AU660735B2 - Topical ophthalmic compositions comprising 4-(3-substituted amino-2-hydroxypropoxy)-1,2,5-thiadiazoles and methods for their use - Google Patents
Topical ophthalmic compositions comprising 4-(3-substituted amino-2-hydroxypropoxy)-1,2,5-thiadiazoles and methods for their use Download PDFInfo
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- AU660735B2 AU660735B2 AU28696/92A AU2869692A AU660735B2 AU 660735 B2 AU660735 B2 AU 660735B2 AU 28696/92 A AU28696/92 A AU 28696/92A AU 2869692 A AU2869692 A AU 2869692A AU 660735 B2 AU660735 B2 AU 660735B2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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Description
OPI DATE 03/05/93 AOJP DATE 08/07/93 APPLN. ID 28696/92 PCT NUMBER PCT/US92/08600 AU9228696 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 93/06827 A61K 31/41, 31/535 Al (43) International Publication Date: 15 April 1993 (15.04.93) (21) International Application Number: PCT/US92/08600 (81) Designated States: AU, CA, JP, European patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, (22) International Filing Date: 9 October 1992 (09.10.92) SE).
Priority data: Published 776,544 I1 October 1991 (11.10.91) US With international search report.
With amended claims.
(71)Applicant: ALCON LABORATORIES, INC. [US/US]; 6201 South Freeway, Fort Worth, TX 76134 (US).
(72) Inventors: DeSANTIS, Louis, Jr. 2316 Winton Terrace 6 West, Fort Worth, TX 76109 ADAMSKI, Robert, J. 7320 Kingswood Circle, Fort Worth, TX 76133 (US).
(74) Agent: PRICE, Robert, Lowe, Price, LeBlanc Becker, 99 Canal Center Plaza, Suite 300, Alexandria, VA 22314
(US).
(54) Title: TOPICAL OPHTHALMIC COMPOSITIONS COMPRISING 4-(3-SUBSTITUTED AMINO-2-HYDROXYPRO- POXY)-1,2,5-THIADIAZOLES AND METHODS FOR THEIR USE (57) Abstract Topical ophthalmic compositions comprising certain thiadiazoles are useful in the treatment of glaucoma and ocular hypertension. The thiadiazoles are slightly less potent than timolol; however, they have greatly reduced systemic side effects as compared to timolol.
I
WO 93/06827 PCT/US92/08600 1 TOPICAL OPHTHALMIC COMPOSITIONS COMPRISING 4-,(3-SUBSTITUTED AMINO-2-HYDROXYPROPOXY)-1,2,5-THIADIAZOLES AND METHODS FOR THEIR USE Background of the Invention This invention relates to topical ophthalmic compositions comprising certain 4-(3-substituted amino-2-hydroxypropoxy)-1,2,5thiadiazoles. These compounds are p-blockers which are effective at relatively low doses. Ophthalmic compositions comprising these compounds are useful in the treatment of glaucoma and ocular hypertension.
This class of compounds was originally disclosed in German Patent No. 1,925,956 (issued in 1969 to B. K. Wasson), which is equivalent to US 3,655,663 (issued in 1972) and US 3,729,469 (issued in 1973). It was later found that topical application of timolol, one of the most effective thiadiazoles disclosed and claimed in US 3,655,663 (the '663 patent), was also useful to treat ocular hypertension. See, for example, Heel, et al., Drugs, 17:38-55 (1979). Although effective in decreasing intraocular pressure, there are often rather severe systemic side effects associated with the use of topical ophthalmic compositions of timolol. Because timolol was the most potent of the compounds tested, other compounds of the class disclosed in the '663 patent were thought to be unsuitable for the treatment of ocular hypertension, as the larger doses which would be needed would be intolerable due to the corresponding increase in systemic and ocular side effects.
Summary of the Invention It has now been found that certain of the thiadiazoles of the '663 patent, while being equal or slightly less efficacious than timolol to lower IOP, are far less likely to cause systemic side effects. Moreover, these thiadiazoles are more efficacious than betaxolol. In particular, it has been found that the thiadiazoles of the present invention are approximately four times less potent WO 93/06827 PCF/US92/0600 2 than timolo to lower IOP, yet they are approximately forty five times less likely to cause systemic side effects. Thus, topical ophthalmic compositions comprising the thiadiazoles of the present invention contain a higher concentration of active than corresponding ophthalmic compositions containing timolol, but cause fewer systemic side effects.
