WO1997002825A1 - Thiophene sulfonamides useful as carbonic anhydrase inhibitors - Google Patents

Thiophene sulfonamides useful as carbonic anhydrase inhibitors Download PDF

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Publication number
WO1997002825A1
WO1997002825A1 PCT/US1995/008149 US9508149W WO9702825A1 WO 1997002825 A1 WO1997002825 A1 WO 1997002825A1 US 9508149 W US9508149 W US 9508149W WO 9702825 A1 WO9702825 A1 WO 9702825A1
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Prior art keywords
alkoxy
sulfonamide
thieno
dioxide
thiazine
Prior art date
Application number
PCT/US1995/008149
Other languages
French (fr)
Inventor
Anura P. Dantanarayana
Thomas R. Dean
Jesse A. May
Original Assignee
Alcon Laboratories, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Alcon Laboratories, Inc. filed Critical Alcon Laboratories, Inc.
Priority to PCT/US1995/008149 priority Critical patent/WO1997002825A1/en
Priority to AU29989/95A priority patent/AU2998995A/en
Publication of WO1997002825A1 publication Critical patent/WO1997002825A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to new thiophene sulfonamides useful in lowering and controlling intraocular pressure.
  • Glaucoma is a disease of the eye which is characterized by a progressive loss of visual field due to irreversible damage to the optic nerve. If tintreated, this condition can result in blindness.
  • This loss of visual field in one form of primary open angle glaucoma, that is, chronic primary open angle glaucoma, hereinafter POAG, is associated with a sustained increase in the intraocular pressure (IOP) of the diseased eye.
  • IOP intraocular pressure
  • elevated intraocular pressure without visual field loss, or ocular hypertension can be indicative of the early stages of POAG.
  • Another less common treatment for ocular hypertension or POAG is the systemic administration of carbonic anhydrase inhibitors; however, this therapy can also bring about unwanted side effects, such as nausea, dyspepsia, fatigue, and metabolic a ⁇ dosis.
  • Topical administration of carbonic anhydrase inhibitors can be used to control IOP with a reduced risk of encountering the
  • the present invention is directed to new thiophene sulfonamides which can be used to lower and control IOP.
  • the compounds are formulated in
  • compositions for delivery are provided.
  • the invention is also directed to methods for treating ocular hypertension and POAG by lowering and controlling IOP by the administration of the thiophene sulfonamides of the present invention.
  • the compounds can be administered systemically and/or topically to the eye.
  • the thiophene sulfonamides of the present invention have the following structure.
  • R 6 is a monocyclic ring system of 5 or 6 atoms composed of C, N, O and/or S, such as furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine pyrimidine, pyridazine, and pyrazine.
  • C, N, O and/or S such as furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine pyrimidine, pyridazine, and pyrazine.
  • R 8 is C 1-4 alkyl; C 1-4 alkoxy; amino, C 1-3 alkylamino, of di-C 1-3 alkylamino.
  • the total number of carbon atoms in a substituent group is indicated by the C i-j prefix where i and j are numbers from 1 to 8, for example.
  • This C i-j definition includes both the straight and branched chain isomers. For example, C 1-3 alkyl would designate methyl through the butyl isomers; and C 1-3 alkoxy would designate methoxy through the butoxy isomers.
  • halogen either alone or in compound words such as “haloalkyl,” means fluorine, chlorine, bromine, or iodine. Further, when used in compound words such as “haloalkyl,” said alkyl may be partially or fully substituted with halogen atoms, which may be the same or different.
  • novel compounds of the structure 1 possess one or more chiral centers and this invention includes all enantiomers, diastereomers, and mixtures thereof.
  • thioether of la by the action of a mild oxidizing agent (Equation 1).
  • Either the sulfoxide or sulfone can be prepared selectively by varying the reaction conditions, temperature, and stoichiometry based on known methods.
  • Oxidizing agents useful for these conversions include mCPBA, Oxone*, hydrogen peroxide and other similar reagents.
  • R 1 , R 7 , and m are as previously defined and X is C 2-8 alkyl or C 4-7 alkenyl.
  • Equation 2 The most direct method useful for the preparation of the thioether compounds la in particular those wherein the R1 group is an alkyl amine group, is shown in Equation 2. This method features the introduction of the key thioether moiety in the last step of the synthesis. In this method the basic ring structure is assembled initially and then converted into a suitable substrate for the
  • TLC thin layer chromatography
  • HPLC nigh pressure liquid chromatography
  • GC gas chromatography
  • the reaction mixture is added to water and the desired product is isolated either by filtration or by extraction (or other methods known to one skilled in the art).
  • the desired compounds la can be isolated in pure form by recrystallization.
  • the preparation of the desired thiolate anions is known.
  • Compounds 3 can be prepared from compounds 4 according to Equation 3.
