MXPA00004722A - Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents - Google Patents
Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agentsInfo
- Publication number
- MXPA00004722A MXPA00004722A MXPA/A/2000/004722A MXPA00004722A MXPA00004722A MX PA00004722 A MXPA00004722 A MX PA00004722A MX PA00004722 A MXPA00004722 A MX PA00004722A MX PA00004722 A MXPA00004722 A MX PA00004722A
- Authority
- MX
- Mexico
- Prior art keywords
- thienyl
- dihydroxy
- cyclopentyl
- hydroxy
- pentenyl
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims description 44
- 239000003814 drug Substances 0.000 title description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 title description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 title 1
- -1 heteroaryl radical Chemical class 0.000 claims abstract description 76
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 150000001408 amides Chemical class 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 150000003180 prostaglandins Chemical class 0.000 claims abstract description 14
- 125000001424 substituent group Chemical group 0.000 claims abstract description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 9
- 125000004432 carbon atoms Chemical group C* 0.000 claims abstract description 8
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 230000001077 hypotensive Effects 0.000 claims abstract description 7
- 239000007787 solid Substances 0.000 claims abstract description 7
- 125000005907 alkyl ester group Chemical group 0.000 claims abstract description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 6
- 101710018145 CLTC Proteins 0.000 claims abstract description 5
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 66
- 125000001544 thienyl group Chemical group 0.000 claims description 60
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Abstract
The invention relates to the use of derivatives of F-type prostaglandins as ocular hypotensives. The compounds used in accordance with the invention are represented by formula (I), wherein wavy line attachments indicate either the alpha (&agr;) or beta (&bgr;) configuration;hatched segments indicate&agr;configuration;the solid triangle is used to indicate&bgr;configuration;dashed bonds represent a double bond, or a single bond;R is a substituted heteroaryl radical having at least two pendant substituents selected from the group consisting of C1 to C6 alkyl;halogen;trifluoromethyl;COR1;COCF3;SO2NR1;NO2 and CN or at least one cyano group;R1 is hydrogen or a lower alkyl radical having up to six carbon atoms, X is selected from the group consisting of -OR1 and -N(R1)2;Y is=O or represents 2 hydrogen radicals and the 9, 11 or 15 lower alkyl esters thereof;provided, however, when said heteroaryl radical is a dichlorothienyl radical, the compound is not a 1-carboxylic acid or amide thereof. Certain of the compounds represented by Formula (I) are novel and comprise another aspect of the present invention.
Description
DERIVATIVES OF 2-HETEROARI ALKENYL OF THE CICLOPENTAN ACID HEPTAN (EN) PEAK AS THERAPEUTIC AGENTS
Field of Invention
The present invention relates to 2-heteroarylalkenyl derivatives of cyclopentane heptanoic acid, which can be substituted in the 1-position with hydroxyl, alkyloxy, amino and amido groups, for example derivatives of 1-OH-cyclopentan-heptanoic acid, 2-heteroarylalkenyl. These compounds are potent ocular hypotensive and are particularly suitable for the management of glaucoma.
Background of the Invention
Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy, glaucoma, and as pre-surgical adjuncts.
Glaucoma is an eye disease characterized by increased pressure
Ref: 119789 intraocular. Based on this etiology, glaucoma is classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) can be either open angle or acute or chronic closed angle. Secondary glaucoma results from pre-existing eye diseases such as uveitis, intraocular tumor or an enlarged cataract.
The root causes of primary glaucoma are not yet known. The increase in intraocular tension is due to the obstruction of the outflow of aqueous humor. In chronic open-angle glaucoma, the anterior chamber and its anatomical structure appear normal, but drainage of the aqueous humor is prevented. In chronic closed angle glaucoma, the anterior chamber becomes shallower, the angle of filtration narrows, and the iris can obstruct the trabeocular meshwork at the entrance to Schlemm's canal. Dilation of the pupil may press the iris root forward against the angle, and may cause blockage of the pupil and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of varying degrees of severity.
Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber in the anterior chamber and subsequently, in the Schlemm canal. Inflammatory disease of the anterior segment can prevent aqueous leakage by causing a complete posterior synechia in the iris pump, and can plug the drainage channel with exudates. Other common causes are infra-ocular tumors, enlarged cataracts, occlusion of the central retinal vein, trauma to the eye, operative procedures and intraocular hemorrhage.
Considering all types together, glaucoma occurs in about 2% of all people over 40 years of age and can be asymptotic for years before progressing to rapid loss of vision. In cases where surgery is not indicated, topical b-adrenoreceptor antagonists are the drugs traditionally chosen for the treatment of glaucoma.
It has been reported that certain eicosanoids and their derivatives have ocular hypotensive activity, and have been recommended for use in the management of glaucoma. Eicosanoids and their derivatives include numerous biologically important compounds such as prostaglandins and their derivatives. Prostaglandins can be described as derivatives of prostanoic acid having the following structural formula:
Various types of prostaglandins are known, depending on their structure and substituents that carry in the alicyclic ring of the skeleton of prostanoic acid. An additional classification is based on the number of unsaturated bonds on the side of the chain indicated by the numerical subscripts after the generic type of taglandino pros [eg, prostaglandin Ei (PGEi), prostaglandin E2 (PGE2)], and in the configuration of the substituents on the alicyclic ring indicated by a or ß [for example protaglandin F2a (PGF2a)].
Prostaglandins were previously regarded as potent ocular hypertensives, however, evidence accumulated in the last decade 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,
Bito, L.Z. Biological Protection with
Prostaglandins, Cohen, M.M., Boca Raton, Florida, CRC Press Inc., 1985, pages 231-252; and Bito, L.Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance, S.M. and Neufeld, A. H. editors, New York, Grunt & Stratton, 1984, pages 477-505. Such prostaglandins include PGF2a, PGFα, PGE 2, and certain lipid soluble esters, such as C 1 to C 2 alkyl esters, for example 1-isopropyl ester, of such compounds.