Brief Description of the Drawing Figure 1 is a graph of time (hr) versus mean percent change in heart rate (beats per minute).
!0 Detailed Description of the Invention The thiadiazoles of the present invention have the following general formula: N CH CH
S
(0o^ H OH (I)
HO
and optically active isomers and pharmacologically acceptable salts thereof; wherein R represents: hydrogen; halogen, preferably chloro or bromo; C 15 lower alkyl having either a straight or branched chain such as methyl, ethyl, propyl, isopropyl, butyl iso-, secondary- or tert-butyl and amyl, including all of its branched chain configurations; C 2 lower alkenyl, such as vinyl, allyl, methallyl and the like; a group having the structure Y-X-Z-, wherein Y is either a straight or branched chain C 1 -4 alkyl optionally substituted with a phenyl group or a phenyl optionally substituted with one or more halogen atoms (especially chloro, bromo, fluoro), hydroxy, C1.3 lower alkyl or alkoxy, X is oxygen or sulfur and Z is a C 1 2 alkyl; a carbamoyl group having the structure R'HNCO, wherein R 1 is a C,_ 5 lower alkyl; C 3 -6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopeny:~, yclohexyl and the like; C1- 5 lower alkoxy, either a straight or branched chain and including methoxy, ethoxy, propoxy, isopropoxy, butoxy, and pentoxy (the latter groups existing in either straight or branched configuration); phenyl or substituted phenyl, wt rein the substitutes are selected from one or more halogen atoms WO 93/06827 PCT/US92/08600 3 (preferably chloro or fluoro) and a C 1 .3 lower alkyl or alkoxy; phenyl-lower alkyl, wherein the lower alkyl moiety is either a straight or branched chain and has from 1 to 4 carbons and the phenyl moiety can be unsubstituted or substituted with one or more halogen atoms (preferably chloro, fluoro, or bromo) or C1-3 lower alkyl or alkoxy; (11) an amino having the structure -NR 2
R
3 wherein
R
2 represents hydrogen, C 1 4 lower alkyl and C2-4 hydroxy-substituted lower alkyl, R 3 represents hydrogen, C.
4 lower alkyl, a hydroxysubstituted lower alkyl and phenyl, or R 2 and R 3 can be joined together either directly to give a 3 to 7 membered ring with the nitrogen to which they are attached thereby forming aziridinyl, azetidinyl, pyrrolidyl, piperidyl, or a hexahydroazepinyl group, said 3 to 7 membered rings being either unsubstituted or substituted, preferably with one or more Ci.- lower alkyl and C 1 .3 hydroxy-lower alkyl, or alternatively R 2 and R 3 can be joined through an oxy5 nitrogen or sulfur atom to form a 5 or 6 membered ring, advantageously a morpholino, hexahydropyrimidyl, thiazolidinyl, pthiazinyl, piperazinyl and the like group optionally substituted by C.1 3 lower elkyl; or (12) R additionally can be a 5 or 6 membered heterocyclic ring having oxygen, nitrogen or sulfur as the hetero atom and preferably the 2-furyl, 2- or 3-thienyl, 2-pyrryl and the m- or p-pyridyl. These thiadiazoles may be prepared by the methods disclosed in US 3,655,663 and US 3,729,469 whose entire contents are incorporated by reference herein. Preferred thiadiazoles'are those of Formula above, wherein R is chloro, ethyl, allyl, cyclopropyl, ethoxy, phenyl, phenyl-chloromethyl, or 2-(cyclopropylmethoxy)ethyl.
Suitable pharmacologically acceptable salts are acid addition salts derived from inorganic acids, for example, hydrochlorides, hydrobromides, phosphates or sulfates, or salts derived from organic acids, for example, oxalates, lactates, malates, maleates, formates, acetates, succinates, tartrates, salicylates, citrates, phenylacetates, benzoates, p-toluenesulfonates and other salts such as those which provide relatively insoluble products which afford a slow release of the active material, for example, a 1,1'-methylenebis(2-hydroxy-3-naphthoate) and the like.
In general, thiadiazoles are present in the compositions of the present invention at a concentration between about 0.005 and WO 93/06827 PCT/US92/08600 4 about 5 percent by weight It is preferred to have a thiadiazole concentration between about 0.1 and about 2.0 wt%. Most preferably, the thiadiazole concentration is about 1.0 wt%.
The compositions of the present invention may be prepared by combining one or more of the thiadiazoles of the present invention with a suitable vehicle to form a solution, dispersion or gel.