  • R 1 is NR 5 R 4 , and X and R 7 are as previously defined ; and Y is a leaving group such as Cl, Br, I, O SO 2 CH 3 , OSO 2 (p-CH 3 Ph) or similar leaving group.
  • Compounds 1 were the R 1 group is other than an amine group can be prepared from compounds of structure 4 (Equation 3).
  • the cyclic sulfonamide group of compounds of structure 4 can be alkylated selectively using alkylating agents which already possess the key thioether moiety.
  • the compounds 4 are then converted to the compounds 1 using standard deprotection conditions.
  • the compounds 4 are known in the art.
  • the compounds of the present invention are exceptionally active relative to known compounds and some are believed to have much shorter half lifes. It is advantageous to have a short half life because the compounds have been designed to be effective upon topical application to the eye. Most of the compound that leaves the eye, for example, via the lacrimal punctum, is absorbed systemically.
  • the compounds can be incorporated into various types of ophthalmic formulations for delivery to the eye. These compounds may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution.
  • sterile ophthalmic ointment formulations the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
  • Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, Carbopol-940 or the like according to the published formulations for analogous ophthalmic
  • Ophthalmic solution formulations may be prepared by dissolving the active ingredient in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the active ingredient A thickener, such as hydroxymethylcellulose,
  • the compounds are preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 4.5 to 8.0.
  • the compounds will normally be contained in these formulations in an amount of 0.1% to 10% by weight, but preferably in an amount of 0.25% to 5.0% by weight.
  • these formulations would be delivered to the surface of a mammal's eye 1 to 3 times a day according to the routine discretion of a skilled clinician.
  • Example 1 represents the preferred thiophene sulfonamide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

New thiophene sulfonamides useful as carbonic anhydrase inhibitors are disclosed. Methods for using the compounds to control IOP are also disclosed.

Description

THIOPHENE SULFONAMIDES USEFUL AS
CARBONIC ANHYDRASE INHIBITORS
Field of the Invention
The present invention relates to new thiophene sulfonamides useful in lowering and controlling intraocular pressure.
Background of the Invention
Glaucoma is a disease of the eye which is characterized by a progressive loss of visual field due to irreversible damage to the optic nerve. If tintreated, this condition can result in blindness. This loss of visual field, in one form of primary open angle glaucoma, that is, chronic primary open angle glaucoma, hereinafter POAG, is associated with a sustained increase in the intraocular pressure (IOP) of the diseased eye. In addition, elevated intraocular pressure without visual field loss, or ocular hypertension, can be indicative of the early stages of POAG.
There are a number of therapies that target reducing the elevated IOP associated with ocular hypertension or POAG. The most common feature the topical administration of a beta adrenergic antagonist (beta-blocker) or a
muscarinic agonist These treatments, while effective in lowering IOP, can also produce significant undesirable side effects.
Another less common treatment for ocular hypertension or POAG is the systemic administration of carbonic anhydrase inhibitors; however, this therapy can also bring about unwanted side effects, such as nausea, dyspepsia, fatigue, and metabolic aάdosis. Topical administration of carbonic anhydrase inhibitors can be used to control IOP with a reduced risk of encountering the
aforementioned systemic side effects. U.S. Patent Nos. 5,153,192; 5,240,923;
4,797,413; 5,308,863; and EPO 91/452,151A1 disclose topically dosed sulfonamides which lower IOP by inhibiting carbonic anhydrase. Summary of the Tnvention
The present invention is directed to new thiophene sulfonamides which can be used to lower and control IOP. The compounds are formulated in
pharmaceutical compositions for delivery.
The invention is also directed to methods for treating ocular hypertension and POAG by lowering and controlling IOP by the administration of the thiophene sulfonamides of the present invention. The compounds can be administered systemically and/or topically to the eye.
Detailed Description of the Invention
The thiophene sulfonamides of the present invention have the following structure.
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof wherein:
R1 is H; OH; C1-6 alkoxy; C1-6 alkyl unsubstituted or substituted optionally with OH, NR3R4, OC(=O)R5 or C(=O)R5; NR3R4 OC(=O)R5; C(=O)R5; C2-4 alkoxy substituted optionally with OH, NR3R4, halogen, C1-4 alkoxy or C(=O)R5; phenyl or R6 either of which can be unsubstituted or substituted optionally with OH, (CH2)nNR3R4, halogen, C1-4 alkoxy, C1-4 haloalkoxy, C(=O)R5, S(=O)mR7 or
SO2NR3R4; wherein m is 0 - 2 and n is 0 - 2; provided that when R1 is OH, alkoxy, NR3R4 or OC(=O)R5 it is attached to the 4-position and when R1 is R6 and is attached to the 3 position, the R6 ring is attached by a carbon carbon single bond. R2 is C2-8 alkyl substituted with S(=O)mR7; C4-7 alkenyl substituted with S(=O)mR7 wherein m is 0 - 2.