Although the precise mechanism is not yet known, experimental results indicate that the reduction induced by the prostaglandin results in a reduction in intraocular pressure from the elevated uveoscleral flow [Nilsson et al., Invest. Ophthalmol, Vis. Sci. (Supl), 284 (1987)].
The isopropyl ester of PGF2a has been found to have significantly greater hypotensive potency than the parent compound, presumably as a result of 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)].
While the prostaglandins appear to be devoid of significant infraocular side effects, hyperemia of the ocular surface (conjuncti val) and sensation of a foreign body that are consistently associated with topical ocular use of such compounds, in particular of PGF2a and its prodrugs, for example, its 1-isopropyl ester, in humans. The clinical potentials of prostaglandins in the management of conditions associated with increased ocular pressure, for example glaucoma, are largely limited by these side effects.
In a series of co-pending United States patents assigned to Allergan, Inc., prostaglandin esters with increased ocular hypotensive activity are described that are accompanied by no side effects or substantially reduced. The co-pending USSN 596,430
(filed October 10, 1990), refers to certain 11-acyl-protaglandins, such as 11-pivaloyl, 11-acetyl, 11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF2? f 15-Acyl prostaglandins Reducing intraocular pressure is described in copending application USSN 175,476 (filed December 29, 1993). Similarly, 11,15-, 9,15- and 9,11-diesters of prostaglandins, for example, 11,15-dipivaloyl PGF 2a are known to have ocular hypotensive activity. See patent applications co-pending USSN Nos. 385,645 (filed July 07, 1989, now US Patent 4,994,274), 584,370 (filed September 18, 1990, now US Patent 5,028,624) and 585,284 (filed September 18, 1990, now US Patent 5,034,413). The description of all of these patent applications is hereby incorporated expressly for full reference. This patent application also relates to U.S. Patent Application. Serial No. 08 / 726,921, which was filed on October 7, 1996 in the name of Burk, which is a Continued Submission of a U.S. Patent Application. Serial No. 08 / 443,992 filed May 18, 1995 in the name of Burk, both patent applications are expressly incorporated herein for full reference.
/ Brief Description of the Invention
The present invention concerns a method for the treatment of ocular hypertension which comprises administering to a mammal having ocular hypertension a therapeutically effective amount of a compound of formula I
where the segments with single stripes represent links to, the solid triangle represents a β bond, the corrugated segments represent a bond to or ß, the dotted lines represent a double bond or a single bond, R is a substituted heteroaryl radical having the minus two pending substituents selected from the group consisting of lower alkyl, for example Ci alkyl to e! halogen; trifluoromethyl; COR1, COCF3; S02NR1; N02; CN or at least one cyano substituent, that is, CN; R1 is hydrogen or a lower alkyl radical having more than six carbon atoms, X is selected from the group consisting of -OR1 and N (R1) 2, Y is = 0 or represents 2 hydrogen radicals, and the alkyl esters lower 9,11, or 15 thereof; provided, however, that when said heteroaryl radical is a dichloro thienyl radical, said compound is not a 1-carboxylic acid or amide thereof. In a further aspect, the present invention relates to an ophthalmic solution comprising a therapeutically effective amount of a compound of formula (I), wherein the symbols have the meanings mentioned above, or a pharmaceutically acceptable salt thereof, in a mixture with an ophthalmically acceptable, non-toxic liquid vehicle, packed in an appropriate container to dose the application. In particular, the substituents on the heteroaryl radical can be selected from the group consisting of lower alkyl, for example Ci to C6 alkyl; halogen, for example fluorine, chlorine and bromine; trifluoromethyl (CF3); COR1, for example COCH3; C0CF3; S02NR1, for example S02NH2; N02; CN; etc .
In still a further aspect, the present invention relates to a pharmaceutical product, comprising a container adapted to distribute its contents in a dosage form; and an ophthalmic solution thereof, as defined above.
Finally, some of the compounds represented by the above formula, described below and used in the method of the present invention are novel and not obvious.
Brief Description of the Drawings.
Figure 1 is a schematic view of the chemical synthesis of certain 1-carboxylic acid compounds of the invention specifically described in Example 5 (a) - (e), below.
Figure 2 is a schematic view of the chemical synthesis of certain 1-carboxylic acid or 1-amido compounds of the invention specifically described in Example 5 (f) and 11 (f), below.
Figure 3 is a schematic view of the chemical synthesis of certain 1-amido compounds of the invention specifically described in Examples 11 (a) - (e), below.
Figure 4 is a schematic view of the chemical synthesis of certain 1-amido compounds of the invention specifically described in Examples ll (g) - (j), below.
Figure 5 is a schematic view of the chemical synthesis of the 1-isopropyl compounds of the invention specifically described in Examples 12 (a) - (b) and 12 (k) - (l), following.
Detailed description of the invention
The present invention relates to the use of 2-heteroaryloalkenyl derivatives of cyclopentane hept an (en) oic acid, as therapeutic agents, for example as ocular hypotensive agents. The compounds used according to the present invention are encompassed by the following structural formula I:
wherein the substituents and symbols are as defined above. The dotted lines between the carbon bonds 5 and 6 (C-5) and carbons 13 and 14 (C-13) indicate a single or double bond. If two solid lines are used as C-5, or C-13, this indicates a specific configuration for a double bond. The single-line lines-s used at position C-8, C-9 and C-ll indicate the configuration a. The triangle at position C-12 represents the orientation ß. A preferred group of the compounds of the present invention includes compounds having the following structural formula II:
wherein Z is selected from the group consisting of O and S; A is selected from the group consisting of C or CR2, R2, R3 and R4 are selected from the group consisting of hydrogen, cyano, halogen and lower alkyl having from 1 to 6 carbon atoms, preferably, when X is -N ( R1) 2, Y is = O. More preferably, at least one of R2, R3 or R4 are independently selected from the group consisting of chlorine, bromine, iodine, cyano and methyl.
