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WO1995019981A1 - Procede de preparation de derives du thienothiazine sulfonamide, intermediaires de preparation, et utilisation comme inhibiteurs d'anhydrases carboniques - Google Patents

Procede de preparation de derives du thienothiazine sulfonamide, intermediaires de preparation, et utilisation comme inhibiteurs d'anhydrases carboniques Download PDF

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Publication number
WO1995019981A1
WO1995019981A1 PCT/US1995/000775 US9500775W WO9519981A1 WO 1995019981 A1 WO1995019981 A1 WO 1995019981A1 US 9500775 W US9500775 W US 9500775W WO 9519981 A1 WO9519981 A1 WO 9519981A1
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Prior art keywords
alkoxy
alkyl
substituted
hydroxyl
halogen
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Jesse Albert May
Hwang-Hsing Chen
Brian Dupre
Thomas R. Dean
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Alcon Vision LLC
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Alcon Laboratories Inc
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms

Definitions

  • glaucoma The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve.
  • IOP intraocular pressure
  • Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be a high risk for the eventual development of visual loss associated with glaucoma.
  • Drug therapies which have proven to be effective for the reduction of intraocular pressure include both agents which decrease aqueous humor production and agents which increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.
  • One class of orally administered drugs which has been used for approximately thirty years to assist in the maintenance of intraocular pressure is carbonic anhydrase inhibitors. These agents inhibit the enzyme carbonic anhydrase, which is present in the ciliary process of the eye and intimately involved in the production of aqueous humor. Drugs of this class act through their ability to decrease the production of aqueous humor. Though these agents are efficacious and nontoxic to ocular tissues following oral administration, they are known to lead to
  • the compounds of the present invention are new sulfonamides which are carbonic anhydrase inhibitors useful for lowering IOP without producing significant systemic side effects when delivered topically to the eye.
  • oxicams e.g. piroxicam
  • piroxicam e.g. piroxicam
  • oxicams can be considered to be structurally related to the compounds of present interest.
  • the compound known as tenoxicam and its numerous substituent variations are similar in that they share a common parent heterocyclic ring structure with the compounds of interest in the present invention: 2H-thieno[2,3-e]-1 ,2-thiazine.
  • a sulfamoyl (SO 2 NH 2 ) group has been contemplated as a substituent within this group of compounds.
  • a primary sulfamoyl group is a required substitution in the context of the present invention.
  • 5,093,332 discloses 2,3-dihydro-1 H-thieno[2,3-b][1 ,4]thiazine-6-sulfonamide 4,4-dioxides, which are shown to be weak inhibitors of carbonic anhydrase, for treating elevated intraocular pressure and glaucoma.
  • U.S. Patent Nos. 4,619,939 and 4,746,745 disclose sulfonamides and a process for reducing intraocular pressure by applying topically to the cornea a carbonic anhydrase inhibitor having a particular set of properties. The compounds of this invention are not disclosed in these patents.
  • the present invention is directed to new sulfonamides which can be used to lower and control IOP and control ocular hypertension and glaucoma in warm blooded animals, including man.
  • the compounds are formulated in pharmaceutical compositions suitable for topical delivery to the eye.
  • New intermediate compounds useful in making the sulfonamides are also disclosed.
  • the invention is also directed to methods for lowering and controlling IOP by the administration of the compositions comprising the sulfonamides of the present invention.
  • the compositions are administered topically to the eye.
  • G, J and the two atoms of the thiophene ring to which they are attached form a six-membered ring chosen from
  • C 1-4 alkyl substituted with an aromatic group chosen from phenyl or Q either of which can be unsubstituted or substituted with one or more of C 1-4 alkyl, C 1-4 alkoxy, hydroxy, halogen, nitrile, NR 2 R 3 , SO n R 4 , C( O)R 5 or C 1-4 alkyl which is substituted with hydroxy, NR 2 R 3 , halogen, CO 2 R 1 or C 1-3 alkoxy;
  • Y is hydrogen
  • C 1-4 alkyl substituted with an aromatic group chosen from phenyl or Q either of which can be unsubstituted or substituted with one or more of C 1-4 alkyl, C 1-4 alkoxy, hydroxy, halogen, nitrile, NR 2 R 3 , SO n R 4 , C( O)R 5 or C 1-4 alkyl which is substituted with hydroxy, NR 2 R 3 , halogen, CO 2 R 1 or C 1-3 alkoxy;
  • C 1-6 alkyl substituted with hydroxyl, halogen, C 1-4 alkoxy, NR 2 R 3 or C( O)R 5 ; phenyl which can be unsubstituted or substituted with one or more of C 1-4 alkyl, alkoxy, hydroxy or halogen;
  • R 2 and R 3 are independently chosen from hydrogen
  • R 4 is C 1-4 alkyl
  • R 6 is C 1-4 alkyl
  • R 7 is hydroxyl, C 1-4 alkoxy, C 1-4 alkoxy substituted with hydroxyl, NR 2 R 3 or C 1-4 alkoxy;
  • n 0,1 , or 2;
  • Q is a monocyclic five or six membered heterocyclic ring system wherein one or more of the heteroatoms nitrogen, oxygen and/or sulfur are incorporated into the ring, such as thiophene, furan, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, thiazole, thiadiazole, pyridine, pyrimidine, pyridazine, and pyrazine.
  • substituent Y can be attached at position 3 or 4, or independent variations of substituent Y can be attached at positions 3 and 4. In the preferred embodiments of this invention substituent Y, when other than hydrogen, is attached at position 3.
  • Selected compounds of Structure I can possess one or more chiral centers within substituents Y or Z, this invention contemplates all enantiomers, diastereomers and mixtures thereof.
  • the total number of carbon atoms in a substituent group is indicated by the C i-j prefix where the numbers i and j define the number of carbon atoms; this definition includes both straight chain and branched chain alkyl groups. It is important to recognize that a substituent may be present either singly or multiply when incorporated into the indicated structural unit.
  • halogen which means fluorine, chlorine, bromine or iodine
  • the alkyl or aryl portion to which it is attached may be substituted with one or more halogen atoms, which may be the same or different.
  • Certain desirable compounds of Formula I can be prepared from the appropriate 2-substituted 2H-thieno[3,2-e]-1 ,2-thiazine 1 ,1-dioxide (1), where T is H, Br or Cl, and Z is as defined previously, as shown in Equation 1.
  • Introduction of the sulfamoyl group at position six can be accomplished by treating compound 1 with a strong organometallic base such as n-butyllithium to form the organolithium intermediate which can be reacted with an appropriate electrophile, such as sulfuryl chloride or sulfur dioxide, to give the sulfonyl chloride or lithium sulfinate, respectively.