R3 & R4 are the same or different and are H; C1-8 alkyl; C2-4alkyl substituted optionally with OH, halogen, C1-4 alkoxy or C(=O)R5; CH alkoxy; C2-4 alkoxy substituted optionally with OH, halogen, C1-4 alkoxy or C(=O)R5; or R3 and R4 can be joined to form a ring of 5 or 6 atoms selected from O, S, C or N which can be unsubstituted or substituted optionally on carbon with OH, (=O), halogen, C1-4 alkoxy, C(=O)R5, C1-6 alkyl, C1-6 alkyl substituted optionally with OH, halogen, C1-4 alkoxy, C(=O)R5 or on nitrogen with C1-4 alkoxy, C(=O)R5, S(=O)mR7, C1-6 alkyl or C2-6 alkyl substituted optionally with OH, halogen, C1-4 alkoxy, C(=O)R5 or on sulfur by (=O)m, wherein m is 0 - 2. R5 is C1-8 alkyl; C1-8 alkyl substituted optionally with OH, NR3R4, halogen, C1-4 alkoxy or C(=O)R8; C1-4 alkoxy; C2-4 alkoxy substituted optionally with OH, NR3R4, halogen or C1-4 alkoxy; or NR3R4. R6 is a monocyclic ring system of 5 or 6 atoms composed of C, N, O and/or S, such as furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine pyrimidine, pyridazine, and pyrazine.
R7 is C1-4 alkyl; C3-5 alkenyl, C2-4 alkyl substituted optionally with OH, NR3R4, C1-4 alkoxy or C(=O)R5; phenyl or R6 either of which can be unsubstituted or
substituted optionally with OH, (CH2)nNR3R4, halogen, C1-4 alkoxy, C1-4 haloalkoxy, C(=O)R5, S(=O)mC1-4 alkyl or SO2NR3R4 ; wherein m is 0 - 2 and n is 0 - 2; and
R8 is C1-4 alkyl; C1-4 alkoxy; amino, C1-3 alkylamino, of di-C1-3 alkylamino. In the above definitions, the total number of carbon atoms in a substituent group is indicated by the Ci-j prefix where i and j are numbers from 1 to 8, for example. This Ci-j definition includes both the straight and branched chain isomers. For example, C1-3 alkyl would designate methyl through the butyl isomers; and C1-3 alkoxy would designate methoxy through the butoxy isomers.
The term "halogen" either alone or in compound words such as "haloalkyl," means fluorine, chlorine, bromine, or iodine. Further, when used in compound words such as "haloalkyl," said alkyl may be partially or fully substituted with halogen atoms, which may be the same or different.
Many of the novel compounds of the structure 1 possess one or more chiral centers and this invention includes all enantiomers, diastereomers, and mixtures thereof.
Compounds of the present invention can be prepared using the methods described below in Equations 1 to 3.
Compounds 1b, where the thioether group has been oxidized to the corresponding sulfone or sulfoxide, can be prepared directly from the
corresponding thioether of la by the action of a mild oxidizing agent (Equation 1). Either the sulfoxide or sulfone can be prepared selectively by varying the reaction conditions, temperature, and stoichiometry based on known methods. Oxidizing agents useful for these conversions include mCPBA, Oxone*, hydrogen peroxide and other similar reagents.
Figure imgf000007_0001
Wherein R1, R7, and m are as previously defined and X is C2-8 alkyl or C4-7 alkenyl.
The most direct method useful for the preparation of the thioether compounds la in particular those wherein the R1 group is an alkyl amine group, is shown in Equation 2. This method features the introduction of the key thioether moiety in the last step of the synthesis. In this method the basic ring structure is assembled initially and then converted into a suitable substrate for the
introduction of the thioether group. This is accomplished by preparing
compounds of structure 3 which possess a suitable leaving group attached to the appropriate X substituent This key intermediate is converted directly to the compounds la via nucleophilic displacement of the leaving group with the appropriate thiolate anion. This transformation can be accomplished by adding the compounds 3 to the thiolate anion in a polar aprotic solvent such as
N,N-dimethylformamide (DMF) or dimethylsulfoxide (DMSO) at temperatures ranging from 0° to 65°. After the reaction is judged to be complete, as analyzed by thin layer chromatography (TLC), nigh pressure liquid chromatography (HPLC), or gas chromatography (GC) (or other means known to one skilled in the art), the reaction mixture is added to water and the desired product is isolated either by filtration or by extraction (or other methods known to one skilled in the art). The desired compounds la can be isolated in pure form by recrystallization. The preparation of the desired thiolate anions is known. Compounds 3 can be prepared from compounds 4 according to Equation 3.
