Thiophene-2-sulfonamides with an alkyl or substituted-alkyl and an alkyl-S(O).sub.n -substituent are carbonic anhydrase inhibitors useful in the treatment of elevated intraocular pressure.

SUMMARY OF THE INVENTION 
This invention relates to novel thiophene-2-sulfonamides useful in the 
treatment of elevated intraocular pressure. More particularly this 
invention relates to compounds having the structural formula: 
##STR1## 
wherein X and Y are hereinafter defined, as well as the pharmaceutically 
and ophthalmologically acceptable salts thereof. This invention also 
relates to pharmaceutical compositions and the use thereof for systemic 
and ophthalmic use employing a novel compound of this invention as active 
ingredient for the treatment of elevated intraocular pressure, especially 
when accompanied by pathological damage such as in the disease known as 
glaucoma. 
BACKGROUND OF THE INVENTION 
Glaucoma is an ocular disorder associated with elevated intraocular 
pressures which are too high for normal function and may result in 
irreversible loss of visual function. If untreated, glaucoma may 
eventually lead to blindness. Ocular hypertension, i.e., the condition of 
elevated intraocular pressure without optic nerve head damage or 
characteristic glaucomatous visual field defects, is now believed by many 
ophthalmologists to represent the earliest phase of glaucoma. 
Many of the drugs formerly used to treat glaucoma proved not entirely 
satisfactory. Indeed, few advances were made in the treatment of glaucoma 
since pilocarpine and physostigmine were introduced. Only recently have 
clinicians noted that many .beta.-adrenergic blocking agents are effective 
in reducing intraocular pressure. While many of these agents are effective 
in reducing intraocular pressure, they also have other characteristics, 
e.g. membrane stabilizing activity, that render them unacceptable for 
chronic ocular use. 
(S)-1-tert-Butylamino-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol 
, a .beta.-adrenergic blocking agent, was found to reduce intraocular 
pressure and to be devoid of many unwanted side effects associated with 
pilocarpine and, in addition, to possess advantages over many other 
.beta.-adrenergic blocking agents, e.g. to be devoid of local anesthetic 
properties, to have a long duration of activity, and to display minimal 
tolerance. 
Although pilocarpine, physostigmine and the .beta.-blocking agents 
mentioned above reduce intraocular pressure, none of these drugs manifests 
its action by inhibiting the enzyme carbonic anhydrase and, thereby, 
impeding the contribution to aqueous humor formation made by the carbonic 
anhydrase pathway. 
Agents referred to as carbonic anhydrase inhibitors, block or impede this 
inflow pathway by inhibiting the enzyme, carbonic anhydrase. While such 
carbonic anhydrase inhibitors are now used to treat intraocular pressure 
by oral, intravenous or other systemic routes, they thereby have the 
distinct disadvantage of inhibiting carbonic anhydrase throughout the 
entire body. Such a gross disruption of a basic enzyme system is justified 
only during an acute attack of alarmingly elevated intraocular pressure, 
or when no other agent is effective. Despite the desirability of directing 
the carbonic anhydrase inhibitor only to the desired ophthalmic target 
tissue, no topically effective carbonic anhydrase inhibitors are available 
for clinical use. 
However, topically effective carbonic anhydrase inhibitors are reported in 
U.S. Pat. Nos. 4,386,098; 4,416,890; and 4,426,388. The compounds reported 
therein are 5 (and 6)-hydroxy-2-benzothiazolesulfonamides and acyl esters 
thereof. 
To be an effective and acceptable topical agent, an ophthalmic carbonic 
anhydrase inhibitor must not only penetrate the ophthalmic tissues to 
reach the active sites within the eye, but it must also be devoid of those 
side effects including irritation, allergic reaction and the like which 
would militate against long term administration. 
DETAILED DESCRIPTION OF THE INVENTION 
The novel compounds of this invention have structural formula: 
##STR2## 
wherein: X is 
(1) --CN, 
(2) halo such chloro, bromo or fluoro, 
(3) R wherein R is C.sub.1-5 alkyl, either straight or branched chain and 
either unsubstituted or substituted with one or more of: 
(i) --OH 
(ii) 
##STR3## 
wherein Rhu 1 and R.sup.2 are independently hydrogen, C.sub.1-5 alkyl, or 
C.sub.2-5 alkanoyl, 
(iii) aryl, such as phenyl or naphthyl, either unsubstituted or substituted 
with one or more of --OH or C.sub.1-3 alkyl, or 
(iv) a 6-membered nitrogen containing heteroaryl such as pyridyl, 
pyrazinyl, or pyrimidinyl; 
(4) 
##STR4## 
or (5) 
##STR5## 
wherein n is 0, 1 or 2. Y is 
(1) C.sub.1-5 alkyl, either straight chain, branched chain or cyclic, and 
either unsubstituted or substituted with 
(a) hydroxy, 
(b) C.sub.1-3 alkoxy, 
(c) methoxyethoxymethoxy, 
(d) amino, 
(e) mono- or di-(C.sub.1-5 alkyl)amino, 
(f) C.sub.2-5 alkanoylamino; 
(g) aryl, such as phenyl or naphthyl, either unsubstituted or substituted 
with one or more of --OH or C.sub.1-3 alkyl, or 
(h) a 6-membered nitrogen containing heteroaryl such as pyridyl, pyrazinyl, 
or pyrimidinyl; 
(2) 
##STR6## 
wherein the alkyl is either straight or branched or cyclic and either 
unsubstituted or substituted with items (a) through (h) as defined above; 
(3) halo such as chloro, fluoro or bromo; 
with the proviso that X and Y are not both halo. 
It is preferred that X is 
##STR7## 
and that it be a 5-substituent. It is further preferred that R and Y are 
independently C.sub.1-5 alkyl or substituted C.sub.1-5 alkyl. 
It is even more preferred that R is C.sub.1-5 alkyl, hydroxy-C.sub.1-5 
alkyl, or mono- or di-(C.sub.1-5 alkyl)amino-C.sub.1-5 alkyl, and that n 
is 0 or 2. 
A novel process for preparing sulfides of this invention comprises treating 
a bromothiophene with an organometallic such as n-butyl lithium at about 
-70.degree. C. in an ethereal solvent such as ether, THF, glyme or the 
like for about 1 to 5 hours. This mixture is then added to a 
dialkyldisulfide in an inert atmosphere in an ethereal solvent at about 
-25.degree. to -5.degree. C. After about 15 minutes to 2 hours the mixture 
is then refluxed for about 1 to 4 hours. The starting reagents are as 
shown below: 
##STR8## 
Functional groups on Y such as hydroxyl must be protected during the 
reaction for example as the methoxyethoxymethyl ether, which is readily 
removed after the reaction with a dilute mineral acid such as sulfuric 
acid at about 15.degree. to 30.degree. C. for about 0.5 to 3 hours. 