These compositions may additionally include finely divided ion exchange resins and/or anionic mucomimetic polymer for enhanced bioavailability and efficacy, as well as for patient comfort. The use of finely divided ion exchange resins and anionic mucomimetic polymers in ophthalmic compositions are detailed in U.S. Patent No.
4,911,920 (Jani et whose entire contents are hereby incorporated by reference herein.
The compositions of the present invention may also include one or more ingredients conventionally found in ophthalmic formulations, such as preservatives benzalkonium chloride or thimerosal), viscosity-imparting agents polyvinyl alcohol or hydroxypropyl methylcellulose) and tonicity agents sodium chloride or mannitol). The compositions will also normally include buffering agents, such as phosphates and citrates, to maintain the pH within the range of physiological pH (between 6.0 and H'ijrochloric acid or sodium hydroxide will typically be used to adjust the pH of the resultant composition.
EXAMPLE 1 The following Table 1 represents some preferred compositions of the present invention.
WO 93/06827 I'MT/US92/08600 Table 1 FORMULATION (wt%) Ingredient #1 #2 #3 #4 #5 #6 1.0 0.5 1.0 1.0 1.0 R=ethyl Benzalkoniu 0.01 0.01 0.01 0.01 0.01 0.01 m Chloride Amberlite® 1.0 0.5 1.0 IRP-69 resin Mannitol 4.0 4.5 4.0 Carbopole 0.5 0.25 1.0 934P Sodium 0.8 0.85 0.65 Chloride Disodium 0.20 Phosohate NaOH and/or q.s. pH q.s. pH q.s. pH q.s. pH q.s. pH q.s. pH HC1 Purified q.s. q.s. q.s. q.s. q.s. q.s.
Water 100% 100% 100% 100% 100% 100% Formulations 1-3, containing finely divided ion exchange resins, may be prepared by first dissolving the drug in water and then slowly dispersing the resin into the solution to form a suspension. Mannitol previously dissolved in an aliquot of water and mixed with benzalkonium chloride is then added to the suspension. Carbopol® 934P is then added to obtain the desired viscosity. The resultant composition can then be suitably sterilized and filled into previously sterilized containers.
Formulations 4-6 may be prepared by dissolving the drug in water, along with the other ingredients. Water is then added to bring the solution to 100% and the pH is adjusted. The resultant composition can then be suitably sterilized and filled into suitable packaging for ocular administration.
WO 93/06827 PCT/US92/08600 6 EXAMPLE 2 A study was conducted to determine the effect on the intraocular pressure of cynomolgus monkeys after a single topical instillation of a composition of the present invention.
Prior to the commencement of the study, the right eyes of all of the monkeys had been given laser trabeculoplasty, which resulted in ocular hypertension in the lasered eyes. All of the left eyes were normal and normotensive. The animals had also been trained to sit in "restraint chairs" and conditioned to accept the pressure measurements without general anesthesia.
A total of 14 cynomolgus monkeys (Macaca fascicularis) were used in this study. The lasered right eyes of half of the monkeys were given 50 microliters (p1) of a 1% solution of 3-ethyl-4-[3-N- (2-hydroxymethylprop-2-yl)amino]hydroxypropoxy-1,2,5-thiadiazole(a composition of the present invention) and the lasered right eyes of the other half were given 50 Ip of 0.9% saline. The left eyes of all of the monkeys remained untreated, for comparison purposes.
Intraocular pressure (IOP) measurements for both eyes of all of the monkeys were taken just before administration and 1,3 and 6 hours after administration. IOP was determined using an Alcon Pneumatonograph (Alcon Laboratories, Inc., Fort Worth, Texas) after light corneal anesthesia with proparacaine. Following each measurement, the residual anesthetic was washed out with saline.
The results are shown in Table 2, below.
WO 93/06827 PCT/US92/08600 7 Table 2 IOP Change Time (hr) OD OS Treatment after dose Mean SEM Mean SEM R=ethyl* 0 0.0 0.00 0.0 0.00 1 -25.7 4.28 1.5 3.24 3 -42.0 3.18 0.6 4.73 6 -33.8 3.67 4.1 5.53 Control OD 0 0.0 0.00 0.0 0.00 1 -1.1 3.77 2.6 2.8 3 -13.4 5.87 -4.1 4.00 6 -7.0 6.74 1.9 3.91 solution The results demonstrate that the composition of the present invention reduces IOP in hypertensive eyes by more than 25% for a period of at least 6 hours after treatment.