  • a strong organometallic base such as n-butyllithium
  • an appropriate electrophile such as sulfuryl chloride or sulfur dioxide
  • Intermediate 1 can be prepared by the methods shown in Equations 2-4.
  • the hydroxyl group of 3 can be activated toward subsequent elimination by formation of an intermediate sulfonate ester, such as by reaction with methanesulfonic anhydride in an inert solvent to give the methanesulfonate ester.
  • Treatment of such sulfonate esters under generally basic conditions results in formation of the desired intermediate olefin 1 (Equation 2).
  • activation of the hydroxyl group of compound 3 toward elimination can be accomplished by reaction with an appropriate aryl thionochloroformate to give intermediate 4.
  • Treatment of 4 under conditions favorable for pyrolytic eliminations of the Chugaev reaction type e.g. see Organic Reactions, 12, 57 (1962), J. Amer. Chem. Soc. 108, 800 (1986)], generally neat, at temperatures between 100°C and 300°C under vacuum, provide the desired olefin compound 1 (Equation 3). Equation 3
  • Equation 4 Chlorination of intermediate 3 with a suitable chlorinating agent such as thionyl chloride either neat or in the presence of an inert solvent provides intermediate 5; dehydrohalogenation under basic conditions provides the desired intermediate olefin 1 (Equation 4). Equation 4
  • Intermediate compounds 3 can also be prepared as shown in Equation 6; this method is particularly preferred for those compounds of Formula I where Z is Z 2 , as previously described.
  • the requisite thiophene ketals (8), where T is H or Cl, can be readily prepared by standard methods well known to one skilled in the art from commercially available thiophene ketones.
  • the incorporation of a sulfonamide or substituted sulfonamide at position two of the thiophene ketal (8) can be
  • the primary hydroxyl group of 12 can be transformed into groups (Z 1 ) of interest in the context of the present invention by a variety of functional group transformations.
  • an amino group can be incorporated by procedures known in the art, preferably by displacement of an aryl or alkyl sulfonate ester under mildly basic conditions with a primary or secondary amine, or by using conditions of the
  • intermediate 15 can be accomplished in a manner analogous to that described for thiophene ketals in Equation 6.
  • Alkylation of intermediate 15 with the desired ⁇ - halo-carboxylic ester, e.g. ethyl bromoacetate provides intermediate 16 which can be cyclized by initial hydrolysis of the acetal followed by treatment of the aldehyde under basic conditions, e.g. DBU, to give 17.
  • Modification of the ester group of 17 by methods known to the art provides desired 2,3 disubstituted compounds of Formula I wherein substituent Y at position three is as defined previously.
  • bromodimethylborane provides the ⁇ -hydroxyalkyl substituent at position two (22) which can be selectively acylated by treatment with the desired acyl chloride under acidic conditions, for example in the presence of trifluoroacetic acid, to give compounds of Formula I wherein Z 1 is an acylated ⁇ -hydroxyalkyl group (23).
  • esters of Formula I can be prepared from an ester so prepared by transesterification using various conditions known to the art (see, Comprehensive Organic Transformations, R. C. Larock, page 985). Amination of the alkylesters 25 by a variety of conditions known to the art provides the substituted alkylamides 26.
  • Additional compounds of Formula I can be prepared according to Equation 11 , where T, Y, and Z are as described previously.
  • Oxidation of alcohol 3 to ketone 33 can be accomplished by any of a variety of procedures known to the art, such as Jones reagent (Cr 2 O 3 /HOAc).
  • Treatment of 33 with the desired Grignard reagent provides tertiary alcohol 34 which can be converted to the olefin 35 by treatment of the sulfonate ester under basic conditions as previously described in Equations 5 and 7.
  • Introduction of the primary sulfonamide can be accomplished by the sequence involving n-butyllithium, sulfur dioxide, and hydroxylamine-O-sulfonic acid (Equation 1) to give compounds of Formula I. Equation 11
  • Equation 12 By following a sequence comparable to that described in Equation 11 , but using instead ketone 36 as starting material, which can be prepared in a manner analogous to that illustrated in Austrian patent 352,744 (1979), it is possible to prepare yet other compounds of Formula I as shown in Equation 12. Equation 12
  • the compounds of this invention can be incorporated into various types of ophthalmic formulations for delivery to the eye.
  • these compounds can 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.
  • 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 (carboxy vinyl polymers available from B.F. Goodrich Company) according to 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. Furthermore, the ophthalmic solution may contain a thickener such as hydroxymethylcellulose, hydroxypropylcellulose, methylcellulose,
  • Ophthalmic solutions, suspensions, ointments, gels are the preferred dosage forms, typically at pH 4-8, the physiologically acceptable range for ophthalmic administration.
  • the compounds will normally be contained in these formulations in the amount of 0.1 % to 10% by weight, but preferably in an amount of 0.25% to 5% by weight. Thus, for topical presentation these formulations would be delivered to the surface of the eye 1-4 times/day depending upon the discretion of a skilled clinician.
  • the following examples are given to illustrate the preparation of compounds which are the subject of this invention but should not be construed as implying any limitations to the claims.
  • the preferred compounds of Formula I are 2-substituted and 2,3-disubstituted 2H-thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide 1 ,1 -dioxides.
  • Example 1 Especially preferred compounds are those set forth in Examples 7, 10, 10.5, 11.1 , 11.3, 11.4, 25 and 27. Most preferred is the compound of Example 11.1.
  • the proton magnetic resonance spectrum of each compound of the Examples was consistent with the assigned structure.
  • the mixture was allowed to warm to room temperature (approximately 1.5 hr) and then once again cooled to -60°C and anhydrous THF (400 mL) added. Sulfur dioxide was passed over the surface of the reaction mixture for 30 min at which point the reaction mixture was allowed to warm to room temperature under a positive SO 2 pressure (approximately 1 hr). The solvent was removed and the residue dissolved in water (1200 mL) to which sodium acetate trihydrate (217.73 g, 1.6 mol) was added. The solution was cooled (ice bath) to 0°C and hydroxylamine-O-sulfonic acid (107 g, 0.95 mol) was slowly added.
  • Step B 3-Acetyl-2-thiophenesulfonamide
  • the product from Step A (174.05 g, crude) was dissolved in a mixture of THF (1000 mL) and 1 N HCI (1000 mL) and heated at reflux temperature for 1.5 hr.