The 4-alkylthio-5-substituted alkylthiophene-2-sulfonamides are prepared 
from known 3-alkylthiothiophene-2-carboxaldehyde. Treatment of the 
aldehyde with a Grignard reagent, LAH or the like yields the corresponding 
alcohol derivatives. Protection of the alcohol as the MEM ether or any 
other suitable protecting group such as THP, tert-butyldimethylsilyl or 
the like followed by the incorporation of the 2-sulfonamide group by 
chemistry described below provides the desired 4-alkylthio-5-substituted 
alkylthiophene-2-sulfonamides. 
The 2-thio compounds may also be prepared by treating a 2-bromothiophene 
with a cuprous hydroxyalkyl mercaptide in refluxing quinoline for about 
3-6 hours. 
The methoxyethoxymethyl group may also be removed by treating the ether 
with dimethylboron bromide in chlorinated alkane such as methylene 
chloride at about -78.degree. C. for about 0.5 to 2 hours. 
A novel process for preparing the sulfones of this invention comprises 
treating the sulfide with an oxidizing agent such as OXONE.RTM. 
(2KHSO.sub.5.K.sub.2 SO.sub.4.KHSO.sub.4) (Dupont) followed by removal of 
any protecting group. It is often advisable to protect hydroxyl groups 
during the oxidation and it is readily accomplished by means of 
methoxyethoxymethyl ethers which can be removed by treatment with a 
mineral acid as described previously. The oxidation proceeds readily in 
aqueous alcohol at about 15.degree. to 30.degree. C. over a period of 
about 4 hours. 
The novel sulfoxides of this invention are prepared by oxidation of the 
sulfides with sodium metaperiodate at about 15.degree. to 25.degree. C. in 
aqueous alcohol for about 8 to 36 hours. 
Those compounds wherein the Y group carries an alkoxy group are prepared by 
treating the methoxyethoxymethyl ether in the appropriate alcohol with 
cold 50% (v/v) aqueous sulfuric acid for about 15 minutes to 1 hour at 
ambient temperature. The reaction is exemplified by the following: 
##STR9## 
The sulfonamide group is introduced to the 2-position of the thiophene by 
treating the thiophene with an organometallic reagent such as n-butyl 
lithium in an ethereal solvent such as THF at -78.degree. C. for about 1-3 
hours. The lithium thiophene solution is then exposed to sulfur dioxide 
gas for about 2 to 5 hours while warming to about -40.degree. C. The 
isolated lithium salt is then dissolved in sodium bicarbonate solution and 
treated with N-chlorosuccinimide. The resulting thiophene sulfonyl 
chloride in an inert solvent such as acetone is then added to concentrated 
ammonium hydroxide dropwise at about ice-bath temperature and the mixture 
is aged for about 0.5 to 2 hours. 
Novel compounds wherein the Y group carries an amino substituent are 
prepared by treating the corresponding hydroxyl compound with sulfuric 
acid in an excess of acetonitrile at about 15.degree. to 25.degree. C. for 
about 18 to 36 hours (Ritter Reaction). The resulting acetylamino compound 
may be reduced with borane dimethylsulfide complex in an ethereal solvent 
at reflux temperature for about 0.5 to 3 hours. 
Alternatively, the monoalkylamino derivative may be prepared by acid 
hydrolysis of the intermediate amide derived from the Ritter reaction 
followed by re-acylation with an alkanoyl chloride or anhydride to provide 
a new amide. Reduction of this amide with borane as described above yields 
the monoalkylamino derivative. The corresponding dialkylamino derivatives 
are prepared from the corresponding monoalkylamino derivative by acylation 
with an alkanoyl chloride or anhydride followed by reduction of the amide 
with diborane to provide the dialkylamino derivatives. 
A process of preparing ketones as exemplified by 8 (Y=--CH.sub.3, 
--CH.sub.2 OH, --CH(CH.sub.3)OH) of the invention is described in Scheme 
I. Functional groups on Y such as hydroxy must be protected during the 
reaction sequence for example as the methoxyethoxymethyl ether. 
Bromination of 1 with NBS/CCl.sub.4 provides the 2 bromothiophene 2. 
Treatment of 2 with n-butyl lithium followed by reaction with either 
dimethylformamide or dimethylacetamide yields the formyl or acetyl 
derivative 3, respectively. Reduction of 3 with chemical reducing agents 
such as LiAlH.sub.4, NaBH.sub.4 or the like yields the alcohol 4. In order 
to differentiate alcohols when another protected hydroxyl is present, the 
second alcohol moiety is protected as the tert-butyldimethylsilyl ether 5. 
Using previously described chemistry the sulfonamide group is next 
incorporated onto 5 to yield 6. The silyl group is removed by the use of 
F.sup.- to provide 7 and the alcohol 7 is oxidized by either MnO.sub.2, 
Sarrett oxidation, a Jones oxidation, or the like to the ketone 8. In the 
examples where Y contains a hydroxyl group protected as a 
methoxyethoxymethyl ether, the group is removed by treatment with aqueous 
methanolic mineral acid. In cases where Y contains an amino group these 
compounds are prepared from the alcohol as previously described above 
(Ritter reaction). 
5-Aralkylsulfone-4-alkylketonethiophene-2-sulfonamides are prepared from 
2,3-dibromothiophene. Treatment with n-BuLi, LDA or the like provides the 
2-lithiothiophene which is then treated with an aralkyldisulfide to 
provide the 2-aralkylsulfide-3-bromothiophene. Treatment with another 
equivalent of base, described above, yields the 3-lithio derivative which 
on reaction with DMF provides the 3-carboxaldehyde derivative. 
Manipulation of this structure as previously described provides the 
desired 5-aralkylsulfone-4-alkylketonethiophene-2-sulfonamides. By 
changing the order of reagents the corresponding 
4-aralkylsulfone-5-alkylketonethiophene-2-sulfonamides may be prepared. 
##STR10## 
Those compounds wherein the X-group is --CN, are prepared from intermediate 
2 (Scheme I). Treatment of aldehyde 3 with hydroxylamine yields the syn- 
and anti-oximes 9. Dehydration of 9 with acetic anhydride, thionyl 
chloride, DMF, trifluoroaceticanhydride or the like provides the nitrile 
10. Treatment of 10 with lithium (diisopropyl)amide (LDA) followed by 
SO.sub.2 and hydroxylamine-O-sulfonic acid yields the sulfonamide 11. 
Examples of Y containing hydroxyl and amino functions are prepared as 
previously described. 
Treatment of 2 with LDA followed by SO.sub.2 and hydroxylamine-O-sulfonic 
acid gives the corresponding 2-sulfonamide-5-bromothiophene derivative. 
The novel pharmaceutical formulations of this invention include 
formulations for systemic administration and ophthalmic formulations 
designed for topical ocular administration, preferably the latter. 
The formulations for systemic administration comprise a non-toxic 
pharmaceutically acceptable carrier and an effective amount of one or more 
of the novel compounds of this invention. They may be in a form (a) for 
oral administration; e.g., as tablets, in combination with other 
compounding ingredients customarily used such as talc, vegetable oils, 
polyols, benzyl alcohols, gums, gelatin, starches and other carriers; 
dissolved or dispersed or emulsified in a suitable liquid carrier; in hard 
or soft capsules, encapsulated in a suitable material; or (b) for 
parenteral administration; e.g., dissolved or dispersed in a suitable 
liquid carrier as a solution, suspension or emulsion, or (c) for 
transdermal application, e.g. as a patch. 