EXAMPLE 3 A study was conducted to determine the effect on the corneal sensitivity of New Zealand albino (NZA) rabbits after a single topical instillation of a composition of the present invention. In this study, corneal sensitivity was measured as a function of blink response. The rabbit consistently exhibits a blink of the eyelid when the cornea is touched with sufficient force. This is a protective reflex which is absent when the cornea is anestetized.
Three NZA rabbits were assigned to each of three test groups.
The eyelashes were trimmed and one eye of each animal selected for use. A 1% solution of 3-ethyl-4-[3-N-(2-hydroxymethylprop-2yl)amino] hydroxypropoxy-1,2,5-thiadiazole (a composition of the present invention) was administered to the selected eye of each animal in one group and either acetate buffered saline or commercially available Timoptic' (Merck, Sharp Dohme, West Point, WO 93/06827 PCT/US92/08600 8 Pennsylvania) were administered to the selected eye of each animal in the other groups.
Corneal sensitivity was measured by tapping the beveled end of a short length of polyethylene tubing on each test eye three times and recording the number of blinks after each tap (maximum 3 blinks/3 taps). Responses were recorded at 15 minute intervals up to ninety minutes after dosing; two baseline measurements were recorded at 15 minute intervals prior to dosing. The results are shown below in Table 3.
WO 93/06827 PCT/US92/08600 9 Table 3 Number of Blinks/Three Touches Treatment Pre-Dose Minutes (Post-Dose) (dose) Rabb Eve Baseline 15 30 45 60 75 1 00 3 3 3 2 3 3 3 3 R=ethyl OS 3 3 3 3 3 3 3 3 2 OD 3 3 3 3 3 3 3 3 OS 3 3 3 3 3 3 3 3 3 OD 3 3 2 3 3 3 3 3 0S 3 3 3- 3 3 3 3 3 Timolol 4 OD 3 3 3 3 3 3 3 3 OS 3 3 3 3 3 3 3 3 00 3 3 3 3 3 3 3 3 OS 3 3 3 3 3 3 3 3 6 OD 3 3 3 3 3 3 3 3 0S 3-1 3 3 3 2 3 Vehicle 7 OD 3 3 3 3 3 3 3 OS 3 3 3 3 3 3 3 3 8 OD 3 3 3 3 3 3 3 3 OS 3 3 3 3 3 3 3 3 9 OD 3 3 3 3 3 3 3 3 *500 .g dose The results demonstrate that there is no significant difference in corneal sensitivity between any of the formulations administered to the rabbits. Beta blockers which cause complete loss of corneal sensitivity are deemed to be unsafe for chronic use as they remove the protective blink response. This renders the cornea subject to injury if touched with sufficient force by a foreign object.
WO 93/06827 PCT/US92/08600 EXAMPLE 4 A study was conducted to determine the effect on isoproterenol-induced tachycardia in conscious cynomolgus monkeys after a single topical instillation of a composition of the present invention.
All of the monkeys used in this study were given laser trabeculoplasty, as detailed in EXAMPLE 2, above, prior to the commencement of the study; however, as hypertensive eyes were not necessary to this study, only the left (normotensive) eyes of the monkeys were studied.
A total of 9 cynomolgus monkeys were used in this study. The left eyes (normotensive) of all of the monkeys were each given a pl aliquot of a 1.5% solution of isoproterenol both immediately after the baseline measurements were taken and again 4 hours later.
The monkeys were separated into two study groups: (Group I) 7 were given a 1% solution of 3-ethyl-4-[3-N-(2-hydroxymethylprop-2yl)amino] hydroxypropoxy-1,2,5-thiadiazole (a composition of the present invention); and (Group II) 2 were given phosphate buffered saline. These solutions were administered to the left eye 3.5 hours after baseline heart rate measurements were taken.
Heart rate was measured with a stethoscope ield to the chest of each animal. The beats in two 15 second intervals were recorded and the two recordings averaged. In addition to the baseline measurements, heart rate was measured at 0.5, 1, 1.5, 2.5 and hours after baseline and at 0.5, 1, 1.5, 2.5 and 3.5 hours after treatment with beta-blocker or vehicle. The results are shown in Table 4, below, and in Figure 1.