Figure imgf000008_0001
Wherein: R1 is NR5R4, and X and R7 are as previously defined ; and Y is a leaving group such as Cl, Br, I, O SO2CH3, OSO2(p-CH3Ph) or similar leaving group. Compounds 1 were the R1 group is other than an amine group can be prepared from compounds of structure 4 (Equation 3). The cyclic sulfonamide group of compounds of structure 4 can be alkylated selectively using alkylating agents which already possess the key thioether moiety. The compounds 4 are then converted to the compounds 1 using standard deprotection conditions. The compounds 4 are known in the art.
Figure imgf000008_0002
Wherein: R1, R7, X, m, and Y are as previously defined; Y' is Y; Z is R7-S(=O)m and Y; Ra and Rb represent protecting groups for the sulfonamide such as H, t-butyl, a formamidine group, an imidate group and/or other similar functionalities. The compounds of the present invention are exceptionally active relative to known compounds and some are believed to have much shorter half lifes. It is advantageous to have a short half life because the compounds have been designed to be effective upon topical application to the eye. Most of the compound that leaves the eye, for example, via the lacrimal punctum, is absorbed systemically.
Compounds with shorter half lives are believed to cause fewer undesirable systemic side effects.
The compounds can be incorporated into various types of ophthalmic formulations for delivery to the eye. These compounds may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution. In order to prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, Carbopol-940 or the like according to the published formulations for analogous ophthalmic
preparations; preservatives and tonicity agents can be incorporated. Ophthalmic solution formulations may be prepared by dissolving the active ingredient in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the active ingredient A thickener, such as hydroxymethylcellulose,
hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the medicament in the conjunctival sac
The compounds are preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 4.5 to 8.0. The compounds will normally be contained in these formulations in an amount of 0.1% to 10% by weight, but preferably in an amount of 0.25% to 5.0% by weight. Thus, for topical presentation these formulations would be delivered to the surface of a mammal's eye 1 to 3 times a day according to the routine discretion of a skilled clinician.
The following examples, which are in no way limiting, illustrate the preparation of selected examples of the compounds of the present invention. The compound set forth in Example 1 represents the preferred thiophene sulfonamide.
EXAMPLE 1
Figure imgf000011_0001
(+)-(R)-4-Ethylamino-3,4-dihydro-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide maleic acid
Step A:
Preparation of 2-(3-Bromopropyl)-4-ethylamino-3,4-dihydro-2H-thieno-[3,2-e]-1. 2-thiazine-6-sulfonamide 1,1-dioxide
A stirred solution of (+)-(R)*4^thylamino-3,4κimydro-2-(3-methoxypropyl)-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide hydrochloride (4.5 g, 110.7 mmol) in 48% HBr (20.0 mL) was heated at 80°C for 72h. The reaction mixture was concentrated in vacuo at 60°C bath temperature to give a pale tan solid (4.8 g, 96%).
Step B:
Preparation of (+)-(R)-4-Ethylamino-3,4-dihydro-2-(3-methylthiopropyl)-2H-thieno- [3,2-e]-1,2-thiazine-6-sulfonamide 1 ,1-dioxide maleic acid
To a stirred suspension of sodium thiomethoxide (1.18 g, 16.8 mmol) in DMF (5.0 mL) at room temperature was added a solution of the compound isolated in Step A above (1.48 g, 2.8 mmol) in DMF (10.0 mL). After 2h, water (50.0 mL) was added and the mixture extracted with ethyl acetate (3 × 50.0 mL). Ethyl acetate extracts were combined, washed with brine (20.0 mL), dried (MgSO4) and
evaporated. The residue was purified by flash chromatography on silica (gradient: 50% ethyl acetate-hexane, 60% ethyl acetate-hexane, ethyl acetate) to yield a solid (1.16 g, 100%) which was dissolved in THF (5.0 mL) and added to a solution of maleic acid (0.44 g, 3.7 mmol) in ether. The voiatiles were evaporated and the solid dried. Recrystallization from ethyl acetate gave the desired product (0.88 g): m.p. 151-152°C; [α]D +8.36° (c=0.67; MeOH); Anal. Calcd for C16H25N3O8S4; C, 37.27; H, 4.89, N, 8.15. Found C, 37.36; H, 4.93; N, 8.12.
Using modifications of the above procedure, but substituting the appropriate alkylamine in Step A the following compounds can be prepared:
1. 3,4-Dihydro-4-propylarrdno-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride;
2. 3,4-Dihydro-4-[(2-methylpropyl)amino]-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride;
3. 3,4- Dihydro-4-[(3-methylbutyl)aminol-2-(3-metiιylthiopropyl)-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride;
4. 3,4-Dihydro4-metiιylamino-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride.