The active drugs of this invention are most suitably administered in the 
form of ophthalmic pharmaceutical compositions adapted for topical 
administration to the eye such as a solution, suspension, gel, ointment, 
or as a solid insert. Formulations of these compounds may contain from 
0.01 to 15% and especially 0.5% to 2% of medicament. They may contain a 
novel compound of this invention as the sole medicament or may contain as 
well an effective amount of a .beta.-adrenergic blocking agent such as 
timolol maleate or a parasympathomimetic agent such as pilocarpine. The 
two active principles are present in approximately equal amounts on a 
weight basis. 
The pharmaceutical preparation which contains the active compound may be 
conveniently admixed with a non-toxic pharmaceutical inorganic or organic 
carrier. Typical of pharmaceutically acceptable carriers are, for example, 
water, mixtures of water and water-miscible solvents such as lower 
alkanols or aralkanols, vegetable oils, polyalkylene glycols, petroleum 
based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, 
polyvinylpyrrolidone, isopropyl myristate and other conventionally 
employed acceptable carriers. The pharmaceutical preparation may also 
contain non-toxic auxiliary substances such as emulsifying, preserving, 
wetting agents, bodying agents and the like, as for example, polyethylene 
glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 
10,000, antibacterial components such as quaternary ammonium compounds, 
phenylmercuric salts known to have cold sterilizing properties and which 
are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl 
alcohol, phenyl ethanol, buffering ingredients such as sodium chloride, 
sodium borate, sodium acetates, gluconate buffers, and other conventional 
ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene 
sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, 
thiosorbitol, ethylenediamine tetraacetic acid, and the like. 
Additionally, suitable ophthalmic vehicles can be used as carrier media 
for the present purpose including conventional phosphate buffer vehicle 
systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, 
isotonic sodium borate vehicles and the like. 
The pharmaceutical preparation may also be in the form of a solid insert 
such as one which after dispensing the drug remains essentially intact, or 
a bio-erodible insert that either is soluble in lacrimal fluids, or 
otherwise disintegrates. 
Generally, doses of the present compounds of about 0.01 to about 50 mg/kg 
and preferably from about 0.1 to about 20 mg/kg of body weight per day may 
be used. Dosage may be single or multiple depending on the daily total 
required and the unit dosage.

EXAMPLE 1 
4-(1-Hydroxypropyl)-5-methylsulfonylthiophene-2-sulfonamide 
Step A: Preparation of 3-(1-Hydroxypropyl)-2-methylthiothiophene 
To a stirred solution of ethylmagnesium bromide (60 ml, 0.12 mol of a 2.0M 
solution in THF) in ether (50 ml) was added dropwise under a nitrogen 
atmosphere 2-methylthiothiophene-3-carboxaldehyde (15.8 g, 0.10 mol) in 
ether (10 ml) over a 1/2 hour period at ice bath temperature. The mixture 
was stirred at room temperature for 2 hours. The mixture was cooled in an 
ice bath and the complexes were decomposed by adding NH.sub.4 Cl (10.6 g) 
in 100 ml of water. The aqueous layer was separated and was extracted with 
ether (2.times.50 ml). These extracts were combined with the ether layer 
and were washed with saturated NaCl solution, saturated NaHCO.sub.3 
solution and again with saturated NaCl solution. The ether solution was 
dried over anhydrous Na.sub.2 SO.sub.4, filtered and concentrated in vacuo 
at room temperature to give 17.7 g of amber liquid (94%). TLC showed only 
minor impurities and NMR confirmed the structure. 
Step B: Preparation of 
3-[1-(Methoxyethoxymethoxy)propyl]-2-methylthiothiophene 
To a stirred solution of 3-(1-hydroxypropyl)2-methylthiothiophene (17.7 g, 
0.094 mol) in dry methylene chloride (100 ml) was added 
methoxyethoxymethyl chloride (20.6 g, 0.165 mol) followed by 
N,N,-diisopropylethylamine (21.3 g, 0.165 mol). The mixture was stirred at 
room temperature overnight. The mixture was washed with water, dried over 
anhydrous Na.sub.2 SO.sub.4, filtered and concentrated in vacuo at room 
temperature to give 24.4 g of amber oil (94% yield). NMR confirmed the 
structure and mass spectral analysis confirmed the molecular weight at 
276.09. 
Step C: Preparation of 
4-[1-(Methoxyethoxymethoxy)propyl]-5-methylthiothiophene-2-sulfonamide 
To a stirred solution of 
3-[1-(methoxyethoxymethoxy)propyl]-2-methylthiothiophene (24.0, 0.087 mol) 
in dry THF (175 ml) cooled to -78.degree. C. was added dropwise under 
nitrogen atmosphere n-butyl lithium (59.4 ml, 0.095 mol of a 1.6M hexane 
solution). The resulting deep red solution was stirred at about 
-70.degree. C. for 2 hours and then SO.sub.2 gas was introduced over the 
surface of the solution at -70 to -40.degree. C. for 1 hour. The solution 
was stirred at about -40.degree. C. for an additional 2 hours and was 
concentrated in vacuo to a viscous amber oil. The lithium salt was taken 
up in saturated NaHCO.sub.3 solution (175 ml) and was stirred at ice bath 
temperature as N-chlorosuccinimide (17.7 g, 0.13 mol) was added 
portionwise over 1/2 hour. The mixture was stirred at ice bath temperature 
for 2 hours and then was extracted with chloroform (3.times.70 ml). The 
combined extracts were washed with water, dried, filtered and concentrated 
in vacuo to an amber liquid. The resulting sulfonyl chloride was taken up 
in acetone (50 ml) and was added dropwise to concentrated NH.sub.4 OH (100 
ml) at ice bath temperature over 1/2 hour. The mixture was stirred for an 
additional hour at that temperature and the acetone was removed in vacuo. 
The oil which separated was extracted into ether (3.times.50 ml), washed 
with water and re-extracted with 0.5N KOH solution (3.times.100 ml). The 
combined KOH extracts were washed with ether, acidified with 6N HCl and 
again extracted into ether (2.times.100 ml). The combined ether extracts 
were washed with saturated solutions of NaCl and NaHCO.sub.3 and again 
with saturated NaCl, dried over anhydrous Na.sub.2 SO.sub.4, filtered and 
concentrated in vacuo at room temperature to give 24.3 g of amber liquid 
which was analytically pure (79%). NMR confirmed the structure and a 
molecular ion of M/Z 355 was observed in the mass spectrum. 
