the following
non-limiting Examples.
EXAMPLE 1
[0074] Cyclopentane Heptenoic Acid,
5-cis-2-(3.alpha.-hydroxy-m-chlorophen-
oxy-1-trans-butenyl)-3,5-dihydroxy,
[1.sub..alpha.,2.sub..beta.,3.sub..alp- ha.,5.sub..alpha.]
[0075] This compound may be purchased from Cayman Chemical Company
of Ann Arbor, Mich. or synthesized by methods known in the art.
EXAMPLE 2
[0076] Cyclopentane methylheptenoate-5-cis-2
(3.alpha.-hydroxy-4-m-chlorop-
henoxy-1-trans-butenyl)-3,5-dihydroxy,
[1.sub..alpha.,2.sub..beta.,3.sub..- alpha.,5.sub..alpha.]
[0077] To a stirred solution of cyclopentane heptenoic acid,
5-cis-2-(3.alpha.-hydroxy-4-m-chlorophenoxy-1-trans-butenyl)-3,5-dihydrox-
y, [1.sub..alpha.,2.sub..beta.,3.sub..alpha., 5.sub..alpha.](24 mg.
0.0565 mmol) in acetone (0.6 ml) at room temperature was added
1,8-diazabicyclo [5.4.0.] undec-7-ene (DBU) (40, ul, 0.27 mmol) and
methyl iodide (20 ul, 0.32 mmol). The reaction turned yellow with
the DBU addition. The reaction was maintained at room temperature
for 6.5 hours, then was diluted with ethyl acetate (30 ml) and
filtered through a plug of celite with the aid of ethyl acetate.
After concentration in vacuo, the residue was flushed with
ethylacetate (EtOAc) through a 20 mm.times.160 mm column of silica
to give the desired methyl ester.
[0078] EXAMPLE 3
Cyclopentane
Heptenamide-5-cis-2-(3.alpha.-hydroxy-4-m-chlorophenoxy-1-tra-
ns-butenyl)-3,5-dihydroxy,
[1.sub..alpha.,2.sub..beta.,3.sub..alpha.,5.sub- ..alpha.]
[0079] A mixture of the methyl ester of the compound of Example 1
(9.2 mg, 0.0222 mmol) and NH.sub.4Cl (10 mg, 0.187 mmol) in
NH.sub.3 was heated at 80.degree. C. for 12 hours. After cooling to
room temperature, the solvents were evaporated and the residue was
subjected to column chromatography to provide the named amide as
7.2 mg of a clear, colorless liquid.
EXAMPLE 4
Cyclopentane Heptenoic
Acid-5-cis2-(3.alpha.-hydroxyl-4-m-trifluoromethylp-
henoxy-1-trans-butenyl)-3,5-dihydroxy
[1.sub..alpha.,2.sub..beta.,3.sub..a- lpha.,5.sub..alpha.
[0080] This compound may be purchased from Cayman Chemical Company
of Ann Arbor, Mich. or synthesized by methods known in the art.
EXAMPLE 5
Cyclopentane
Heptenamide-5-cis2-(3.alpha.-hydroxyl-4-m-trifluoromethylphen-
oxy-1-trans-butenyl)-3,5-dihydroxy
[1.sub..alpha.,2.sub..beta.,3.sub..alph- a.,5.sub..alpha.
[0081] A mixture of the methyl ester of the compound of Example 4
(fluprostenol) and NH.sub.4Cl in NH.sub.3 is heated at 80.degree.
C. for 12 hours. After cooling to room temperature the solvents are
evaporated and the residue is subjected to column chromatography to
provide the named amide.
EXAMPLE 6
[0082] Measurement of intraocular pressure studies in dogs involved
pneumatonometry performed in conscious, Beagle dogs of both sexes
(10-15 kg). The animals remained conscious throughout the study and
were gently restrained by hand. Drugs were administered topically
to one eye as a 25 .mu.L volume drop, the other eye received
25.mu.: vehicle (0.1% polysorbate 80:10 mM TRIS) as a control. 0.1%
proparacaine was used for corneal anesthesia during tonometry.