EXAMPLE 2
Figure imgf000013_0001
3,4-Dihydro-4-hydroxy-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide
To a stirred solution of 3,4-dihydro-4-hydroxy-N-(1,1-dimethyl)ethyl-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide (2.4 g, 7.1 mmol) in DMF (15.0 mL) was added NaH (60% dispersion in mineral oil, 0.508 g, 12.7 mmol) at 0°C. After 30 min, a solution of 3-methylthiopropane p-toluene sulfonate (3.3 g, 12.7 mmol) in DMF (3.0 mL) was added dropwise. The mixture was stirred an additional 5h at which point TLC analysis indicated that the reaction was complete. The reaction mixture was poured into a saturated solution of aminonium chloride (20.0 mL) and the mixture extracted with ethyl acetate (4 × 50.0 mL). The ethyl acetate extracts were combined, washed with water and then brine (20.0 mL), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica (30% ethyl acetate-hexane, 40% ethyl acetate-hexane, 50% ethyl acetate-hexane) to yield the product as a yellow oil. Without further manipulation, TFA (20.0 mL) was added to the oil and the mixture stirred for 24 h after which time TLC analysis indicated that the reaction was finished. The TFA was evaporated and the residue was combined with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine (10 mL), dried (MgSO4), and evaporated. The residue was purified by flash chromatography on silica (50% ethyl acetate-hexane) to furnish the desired product as an oil. EXAMPLE 3
Figure imgf000014_0001
(R)-4-Ethylaιruno-3,4-dihydro-2-[3-(1-methylethylthio)propyl]-2H-thieno- [3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride
To a stirred suspension of sodium 2-propanethiolate (1.13 g, 11.6 mmol) in DMF (5.0 mL) at room temperature was added a solution of the compound prepared in Example 1, Step A, (0.99 g, 1.9 mmol) in DMF (10.0 mL). After 2 h, water (50.0 mL) was added and the mixture extracted with ethyl acetate (3 × 50.0 mL). Ethyl acetate extracts were combined, washed with brine (20.0 mL), dried MgSO4) and evaporated. The residue was purified by flash chromatography on silica (gradient 50% ethyl acetate-hexane, 60% ethyl acetate-hexane, ethyl acetate) to yield a solid (0.78 g, 95%) which was dissolved in ethanol (5.0 mL) and added to a solution of ethanolic HCl (2 mL). The voiatiles were evaporated and the solid dried.
Recrystallization from methanol-methylene chloride gave the product (0.78 g): m.p. 165-167°C; [α]D + 6.88 (c = 0.64; MeOH); Anal. Calcd for C14H26ClN3O4S4• 0.5 H2O; C, 35.54; H, 5.75, N, 8.88. Found: C, 35.52; H, 5.71; N, 8.84.
Using modifications of the above procedure, but substituting the appropriate thiolate, the following compounds can be prepared:
1. 4-Ethylamino-3,4-dihydro-2-(3-propylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride;
2. 4-Ethylanιino-3,4-dihydro-2-(3-euhylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride; 3. 4-Ethylamino-3,4-dihydro-2-[3-(2-methoxyethylthio)propyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride;
4. 4-Ethylamino-3,4-dihydro-2-[3-(3-methoxypropylthio)propyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride.
Using modifications of the above procedure and that described in Example 1, but substituting the appropriate thienothiazine in Step A, Example 1 and the desired thiolate, the following compounds can be prepared:
1. 4-Ethylamino-3,4-dihydro-2-[3-(2-methoxyethylthio)ethyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride;
2. 4-Ethylamino-3,4-dihydro-2-[(2-methylthio)ethyl]-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride;
3. 3,4-Dihydro-4-propylamino-2-[(2-methylthio)ethyl)]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride; 4. 3,4-Dihydro-4-[(2-methylpropyl)amino]-2-[(2-methylthio)ethyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride;
5. 4-Ethylamino-3,4-dihydro-2-[(4-methylthio)butyl]-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride;
6. 3,4-Dihydxo-4-propylamino-2-[(4-methylthio)butyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride;
7. 3,4-Dihydro-4-[(2-methylpropyl)amino]-2-[(4-methylthio)butyl]-2H-thieno-[3,2-e]-1,2 thiazine-6-sulfonamide 1,1-dioxide hydrochloride. Using the procedures described in equations 1 to 3, Examples 1 to 3, and known procedures, one skilled in the art can prepare the compounds disclosed herein.