WO 93/06827 PCT/US92/08600 11 fable 4 Treat- TIME ment
(HR)
Group I 0.0 Group 0.0 I7 r Me 136 195 192 172 145 138 120 142 151 150 129 124 Heart Rate Beats /Minute an SEM i.3 4.15 .2 6.44 .9 6.47 8.02 i.7 6.27 1.0 3.68 5.15 .3 7.64 .1 7.12 .8 10.08 ,2 5.16 .3 5.86 Cha from Baseline Mean 0.0 43.3 41.7 27.1 6.9 1.5 -11.7 4.6 10.9 11.0 -4.8 -8.1 0.0 44.3 52.7 39.7 2.9 -8.5 -13.0 37.6 38.8 31.8 5.3 -9 r,
SEM
0.00 2.86 3.80 5.31 2.84 2.32 3.68 5.01 4.27 7.31 4.33 5.45 0.00 0.40 7.95 4.20 1.60 0.60 5.40 13.90 11.20 12.10 14.45 r Ar 142.0 205.2 216.0 198.0 146.0 130.0 123.2 194.0 196.0 186.0 148.0 1? 10.00 15.00 4.00 8.00 8.00 10.00 1.00 6.00 2.00 4.00 10.00 9 nnl The results show that, although the heart rate in both groups increased, the monkeys in Group II experienced a greater increase in heart rate than those in Group I (this is best observed in Figure It therefore appears that topical application of a composition of the present invention partially suppresses isoproterenol-induced tachycardia in conscious cynomolgus monkeys.
WO 93/06827 PCT/US92/08600 12 The present invention is also directed to use of the composition of the invention in treating and controlling ocular hypertension associated with glaucoma and other ophthalmic diseases and abnormalities. The methods comprise topically applying to the affected eye(s) of the patient a therapeutically effective amount of a composition according to the present invention. The frequency and amount of dosage will be determined by the clinician based on various clinical factors. The methods will typically comprise topical application of one or two drips (a drop is approximately microliters), or am equivalent amount of a solid or semi-solid dosage form, to the affected eye one to two times per day.
Concentration range Amount of drug (per 30 pI drop) 0.005 5.0 1.5 pLg 1.5 mg 0.1 2.0 30 600 pg 300 pg The invention has been described by reference to certain preferred embodiments; however, it should be understood that it may be embodied in other specific forms or variations thereof without departing from its spirit or essential characteristics. The embodiments described above are therefore considered to be illustrative in all respects and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description.
Claims (21)
1. A topical ophthalmic composition for lowering intraocular pressure with reduced systemic side effects comprising a thiadiazole of formula: N R CH 3 CH 3 H 0 NH OH HO and optically active isomers and pharmacologically acceptable salts thereof, wherein R is selected from the group consisting of: hydrogen, halogen, C1. 5 alkyl, C 2 mono-alkenyl, C2-5 alkoxy, C3.6 cycloalkyl, phenyl, phenalkyl, morpholino, furyl, thienyl and pyrryl, and an opthalmically acceptable carrier.
2. The composition of claim 1, wherein R is selected from the group consisting of: chlorine, ethyl, allyl, cyclopropyl, ethoxy, phenyl-chloromethyl and 2- (cyclopropylmethoxy) ethyl.
3. The composition of claim 2, wherein R is ethyl.
4. The composition of claim 2, wherein P. is 2- (cyclopropylmethoxy)ethyl. The composition of claim 1, wherein the thiadiazole is present in an amount between about 0.005 and about 5.0 percent by weight.
SUBSTITUTE SHEET 4' PCTUS 92/08 6 00 'IPEMJS 270CT1993 14
6. The composition of claim 5, wherein the thiadiazole is present in an amount between about 0.1 and about 2.0 percent by weight.
7. The composition of claim 6, wherein the thiadiazole is present in an amount of about 1.0 percent by weight.
8. The composition of claim 1, wherein the carrier is an anionic mucomimetic polymer.
9. The composition of claim 8, wherein the carrier is finely divided ion exchange resin.
Use of thiadiazole of formula: N N R CH 3 CH 3 N NH OH HO and optically active isomers and pharmacologically acceptable salts thereof, wherein R is selected from the group consisting of: hydrogen, halogen, C 1 .alkyl, CS. mono-alkenyl, C2-. alkoxy, C3. 6 cycloalkyl, phenyl, phenalkyl, morpholino, furyl, thienyl and pyrryl in an ophthalmic composition with an opthalmically acceptable carrier for the treatment of ocular hypertension with reduced systemic side effects.