Step D: Preparation of 
4-[1-(Methoxyethoxymethoxy)propyl]-5-methylsulfonylthiophene-2-sulfonamide 
The 4-[1-(methoxyethoxymethoxy)propyl]-5-methylthiothiophene-2-sulfonamide 
(7.1 g, 0.02 mol) was dissolved in 50/50 ethanol/water (60 ml). To the 
stirred solution was added OXONE.RTM. (18.4 g, 0.03 mol) and the mixture 
was stirred at room temperature for 4 hours. The acidic mixture was made 
slightly basic with sodium bicarbonate and the mixture was concentrated in 
vacuo to an oily solid residue. Extraction of this material with ethyl 
acetate (2.times.25 ml), washing with water, drying over anhydrous 
Na.sub.2 SO.sub.4, filtering and concentration of the filtrate in vacuo 
gave a viscous yellow gum which contained minor impurities. The yield was 
essentially quantitative. NMR supported the structure and a molecular ion 
of M/Z 388 (M+H) was observed. 
Step E: Preparation of 
4-(1-Hydroxypropyl)-5-methylsulfonylthiophene-2-sulfonamide 
To a stirred solution of 
4-[1-(methoxyethoxymethoxy)propyl]-5-methylsulfonylthiophene-2-sulfonamide 
(8.0 g, 0.02 mol) in methanol (20 ml) was added a cold solution of 
concentrated sulfuric acid (20 ml) in water (20 ml). The mixture was 
stirred at room temperature for 1 hour and the solution was basified with 
a slight excess of 40% NaOH and the suspension was filtered to remove 
precipitated salts. The filtrate was washed with ether and acidified with 
HCl. The acidified mixture was extracted with ethyl acetate (4.times.25 
ml). The combined extracts were washed with saturated NaCl solution and 
dried over anhydrous Na.sub.2 SO.sub.4. The solution was filtered and 
concentrated in vacuo at room temperature to give a viscous yellow oil 
which was a mixture of five components. Chromatography on 300 g of silica 
gel eluting with 5% methanol/CHCl.sub.3 gave 3.0 g of a pure colorless 
oil. Trituration of the oil in n-butyl chloride gave a white solid (2.8 g) 
(45%). The product was recrystallized from 1,2-dichloroethane; m.p. 
125.5-126.5.degree. C. 
Employing the procedures substantially as described in Example 1, but using 
as starting materials the alkylthiothiophenes and Grignard reagents 
described in Table I, there are produced the 
4,5-disubstituted-thiophene-2-sulfonamides also described in Table I in 
accordance with the following reaction scheme: 
##STR11## 
TABLE I 
______________________________________ 
R 
m.p. (.degree.C.) 
______________________________________ 
CH.sub.3 
##STR12## 127-131 
CH.sub.2 CH.sub.3 
##STR13## 122-124 
CH.sub.3 
##STR14## 
CH.sub.2 CH.sub.3 
##STR15## 
CH.sub.2 CH.sub.3 
##STR16## 
CH.sub.2 CH.sub.2 CH.sub.3 
##STR17## 
CH.sub.2 CH.sub.2 CH.sub.3 
##STR18## 
CH(CH.sub.3).sub.2 
##STR19## 
CH(CH.sub.3).sub.2 
##STR20## 
CH.sub.2 CH.sub.2 OH 
##STR21## 
##STR22## CH.sub.3 CH.sub.2 
##STR23## CH.sub.3 CH.sub.2 
______________________________________ 
EXAMPLE 2 
4-(2-Hydroxyethyl)-5-methylsulfonylthiophene-2-sulfonamide 
Step A: Preparation of 2-Bromo-3-(2-hydroxyethyl)thiophene 
To a stirred solution of 2-(3-thienyl)ethanol (25.0 g, 0.195 mol) in carbon 
tetrachloride (250 ml) was added N-bromosuccinimide (34.7 g, 0.195 mol) in 
several portions over a 15 minute period. The mixture was stirred at room 
temperature for one hour. The succinimide was removed by filtration and 
the filtrate was concentrated in vacuo at room temperature to give the 
product as a viscous amber oil (40.2 g) (99%). TLC indicated that the 
product was pure and mass spectral analysis showed a molecular ion at M/Z 
206. NMR supported the structure. 
Step B: Preparation of 2-Bromo-3-[2-(methoxyethoxymethoxy)ethyl]thiophene 
A solution of 2-bromo-3-(2-hydroxyethyl)thiophene (40.0 g, 0.193 mol) in 
methylene chloride (200 ml) was cooled in ice and methoxyethoxymethyl 
chloride (41.9 g, 0.336 mol) was added with stirring. After several 
minutes N,N-diisopropylethylamine (44.3 g, 0.336 mol) was added and the 
solution was stirred overnight at room temperature. The solvent was 
removed in vacuo and the residue was taken up in ether (150 ml) and water 
(75 ml). The ether layer was separated and was washed with saturated 
NaHCO.sub.3 solution and with water, dried over anhydrous Na.sub.2 
SO.sub.4, filtered and concentrated in vacuo at room temperature to give 
52.1 g of an amber liquid. TLC indicated that the product was pure and NMR 
confirmed the structure. Field desorption mass spectral analysis gave a 
molecular ion of M/Z 294. The yield was 91%. 
Step C: Preparation of 
3-[2-(Methoxyethoxymethoxy)ethyl]-2-methylthiothiophene 
To a stirred solution of 2-bromo-3-[2(methoxyethoxymethoxy)ethyl]thiophene 
(51.8 g, 0.175 mol) in anhydrous ether (125 ml) cooled to -70.degree. C. 
was added n-butyl lithium (109.4 ml of a 1.6M solution in hexane, 0.175 
mol) under a nitrogen atmosphere over a 11/2 hour period. A tan suspension 
resulted which was stirred for an additional 1 hour and then was diluted 
with dry THF (100 ml) and was passed under nitrogen into a stirred 
solution of dimethyldisulfide (18.8 g, 0.20 mol) in anhydrous ether (50 
ml) at -15.degree. C. The resulting mixture was stirred at -15.degree. C. 
for 1/2 hour and at reflux for 2 hours. The dark mixture was cooled to 
0.degree. C. and water (100 ml) was added carefully. The organic layer was 
separated and washed with saturated NaCl solution, dried over anhydrous 
Na.sub.2 SO.sub.4, filtered and concentrated in vacuo at room temperature. 
The crude liquid (44.6 g) was distilled, the product being collected at 
110-140.degree. C. at 0.7 mm to give 34.6 g of pure product. Yield 75%. 
NMR supported the structure. 