EXAMPLE 4
Ophthalmic Solution
Figure imgf000016_0001
EXAMPLE 5
Ophthalmic Suspension
Figure imgf000017_0001

Claims

We Claim;
1. A compound having the following structure:
Figure imgf000018_0001
or a pharmaceutically acceptable salt thereof wherein: R, is H; OH; C1-6 alkoxy; C1-6 alkyl unsubstituted or substituted optionally with OH,
NR3R4, OC(=O)R5 or C(=O)R5; NR3R4; OC(=O)R5; C(=O)R5; C2-4 alkoxy substituted optionally with OH, NR3R4, halogen, C1-4 alkoxy or C(=O)R5; phenyl or R6 either of which can be unsubstituted or substituted optionally with OH, (CH2)nNR3R4, halogen, C1-4 alkoxy, C1-4 haloalkoxy, C(=O)R5, S(=O)mR7 or SO2NR3R4; wherein m is 0 - 2 and n is 0 - 2; provided that when R1 is OH, alkoxy, NR3R4 or OC(=O)R5 it is attached to the 4-position and when R1 is R6 and is attached to the 3 position, the R6 ring is attached by a carbon carbon single bond; R1 is C2-8 alkyl substituted with S(=O)mR7; C4-7 alkenyl substituted with S(=O)mR7 wherein m is 0 - 2; R3 & R4 are the same or different and are H; C1-8 alkyl; C2-4alkyl substituted optionally with OH, halogen, C1-4 alkoxy or C(=O)R5; C1-4 alkoxy; C2-4 alkoxy substituted optionally with OH, halogen, C1-4 alkoxy or C(=O)R5; or R3 and R4 can be joined to form a ring of 5 or 6 atoms selected from O, S, C or N which can be unsubstituted or substituted optionally on carbon with OH, (=O), halogen, C1-4 alkoxy, C(=O)R5, C1-6 alkyl, C1-6 alkyl substituted optionally with OH, halogen, C1-4 alkoxy, C(=O)R5 or on nitrogen with C1-4 alkoxy, C(=O)R5, S(=O)mR7, C1-6 alkyl or C2-6 alkyl substituted optionally with OH, halogen, C1-4 alkoxy, C(=O)R5 or on sulfur by (=O)m, wherein m is 0 - 2; R5 is C1-8 alkyl; C1-8 alkyl substituted optionally with OH, NR3R4, halogen, C1-4 alkoxy or C(=O)R8; C1-4 alkoxy; C2-4 alkoxy substituted optionally with OH, NR3R4, halogen or C1-4 alkoxy; or NR3R4; R6 is a monocyclic ring system of 5 or 6 atoms composed of C, N, O and/or S, such as furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine pyrimidine, pyridazine, and pyrazine;
R7 is C1-4 alkyl; C3-5 alkenyl, C2-4 alkyl substituted optionally with OH, NR3R4, C1-4 alkoxy or C(=O)R5; phenyl or R6 either of which can be unsubstituted or substituted optionally with OH, (CH2)nNR3R4, halogen, C1-4 alkoxy, C1-4 haloalkoxy, C(=O)R5, S(=O)mC1-4 alkyl or SO2NR3R4; wherein m is 0 - 2 and n is 0 - 2; and R8 is C1-4 alkyl; C1-4 alkoxy; amino, C1-3 alkylamino, of di-C1-3 alkylamino. 2. The compound of Claim 1 selected from the group consisting of: (R)-4-Ethylarmno-3,4-dihydro-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-propylarrtino-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-[(2-methylpropyl)amino]-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-[(3-methylbutyl)amino]-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-methylamino-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-hydroxy-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
(R)-4-Ethylamino-3,4-ciihydro-2-[3-(1-methylethylthio)propyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide; 4-Ethylamino-3,4-dihydro-2-(3-propylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-(3-ethylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-[3-(2-methoxyethylthio)propyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-[3-(3-methoxypropylthio)propyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulforamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-[3-(2-methoxyethylthio)ethyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylaιnino-3,4-dihydro-2-[(2-methylthio)ethyl]-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-propylamino-2-[(2-methylthio)ethyl)]-2H-tiιieno-l3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-[(2-metiιylpropyl)amino]-2-[(2-methylthio)ethyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-[(4-methylthio)butyl]-2H-thieno-[3,2-e]- 1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-propylamino-2-[(4-methylthio)butyl]-2H-thieno-[3,2-e]- 1,2-thiazine-6-sulfonamide 1,1-dioxide; and
3,4-Dihydro-4-[(2-metiιylpropyl)amino]-2-[(4-methylthio)butyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide. 3. The compound of Claim 2 which is (R)-4-Ethylamino-3,4-dihydro-2-(3-methylthiopropyl)-2H-thieno--[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide.