  • Step C 3,4-Dihydro-2H-thieno[3,2-e]-1 ,2-thiazine-4-ol 1 ,1-dioxide
  • a solution of the product from Step B (102.6 g, 0.50 mol) in THF (3000 mL) was cooled to 10°C and the addition of pyridinium bromide perbromide (183 g, 0.515 mol) commenced and continued as the temperature continued to drop to 0°C. After the addition was completed, the reaction mixture was allowed to warm to 14°C (approximately 3 hr).
  • Step D 4-(1-Ethoxyethoxy)-2-(1-ethoxyethyl)-3,4-dihydro-2H-thieno[3,2-e]-1 ,2- thiazine 1 ,1-dioxide
  • Ethyl vinyl ether 250 mL, 2.6 mol was added over a period of 1 .75 hr while maintaining the temperature of the reaction mixture below 5°C.
  • Step E 4-(1-Ethoxyethoxy)-2-(1-ethoxyethyl)-3,4-dihydro-N-(1 ,1-dimethylethyl)- 2H-thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide 1 ,1 -dioxide
  • THF 1200 mL, dry
  • n-Butyllithium 2.5 M in hexanes, 215 mL, 0.538 mol
  • reaction mixture was stirred at room temperature for 1 hr.
  • the solvent was evaporated to give a residue which was dried in vacuo.
  • the residue was dissolved in methylene chloride (1500 mL) and cooled to 0°C, N-chlorosuccinimide (62.3 g, 0.467 mol) was added in portions while maintaining the temperature of the reaction mixture at 0°C.
  • the mixture was allowed to warm to room temperature and stirred at this temperature for 2 hr.
  • Step F 3,4-Dihydro-4-hydroxy-N-(1 ,1 -dimethylethyl)-2H-thieno[3,2-e]-1 ,2- thiazine-6-sulfonamide 1 ,1-dioxide
  • THF 700 mL
  • 2 N HCI 180 mL
  • the aqueous mixture was cooled to 0°C and sodium bicarbonate (50 g) was carefully added followed by water (400 mL) and ethyl acetate (500 mL).
  • Step G 3,4-Dihydro-4-hydroxy-N-(1 ,1 -dimethylethyl)-2-(2-methoxyethyl)-2H- thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide 1 ,1 -dioxide
  • the product from Step F (0.3 g, 0.88 mmol) was added to a suspension of sodium hydride (0.05 g of a 60% suspension in mineral oil, rinsed once with hexane, 1.25 mmol) in DMF (5 mL) at 0°C.
  • Step H 2-(2-Methoxyethyl)-N-(1 ,1-dimethylethyl)-2H-thieno[3,2-e]-1 ,2-thiazine- 6-sulfonamide 1 ,1 -dioxide
  • the product from Step G (4.11 g, 10.31 mmol) and 4-dimethylaminopyridine (2.52 g, 20.6 mmol) were combined in dichloromethane (50 mL) and the mixture was cooled by means of an ice bath. Phenyl chlorothionoformate (2.1 mL, 15.5 mmol) was added rapidly to the mixture and the cooling bath removed.
  • Step I 2-(2-Methoxyethyl)-2H-thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide 1 ,1- dioxide sodium salt
  • the product from Step H (1.48 g, 3.89 mmol) was mixed with trifluoroacetic acid (15 mL) and stirred for 36 hr at room temperature.
  • Step B 6-Chloro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1 ,2-thiazine 1 ,1 -dioxide
  • the product of Step A (5.1 g, 11.38 mmol) was heated under vacuum (200°C/0.5 mm Hg) until no more condensate formed (approximately 5 min).
  • Step C 2-(3-Methoxypropyl)-2H-thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide 1 ,1 - dioxide sodium salt
  • the product from Step B (2.31 g, 7.86 mmol) was dissolved in dry THF (35 mL) and cooled in a dry ice/isopropanol bath (-78°C) under nitrogen.
  • n-Butyllithium (4.1 mL of a 2.1 M solution in hexanes, 8.65 mmol) was added dropwise and the mixture stirred for 45 min; excess sulfur dioxide was introduced into the flask until the solution tested acidic to moist litmus paper.
  • the reaction mixture was evaporated to a residue which was dissolved in water (40 mL) followed by the addition of sodium acetate trihydrate (5.35 g, 39.3 mmol) and hydroxylamine-O-sulfonic acid (2,67 g, 23.58 mmol). This mixture was stirred at room temperature for 4 hr and extracted with ethyl acetate (5 x 8 mL).
  • Step B 2-(3-Ethoxypropyl)-3,4-dihydro-2H-thieno[3,2-e]-1 ,2-thiazine-4-ol 1 ,1- dioxide
  • a solution of the product from Example 1 , Step C (13.0 g, 63.3 mmol) in DMF (50 mL) was added to a suspension of sodium hydride (2.5 g of a 60% slurry in mineral oil, washed with hexane, 63.3 mmol) in DMF (300 mL) at 0°C. After stirring for 45 min, the product from Step A (10.6 g, 63.3 mmol) was added and the mixture was stirred for 18 hr, during this time the temperature slowly increased to room
  • the reaction mixture was diluted with cold water (300 mL) and extracted with ethyl acetate (5 ⁇ 10 mL). The combined extracts were washed with water (3 ⁇ 10 mL), saturated aqueous sodium chloride (20 mL), dried (MgSO 4 ) and evaporated to a residue which was purified by column chromatography (silica, gradient, 3:1 hexane/ethyl acetate to 7:3 methylene chloride/methanol) to provide a clear oil (13.1 g, 71%) which was used in the next step.
  • Step C 4-(1-Ethoxyethoxy)-2-(3-ethoxypropyl)-3,4-dihydro-2H-thieno[3,2-e]- 1 ,2-thiazine 1 ,1 -dioxide
  • a solution of the product from Step B (13.0 g, 44.77 mmol) and p-toluenesulfonic acid (0.20 g) in THF (250 mL) was cooled in an ice bath and ethyl vinyl ether (4.7 mL, 49.24 mmol) was added slowly; this mixture was stirred at room temperature for 18 hr.
  • Step D 2-(3-Ethoxypropyl)-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1 ,2-thiazine- 6-sulfonamide 1 ,1 -dioxide
  • THF 250 mL
  • n- Butyllithium 16.0 mL of a 2.5 M solution, 40 mmol
  • Step E 2-(3-Ethoxypropyl)-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1 ,2-thiazine- 6-(sulfonylacetimidate methyl ester) 1 ,1-dioxide
  • the product from Step D (1.6 g, 4.32 mmol) was dissolved in dry acetonitrile (20 mL) and trimethylorthoacetate (11 mL) was added. The mixture was heated at reflux temperature for 18 hr and then evaporated to provide an oil (1.88 g, 100%) which was used without further purification.