11. Use of claim 10, wherein R is selected from the group consisting of: chlorine, ethyl, allyl, cyclopropyl, ethoxy, phenyl, phenyl-chloromethyl and 2- (cyclopropylmethoxy)ethyl. Q\ SUBSTITUTE SHEET ''A PCT/US 92/08 6 00 SIPENUS 27 OCT 1993
12. Use of claim 11, wherein R is ethyl.
13. Use of claim 11, wherein R is 2- (cyclopropylmethoxy)ethyl.
14. Use of claim 10, wherein the thiadiazole is present in an amount between about 0.005 and about percent by weight.
Use of claim 14, wherein the thiadiazole is present is an amount between about 0.1 and about percent by weight.
16. Use of claim 15, wherein the thiadiazole is present in an amount of about 1.0 percent by weight.
17. Use of claim 10, further comprising an anionic mucomimetic polymer.
18. Use of claim 17, further comprising finely divided ion exchange resin.
19. A topical ophthalmic composition comprising a thiadiazole of formula: R CH 3 CHS HO and optically active isomers and pharmacologically acceptable salts thereof, wherein R is selected from the group consisting of: hydrogen, halogen, C1.5 alkyl, C 2 mono-alkenyl, C 2 -5 alkoxy, C 3 6 cycloalkyl, phenyl, SUBSTITUTE SHEET POT/US 92/086 00 IPENUS 27 OCT 1993 phenalkyl, morpholino, furyl, thienyl and pyrryl, and an ophthalmically acceptable carrier for the preparation of a medicament for the treatment of ocular hypertension.
SUBSTITUTE SHEET A topical opthalmic composition according to claim 1 or 19 substantially as hereinbefore described with reference to any of Examples 1 to 3.
21. Use of a thiadiazole according to claim substantially as hereinbefore described. DATED this 5th day of May 1995 ALCON LABORATORIES, INC. Patent Attorneys for the Applicant: F.B. RICE CO. e
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US77654491A | 1991-10-11 | 1991-10-11 | |
US776544 | 1991-10-11 | ||
PCT/US1992/008600 WO1993006827A1 (en) | 1991-10-11 | 1992-10-09 | Topical ophthalmic compositions comprising 4-(3-substituted amino-2-hydroxypropoxy)-1,2,5-thiadiazoles and methods for their use |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2869692A AU2869692A (en) | 1993-05-03 |
AU660735B2 true AU660735B2 (en) | 1995-07-06 |
Family
ID=25107688
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU28696/92A Ceased AU660735B2 (en) | 1991-10-11 | 1992-10-09 | Topical ophthalmic compositions comprising 4-(3-substituted amino-2-hydroxypropoxy)-1,2,5-thiadiazoles and methods for their use |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0606393A1 (en) |
JP (1) | JPH06511242A (en) |
AU (1) | AU660735B2 (en) |
CA (1) | CA2120603A1 (en) |
WO (1) | WO1993006827A1 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3655663A (en) * | 1969-04-21 | 1972-04-11 | Burton K Wasson | 4-(3-secondary amino-2-hydroxy-proxy) 1 2 5-thiadiazoles |
AU4575389A (en) * | 1986-07-30 | 1991-08-01 | Alcon Laboratories, Inc. | Sustained release, comfort formulation for glaucoma therapy |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1253709A (en) * | 1968-05-22 | 1971-11-17 | Frosst & Co Charles E | Thiadiazole derivatives |
US4508725A (en) * | 1982-12-22 | 1985-04-02 | American Hospital Supply Corporation | Esters of 3-(3-substituted-amino-2-hydroxypropoxy)-4-substituted-1,2,5-thiadiazole derivatives |
-
1992
- 1992-10-09 WO PCT/US1992/008600 patent/WO1993006827A1/en not_active Application Discontinuation
- 1992-10-09 EP EP92922070A patent/EP0606393A1/en not_active Withdrawn
- 1992-10-09 JP JP5506451A patent/JPH06511242A/en active Pending
- 1992-10-09 AU AU28696/92A patent/AU660735B2/en not_active Ceased
- 1992-10-09 CA CA002120603A patent/CA2120603A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3655663A (en) * | 1969-04-21 | 1972-04-11 | Burton K Wasson | 4-(3-secondary amino-2-hydroxy-proxy) 1 2 5-thiadiazoles |
AU4575389A (en) * | 1986-07-30 | 1991-08-01 | Alcon Laboratories, Inc. | Sustained release, comfort formulation for glaucoma therapy |
Also Published As
Publication number | Publication date |
---|---|
AU2869692A (en) | 1993-05-03 |
CA2120603A1 (en) | 1993-04-15 |
EP0606393A1 (en) | 1994-07-20 |
WO1993006827A1 (en) | 1993-04-15 |
JPH06511242A (en) | 1994-12-15 |
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