4. A composition for lowering and controlling IOP comprising a pharmaceutically effective amount of a compound having the following structure:
Figure imgf000021_0001
or a pharmaceutically acceptable salt thereof wherein:
R1 is H; OH; C1-6 alkoxy; C1-6 alkyl unsubstituted or substituted optionally with OH, NR3R4, OC(=O)R5 or C(=O)R5; NR3R4; OC(=O)R5; C(=O)R5; C2-4 alkoxy substituted optionally with OH, NR3R4, halogen, C1-4 alkoxy or C(=O)R5; phenyl or R6 either of which can be unsubstituted or substituted optionally with OH, (CH2)nNR3R4, halogen, C1-4 alkoxy, C1-4 haloalkoxy, C(=O)R5, S(=O)mR7 or SO2NR3R4; wherein m is 0 - 2 and n is 0 - 2; provided that when R, is OH, alkoxy, NR3R4 or OC(=O)R5 it is attached to the -4-position and when R1 is R6 and is attached to the 3 position, the R6 ring is attached by a carbon carbon single bond;
R2 is C2-8 alkyl substituted with S(=O)mR7; C4-7 alkenyl substituted with S(=O)mR7 wherein m is 0 - 2;
R3 & R4 are the same or different and are H; C1-8 alkyl; C2-4alkyl substituted optionally with OH, halogen, C1-4 alkoxy or C(=O)R5; C1-4 alkoxy; C2-4 alkoxy substituted optionally with OH, halogen, C1-4 alkoxy or C(=O)R5; or R3 and R4 can be joined to form a ring of 5 or 6 atoms selected from O, S, C or N which can be unsubstituted or substituted optionally on carbon with OH, (=O), halogen, C1-4 alkoxy, C(=O)R5, C1-6 alkyl, C1-6 alkyl substituted optionally with OH, halogen, C1-4 alkoxy, C(=O)R5 or on nitrogen with C1-4 alkoxy, C(=O)R5, S(=O)mR7, C1-6 alkyl or C2-6 alkyl substituted optionally with OH, halogen, C1-4 alkoxy, C(=O)R5 or on sulfur by (=O)m, wherein m is 0 - 2; R5 is C1-8 alkyl; C1-8 alkyl substituted optionally with OH, NR3R4, halogen, C1-4 alkoxy or C(=O)R8; C1-4 alkoxy; C2-4 alkoxy substituted optionally with OH, NR3R4, halogen or C1-4 alkoxy; or NR3R4; R6 is a monocyclic ring system of 5 or 6 atoms composed of C, N, O and/or S, such as furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine pyrimidine, pyridazine, and pyrazine; R7 is C1-4 alkyl; C3-5 alkenyl, C2-4 alkyl substituted optionally with OH, NR3R4, C1-4 alkoxy or C(=O)R5; phenyl or R6 either of which can be unsubstituted or substituted optionally with OH, (CH2)nNR3R4, halogen, C1-4 alkoxy, C1-4 haloalkoxy, C(=O)R5, S(=O)mC1-4 alkyl or SO2NR3R4; wherein m is 0 - 2 and n is 0 - 2; and R8 is C1-4 alkyl; C1-4 alkoxy; amino, C1-3 alkylamino, of di-C1-3 alkylamino.
5. The composition of Claim 2 wherein the compound is selected from the group consisting of: (R)-4-Ethylamino-3,4-dihydro-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dmydxo-4-propylamino-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-[(2-methylpropyl)amino]-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-[(3-methylbutyl)anιino]-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-methylamino-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-hydroxy-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide; (R)-4-Ethylamino-3,4-dihydro-2-[3-(1-methylethylthio)propyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-(3-propylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-(3-ethylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-[3-(2-methoxyethylthio)propyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-[3-(3-methoxypropylthio)propyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylaιnmo-3,4-dihydro-2-[3-(2-methoxyethylthio)ethyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-[(2-methylthio)ethyl]-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-propylamino-2-[(2-methylthio)ethyl)]-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-[(2-methylpropyl)amino]-2-[(2-methylthio)ethyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4- dihydro-2-[(4-methylthio)butyl]-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-propylamino-2-[(4-methylthio)butyl]-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide; and
3,4-Dihydro-4-[(2-methylpropyl)amino]-2-[(4-methylthio)butyl]-2H-thieno-[3,2-e]-1,2-tiuazine-6-sulfonamide 1,1-dioxide.
6. The composition of Claim 3 wherein the compound is (R)-4-Ethylamino-3,4-dihydro-2-(3-methyltmopropyl)-2H-thieno [3,2-e]-1,2-thiazine-6-sulfonamide 1, 1-dioxide.