In one aspect of the invention, at least one of R2, R3 or R4 is bromine, and at least the other of R2, R3 or R4 is bromine or methyl, or R2, R3 and R4 are chlorine, or at least the other R2, R3 or R4 is methyl and at least the other of R2, R3 and R4 is bromine or iodine. In another aspect of this invention, R2 is cyano and R3 and
R are hydrogen Another preferred group includes compounds having the formula III:
In the above formulas, the substituents and symbols are as defined above and R5 is hydrogen.
The above compounds of the present invention can be prepared by methods that are known in the art or in accordance with the following working examples. The following compounds are especially preferred representatives of the compounds of the present invention.
7- [3a, 5a-Dihydroxy-2- (3a-hydroxy-5- (5- (2-cyano) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenic acid (5a)
Acid 7 - [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2, 3, 4-trichloro) thienyl) -lE-pentyl) cyclopentyl] -5Z-heptenic (5b)
7- [3,5-Dihydroxy-2- (3a-hydroxy-5- (5- (2,3-dichloro-thienyl) -lE-pentenyl) -cyclopentyl-] 5-heptenic acid (5c) acid
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2-iodo-methyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenic acid (5d) acid
7- [3a, 5a-Dihydroxy-2- (3-hydroxy-5- (4- (3-bromo-2, 5-dimethyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenic acid (5e) )
7- [3a, 5a-Dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dichloro) thienyl) pentyl) -cyclopentyl] -5Z-heptenic acid (5f) 7- [3a, 5a -dihydroxy-2- (3a-hydroxy-5- (5- (2-cyano) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide (lia)
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2, 3, 4 trichloro) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide (11b)
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2,3-dichloro) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide (11c)
7- [3a, 5a-dihydroxy-2- (3-hydroxy-5- (5- (2-iodo-4-methyl) -thienyl) -lE-pentenyl) -cyclopentyl] -5Z-heptenamide (lid)
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dichloro) thienyl) -pentyl) cyclopentyl] -5 Z -heptenamide (llf)
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (3-bromo-2-methyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide of N-2-hydroxyethyl ( llg) 7- [3och, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (3-bromo-2'-methyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide of N-ethyl ( 1 lh)
7- [3a, 5a-dihydroxy-2- (3-hydroxy-5- (3- (2, 5-dibromo) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-N-2-hydroxyethylheptynamide (11) i)
7- [3,5-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dibromo) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-N-ethylheptenamide (11 j)
7- [3a, 5-dihydroxy-2- (3a-hydroxy-5- (5- (2-cyano) thienyl) -lE-pentenyl) cyclopentyl] -5Z-isopropyl heptenoate (12a)
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2, 3, 4-trichloro) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-isopropyl heptanoate (12b)
7- [3a, 5-dihydroxy-2- (3a-hydroxy-5- (5- (3-bromo-2-methyl) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-isopropyl heptenoate (12 k) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dibromo) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-isopropyl heptenoate (121).
A pharmaceutically acceptable salt is any salt that retains the vity of the parent compound and does not impart any undesirable or detrimental effect to the subject to which it is administered and in the context in which it is administered. Of particular interest are the salts formed with inorganic ions, such as sodium, potassium, caicio, magnesium and zinc.
The pharmaceutical compositions can be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or an addition salt of a pharmaceutically acceptable acid thereof, as an active ingredient, with ophthalmically conventional pharmaceutically acceptable excipients, and by preparation of appropriate unit dosage forms for topical ocular use. The therapeutically effective amount is typically between about 0.0001 and about 5% (w / v), preferably about 0.001 to about 1.0% (w / v) in liquid formulations.
For ophthalmic application, preferred solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 6.5 and 7.2 with an appropriate buffer system. The formulations may also contain pharmaceutically acceptable, conventional preservatives, stabilizers and surfactants.
Preferred preservatives that can 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. In the same way, several preferred vehicles can 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 and purified water.
Tonicity adjusters may be added as necessary or convenient. These include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other ophthalmically appropriate tonicity adjuster.
Various buffer solutions and means for adjusting the pH can be used throughout the resulting preparation being ophthalmically acceptable. Accordingly, buffer solutions include acetate buffer solutions, citrate buffer solutions, phosphate buffer solutions, and borate buffer solutions. The acids or bases can be used to adjust the pH of these formulations as necessary.
In a similar manner, an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfide, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole butylated hydroxytoluene.
Other components. excipients that can be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is disodium edentate, although other chelating agents can be used in place or in conjunction with it.
The ingredients are usually used in the following amounts:
Ingredient Amount (% w / v) Active ingredient Around 0.001-5 Conservative 0-0.10 Vehicle 0-40 Tonicity adjuster 1-10 Buffer solution 0.01-10 pH adjuster is. pH 4.5-7.5 Antioxidant As needed surfactant As needed Purified water As needed to make 100% The current dosage of the active compounds of the present invention depends on the specific compound, and the condition to be treated; the selection of the appropriate dose is well within the skillful artisan's knowledge.
The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for dosed application, such as containers equipped with a dropper, to facilitate application to the eye. The containers suitable for drip application are usually made of a non-toxic, appropriately inert plastic material, and generally contain between about 0.5 and about 15 ml of solution.
The invention is further illustrated by the following non-limiting Examples, which are summarized in the reaction schemes of Figures 1 through 5, wherein the compounds are identified by the same designator in both the Examples and the Figures.
Example 1
7- [3a, 5a-Dihydroxy-2- (3a-hydroxy-5- (5- (2-cyano) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenic acid (5a)
Step 1: Preparation of the enone (2a)
To a suspension of sodium hydride (26 mg, 1.14 mmol) in tetrahydrofuran (THF) (2.1 mL) cooled to 0 ° C was added dimethyl 4- (5- (2-cyano) thienyl) -2-oxobutylphosphonate ( 325 mg, 1.14 mmol) in THF (2.1 mL). After 15 minutes a solution of aldehyde 1 (500 mg, 1.03 mmol) in THF (3.0 mL) was added and the reaction solution allowed to warm slowly to 23 ° C over a period of 8 hours. The reaction was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate (EtOAc). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (FCC) (silica gel, 3: 1 hexaho / EtOAc) gave 231 mg (37%) of enone 2a.