Step D: Preparation of 
4-[2-(Methoxyethoxymethoxy)ethyl]-5-methylthiothiophene-2-sulfonamide 
To a stirred solution of 
4-[2-(methoxyethoxymethoxy)ethyl]-5-methylthiothiophene (34.4 g, 0.13 mol) 
in THF (250 ml) cooled to -40.degree. C. was added dropwise over 1/2 hour 
under nitrogen atmosphere n-butyl lithium (89.4 ml of a 1.6M solution in 
hexane, 0.143 mol). The resulting yellow solution was stirred at 
-40.degree. C. for an additional one hour. Then anhydrous SO.sub.2 was 
introduced over the surface of the solution for 11/2 hour at about 
-20.degree. C. The solution was concentrated in vacuo at room temperature 
to a viscous yellow oil. The oil was dissolved in saturated NaHCO.sub.3 
solution (200 ml) and N-chlorosuccinimide (24.4 g, 0.183 mol) was added 
portionwise over 1/2 hour at 5.degree. C. Stirring was continued for an 
additional 21/2 hours at 0.degree. C. The oil which had separated was 
extracted into chloroform, washed with water and dried over anhydrous 
Na.sub.2 SO.sub.4. Filtration and concentration of the filtrate in vacuo 
gave the sulfonyl chloride as an amber liquid. The liquid was dissolved in 
acetone (75 ml) and was added dropwise to concentrated NH.sub.4 OH (150 
ml) over 1/2 hour with ice bath cooling. The acetone was removed in vacuo 
and the sulfonamide was extracted into chloroform. This solution was 
dried, filtered and concentrated in vacuo to give the crude sulfonamide as 
an oil. The sulfonamide was extracted into 0.5N KOH solution (300 ml). The 
basic solution was washed with ether, acidified with 6N HCl, and extracted 
with ether. The ether extract was washed with water, dried over anhydrous 
Na.sub.2 SO.sub.4, filtered and concentrated in vacuo at room temperature 
to give 31.8 g (72%) of an amber oil. NMR supported the structure. Mass 
spectrum showed a molecular ion of M/Z 341. 
Step E: Preparation of 
4-[2-(Methoxyethoxymethoxy)ethyl]-5-methylsulfonylthiophene-2-sulfonamide 
The 4-[2-(methoxyethoxymethoxy)ethyl]-5-methylthiothiophene-2-sulfonamide 
(6.8 g, 0.02 mol) was dissolved in 50% aqueous ethanol (60 ml) and 
OXONE.RTM. (18.4 g, 0.03 mol) was added. The mixture was stirred at room 
temperature for 3 hours, then basified with NaHCO.sub.3, filtered, and 
concentrated in vacuo at room temperature to an oily solid residue. The 
residue was extracted with 50/50 ethyl acetate/chloroform. The extracts 
were dried over anhydrous Na.sub.2 SO.sub.4, filtered and concentrated in 
vacuo to 6.6 g of colorless oil (88%). NMR supported the structure. 
Step F: Preparation of 
4-(2-Hydroxyethyl)-5-methylsulfonylthiophene-2-sulfonamide 
The 
4-[2-(methoxyethoxymethoxy)ethyl]-5-methylsulfonylthiophene-2-sulfonamide 
(6.6 g, 0.0177 mol) was dissolved in methanol (25 ml) and was stirred at 
room temperature as cold 50% (v/v) sulfuric acid (40 ml) was added 
dropwise over 10 minutes. An additional quantity of methanol (25 ml) was 
added to dissolve the gum which separated and the solution was stirred for 
1/2 hour. The solution was basified with sodium hydroxide and was washed 
with ether. The solution was acidified with HCl and was extracted with 
CHCl.sub.3 and then with ethyl acetate. The ethyl acetate extract was 
washed with saturated NaCl solution, dried over anhydrous Na.sub.2 
SO.sub.4, filtered and concentrated in vacuo at room temperature to give 
4.1 g of crude oil which was chromatographed on silica gel (100 g) eluting 
with 5% methanol in chloroform. There was recovered 2.5 g of white solid 
which provided 1.5 g of analytically pure, material, m.p. 120-124.degree. 
C. 
EXAMPLE 3 
4-(1-Hydroxyethyl)-5-methylsulfinylthiophene-sulfonamide 
Step A: Preparation of 
4-[1-(Methoxyethoxymethoxy)ethyl]-5-methylsulfinylthiophene-sulfonamide 
To a stirred solution of 
4-[1-(methoxyethoxymethoxy)ethyl]-5-methylthiothiophene-2-sulfonamide (6.8 
g, 0.02 mol) in 50% aqueous ethanol (40 ml) was added sodium metaperiodate 
(4.8 g, 0.0224 mol). After several minutes solid began to separate. The 
mixture was stirred for 17 hours at room temperature. The suspension was 
filtered and the filtrate was concentrated to dryness in vacuo. The 
residual oily solid was chromatographed on silica gel (100 g) using 5% 
methanol in chloroform to give 6.68 g (94%) of pale yellow gum 
Step B: Preparation of 
4-(1-Hydroxyethyl)-5-methylsulfinYlthiophene-2-sulfonamide 
To a stirred solution of 
4-[1-(methoxyethoxymethoxy)ethyl]-5-methylsulfonylthiophene-sulfonamide 
(6.58 g, 0.0186 mol) in methanol (25 ml) was added dropwise over a 10 
minute period a cold solution of 50% (by volume) sulfuric acid. The 
solution was stirred for an additional 20 minutes at room temperature. The 
reaction solution was basified with NaHCO.sub.3 with cooling and was 
concentrated to dryness in vacuo at 40.degree. C. bath temperature. The 
solid residue was extracted with hot ethyl acetate and with 20% 
methanol/ethyl acetate. Concentration of the extracts in vacuo gave 4.0 g 
of solid which was purified by chromatography on silica gel using 5% 
methanol in methylene chloride. There was obtained 3.0 g (60%) of product, 
m.p. 172-185.degree. C. 
EXAMPLE 4 
4-(1-Methoxyethyl)-5-methylthiothiophene-2-sulfonamide 
To a stirred solution of 
4-[1-(methoxyethoxymethoxy)ethyl]-5-methylthiothiophene-2-sulfonamide (6.8 
g, 0.02 mol) in methanol (25 ml) was added dropwise 50% (by volume) cold 
sulfuric acid (50 ml) over a 10 minute period. The solution was stirred 
for an additional 1/2 hour at room temperature and the mixture was 
basified with NaHCO.sub.3 with cooling. The gum which separated was 
extracted into ethyl acetate. The aqueous layer was concentrated to 
dryness in vacuo and the solid residue was extracted with hot ethyl 
acetate. The ethyl acetate extracts were combined, dried over anhydrous 
Na.sub.2 SO.sub.4, filtered and concentrated in vacuo to give an amber 
liquid which was purified by chromatography on silica gel (100 g) using 
ethyl acetate (40%)/hexane (60%). There was recovered 1.9 g (36%) of white 
solid, m.p. 86-94.degree. C. 
EXAMPLE 5 
4-(1-Hydroxyethyl)-5-methylthiothiophene-2-sulfonamide 
To boron tribromide (40 ml of a 1.0M solution in methylene chloride) cooled 
under a nitrogen atmosphere to -50.degree. C. was added dropwise over 1/2 
hour tetramethyl tin (7.15 g, 0.04 mol). The resulting solution was 
stirred for 1/2 hour at -50.degree. C. and then for 1/2 hour at 15.degree. 