  • Step F 2-(3-Ethoxypropyl)-3,4-dihydro-4-phenoxythiocarbonyl-2H-thieno[3,2- e]-1 ,2-thiazine-6-(sulfonylacetimidate methyl ester) 1 ,1-dioxide
  • the crude product from Step E (1.88 g, 4.32 mmol) and 4-dimethylaminopyridine (0.8 g, 6.48 mmol) were mixed with 1 ,2-dichloroethane (25 mL) and cooled in an ice bath.
  • Phenylthionocarbonyl chloride 0.7 mL, 5.2 mmol
  • the mixture was stirred for 18 hr, diluted with 3:1 hexane/ethyl acetate (100 mL) and filtered through silica gel. The filtrate was evaporated to a residue which was purified by column
  • Step G 2-(3-Ethoxypropyl)-2H-thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide 1 ,1- dioxide
  • the combined products from Step F (0.79 g, 1.4 mmol and 0.35 g, 0.69 mmol) were heated under vacuum (200°C/0.5 mm Hg) until no more condensate formed (approximately 5 min).
  • Step B 3-Acetyl-5-chloro-N-(4-methoxyphenyl)thiophene-2-sulfonamide
  • the product from Step A (15 g, 0.058 mol) was dissolved in glacial acetic acid (150 mL), water (15 mL) was added and the solution cooled to 3°C. Chlorine gas was slowly passed through the solution until the temperature reached 15°C at which point the mixture was cooled to 5°C before the addition of chlorine was continued; this sequence was repeated four times.
  • the reaction mixture was poured into ice water (300 mL) and extracted with methylene chloride (2 ⁇ 200 mL). The
  • Step C 6-Chloro-3,4-dihydro-4-hydroxy-2-(4-methoxyphenyl)-2H-thieno[3,2-e]- 1 ,2-thiazine 1 ,1-dioxide
  • the product from Step B (4.20 g, 12.14 mmol) was dissolved in THF (40 mL) containing 30% HBr in acetic acid (0.1 equiv, 0.25 mL) and cooled to 3°C.
  • Step D 6-Chloro-2-(4-methoxyphenyl)-2H-thieno[3,2-e]-1 ,2-thiazine 1 ,1 -dioxide
  • a solution of the product from Step C (1.4 g, 4.05 mmol) and 4-dimethylaminopyridine (0.74 g, 6.08 mmol) in 1 ,2-dichloroethane (10 mL) were cooled in an ice bath. Phenyl chlorothionoformate (0.67 mL, 4.86 mM) was added slowly. The cooling bath was removed and the mixture was stirred at room temperature for 18 hr, mixed with 3:1 hexane/ethyl acetate (25 mL) and filtered through silica gel. The filtrate was concentrated and heated under vacuum
  • Step E 2-(4-Methoxyphenyl)-2H-thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide 1 ,1- dioxide
  • the product from Step D (0.9 g, 2.75 mmol) was dissolved in dry THF (10 mL) and degassed under nitrogen.
  • reaction mixture was poured into water and the aqueous mixture was extracted with ether.
  • the combined extracts were dried (MgSO 4 ) and evaporated to an oil which was purified by column chromatography (silica, 30% ethyl acetate/hexane) to give 1.52 g (53%) of the desired product as a viscous syrup which was used in the next step.
  • Step B 6-Chloro-2-[2-(4-morpholinyl)ethyl]-2H-thieno[3,2-e]-1 ,2-thiazine 1 ,1 - dioxide
  • tetrahydrofuran (30 mL) containing triethylamine (0.56 g, 5.5 mmol)
  • methanesulfonic anhydride (0.75 g, 4.3 mmol)
  • Step C 2-[2-(4-Morpholinyl)ethyl]-2H-thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide
  • Step B Ethyl 2-methyl-2H-thieno[3,2-e]-1 ,2-thiazine-3-carboxylate A mixture of the product from Step A (8.80 g, 26.3 mmol) and 4-toluenesulfonic acid (1.0 g) in acetone (250 mL) was stirred overnight at ambient temperature.
  • Step C 2-Methyl-2H-thieno[3,2-e]-1 ,2-thiazine-3-methanol To a solution of the product from Step B (1.00 g, 3.66 mmol) in anhydrous THF (20 mL) at -70°C was added DIBAL (1.0 M, 7.69 mL, 7.69 mmol).
  • Step D 2-Methyl-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1 ,2-thiazine
  • a solution of the product from Step C (0.79 g, 3.42 mmol) and triethylamine (1.04 g, 10.3 mmol) in anhydrous THF (30 mL) at ambient temperature was added methanesulfonic anhydride (0.89 g, 5.13 mmol) with stirring.
  • methanesulfonic anhydride (0.89 g, 5.13 mmol
  • morpholine 2 mL
  • the volatiles were evaporated and a saturated aqueous solution of sodium bicarbonate (80 mL) was added.
  • Step E 2-Methyl-3-(4-morphoiinylmethyl)-2H-thieno[3,2-e]-1 ,2-thiazine-6- sulfonamide 1 ,1-dioxide hydrochloride
  • a mixture of the product from Step D (0.30 g, 1.04 mmol) in anhydrous THF (30 mL) under nitrogen at -65°C was added 2.5 N n-butyllithium (0.63 mL, 1.56 mmol) over 5 min.
  • the mixture was stirred at -50°C for 10 min and at -65°C for 1 h. Sulfur dioxide was passed over the mixture for 5 min and the mixture was allowed to warm to ambient temperature followed by evaporation to dryness.
  • Step A 2-[2-(Acetyloxy)ethyl]-3,4-dihydro-4-hydroxy-N-(1 ,1 -dimethyl)ethyl-2H- thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide 1 ,1-dioxide
  • Step F 2-[2-(Acetyloxy)ethyl]-3,4-dihydro-4-hydroxy-N-(1 ,1 -dimethyl)ethyl-2H- thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide 1 ,1-dioxide
  • Step B 2-(2-Hydroxyethyl)-N-(1 ,1-dimethylethyl)-2H-thieno[3,2-e]-1 ,2-thiazine- 6-sulfonamide 1 ,1-dioxide
  • 2-(2-Hydroxyethyl)-N-(1 ,1-dimethylethyl)-2H-thieno[3,2-e]-1 ,2-thiazine- 6-sulfonamide 1 ,1-dioxide To a solution of the product from Step A (3.36 g, 7.89 mmol) and 2,6-lutidine (3.00 mL, 25.7 mmol) in anhydrous THF (30 mL) under nitrogen was added
  • methanesulfonic anhydride (2.06 g, 11.8 mmol). This mixture was stirred for 30 min at ambient temperature followed by evaporation to a residue. Anhydrous DMF (50 mL) and DBU (1 mL) were added to the residue and this mixture was heated at 165°C (bath temperature) for 20 min and evaporated to dryness. Methanol (50 mL) and 2 N NaOH (20 mL) were added to the residue and this mixture was stirred for 2 h at ambient temperature. Methanol was evaporated and the aqueous mixture was extracted with ethyl acetate (2 ⁇ 100 mL).