Step 2: Preparation of a-alcohol (3a)
Tetrahydruroborate or sodium (15 mg, 0.40 mmol) was added to a solution of enone 2_a (231 mg, 0.38 mmol) in MeOH (3.0 mL) at 0 ° C. After 1 hour the solvent was removed in vacuo and the residue was stirred with IN NaOH and EtOAc for 0.5 hour. The resulting mixture was extracted twice with EtOAc. The recombinant organic portions were washed with brine, dried over MgSO4 / filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 2: 1 hexane / EtOAc) afforded 66 mg (29%) of a 3-a-pure a-alcohol.
Step 3: Preparation of the trihydroxy ester (4b)
A solution of the α-alcohol 3_b (66 mg, 0.11 mmol) and pyridinium p-toluenesulfonate (33 mg, 0.13 mmol) in MeOH (1.0 mL) was stirred at 23 ° C for 12 hours. The solvent was removed in va cuo. The residue was diluted with EtOAc and then washed with IN HCl, saturated aqueous NaHCO 3, and brine. The organic portion was dried over MgSO4, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 100% EtOAc) gave 28 mg (59%) of the trihydroxy ester 4b.
Step 4: Saponification of the trihydroxy ester (4a)
Lithium hydroxide (0.3 mL of a 0.5 N solution in H20, 0.15 mmol) was added to a solution of the trihydroxy ester 4 a (28 mg, 0.081 mmol) in THF (0.6 mL) at 23 ° C. After 16 hours the reaction mixture was acidified with IN HCl and extracted with EtOAc. The organic portion was washed twice with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9: 1 CH2Cl2 / MeOH) to give 16 mg (60%) of the title compound 5a.
Example 2
Acid 7- [3a, 5a-dihydroxy-2 - (3a-hydroxy-5- (5- (2,3,4-trisloro) thienyl) -lE-pentyl) cyclopentyl] -5Z-heptenóiso (5b) In accordance with the procedures described above for the synthesis of 5_a, the use of dimethyl 4- (5- (2, 3, -triyodo) thienyl) -2-oxobutylphosphonate yielded 38 mg of the free acid 5b.
Example 3
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2, 3-dichloro) thienyl) -lE-pentenyl) cyclopentyl-] 5Z-heptenic acid (5c)
In accordance with the procedures described above for the synthesis of 5a, the use of dimethyl 4- (2, 3-dichloro) thienyl) -2-oxobutylphosphonate gave 10 mg of free acid 5c.
Example 4
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5-. {2-iodo-4-methyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenic acid (5d) acid In accordance with the procedures described above for the synthesis of 5a, the use of dimethyl 4- (5- (2-iodo-4-methyl-yl) thienyl) -2-oxobutylphosphonate afforded 22 mg of the free acid 5d.
Example 5
7- [3a, 5a-Dihydroxy-2- (3a-hydroxy-5- (4- (3-bromo-, 5-dimethyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenic acid (5e)
In accordance with the procedures described above for the synthesis of 5_a, the use of 4 - (4 - (3-bromo-2, 5-dimethyl) thienyl) -2-oxobutyl dimethyl ifosphonate yielded 9 mg of the free acid 5e.
6
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (3- (2,5'-dichloro) thienyl) pentyl) -cyclopentyl] -5Z-heptenic acid (5f)
Step 1: Preparation of the enone (7) To a suspension of sodium hydride (370 mg, 15.4 mmol) in tetrahydrofuran (THF) (12.0 mL) cooled to 0 ° C was added 4- (3- (2,5- dimethyl dichloro) thienyl) -2-oxobutyl-phosphonate
(5.1 g, 15.4 mmol) in THF (8.0 mL). After 15 minutes an aldehyde solution was added _6_
(3.55 g, 14.0 mmol) in THF (5.0 mL) and the reaction solution allowed to slowly warm to 23 ° C over a period of 8 hours. The reaction was quenched with saturated aqueous NH4C1 and extracted with EtOAc. The combined organics were washed with brine, dried over MgSO 4, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 3: 1 hexane / EtOAc) gave 4.4 g (69%) of enone 7.
Step 2: Preparation of THP ether (8)
Sodium tetrahydridoborate (194 mg, 5.14 mmol) was added to a stirred solution of enone 7_ (2.36 g, 5.14 mmol) in MeOH (10.3 mL) at 0 ° C. After 2 hours the solvent was removed and the residue was diluted with saturated aqueous ammonium chloride and EtOAc. The organic portion was separated, washed with brine, dried (MgSO 4), filtered and concentrated in vacuo to provide the corresponding allyl alcohol as a viscous oil.
A solution of the alkinyl alcohol and ilkinson catalyst (775 mg, 0.84 mmol) in THF (7.0 mL) was evacuated and purged under an atmosphere of hydrogen gas. After 12 hours, the solvent was removed in vacuo and the residue was purified by FCC (silica gel, 3: 1 hex / EtOAc) to give 824 mg (29%) of the corresponding dihydro alcohol.
The dihydric alcohol (prepared above), 3,4-2H-pyran (1.4 mL, 15.4 mmol) and pyridinium p-toluenesulfonate (39 mg, 0.15 mmol) in
CH2C12 (3.1 mL) was stirred at 23 ° C for 12 hours. The reaction was diluted with EtOAc and washed with IN HCl,
Saturated aqueous NaHC03 and brine. The organic portion was dried (MgSO 4), filtered and concentrated in vacuo. The residue was purified by FCC (silica gel, 3: 1 hex / EtOAc) to provide 727 mg
(75%) of the THP 8_ protective ether.