Intraocular pressure was determined just before drug administration
and at 2, 4 and 6 hour thereafter on each day of the 5 day study.
Drug was administered twice a day, with a 6 hour interval between
doses that spanned the intraocular pressure measurement time frame.
The result reported in Table 1, below.
2TABLE 1 INTRAOCULAR PRESSURE (mmHg) CHANGE AT PREDETERMINED TIMES
(HR) COMPOUND DOSE % 2 4 6 24 Example 1 0.01 -0.1 .+-. 0.8 -5.2
.+-. 1.4** -4.3 .+-. 0.8 -4.4 .+-. 0.8 Example 1 0.1 -3.1 .+-.
0.8** -3.2 .+-. 0.7 -2.7 .+-. 0.8 -- Example 3 0.01 -2.2 .+-. 1.0*
5.5 .+-. 1.1** -4.0 .+-. 1.4* 2.7 .+-. 1.1* Example 3 0.1 -1.3 .+-.
0.4* 2.3 .+-. 0.7** -2.6 .+-. 0.6** -- Example 5 0.1 -2.7 .+-. 0.8*
-3.4 .+-. 0.9* -2.8 .+-. 0.4** -2.1 .+-. 1.6* Example 4 0.01 -0.9
.+-. 0.7 -2.5 .+-. 0.7* -3.2 .+-. 0.7** -1.3 .+-. 0.7 Fluprostenol
0.1 -1.3 .+-. 0.1 -2.1 .+-. 1.1 -2.7 .+-. 1.3 -3.1 .+-. 0.9*
Comparison of effects of certain compounds of the invention on dog
intraocular pressure. Values indicate mean changes from baseline
introcular pressure (.+-. SEM) at predetermined times post-dosing.
n = 8, *p < 0.05, **p < 0.01.
EXAMPLE 7
[0083] Measurement of ocular surface hyperemia was visually
assessed and scored according to the following schematic:
3 Hyperemia Score Assigned Value <1 1 1 slight 2 >1<2 3 2
moderate 4 >2>3 5 3 severe 6 (baseline scores for dogs are
typically < 1)
[0084] The hyperemia value for each dog at a single time point (x)
is obtained as follows: (treated eye value at hr x-baseline
value)-(control eye value at hr x-baseline value). A composite
value is then obtained by dividing the sum of the post-treatment
measurement at each time point by the number of animals in the
group: i.e. m where m=n measurements of ocular surface hyperemia.
Ocular surface hyperemia is evaluated at the same time points as
intraocular pressure measurement. It should be noted that untreated
dog eyes frequently have a pink/red tone. Thus, values of <1 and
1 are essentially within the normal range. The results are reported
in Table 2, below.
4TABLE 2 Comparison of effects of certain compounds of the
invention on dog ocular surface hyperemia. Values are composite
scores as indicated in the methods. OCULAR SURFACE HYPEREMIA:
COMPOUND DOSE % COMPOSITE SCORE Example 1 0.01 -- Example 1 0.1
0.33 Example 3 0.01 -- Example 3 0.1 0.81 Example 5 0.1 0.81
Example 4 0.01 1.08 Fluprostenol 0.1 1.50
[0085] It is clear that the compounds of Examples 1, 3 and 5,
unexpectedly, show better efficacy at lowering IOP than Example 4
while showing less hyperemia.
[0086] The compounds of the invention may also be useful in the
treatment of various pathophysiological diseases including acute
myocardial infarction, vascular thrombosis, hypertension, pulmonary
hypertension, ischemic heart disease, congestive heat failure, and
angina pectoris, in which case the compounds may be administered by
any means that effect vasodilation and thereby relieve the symptoms
of the disease. For example, administration may be by oral,
transdermal, parenterial, subcutaneous, intravenous, intramuscular,
intraperitoneal, transdermal, or buccal routes.