  • Step C 2-[2-[Bis(2-methoxyethyl)amino]ethyl]-N-(1 ,1 -dimethylethyl)-2H- thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide 1 ,1-dioxide
  • Methanesulfonic anhydride 0.80 g, 4.18 mmol
  • Step D 2-[2-[Bis(2-methoxyethyl)]amino]ethyl]-2H-thieno[3,2-e]-1 ,2-thiazine-6- sulfonamide 1 ,1-dioxide hydrochloride
  • the product from Step C (0.89 g, 1.85 mmol) was dissolved in trifluoroacetic acid (8 mL) and the resulting solution was stirred at ambient temperature for 18 h.
  • Step A 2-[2-(Propylamino)ethyl]-N-(1 ,1-dimethylethyl)-2H-thieno[3,2-e]-1 ,2- thiazine-6-sulfonamide 1 ,1-dioxide
  • Step B 2-[2-(Propylamino)ethyl]-N-(1 ,1-dimethylethyl)-2H-thieno[3,2-e]-1 ,2- thiazine-6-sulfonamide 1 ,1-dioxide
  • Step B To a solution of the product from Example 7, Step B (1.02 g, 2.79 mmol) and triethylamine (0.84 g, 8.36 mmol) in anhydrous THF ( 50 mL) was added methanesulfonic anhydride (0.80 g, 4.18 mmol) with stirring under nitrogen.
  • Step B 2-[2-(Propylamino)ethyl]-2H-thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide
  • Step B 2-[2-[4-Acetyl-(1-piperazinyl)]ethyl]-2H-thieno[3,2-e]-1 ,2-thiazine-6- sulfonamide 1 ,1-dioxide
  • a solution of the product from Step A (1.30 g) in trifluoroacetic acid (15 mL) was stirred at ambient temperature for 18 h and evaporated to dryness. The residue was suspended in a saturated aqueous solution of sodium bicarbonate (80 mL) and this mixture was extracted with ethyl acetate (2 ⁇ 100 mL).
  • Step B Ethyl 2-(3-methoxypropyl)-2H-thieno[3,2-e]-1 ,2-thiazine-3-carboxylate
  • Step C 2-(3-Methoxypropyl)-2H-thieno[3,2-e]-1 ,2-thiazine-3-methanol 1 ,1 - dioxide
  • DIBAL 50 mL of a 1.0 M solution, 50.0 mmol
  • THF was evaporated and the aqueous mixture was extracted with ethyl acetate (2 ⁇ 100 mL).
  • Step D 2-(3-Methoxypropyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1 ,2- thiazine 1 ,1-dioxide
  • Methanesulfonic anhydride 1.18 g, 6.75 mmol
  • Step E 2-(3-Methoxypropyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1 ,2- thiazine-6-sulfonamide 1 ,1-dioxide hydrochloride n-Butyllithium (3.35 mL of a 2.5 M solution, 8.38 mmol) was added to a solution of the product from Step D (1.50 g, 4.19 mmol) in anhydrous THF (60 mL) under nitrogen at -70°C. After stirring at this temperature for 30 min, a stream of sulfur dioxide was passed through the mixture (5 min) which was allowed to warm to room temperature and then evaporated to a residue.
  • Step A N-[[3-(1 ,3-Dioxolan-2-yl)-2-thienyl]sulfonyl]-N-(4-methoxyphenylmethyl) glycine ethyl ester
  • Step A N-[[3-(1 ,3-Dioxolan-2-yl)-2-thienyl]sulfonyl]-N-(4-methoxyphenylmethyl) glycine ethyl ester
  • Step B Ethyl 2-(4-methoxyphenylmethyl)-2H-thieno[3,2-e]-1 ,2-thiazine-3- carboxylate 1 ,1 -dioxide
  • acetone 150 mL
  • a saturated solution of sodium bicarbonate 50 mL
  • the aqueous mixture was extracted with ethyl acetate (2 ⁇ 10 mL) and the combined extracts were dried (MgSO 4 ) and filtered.
  • Step C 3-Hydroxymethyl-2-(4-methoxyphenylmethyl)-2H-thieno[3,2-e]-1 ,2- thiazine-3-methanol 1 ,1-dioxide
  • DIBAL 1.0 M, 11.87 mL, 11.87 mmol
  • Step D 3-[[Bis(2-methoxyethyl)amino]methyl]-2-(4-methoxyphenylmethyl)-2H- thieno[3,2-e]-1 ,2-thiazine 1 ,1-dioxide
  • a solution of the product from Step C (1.60 g, 4.75 mmol) and triethylamine (1.44 g, 14.2 mmol) in anhydrous THF (100 mL) at ambient temperature was added methanesulfonic anhydride (1.24 g, 7.13 mmol). After 1 h, the reaction mixture was divided into two equal portions; to one of these portions was added bis(2-methoxyethyl)amine (6 mL).
  • Step E 3-[[Bis(2-methoxyethyl)aminoJmethyl]-2-(4-methoxyphenylmethyl)-2H- thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide 1 ,1-dioxide
  • n-butyllithium 2.5 M, 1.91 mL, 4.78 mmol
  • Step B N-(1 ,1-dimethylethyl)-2-[4-(4-morpholinyl)-2-butenyl]-2H-thieno[3,2-e]- 1 ,2-thiazine-6-sulfonamide 1 ,1 -dioxide
  • methanesulfonic anhydride 0.349 g, 2.00 mmol
  • 2,6-lutidine 0.431 g, 4.02 mmol
  • Step C 2-[4-(4-Morpholinyl)-2-butenyl]-2H-thieno[3,2-e]-1 ,2-thiazine-6- sulfonamide 1 ,1-dioxide hydrochloride A solution of the product from Step B (0.35 g) in trifluoroacetic acid (5 mL) was stirred at ambient temperature for 3 days and evaporated to dryness.
  • Step B 2-(4-Methoxyphenylmethyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]- 1 ,2-thiazine-6-sulfonamide 1 ,1-dioxide hydrochloride
  • the product of Step A (0.70 g, 1.72 mmol) was treated in a manner analogous to that described for Example 11 , Step E to give, after purification by column chromatography (silica, 50% to 80% ethyl acetate/hexane), a viscous oil (0.34 g).