Step 3: Adding the string to
Diisobutylaluminium hydride (0.86 mL of a 1. OM solution in CH2C12, 0.86 mmol) was added to a solution of lactone 8_ (313 mg, 0.57 mmol) in CH2C12 (1.2 mL) at -78 ° C. After 0.5 hours the reaction was quenched with saturated aqueous sodium potassium tartrate and allowed to warm to room temperature. The mixture was extracted with CH2C12 and the organic portion was washed with brine, dried (Na2SO4), filtered and then concentrated in vacuo to provide the corresponding lactol as a clear, colorless oil.
To a suspension of (4-carboxybutyl) triphenylphosphonium bromide (800 mg, 1.80 mmol) in THF (7.2 mL) was added potassium bis (trimethylsulul) amide (718 mg, 3.6 mmol) at 0 ° C. After 0.5 hours, the reddish-orange mixture was cooled to -78 ° C and a solution of the lactol (prepared above) in THF (3.0 mL) was added. The reaction mixture was allowed to warm to room temperature spontaneously. At this time it was quenched with saturated aqueous NH4C1 and then extracted with EtOAc. The organic portion was washed with brine, dried (MgSO 4), filtered and concentrated in vacuo. The FCC (silica gel, 3: 2
EtOAc / hex) gave 180.5 mg (50%) of the free acid 10.
Step 4: Deprotection of protected bis-THP acid 10: '
A solution of 1_0_ (44 mg, 0.07 mmol) and pyridinium p-toluenesulfonate (21 mg, 0.084 mmol) in MeOH (1.0 mL) was stirred at 23 ° C for 12 hours. The solvent was removed in vacuo. The residue was diluted with EtOAc and then washed with IN HCl, saturated aqueous NaHCO 3, and brine. The organic portion was dried over MgSO, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 100% EtOAc) gave 15 mg (46%) of the trihydoxoxy acid 5 f.
Example 7
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2-cyano) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide (lia) Ammonia gas condensed (~ 4.5 mL) at -78 ° C in a tube containing trihydroxy ester 4a (52 mg, 0.12 mmol) and ammonium chloride (192 mg, 3.56 mmol). The tube was then sealed and heated to 60 ° C for 24 hours. At this time the tube was cooled to -78 ° C, discharged and allowed to warm to room temperature spontaneously. The residue was dissolved in saturated aqueous NH4C1 and EtOAc. The organic portion was separated, dried over anhydrous MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9: 1 CH2Cl2 / MeOH) to give 15 mg (30%) of the title compound lia.
Example 8
7- [3a, 5a-dihydroxy -2- (3a-hydroxy-5- (5- (2,3,4-trichloro) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide (11b)
In accordance with the procedures described above for the synthesis of lia, the use of the trihydroxy ester 4_b provides 22 mg of the amide 11b.
Example 9
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2,3-dichloro) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide (11c)
In accordance with the procedures described above for the synthesis of lia, the use of the trihydroxy ester _4_c provides 6 mg of the amide 11c.
Example 10
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2-iodo-4-methyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptena ida (lid)
In accordance with the procedures described above for the synthesis of lia, the use of the trihydroxy ester 4 d provides 6 mg of the amide lid.
Example 11
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dichloro) thienyl) -pentyl) cyclopentyl] -5Z-heptenamide (llf)
A solution of the free acid 1_0_ (78 mg, 0.123 mmol), iodomethane (77 mL, 1.23 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.11 mL, 0.74 mmol) in acetone (1.0 mL) ) was stirred at 23 ° C for 12 hours. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 3: 1 EtOAc / hexane) to yield 53 mg of the corresponding methyl ester.
A solution of the methyl ester (53 g, 0.082 mmol) and pyridinium p-toluenesulfonate (25 mg, 0.098 mmol) in MeOH (0.5 mL) was stirred at 23 ° C for 12 hours. The solvent was removed in vacuo. The residue was diluted with EtOAc and then washed with 1 N HCl, saturated aqueous NaHCO 3, and brine. The organic portion was dried over MgSO4, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 100% EtOAc) gave 28 mg of the corresponding trihydroxy ester.
Ammonia gas (-4.0 mL) was condensed at -78 ° C in a tube containing the trihydroxy ester (52 mg, 0.12 mmol (52 mg, 0.12 mmol) prepared above and ammonium chloride (122 mg, 2.28 mmol) The tube was then sealed and heated to 60 ° C for 72 hours.At this time the tube was cooled to -78 ° C, discharged and allowed to warm to room temperature spontaneously.The residue was dissolved in aqueous NH4C1 Saturated and EtOAc The organic portion was separated, dried over anhydrous MgSO4, filtered and the filtrate was concentrated in vacuo.The residue was purified by flash column chromatography (silica gel, 9: 1 CH2Cl2 / MeOH) to give 17 mg (52%) of the title compound llf.
Example 12
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (3-bromo-2-methyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide of N-2-hydroxyethyl (IIg) ) A solution of trihydroxy ester 4g (36 mg, 0.742 mmol) and 2-hydroxyethylamine (0.43 mL, 7.2 mmol) in MeOH (4.0 mL) was heated to 80 ° C for 48 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by FCC (silica gel, 9: 1 CH2Cl2 / MeOH) to provide 35 mg (92%) of amide IIg.
Example 13
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (3-bromo-2-methyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide of N-ethyl (IIh)
In accordance with the procedures described above for the synthesis of llg, the use of ethylamine gave 25 mg (66%) of amide llh.
Example 14
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dibromo) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide of N-2-hydroxyethyl (lli In accordance with the procedures described above for the synthesis of llg, the use of the trihydroxy ester 4i gave 30 mg (58%) of the amide Ili.
Example 15
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dibromo) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide of N-ethyl (11j)
In accordance with the procedures described above for the synthesis of llh, the use of the trihydroxy ester 4j gave 30 mg (61%) of the amide 11 j.
Example 16
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2-cyano) thienyl) -lE-pentenyl) cyclopentyl] -5Z-isopropyl heptenoate (12a)
A solution of the free acid 5_a_ (38 mg, 0.090 mmol), 2-iodopropane (45 mL, 0.45 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (40 mL, 0.27 mmol) n acetone ( 0.18 mL) was stirred at 23 ° C for 12 hours. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 3: 1 EtOAc / hexane) to give 15 mg (36%) of the isopropyl ester 12a.