7. A method for lowering and controlling IOP by administering a
pharmaceutically effective amount of a compound having the following structure:
Figure imgf000024_0001
or a pharmaceutically acceptable salt thereof wherein: R1 is H; OH; C1-6 alkoxy; C1-6 alkyl unsubstituted or substituted optionally with OH, NR3R4, OC(=O)R5 or C(=O)R5; NR3R4; OC(=O)R5; C(=O)R5; C2-4 alkoxy substituted optionally with OH, NR3R4, halogen, C1-4 alkoxy or C(=O)R5; phenyl or R6 either of which can be unsubstituted or substituted optionally with OH, (CH2)nNR3R4, halogen, C1-4 alkoxy, C1-4 haloalkoxy, C(=O)R5, S(=O)mR7 or SO2NR3R4; wherein m is 0 - 2 and n is 0 - 2; provided that when R1 is OH, alkoxy, NR3R4 or OC(=O)R5 it is attached to the 4-position and when R, is R« and is attached to the 3 position, the R6 ring is attached by a carbon carbon single bond; R2 is C2-8 alkyl substituted with S(=O)mR7; C4-7 alkenyl substituted with S(=O)mR7 wherein m is 0 - 2; R3 & R4 are the same or different and are H; C1-8 alkyl; C2-4alkyl substituted optionally with OH, halogen, C1-4 alkoxy or C(=O)R5; C1-4 alkoxy; C2-4 alkoxy substituted optionally with OH, halogen, C1-4 alkoxy or C(=O)R5; or R3 and R4 can be joined to form a ring of 5 or 6 atoms selected from O, S, C or N which can be unsubstituted or substituted optionally on carbon with OH, (=O), halogen, C1-4 alkoxy, C(=O)R5, C1-6 alkyl, C1-6 alkyl substituted optionally with OH, halogen, C1-4 alkoxy, C(=O)R5.or on nitrogen with C1-4 alkoxy, C(=O)R5, S(=O)mR7, C1-6 alkyl or C2-6 alkyl substituted optionally with OH, halogen, C1-4 alkoxy, C(=O)R5 or on sulfur by (=O)m, wherein m is 0 - 2; R5 is C1-8 alkyl; C1-8 alkyl substituted optionally with OH, NR3R4, halogen, C1-4 alkox or C(=O)R8; C1-4 alkoxy; C2-4 alkoxy substituted optionally with OH, NR3R4, halogen or C1-4 alkoxy; or NR3R4; R1 is a monocyclic ring system of 5 or 6 atoms composed of C, N, O and/or S, such as furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine pyrimidine, pyridazine, and pyrazine; R7 is C1-4 alkyl; C3-5 alkenyl, C2-4 alkyl substituted optionally with OH, NR3R4, C1-4 alkoxy or C(=O)R5; phenyl or R6 either of which can be unsubstituted or substituted optionally with OH, (CH2)nNR3R4, halogen, C1-4 alkoxy, C1-4 haloalkoxy, C(=O)R5, S(=O)m C1-4 alkyl or SO2NR3R4; wherein m is 0 - 2 and n is 0 - 2; and R8 is C1-4 alkyl; C1-4 alkoxy; amino, C1-3 alkylamino, of di-C1-3 alkylamino.
8. The method of Claim 7 wherein the compound is selected from the group consisting of: (R)-4-Ethylamino-3,4-dihydro-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-propylamino-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-[(2-methylpropyl)amino]-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-[(3-methylbutyl)amino]-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-methylamino-2-(3-methiylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-hydroxy-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide; (R)-4-Ethylamino-3,4-dihydro-2-[3-(1-methylethylthio)propyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-(3-propylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-(3-ethylthiopropyl)-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-[3-(2-methoxyethylthio)propyl]-2H-thieno-[3,2-e]-1,2-thiazme-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-[3-(3-methoxypropylthio)propyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-[3-(2-methoxyethylthio)ethyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-[(2-methylthio)ethyl]-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-propylamino-2-[(2-methylthio)ethyl)]-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-[(2-methylpropyl)amino]-2-[(2-methylthio)etiιyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide;
4-Ethylamino-3,4-dihydro-2-[(4-methylthio)butyl]-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide;
3,4-Dihydro-4-propylamino-2-[(4-methylthio)butyl]-2H-thieno-[3,2-e]-1,
2-thiazine-6-sulfonamide 1,1-dioxide; and
3,4-Dihydro-4-[(2-methylpropyl)amino]-2-[(4-methylthio)butyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide.
9. The method of Claim 8 wherein the compound is (R)-4-Ethylamino-3,4-dihydro-2-(3-methylthiopropyl)-2H-thieno-[3,2-e]-1,2- thiazine-6-sulfonamide 1,1-dioxide.
PCT/US1995/008149 1995-07-12 1995-07-12 Thiophene sulfonamides useful as carbonic anhydrase inhibitors WO1997002825A1 (en)

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WO1998019707A1 (en) * 1996-11-05 1998-05-14 Alcon Laboratories, Inc. Polyhydroxy monocarboxylic and dicarboxylic acids and their lactones in ophthalmic compositions

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US5153192A (en) * 1990-04-09 1992-10-06 Alcon Laboratories, Inc. Thiophene sulfonamides useful as carbonic anhydrase inhibitors

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US5153192A (en) * 1990-04-09 1992-10-06 Alcon Laboratories, Inc. Thiophene sulfonamides useful as carbonic anhydrase inhibitors
US5240923A (en) * 1990-04-09 1993-08-31 Alcon Laboratories, Inc. Sulfonamides useful as carbonic anhydrase inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998019707A1 (en) * 1996-11-05 1998-05-14 Alcon Laboratories, Inc. Polyhydroxy monocarboxylic and dicarboxylic acids and their lactones in ophthalmic compositions

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