C. The solution was cooled to -78.degree. C. and 
4-[1-(methoxyethoxymethoxy)ethyl]-5-methylthiothiophene-2-sulfonamide 
(3.41 g, 0.01 mol) in methylene chloride (15 ml) was added dropwise over 
15 minutes. The mixture was stirred at -78.degree. C. for 3/4 hour and 
then poured into saturated NaHCO.sub.3 solution. Some additional solid 
NaHCO.sub.3 was added and the basic mixture was filtered. The filtrate was 
extracted with ethyl acetate (2.times.100 ml). The ethyl acetate solution 
was extracted with 0.5M KOH solution (2.times.100 ml). The KOH extracts 
were washed with ether and acidified with 6N HCl. The acidified mixture 
was extracted with ethyl acetate (2.times.50 ml). This extract was washed 
with saturated NaHCO.sub.3, water, dried over anhydrous Na.sub.2 SO.sub.4, 
filtered and concentrated in vacuo at ambient temperature. A pale amber 
oil was obtained (1.5 g). NMR confirmed the structure. After trituration 
in n-butyl chloride the oil solidified. Recrystallization from 
1,2-dichloroethane gave 0.54 g (21%) of white solid, m.p. 100-102.degree. 
C. 
EXAMPLE 6 
4-(1-Acetamidoethyl)-5-methylsulfonylthiophene-2-sulfonamide 
To acetonitrile (30 ml) was added concentrated sulfuric acid (2.94 g, 0.03 
mol) followed by 
4-(1-hydroxyethyl)-5-methylsulfonylthiophene-2-sulfonamide (2.85 g, 0.01 
mol). The resulting solution was stirred at room temperature for 24 hours. 
Only about 1/2 of the alcohol had reacted so additional sulfuric acid 
(2.94 g, 0.03 mol) was added. After another 16 hours at room temperature 
the reaction was complete. The mixture was basified with excess 
NaHCO.sub.3. Acetonitrile (100 ml) was added, the mixture was filtered and 
the acetonitrile was evaporated in vacuo. The residue was taken up in 
ethyl acetate, washed with saturated NaCl solution, dried over anhydrous 
Na.sub.2 SO.sub.4, filtered and concentrated in vacuo. The solid obtained 
was recrystallized from water to give 1.1 g (34%) of yellow solid, m.p. 
114-117.degree. C. HPLC and TLC confirmed the purity and NMR confirmed the 
structure. 
EXAMPLE 7 
4-[1-(Ethylamino)ethyl]-5-methylsulfonylthiophene-2-sulfonamide 
To a stirred refluxing solution of 
4-(1-acetamidoethyl)-5-methylsulfonylthiophene-2-sulfonamide (2.52 g, 
0.0077 mol) in dry tetrahydrofuran (25 ml) under nitrogen atmosphere was 
added dropwise a solution of borane dimethylsulfide complex (2.3 ml, 0.023 
mol) in THF (10 ml) over 1/2 hour. Reflux was continued for 1 hour. The 
solution was cooled in ice and acidified with 6N HCl (10 ml). The 
acidified solution was concentrated in vacuo. The residue was basified 
with saturated NaHCO.sub.3 solution and was extracted with ethyl acetate. 
The product was extracted into 3N HCl. This was again basified with 
saturated NaHCO.sub.3 solution, extracted with ethyl acetate, washed with 
saturated NaCl solution, dried over anhydrous Na.sub.2 SO.sub.4, filtered 
and concentrated in vacuo. A white solid was obtained (1.33 g) (55%), m.p. 
162.5-165.degree. C. Recrystallization from ethyl acetate gave 1.23 g of 
product, m.p. 164-165.5.degree. C. HPLC and TLC confirmed the purity and 
NMR confirmed the structure. 
EXAMPLE 8 
5-(2-Hydroxyethylsulfonyl)-4-methylthiophene-2-sulfonamide 
Step A: Preparation of 2-(2-Hydroxyethylthio)-3-methylthiophene 
A mixture of 2-bromo-3-methylthiophene (53.1 g, 0.30 mol), cuprous 
hydroxyethylmercaptide (46.4 g, 0.33 mol), pyridine (50 ml) and quinoline 
(200 ml) was stirred at reflux under nitrogen atmosphere for 41/2 hours. 
The mixture was cooled, poured into 6N HCl and ice (800 ml), and 
repeatedly extracted with ether. The ether extract was washed with water, 
saturated NaHCO.sub.3 solution and saturated NaCl solution and dried over 
anhydrous Na.sub.2 SO.sub.4. The solution was filtered and concentrated in 
vacuo to obtain a brown liquid (41.9 g). Chromatography on silica gel gave 
36.6 g of a pale yellow oil, (70%). TLC indicated that the product was 
pure. The structure was supported by NMR and mass spectrometry showed a 
molecular ion of M/Z=174. 
Employing the procedures substantially as described in Example 1, Steps B, 
C, D and E there are produced in sequence starting with the product of 
Step A hereof: 
Step B: 2-[2-(methoxyethoxymethoxy)ethylthio]-3-methylthiophene, as an oil 
in 98% yield; 
Step C: 
5-[2-(methoxyethoxymethoxy)ethylthio]-4-methylthiophene-2-sulfonamide, as 
an oil in 76% yield; 
Step D: 
5-[2-(methoxyethoxymethoxy)ethylsulfonyl]-4-methylthiophene-2-sulfonamide, 
as an oil in quantitative yield; and 
Step E: 5-(2-hydroxyethylsulfonyl)-4-methylthiophene-2-sulfonamide, m.p. 
144.5-148.degree. C., in 29% yield. 
EXAMPLE 9 
4,5-Bis(ethylthio)thiophene-2-sulfonamide 
To a stirred solution of 2,3-bis(ethylthio)thiophene (11.2 g, 0.055 mol) in 
dry tetrahydrofuran (100 ml) cooled to -78.degree. C. under nitrogen 
atmosphere was added dropwise over 1/2 hour 1.55M n-butyl lithium in 
hexane (39 ml, 0.0605 mol). The resulting amber solution was stirred at 
about -75.degree. C. for 11/2 hours. Anhydrous sulfur dioxide gas was 
introduced over the surface of the solution over 1/2 hour at -75.degree. 
to -20.degree. C. The solution was stirred at -10.degree. to -20.degree. 
C. for 11/2 hours. Concentration of the solution in vacuo gave the lithium 
salt as a pale yellow gum. The gum was dissolved in saturated NaHCO.sub.3 
solution (100 ml) and N-chlorosuccinimide (11.2 g, 0.0825 mol) was added 
portionwise over 1/2 hour at ice bath temperature. After 3 hours at ice 
bath temperature the mixture was extracted with chloroform. The extract 
was washed with water, dried over anhydrous Na.sub.2 SO.sub.4, filtered 
and concentrated in vacuo to give the sulfonyl chloride as an amber oil. 
The sulfonyl chloride was dissolved in acetone (25 ml) and was added 
dropwise to concentrated NH.sub.4 OH (100 ml) over 1/2 hour at ice bath 
temperature. After an additional hour at ice bath temperature the acetone 
was removed in vacuo and the oil which separated was extracted into ether. 
The product was extracted from the ether solution into 0.5N KOH solution. 
The KOH extract was acidified with excess 6N HCl and the oil was 
re-extracted into ether, washed with saturated NaHCO.sub.3 solution and 
water. It was dried over anhydrous Na.sub.2 SO.sub.4, filtered and 
concentrated in vacuo to a solid (8.1 g, 52%). Recrystallization from 
n-butyl chloride gave 5.74 g of white solid, m.p. 82-84.degree. C. 