  • Step B N-[(3-formyl-2-thienyl)sulfonyl]-N-(4-methoxyphenyl)-glycine methyl ester
  • sodium hydride 60% dispersion in mineral oil, 1.32 g, 32.9 mmol.
  • methyl 2-bromoacetate 5.49 g, 35.9 mmol was added and stirring continued at ambient temperature for 4 h.
  • the reaction mixture was poured into a saturated solution of sodium
  • Step C Methyl 2-(4-methoxyphenyl)-2H-thieno[3,2-e]-1 ,2-thiazine-3- carboxylate 1 ,1-dioxide
  • a mixture of the product from Step B (3.67 g, 9.95 mmol), DBU (1.0 mL) and molecular sieves (1 .5 g) in ethyl acetate (100 mL) was heated at reflux temperature for 4 h, cooled to room temperature, washed with 2 N HCI (50 mL) and brine (50 mL), and dried (MgSO 4 ). Evaporation of the solvent provided the desired ester (1 .92 g) as an oil which was used without further purification.
  • Step D 2-(4-Methoxyphenyl)-2H-thieno[3,2-e]-1 ,2-thiazine-3-methanol 1 ,1 - dioxide
  • a 1 M solution of DIBAL in THF 45 mL, 45 mmol was added to a solution of the product from Step C (1.92 g) in anhydrous THF (100 mL) and this mixture was stirred at ambient temperature for 18 h. After cooling (ice bath) the reaction was quenched by the addition of 1 N HCI (100 mL).
  • Step E 3-[[Bis(2-methoxyethyl)amino]methyl]-2-(4-methoxyphenyl)-2H- thieno[3,2-e]-1 ,2-thiazine 1 ,1-dioxide
  • a solution of the product of Step D (1.19 g, 3.68 mmol) and triethylamine (1.24 g, 12.3 mmol) in anhydrous THF (50 mL) was added methanesulfonic anhydride (1.07 g, 6.13 mmol). After 30 min, bis(2-methoxyethyl)amine (3 mL) was added and stirring continued for 18 h at ambient temperature.
  • Step F 3-[[Bis(2-methoxyethyl)amino]methyl]-2-(4-methoxyphenyl)-2H- thieno[3,2-e]-1 ,2-thiazine-6-sulf onamide 1 ,1 -dioxide
  • the product of Step E (1 .12 g, 2.56 mmol) was treated in a manner analogous to that described for Example 11 , Step E to give, after purification by column chromatography (silica, 60% to 80% ethyl acetate/hexane) a colorless glass (0.41 g, 31%): mp 48-51 °C. Analysis.
  • Step B N-[[3-(1 ,3-Dioxolan-2-yl)-2-thienyl]sulfonyl]-N-(1-methylethyl)-glycine ethyl ester
  • a 1 M solution of potassium t-butyloxide in t-butanol 99.3 mL, 99.3 mmol
  • ethyl bromoacetate 12.0 mL, 18.1 g, 108.4 mmol.
  • Step C Ethyl 2-(1-methylethyl)-2H-thieno[3,2-e]-1 ,2-thiazine-3-carboxylate 1 ,1- dioxide
  • acetone 300 mL
  • acetone 300 mL
  • Acetone 100 mL
  • Acetone was evaporated and the aqueous mixture was extracted with ether (2 ⁇ 100 mL).
  • Step D 2-(1-Methylethyl)-2H-thieno[3,2-e]-1 ,2-thiazine-3-methanol 1 ,1-dioxide
  • DIBAL 1.0 M, 145 mL, 145 mmol
  • Step E 3-Hydroxymethyl-2-(1-methylethyl)-2H-thieno[3,2-e]-1 ,2-thiazine-6- sulfonamide 1 ,1 -dioxide
  • n-butyllithium 2.5 M, 12.5 mL, 31.4 mmol
  • the suspension was stirred for 1 h before a stream of sulfur dioxide was passed over the surface of the reaction mixture for 5 min.
  • the mixture was warmed to ambient temperature and evaporated to give a residue which was combined with water (100 mL); this mixture was cooled (ice bath) and
  • hydroxylamine-O-sulfonic acid (4.24 g, 37.5 mmol) and NaOAc (8.5 g, 62.5 mmol) were added.
  • the reaction mixture was stirred at ambient temperature for 18 h and extracted with ethyl acetate (2 ⁇ 200 mL). The combined extracts were dried (MgSO 4 ), filtered, and evaporated to a residue which was purified by column chromatography (silica, 50% ethyl acetate/hexane) to give a viscous oil (4.20 g, 98%).
  • Step F 2-(1-Methylethyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1 ,2- thiazine-6-sulfonamide 1 ,1-dioxide
  • ptoluenesulfonyl chloride 2.44 g, 12.8 mmol
  • reaction mixture was evaporated to a residue which was mixed with 2 N HCI (60 mL) and this mixture was extracted with ethyl acetate (2 ⁇ 50 mL).
  • the aqueous layer was separated and adjusted to pH 7.5 by the addition of a saturated aqueous solution of sodium bicarbonate (100 mL) followed by extraction with ethyl acetate (2 ⁇ 60 mL).
  • Step B N-[[3-(1 ,3-Dioxolan-2-yl)-2-thienyl]sulfonyl]-N-(3-methoxyphenyl)- glycine ethyl ester
  • Step B N-[[3-(1 ,3-Dioxolan-2-yl)-2-thienyl]sulfonyl]-N-(3-methoxyphenyl)- glycine ethyl ester
  • Step D 2-(3-Methoxyphenyl)-2H-thieno[3,2-e]-1 ,2-thiazine-3-methanol 1 ,1- dioxide
  • a solution of the product of Step C (5.64 g, 15.45 mmol) in anhydrous THF (150 mL) was treated with DIBAL (66 mmol) in a manner essentially analogous to that described in Example 15, Step D to provide the desired product as a white solid (3.62 g, 73%): mp 141-143°C.
  • Step E 3-Hydroxymethyl-2-(3-methoxyphenyl)-2H-thieno[3,2-e]-1 ,2-thiazine-6- sulfonamide 1 ,1-dioxide
  • a solution of the product from Step D (2.0 g, 6.19 mmol) was treated sequentially with n-butyllithium, sulfur dioxide and hydroxylamine-O-sulfonic acid in a manner essentially analogus to that described in Example 15, Step E to give an orange solid (1.78 g, 72%): mp 180-182°C.