Example 17
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2, 3, 4-trichloro) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-isopropyl heptanoate (12b)
In accordance with the procedures described above for the synthesis of 12a, the use of the free acid 5_b provides 12 mg (50%) of the amide 12b.
Example 18
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (3-bromo-2'-methyl) -thienyl) -lE-pentenyl) -cyclopentyl] -5Z-isopropyl heptenoate (12k)
In accordance with the procedures described above for the synthesis of 12a, the use of the free acid 5k provides 24 mg (56%) of the amide 12k.
Example 19
7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dibromo) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-isopropyl heptenoate (121).
In accordance with the procedures described above for the synthesis of 12a, the use of the free acid gave 1 mg (14%) of the amide 121.
Several of the above compounds were tested for activity in several tests described below and the results are reported in the Table.
Activity in different prostanoid receptors was measured in vitro and isolated flat muscle preparations. The FP activity was measured as the sphincter contraction of the isolated feline iris. The EPi activity was measured as the contraction of the longitudinal flat muscle of the isolated guinea pig ileum. The EP3 activity was measured as the inhibition of the contraction response induced by an electric field stimulation in isolated guinea pig subjected to a contraction of the longitudinal flat muscle of the isolated chicken ileum. The activity was also measured as the jugular vein flat muscle relaxation of rabbit isolated a preparation that appears to contain a single terminal provisionally sensitive to the PGF2a receptor FPVASC. The vasoconstrictor activity TP was measured as the contraction of rings of the isolated thoracic aorta. The effects on platelets of healthy human donors were measured by incubation of platelet-rich plasma with the compounds described herein. The inhibition of aggregation was determined by the ability of the compounds described herein to inhibit the aggregation of platelets in the platelet-rich plasma induced by 20 μm of ADP.
In addition to stimulating the FP receptor associated with the cat's iris, several examples also stimulate the EP3 receptor. Compounds with agonist activity at EP3 receptors can be used for gastric treatment or duodenal ulcer by virtue of their cytoprotective and anti-secretory properties. They can also be used as adjunctive therapy in combination with aspirin-like drugs and steroids to limit gastrointestinal side effects. EP3 agonists stimulate the uterine flatus muscle and can be used for the end of pregnancy in female humans. EP3 agonists are also useful in cervical maturation processes and can be used to induce labor.
Inhb. of ECso (Nm) IC25 ratio platelets IOP Dog IOP Mono Hyp /
AGN - # FP EPi EP3 DP / EP2 EP4 FP / EP4 TP added (1 day) (5 days) miosis
Inhb. of EC50 (Nm) IC25 platelet ratio lOP Dog lOP Mono Hyp / AGN - # FP EP1 EP3 EP / EP2 EP4 FP / EP4 TP added (1 day) (5 Days) miosis
-C-
Inhb. of ECso (Nm) I025 platelets relation lOP Dog lOP Mono Hyp /
AGN - # FP EPi EP3 DP / EP2 EP4 FP / EP4 TP added (1 day) (5 Days) miosis
Inhb of EC50 (Nm) IC25 ratio platelets lOP Dog lOP Mono Hyp /
AGN - # FP EP, EP3 EP / EP2 EP4 FP / EP4 TP added (1 day) (5 Days) miosis
Inhb. of ECso (Nm) IC25 platelet ratio lOP Dog lOP Mono Hyp / AGN - # FP EPi EP3 EP / EP2 EP4 FP / EP4 TP added (1 day) (5 days) miosis
4r-
Inhb. of ECso (Nm) IC25 relation platelets lOP Dog lOP Mono Hyp /
Inhb. of EC50 (Nm) IC25 ratio platelets lOP Dog lOP Mono Hyp /
AGN - # FP EP1 EP3 DP / EP2 EP4 FP / EP4 TP added (1 day) (5 Days) míosis
Other potential therapeutic applications are in osteoporosis, constipation, renal disorders, sexual dysfunctions, baldness, diabetes, cancer and in disorders of immune regulation.
Many examples also have pronounced activity on the FP receptor, provisionally terminated FPVA [beta] C associated with the vascular endothelium in the preparation of the rabbit jugular vein. Since such agents can be vasodilators, they have potential in hypertension and in any disorder where perfusion of blood tissue is compromised. Such indications include, but are not limited to, systemic hypertension, angina, stroke, retinal vascular disease, claudication, Raynauds disease, diabetes, and pulmonary hypertension.
The compounds of the invention may also be useful in the treatment of various diseases of the body, including acute myocardial infarction, vascular thrombosis, hypertension, pulmonary hypertension, ischemic heart disease, congestive heat failure, and angina pectoris, in in which case the compounds can be administered by any means that effect vasodilatation and thereby alleviate the symptoms of the disease. For example, administration may be by oral, transdermal, parenteral, subcutaneous, intravenous, intramuscular, int raperitonal, transdermal, or buccal route.
The compounds of the invention can be used alone, or in combination with other known vasodilator drugs.
The compounds of the invention can be formulated in an ointment containing about 0.10 to 10% of the active ingredient in an appropriate base of, for example, white petrolatum, mineral oil and petrolatum alcohol and lanolin. Other appropriate bases will be apparent to those skilled in the art.
The pharmaceutical preparations of the present invention are made in a manner that is known per se, for example, by dissolving or suspending the compounds, which are all either soluble or suspensible in water. For administration in the treatment of the other pathophysiological disorders mentioned. Pharmaceutical preparations that can be used orally include pressure-sensitive capsules made of gelatin, such as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The capsules that can be pressed can contain the active compounds in liquid form which can be mixed with such fillers, such as lactose, linkers 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 a buffer salt solution. In addition, stabilizers can be added.
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 in the preparations that can be used pharmaceutically.
In this way, 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, then adding appropriate auxiliaries, if desired or necessary. , to obtain tablets or core tablets.