[0087] The compounds of the invention may be used alone, or in
combination with other of the known vasodilator drugs. The
compounds of the invention may be formulated into an ointment
containing about 0.10 to 10% of the active ingredient in a suitable
base of, for example, white petrolatum, mineral oil and petroatum
and lanolin alcohol. Other suitable bases will be readily apparent
to those skilled in the art.
[0088] The pharmaceutical preparations of the present invention are
manufactured in a manner which is itself known, for example, by
means of conventional dissolving or suspending the compounds, which
are all either water soluble or suspendable. For administration in
the treatment of the other mentioned pathophysiological disorders.
The pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
make of gelatin and a plasticizer such as glycerol or sorbitol. The
push-fit capsules can contain the active compounds in liquid form
that may be mixed with fillers such as lactose, binders such as
starches, and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds are
preferably dissolved or suspended in suitable liquids, such as in
buffered salt solution. In addition, stabilizers may be added.
[0089] In addition to being provided in a liquid form, for example
in gelatin capsule or other suitable vehicle, the pharmaceutical
preparations may contain suitable excipients to facilitate the
processing of the active compounds into preparations that can be
used pharmaceutically. Thus, pharmaceutical preparations for oral
use can be obtained by adhering the solution of the active
compounds to a solid support, optionally grinding the resulting
mixture and processing the mixture of granules, after adding
suitable auxiliaries, if desired or necessary, to obtain tablets or
dragee cores.
[0090] Suitable excipients are, in particular, fillers such as
sugars, for example lactose or sucrose, mannitol or sorbitol,
cellulose preparations and/or calcium phosphates, for example
tricalcium phosphate or calcium hydrogen phosphate, as well as
inders such as starch, paste using for example, maize starch, wheat
starch, rich starchy, potato starch, gelatin, tragacanth, methyl
cellulose, hydroxypropylmethylcellulose, sodium
carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,
disintegrating agents may be added such as the above-mentioned
starches and also carboxymethyl-starch, crosslinked polyvinyl
pyrrolidone, agar, or algenic acid or a salt thereof, such as
sodium alginate. Auxiliaries are, above all, flow-regulating agents
and lubricants, for example, silica, talc, stearic acid or salts
thereof, such as magnesium stearate or calcium stearate, and/or
polyethylene glycol. Dragee cores are provided with suitable
coatings which if desired, are resistant to gastric juices. For
this purpose, concentrated sugar solutions may be used, which may
optionally containing gum arabic, talc, polyvinyl pyrrolidone,
polyethylene glycol and/or titanium dioxide, lacquer solutions and
suitable organic solvents or solvent mixtures. In order to produce
coatings resistant to gastric juices, solutions of suitable
cellulose preparations such as acetylcellulose phthalate or
hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or
pigments may be added to the tables or dragee coatings, for
example, for identification or in order to characterize
combinations of active compound doses.
[0091] Suitable formulations for intravenous or parenteral
administration include aqueous solutions of the active compounds.
In addition, suspensions of the active compounds as oily injection
suspensions may be administered. Aqueous injection suspensions may
contain substances which increase the viscosity of the suspension
include, for example, sodium carboxymethyl cellulose, soribitol,
and/or dextran. Optionally, the suspension may also contain
stabilizers.
[0092] The foregoing description details specific methods and
compositions that can be employed to practice the present
invention, and represents the best mode contemplated. However, it
is apparent for one of ordinary skill in the art that further
compounds with the desired pharmacological properties can be
prepared in an analogous manner, and that the disclosed compounds
can also be obtained from different starting compounds via
different chemical reactions. For example, the present invention
contemplates certain prodrugs of the above disclosed compounds,
wherein R.sup.4 is 13
[0093] These compounds may be made by acylation or esterification
of the corresponding hydroxy or amino derivative. Similarly,
different pharmaceutical compositions may be prepared and used with
substantially the same result. Thus, however detailed the foregoing
may appear in text, it should not be construed as limiting the
overall scope hereof; rather, the ambit of the present invention is
to be governed only by the lawful construction of the appended
claims.
* * * * *