  • Step F 2-(3-Methoxyphenyl)-3-[(2-propynyiamino)methyl]-2H-thieno[3,2-e]-1 ,2- thiazine-6-sulfonamide 1 ,1-dioxide
  • p-toluenesulfonyl chloride 0.54 g, 2.84 mmol
  • Step A 3-Chloromethyl-N-(1 ,1-dimethylethyl)-2-(3-methoxyphenyl)-2H- thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide 1 ,1 -dioxide
  • Step D To a solution of the product from Example 18, Step D (4.81 g, 14.89 mmol) in anhydrous THF (80 mL) under nitrogen at -70°C was added n-butyllithium (2.5 M, 14.89 mL, 37.22 mmol) over 5 min. After stirring for 1 h, a stream of sulfur dioxide was passed over the surface of the reaction mixture for about 5 min. The mixture was warmed to ambient temperature and evaporated to a residue which was mixed with methylene chloride (250 mL). This suspension was cooled on an ice bath and N-chlorosuccinimide (6.96 g, 52.1 mmol) was added.
  • reaction mixture was stirred at ambient temperature for 2 h and t-butylamine (15 mL, 143 mmol) was added; the mixture was evaporated to dryness after 16 h. The residue was mixed with a saturated aqueous solution of sodium bicarbonate (200 mL) and extracted with ethyl acetate (2 ⁇ 200 mL).
  • Step B 2-(3-Hydroxyphenyl)-3-[(2-propynylamino)methyl]-2H-thieno[3,2-e]-1 ,2- thiazine-6-sulfonamide 1 ,1 -dioxide hydrochloride
  • a solution of the product from Step A (1.00 g, 2.10 mmol) in anhydrous DMF (20 mL) was added propargylamine (1.77 g, 32.1 mmol).
  • the oil was dissolved in methylene chloride (50 mL), cooled to 0°C, and a 1 M solution of BBr 3 in methylene chloride (5.25 mL) was added over 3 min. The mixture was allowed to warmed to ambient temperature and maintained at this temperature for 2 h. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (2 x 100 mL).
  • Step B N-[[6-(Aminosulfonyl)-2-methyl-2H-thieno[3,2-e]-1 ,2-thiazin-3- yl]methyl]-N-methyl-glycine ethyl ester S 1 , S 1 -dioxide
  • Methanesulfonic anhydride 0.844 g, 4.85 mmol
  • Step B N-[(3-Formyl-2-thienyl)sulfonyl]-N-[2-(4-morpholinyl)ethyl]-glycine methyl ester
  • sodium hydride 50% dispersion in mineral oil, 0.80 g, 20.0 mmol
  • methyl 2-bromoacetate 3.62 g, 23.7 mmol
  • a 2N HCI aqueous solution 50 mL
  • Step C 2-[2-(4-Morpholinyl)ethyl]-2H-thieno[3,2-e]-1 ,2-thiazine-2-carboxylic acid methyl ester 1 ,1 -dioxide
  • Step D 2-[2-(4-Morpholinyl)ethyl]-2H-thieno[3,2-e]-1 ,2-thiazine-3-methanol 1 ,1- dioxide
  • a stirred solution of the product from Step C (3.80 g, 10.6 mmol) in anhydrous THF (50 mL) at 0°C was added a 1 M solution of diisobutylaluminium hydride in THF (31.8 mL, 31.8 mmol).
  • Step E 3-Hydroxymethyl-2-[2-(4-morpholinyl)ethyl]-2H-thieno[3,2-e]-1 ,2- thiazine-6-sulfonamide 1 ,1 -dioxide
  • n-butyllithium 2.5 M in hexanes, 9.06 mL, 22.7 mmol
  • Step F 3-(Acetyloxymethyl)-2-[2-(4-morpholinyl)ethyl]-2H-thieno[3,2-e]-1 ,2- thiazine-6-sulfonamide 1 ,1-dioxide hydrochloride
  • acetic acid 20 mL
  • acetic anhydride 0.45 g, 4.41 mmol
  • Step B 4-[(2-methoxyethyl)[[6-(aminosulfonyl)-2-(2-methoxyethyl)-2H- thieno[3,2-e]-1 ,2-thiazin-2-yl]methyl]amino]butyronitrile S 1 , S 1 -dioxide
  • 3-hydroxymethyl-2-(2-methoxyethyl)-2H-thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide 1 ,1 -dioxide prepared as described in Example 11.3) (2.54 g, 7.18 mmol) and triethylamine (1.45 g, 14.4 mmol) in anhydrous THF (30 mL) at 0°C was added methanesulfonic anhydride (1.88 g, 10.8 mmol) with stirring, when the addition was complete, the ice bath was removed and the mixture was allowed to warm to ambient temperature and stirred for 30 min.
  • Step C Ethyl 4-[(2-methoxyethyl)[[6-(aminosulfonyl)-2-(2-methoxyethyl)-2H- thieno[3,2-e]-1 ,2-thiazin-2-yl]methyl]amino]butanoate S 1 , S 1 -dioxide hydrochloride
  • a stream of hydrogen chloride gas was passed through (10 min) a solution of the product from Step B (1 .40 g, 2.93 mmol) in ethanol (150 mL) at 0°C (exothermic reaction). After stirring for 2 h, additional hydrogen chloride was passed through the reaction mixture (10 min) which was then maintained at 5°C for 72 h. Water (50 mL) was added to the mixture which was stirred for 2 h and then evaporated to a residue which was mixed with a saturated aqueous solution of sodium
  • Step B 2-(4-Hydroxybutyl)-2H-thieno[3,2-e]-1 ,2-thiazine-3-carboxylic acid 1 ,1 - dioxide methyl ester
  • NaH 50% dispersion in mineral oil, 1.45 g, 36.3 mmol
  • methyl bromoacetate 3.92 mL, 6.33 g, 41.4 mmol
  • Step D 2-[4-(1 -Ethoxyethoxy)butyl]-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]- 1 ,2-thiazine 1 ,1-dioxide
  • Methanesulfonic anhydride (1.58 g, 9.07 mmol).
  • Step E 2-(4-Hydroxybutyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1 ,2- thiazine-6-sulfonamide 1 ,1-dioxide
  • n-butyllithium 2.5 M in hexanes, 3.30 mL, 8.24 mmol
  • Step F 3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide-2- butanoic acid 1 ,1-dioxide ethyl ester hydrochloride
  • acetone 100 mL
  • Jones reagent 1.1 M, 10 mL, 11 mmol
  • the reaction mixture was stirred at ambient temperature for 2 h and then maintained at a temperature of 5°C for 16 hr followed by quenching the reaction with an excess of isopropanol and sodium bicarbonate.