Suitable excipients are, in particular, fillers such as sugars, for example, lactose or sucrose, mannitol or sorbitol, cellulose and / or calcium phosphate preparations, for example tricalcium phosphate or calcium hydrogen phosphate, as well as aggregates such as starch, pasta using for example, corn starch, wheat starch, enriched starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If desired, disintegrating agents such as the aforementioned starches and also carboxymethyl starch, cross-linked poly inylpyrrolidone, agar, or algenic acid or salt thereof, such as sodium alginate can be added. The auxiliaries are, all of the above, 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. The core pellets are provided with appropriate coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquered solutions and appropriate organic solvents or solvent mixtures. In order to produce resists resistant to gastric juices, solutions of appropriate cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl cellulose phthalate are used. A dye material or pigments may be added to coated tablets or lozenges, for example, for identification in order to characterize the combinations of active compound doses.
Formulations suitable for intravenous or parenteral administration include aqueous solutions of the active compounds. In addition, suspensions of the active compounds such as oily injection suspensions may be administered. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethyl cellulose, sorbitol, and / or dextran. Optionally, the suspension may also contain stabilizers.
The foregoing description details the specific methods and compositions that may be employed for the practice of the present invention, and represent the best mode contemplated. However, it will be apparent to one of ordinary skill in the art that additional compounds with the desired pharmacological properties can be prepared in an analogous manner, and that the described compounds can also be obtained from different starting compounds by means of different chemical reactions. Similarly, different pharmaceutical compositions can be prepared and used with substantially the same results. In this way, however, the detail of the previous ones that appear in the text, is not constructed as limiting the general scope of the same; on the contrary, the scope of the present invention is to govern itself only by the legal construction of the appended claims.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, the content of the following is claimed as property.
Claims (29)
1. A method for the treatment of ocular hypertension, characterized in that it comprises administering to a mammal having ocular hypertension a therapeutically effective amount of a compound represented by formula I: where the segments with simple lines represent links to, the solid triangle represents a link, the wavy segments indicate either the alpha (a) or beta () configuration, the dotted lines represent a double bond or a single link, R is a substituted heteroaryl radical having at least two pendant substituents selected from the group consisting of Ci to C6 alkyl; halogen; trifluoromethyl; COR1, COCF3; S02NR1; N02; CN or at least one cyano group; R1 is hydrogen or a lower alkyl radical having more than six carbon atoms, X is selected from the group consisting of -OR1 and N (RX) 2, Y is = 0 or represents 2 hydrogen radicals, and the alkyl esters lower 9,11, or 15 thereof; with the proviso, however, that when the heteroaryl radical is a dichloro thienyl radical, the compound is not a 1-carboxylic acid or amide thereof.
2. The method according to claim 1, characterized in that the substituents on the heteroaryl radical is selected from the group consisting of Ci to C? , chlorine, bromine, iodine and CN.
3. The method according to claim 1, characterized in that the compound is represented by formula II: wherein Z is selected from the group consisting of 0 and S, A is selected from the group consisting of C or CR2, R2, R3 and R4 are selected from the group consisting of hydrogen, halogen, cyano and lower alkyl having from 1 up to 6 carbon atoms.
4. The method according to claim 3, characterized in that the compound is represented by the formula III: wherein R5 is hydrogen.
5. The method according to claim 4, characterized in that X is -OH or -NH2.
6. The method according to claim 4, characterized in that Y is = O and X is -OH.
7. The method according to claim 4, characterized in that Y is = O and X is -NH2.
8. The method according to claim 4, characterized in that Z is S
9. The method according to claim 8, characterized in that at least one of R2, R3 and R4 are selected from the group consisting of cyano, chloro, bromo, iodo and methyl.
10. The method according to claim 8, characterized in that at least one of R2, R3 and R4 is cyano.
11. The method according to claim 8, characterized in that at least two of R2, R3 and R4 are chlorine.
12. The method according to claim 8, characterized in that at least two of R2, R3 and R4 are bromine.
13. The method according to claim 8, characterized in that at least two of R2, R3 and R4 are methyl.
14. The method according to claim 8, characterized in that at least one of R2, R3 and R4 is methyl and at least one of R2, R and R are • chlorine
15. The method according to claim 13, characterized in that at least one of R2, R3 and R4 are bromine and at least one of R2, R3 and R4 are methyl.
16. The method according to claim 15, characterized in that the compound is selected from the group consisting of 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2-cyano) thienyl) - L-pentenyl) cyclopentyl] -5Z-heptenic (5a) 7 - [3, 5a-Dihydroxy-2 - (3a-hydroxy-5- (5- (2, 3, 4-trichloro) thienyl) -lE-pentyl) cyclopentyl] -5Z-heptenic acid (5b) 7- [3a, 5-Dihydroxy-2- (3a-hydroxy-5- (5- (2, 3-dichloro) thienyl) -lE-pentenyl) cyclopentyl-] 5Z-heptenic acid (5c) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2-iodo-4-methyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenic acid (5d) acid 7- [3a, 5a-Dihydroxy-2- (3a-hydroxy-5- (4- (3-bromo-2, 5-dimethyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenic acid (5e) 7- [3a, 5-Dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dichloro) thienyl) pentyl) -cyclopentyl] -5Z-heptenic acid (5f) 7- [3a, 5a- dihydroxy-2- (3a-hydroxy-5- (5- (2-cyano) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide (lia) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2, 3, 4 trichloro) thienyl) -lE-pentenyl) cyclopentyl] -5 Z -heptenamide (11b) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2,3-dichloro) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide (11c) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2-iodo-4-methyl) thienyl) -lE-pentenyl) cyclopentyl] - 5 Z -heptenamide (lid) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dichloro) thienyl) -pentyl) cyclopentyl] -5Z-heptenamide (llf) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (3-bromo-2-methyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-N-2-hydroxyethyl heptynamide ( llg) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (3-bromo-2-methyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide of N-ethyl ( llh) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dibromo) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide of N-2-hydroxyethyl ( 1 li) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dibromo) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide of N-ethyl (11 j) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2-cyano) thienyl) -lE-pentenyl) cyclopentyl] -5Z-isopropyl heptenoate (12a) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2, 3, 4-trichloro) -thienyl) -lE-pentenyl) cyclopentyl] -5-isopropyl heptanoate (12b) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (3-bromo-2'-methyl) -thienyl) -lE-pentenyl) cyclopentyl] -5-isopropyl heptenoate (12 k) 7- [3a, 5-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dibromino) -thienyl) -lE-pentenyl) cyclopentyl] -5-isopropyl-heptenoate (121) .