EXAMPLE 10 
4.5-Bis(ethylsulfonyl)thiophene-2-sulfonamide 
The 4,5-bis(ethylthio)thiophene-2-sulfonamide (2.83 g, 0.01 mol) was 
dissolved in 50/50 ethanol/water (70 ml) and OXONE.RTM. (18.4 g, 0.03 mol) 
was added. The mixture was stirred at room temperature for 72 hours. The 
suspension was filtered and the filtrate was basified with NaHCO.sub.3 and 
was concentrated in vacuo to dryness. Both the solid residue obtained and 
the solids filtered from the reaction suspension were extracted with 
methanol. The solid obtained upon evaporation of the methanol was taken up 
in ethyl acetate, washed with water, dried over anhydrous Na.sub.2 
SO.sub.4 filtered and concentrated in vacuo at room temperature. White 
solid product was obtained (3.15 g) which contained some sulfoxide 
impurity. Recrystallizations from isopropanol and 50% aqueous methanol 
gave pure title compound (1.94 g, 56%), m.p. 175.5-177.degree. C. HPLC and 
TLC confirmed the purity and NMR and mass spectrometry supported the 
structure. 
EXAMPLE 11 
5-(1-Hydroxyethyl)-4-methylsulfonyl-2-sulfonamide 
Step A: Preparation of 2-(1-Hydroxyethyl)-3-methylthiothiophene 
To a stirred solution of methylmagnesium bromide (51.7 g, 0.15 mol) in dry 
ether (50 ml) under nitrogen atmosphere was added dropwise 
3-methylthiothiophene-2-carboxaldehyde (15.8 g, 0.10 mol) in dry ether (25 
ml) at about 10.degree. C. The solution was stirred at room temperature 
for 23/4 hours, cooled and decomposed by cautiously adding NH.sub.4 Cl (16 
g, 0.3 mol) in water (100 ml). The aqueous layer was separated and 
extracted with ether. The combined ether solution and extract were washed 
with saturated NaCl solution, dried over anhydrous Na.sub.2 SO.sub.4, 
filtered and concentrated in vacuo at room temperature to a pale yellow 
oil which contained two components. Chromatography on silica gel gave pure 
product (13.5 g, 78%). NMR supported the structure. 
Step B: Preparation of 
2-[1-(Methoxyethoxymethoxy)ethyl]-3-methylthiothiophene 
To a stirred solution of 2-(1-hydroxyethyl)3-methylthiothiophene (13.5 g, 
0.077 mol) in dry methylene chloride (100 ml) was added 
methoxyethoxymethyl chloride (11.5 g, 0.092 mol) followed by 
N,N-diisopropylethylamine (12.1 g, 0.092 mol) with cooling. The solution 
was stirred at room temperature for 18 hours. Some starting material 
remained upon work up at this point. The material was recycled as above 
using 1/2 the above quantities of methoxyethoxymethyl chloride and 
N,N-diisopropylethyl amine. After 5 hours at room temperature the reaction 
was completed. The solution was washed with water, dilute HCl, saturated 
NaHCO.sub.3 solution and again with water. Then it was dried over 
anhydrous Na.sub.2 SO.sub.4, filtered and concentrated in vacuo. Pure 
product was obtained as a yellow oil (17.6 g, 87%). TLC confirmed the 
purity and NMR and mass spectrometry (M/Z=262) supported the structure. 
Step C: Preparation of 
5-[1-(Methoxyethoxymethoxy)ethyl]-4-methylthiothiophene-2-sulfonamide 
To a stirred solution of 
2-[1-(methoxyethoxymethoxy)ethyl]-3-methylthiothiophene (17.6 g, 0.067 
mol) in dry THF (100 ml) under nitrogen atmosphere and cooled to 
-78.degree. C. was added dropwise over 1 hour 1.55M n-butyl lithium (47.5 
ml, 0.0737 mol) in hexane. The deep red solution was stirred at 
-78.degree. C. for 11/2 hours. Then anhydrous sulfur dioxide gas was 
introduced over the surface of the solution at -78.degree. to -40.degree. 
C. over 1 hour. Stirring at -40.degree. C. was continued for 11/2 hours 
and the solution was concentrated in vacuo to give the lithium salt as a 
yellow oil. The lithium salt was dissolved in saturated NaHCO.sub.3 
solution, (100 ml) and N-chlorosuccinimide (13.6 g, 0.10 mol) was added 
portionwise over 1/2 hour with ice bath cooling. After stirring for an 
additional 3 hours at ice bath temperature the mixture was extracted with 
chloroform. The extract was washed with water, dried over anhydrous 
Na.sub.2 SO.sub.4, filtered and concentrated in vacuo to obtain the 
sulfonyl chloride as a yellow oil. The sulfonyl chloride was taken up in 
acetone (50 ml) and was added dropwise to concentrated NH.sub. 4 OH (100 
ml) at ice bath temperature over 1/2 hour. After another 11/2 hours at ice 
bath temperature the acetone was removed in vacuo. The oil which separated 
was extracted into ether and then from the ether into 0.5N KOH. The KOH 
extract was acidified with excess 6N HCl and the product was re-extracted 
into ether. The ether extract was washed with saturated NaHCO.sub.3 
solution, water, dried over anhydrous Na.sub.2 SO.sub.4 filtered and 
concentrated in vacuo. The product was obtained pure as an amber oil (14.6 
g, 64%). NMR supported the structure and TLC confirmed the purity. 
Step D: Preparation of 
5-[1-(Methoxyethoxymethoxy)ethyl]-4-methylsulfonylthiophene-2-sulfonamide 
To a stirred solution of 
5-[1-(methoxyethoxymethoxy)ethyl]-4-methylthiothiophene-2-sulfonamide 
(5.98 g, 0.0175 mol) in 50/50 ethanol/water (70 ml) was added OXONE.RTM. 
(14.4 g, 0.0263 mol). The suspension was stirred at room temperature for 
41/2 hours. The mixture was basified with excess NaHCO.sub.3 and the 
entire mixture was concentrated to near dryness in vacuo. The residual 
moist solid was suspended in ethyl acetate and was filtered. The ethyl 
acetate extract was washed with water, dried over anhydrous Na.sub.2 
SO.sub.4, filtered and concentrated in vacuo to give a white solid, m.p. 
93-102.5.degree. C. (6.4 g, 98%). NMR supported the structure and TLC 
confirmed that the material was pure. 
Step E: Preparation of 
5-(1-Hydroxyethyl)-4-methylsulfonylthiophene-2-sulfonamide 
The 
5-[1-(methoxyethoxymethoxy)ethyl]-4-methylsulfonylthiophene-2-sulfonamide 
(5.94 g, 0.0159 mol) was dissolved in 50/50 methanol/water (30 ml) with 
warming and concentrated sulfuric acid (15 ml) was added. The solution was 
cooled to ambient temperature and stirred for 1 hour. The methanol was 
removed in vacuo and the aqueous acid was diluted with water (50 ml). The 
product was extracted into ethyl acetate. The extract was washed with 
saturated NaHCO.sub.3 solution, water, dried over anhydrous Na.sub.2 
SO.sub.4, filtered and concentrated in vacuo. A colorless oil was obtained 
which solidified to a white solid. Several recrystallizations from water 
gave pure product (1.04 g, 23%), m.p. 121-127.degree. C. NMR supported the 
structure and HPLC confirmed the purity. 