  • Step B 2-(2-Hydroxyethyl)-3-(4-morphoiinylmethyl)-2H-thieno[3,2-e]-1 ,2- thiazine-6-sulfonamide 1 ,1-dioxide
  • a mixture of the product from Step A (1.56 g), 48% HBr(16 mL) and water (4 mL) was heated at reflux temperature for 18 h, evaporated to dryness, mixed with a saturated solution of sodium bicarbonate (60 mL) and extracted with ethyl acetate (2 ⁇ 80 mL). The combined extracts were dried (MgSO 4 ) and evaporated to a residue which was purified by column chromatography (silica, 5%
  • Step B 3,5-Dibromo-2-(1 ,3-dioxolan-2-yl)-thiophene
  • a mixture consisting of the product from Step A (1 1.0 g, 40.7 mmol), TsOH (0.25 g) and ethylene glycol (5.06 g, 81.5 mmol) in toluene (150 mL) was heated at reflux temperature for 1 .5 h, water was removed by a Dean-Stark trap.
  • the reaction mixture was cooled and poured into a saturared aqueous solution of sodium bicarbonate (100mL).
  • the organic layer was separated, dried (MgSO 4 ), and evaporated to dryness. Purification of this crude material by column
  • Step C N-[[2-(1 ,3-dioxolan-2-yl)-3-thienyl]sulfonyl]-N-methyl-glycine ethyl ester
  • anhydrous ether 150 mL
  • butyllithium 2.5 M in hexanes, 13.37 mL, 33.43 mmol
  • n-propanol (1.91 g, 31.85 mmol) was added and the solution turned homogenous.
  • a solution of n-butyllithium (2.5 M in hexanes, 13.37 mL, 33.43 mmol) was slowly added over 10 min and then sulfur dioxide was passed over the reaction mixture for about 10 min. The mixture was warmed to ambient temperature and evaporated to dryness. The residue was mixed with methylene chloride (150 mL), cooled to 0°C, and N-chlorosuccinimide was added with stirring.
  • Step D Ethyl 2-methyl-2H-thieno[2,3-e]-1 ,2-thiazine-3-carboxylate 1 ,1-dioxide
  • acetone 50 mL
  • acetone 50 mL
  • Acetone was evaporated and the aqueous was combined with a saturated aqueous solution of sodium bicarbonate (50 mL) and this mixture was extracted with ethyl acetate (2 ⁇ 150 mL).
  • Step E 2-Methyl-2H-thieno[2,3-e]-1 ,2-thiazine-3-methanol 1 ,1 -dioxide
  • DIBAL 1.0 M, 29.0 mL, 29.0 mmol
  • Step G 2-Methyl-3-(4-morpholinylmethyl)-2H-thieno[2,3-e]-1 ,2-thiazine-5- sulfonamide 1 ,1 -dioxide
  • a solution of the product from Step F (0.78 g, 2.52 mmol) and triethylamine (1.02 g, 10.1 mmol) in anhydrous THF (30 mL) at ambient temperature was added tosyl chloride (0.961 g, 5.04 mmol).
  • morpholine (2 mL) was added and the mixture was stirred for 1 h followed by heating at reflux
  • Example 29 Ophthalmic Suspension Ingredient Concentration (wt %) 2-(2-Methoxyethyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1 ,2-thiazine-6-sulfonamide 1 ,
  • a hydroxypropylmethylcellulose vehicle can be prepared by mixing 2% aqueous hydroxypropylmethylcellulose (40 g), sodium chloride (1.28 g), dibasic sodium phosphate (0.32 g), disodium edetate (0.016 g), sodium chloride (1.28 g) and water (35 g) together and the pH adjusted to 7.4 by the addition of 1 N HCI (250 ⁇ L). A portion of this vehicle (1.5 mL) can be added to the mixture containing the
  • HCI/NaOH pH 5.0 The Compound (0.06 g) and sodium chloride (0.014 g) were mixed together in water (1.44 g) and the pH of the solution was adjusted to 5.02 by the addition of 1 N NaOH (10 ⁇ L).
  • the hydroxyethylcellulose vehicle was prepared by mixing together monobasic sodium phosphate (0.26 g), dibasic sodium phosphate (0.02 g) and disodium edetate (0.02 g) in water (96.7 g).
  • the benzalkonium chloride (2.0 g) and hydroxyethylcellulose were added to the mixture and the pH was adjusted to 5.01 by the addition of 1 N HCI (100 ⁇ L).

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Abstract

La présente invention concerne des inhibiteurs d'anhydrases carboniques correspondant à la formule générale (1) ainsi que les procédés d'utilisation correspondants. G, J et les deux atomes de l'anneau thiophène auquel ils sont attachés forment un anneau à six segments correspondant à la formule (a) ou (b).
PCT/US1995/000775 1994-01-21 1995-01-20 Procede de preparation de derives du thienothiazine sulfonamide, intermediaires de preparation, et utilisation comme inhibiteurs d'anhydrases carboniques Ceased WO1995019981A1 (fr)

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Cited By (2)

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US5681834A (en) * 1995-12-04 1997-10-28 Alcon Laboratories, Inc. Heterocyclic sulfonamides
US7060704B2 (en) 1998-05-19 2006-06-13 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders

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WO1991015486A1 (fr) * 1990-04-09 1991-10-17 Alcon Laboratories, Inc. Sulfamides de thiophene utiles en tant qu'inhibiteurs d'anhydrase carbonique
EP0479480A2 (fr) * 1990-10-01 1992-04-08 Merck & Co. Inc. Thiéno(2,3-B)(1,4)thiazine-6-sulfonamides substitués comme agents antiglaucomiques
WO1994005674A1 (fr) * 1992-09-09 1994-03-17 Merck & Co., Inc. Derives tricycliques des classes de composes de thienodiazocine et thienothiadiazocine
EP0617038A1 (fr) * 1993-02-18 1994-09-28 Alcon Laboratories, Inc. Préparation d'inhibiteurs de l'anhydrase carbonique

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WO1991015486A1 (fr) * 1990-04-09 1991-10-17 Alcon Laboratories, Inc. Sulfamides de thiophene utiles en tant qu'inhibiteurs d'anhydrase carbonique
EP0479480A2 (fr) * 1990-10-01 1992-04-08 Merck & Co. Inc. Thiéno(2,3-B)(1,4)thiazine-6-sulfonamides substitués comme agents antiglaucomiques
WO1994005674A1 (fr) * 1992-09-09 1994-03-17 Merck & Co., Inc. Derives tricycliques des classes de composes de thienodiazocine et thienothiadiazocine
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5681834A (en) * 1995-12-04 1997-10-28 Alcon Laboratories, Inc. Heterocyclic sulfonamides
US7060704B2 (en) 1998-05-19 2006-06-13 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
US7285553B2 (en) 1998-05-19 2007-10-23 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders

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