17. An ophthalmic solution, characterized in that they comprise a therapeutically effective amount of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in a mixture with an ophthalmically acceptable, non-toxic liquid carrier, packaged in a appropriate container for your dosed application.
18. The ophthalmic solution according to claim 17, characterized in that the compound is a compound of formula III.
19. A pharmaceutical product, characterized in that it comprises a container adapted to distribute the contents of the container in dosage form; and an ophthalmic solution in the container comprising a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, in a mixture with an ophthalmically acceptable, non-toxic liquid vehicle.
20. The product according to claim 19, characterized in that the compound is a compound of formula III.
21. The compound represented by the formula III: characterized in that the single-striped segments represent links to, the solid triangle represents a β-bond, the undulated segments represent a bond to or β, R5 represents hydrogen or a lower alkyl radical having more than six carbon atoms; X is selected from the group consisting of -OR1 and N (R1) 2, Y is = 0 or represents 2 hydrogen radicals; R1 is hydrogen or a lower alkyl radical having more than six carbon atoms; and the lower alkyl esters 9, 11, or 15 thereof; with the proviso, however, that when the heteroaryl radical is a dichlorotienyl radical, the compound is not a 1-carboxylic acid or amide thereof
22. A compound according to claim 21, characterized in that Z is S
23. The compound according to claim 22, characterized in that at least one of R2, R3 and R4 are selected from the group consisting of cyano, chloro, bromo, iodo and methyl.
24. The method according to claim 23, characterized in that at least one of R2, R3 and R4 is cyano.
25. The method according to claim 23, characterized in that at least two of R2, R3 and R4 are chlorine.
26. The method according to claim 23, characterized in that at least two of R2, R3 and R4 are bromine.
27. The method according to claim 23, characterized in that at least two of R2, R3 and R4 are methyl.
28. The method according to claim 23, characterized in that at least one of R2, R3 and R4 is methyl and at least one of R2, R3 and R4 are chlorine.
29. The method according to claim 23, characterized in that at least one of R2, R3 and R4 are bromine and at least one of R2, R3 and R4 are methyl. 7- [3a, 5a-Dihydroxy-2- (3a-hydroxy-5- (5- (2-cyano) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenic acid (5a) Acid 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2, 3, 4-trichloro) thienyl) -lE-pentyl) cyclopentyl] -5Z-heptenic (5b) 'Acid 7 - [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2, 3-dichloro) thienyl) -lE-pentenyl) cyclopentyl-] 5Z-heptenic (5c) 7 - [3a, 5a-Dihydroxy-2 - (3a-hydroxy-5- (5- (2-iodo-4-methyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenic acid (5d) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (4- (3-bromo-2, 5-dimethyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenic acid (5e) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dichloro) thienyl) pentyl) -cyclopentyl] -5Z-heptenic acid (5f) 7- [3a, 5-dihydroxy-2- (3a-hydroxy-5- (5- (2-cyano) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide (lia) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2, 3, 4-trichloro) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide (11b) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2,3-dichloro) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide (11c) 7- [3a, 5a-dihydroxy-2- (3-hydroxy-5- (5- (2-iodo-4-methyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide (lid) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dichloro) thienyl) -pentyl) cyclopentyl] -5Z-heptenamide (llf) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (3-bromo-2-methyl) thienyl) -lE-pentenyl) cyclopentyl] -5 Z -heptenamide of N-2-hydroxyethyl (llg) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (3-bromo-2'-methyl) thienyl) -lE-pentenyl) cyclopentyl] -5Z-N-ethyl heptyneamide (llh) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dibromo) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-heptenamide of N-2-hydroxyethyl (1 li) 7- [3,5-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dibromo) -thienyl) -lE-pentenyl) cyclopentyl] -5Z 'N-ethyl heptenamide (11 j) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2-cyano) thienyl) -lE-pentenyl) cyclopentyl] -5Z-isopropyl heptenoate (12a) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (2, 3, 4-trichloro) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-isopropyl heptanoate (12b) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (5- (3-bromo-2-methyl) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-isopropyl heptenoate (12 k) 7- [3a, 5a-dihydroxy-2- (3a-hydroxy-5- (3- (2, 5-dibromo) -thienyl) -lE-pentenyl) cyclopentyl] -5Z-isopropyl heptenoate (121). Summary of the Invention The invention relates to the use of prostaglandin derivatives of type F as ocular hypotensive. The compounds used according to the invention are represented by the following formula I: where the wavy segments indicate either the alpha (a) or beta (ß) configuration, the single-striped segments represent links, the solid triangle represents a β-link, the dotted lines represent a double bond or a single bond, R is a substituted heteroaryl radical having at least two pendant substituents selected from the group consisting of Ci to C6 alkyl; halogen; trifluoromethyl; COR1, COCF3; SO? NR1; N02 and CN or at least one cyano group; R1 is hydrogen or a lower alkyl radical having more than six carbon atoms, X is selected from the group consisting of -OR1 and N (R1) 2, Y is = 0 or represents 2 hydrogen radicals, and the alkyl esters lower 9,11, or 15 thereof; with the proviso, however, that when said heteroaryl radical is a dichlorotienyl radical, the compound is not a 1-carboxylic acid or amide thereof. Some of the compounds represented by Formula I are novel and comprise another aspect of the present invention.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08974067 | 1997-11-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00004722A true MXPA00004722A (en) | 2001-09-07 |
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