EXAMPLE 13 
5-Hydroxymethyl-4-methylsulfonylthiophene-2-sulfonamide 
Step A: Preparation of 2-Hydroxymethyl-3-methylthiothiophene 
To a stirred solution of 3-methylthiothiophene-2-carboxaldehyde (15.8 g, 
0.10 mol) in ethanol (150 ml) cooled to 10.degree. C. was added dropwise 
under nitrogen atmosphere a solution of sodium borohydride (3.78 g, 0.10 
mol) in water (30 ml) and 1N KOH (5 ml) over 1/2 hour. The mixture was 
stirred at room temperature for 2 hours. The mixture was concentrated in 
vacuo at room temperature and the oily residue was taken up in chloroform 
(100 ml) and water (100 ml). The chloroform was separated and the aqueous 
layer was extracted with chloroform (50 ml). The combined chloroform 
extracts were washed with saturated NaCl, dried over anhydrous Na.sub.2 
SO.sub.4, filtered and concentrated in vacuo at room temperature to give a 
pale yellow liquid (14.2 g) which contained two components. Chromatography 
on silica gel gave 9.5 g (59%) of the title compound as a colorless oil. 
NMR supported the structure and mass spectral analysis by low resolution 
showed a molecular ion of M/Z=160. 
Employing the procedures substantially as described in Example 12, Steps B 
through E, there was produced in sequence starting with the product from 
Step A hereof: 
Step B: 2-(Methoxyethoxymethoxymethyl)-3-methylthiothiophene as a yellow 
liquid in 95% yield; 
Step C: 5-(Methoxyethoxymethoxymethyl)-4-methylthiothiophene-2-sulfonamide 
as an oil in 64% yield; 
Step D: 
5-(Methoxyethoxymethoxymethyl)-4-methylsulfonylthiophene-2-sulfonamide in 
95% yield, m.p. 104-107.degree. C.; and 
Step E: 5-Hydroxymethyl-4-methylsulfonylthiophene-2-sulfonamide in 72% 
yield, m.p. 175-177.5.degree. C. 
EXAMPLE 14 
5-Bromo-4-(l-hydroxyethyl)thiophene-2-sulfonamide 
Step A: Preparation of 2-Bromo-3-(l-hydroxyethyl)thiophene 
To a stirred solution of 3-(1-hydroxyethyl)thiophene (61.4 g, 0.48 mol) in 
carbon tetrachloride (550 ml) was added N-bromosuccinimide (89.4 g, 0.504 
mol) portionwise over 11/2 hours at 40.degree. C. Stirring was continued 
for an additional 2 hours at ambient temperature. The reaction mixture was 
filtered and the filtrate was washed with water, saturated NaHCO.sub.3 and 
again with water. The solution 
was dried over anhydrous Na.sub.2 SO.sub.4 filtered and concentrated in 
vacuo at room temperature. This procedure gave 95.5 g (96%) of pale yellow 
oil. NMR supported the structure. 
Step B: Preparation of 2-Bromo-3-[l-(methoxyethoxymethoxy)ethyl]thiophene 
A solution of 2-bromo-3-(l-hydroxyethyl)thiophene (97.5 g, 0.47 mol) in dry 
methylene chloride (400 ml) was cooled in ice and 
N,N-diisopropylethylamine (68.2 g, 0.517 mol) was added followed by 
methoxyethoxymethYl chloride (64.4 g, 0.517 mol). The solution was stirred 
at room temperature over night. The dark solution was washed with water, 
3N HCl, saturated NaHCO.sub.3 and finally with water. The solution was 
dried over anhydrous Na.sub.2 SO.sub.4 filtered and concentrated in vacuo 
at room temperature. A dark amber oil was obtained (123.1 g). The impure 
product was distilled and the product was collected at 108-116.degree. C. 
at 0.7 mm Hg. to give 91.1 g (66%) of colorless liquid. NMR supported the 
structure. 
Step C: Preparation of 
5-Bromo-4-[l-(methoxyethoxymethoxy)ethyl1thiophene-2-sulfonamide 
To a stirred solution of dry diisopropylamine (12.6 g, 0.125 mol) in dry 
THF (100 ml) cooled to -5.degree. C. under nitrogen atmosphere n-butyl 
lithium (66.7 ml of a 1.55 M hexane solution, 0.105 mol) was added 
dropwise over 1/2 hour. The solution was stirred for 11/2 hours at 
-5.degree. C. The resulting lithium diisopropylamide solution was added 
dropwise over 1 hour at below -70.degree. C. to a stirred solution of 
2-bromo-3-[l-(methoxyethoxymethoxy)ethyl]thiophene (29.5 g, 0.10 mol) in 
dry THF (50 ml). The solution was stirred at -70.degree. C. for 1/2 hour 
and then at -70.degree. to -50.degree. C. for 1/2 hour. Recooled to 
-70.degree. C. and anhydrous sulfur dioxide was introduced over the 
surface of the solution until the mixture became acidic. Stirring was 
continued at -40.degree. to -60.degree. C. for 1 hour and then the mixture 
was concentrated in vacuo at room temperature to give the lithio salt as a 
brown gum. The gum was dissolved in water (200 ml) containing sodium 
acetate (l8.0 g, 0.22 mol) and the solution was cooled in an ice bath. 
Hydroxylamine-O-sulfonic acid (22.6 g, 0.20 mol) was added. The mixture 
was slightly acidic so another portion of sodium acetate (18.0 g, 0.22 
mol) was added. The nearly neutral solution was stirred at room 
temperature over night. The mixture was extracted with chloroform (200 ml 
in 3 portions) and the sulfonamide was extracted into 0.5N KOH (200 ml). 
The KOH extract was washed with ether, acidified with excess 6N HCl and 
re-extracted into ether (300 ml). The ether extract was washed with 
saturated NaHCO.sub.3 and water, dried over anhydrous Na.sub.2 SO.sub.4 
filtered and concentrated in vacuo to give 26.0 g (69%) of a viscous oil 
which solidified to a waxy solid. NMR supported the structure. 
Step D: Preparation of 5-Bromo-4-(l-hydroxyethyl)thiophene-2-sulfonamide 
5-Bromo-4-[l-(methoxyethoxymethoxy)ethyl]thiophene-2-sulfonamide (5.3 g, 
0.014 mol) was dissolved in methanol (25 ml) and water (25 ml) was added. 
Some oil separated. To this stirred mixture was added sulfuric acid (25 
ml) dropwise with cooling over 20 minutes. The resulting solution was 
stirred at room temperature over night. The methanol was removed in vacuo 
and the residual suspension was diluted with two volumes of water. The 
product was extracted into ethyl acetate. The extract was washed with 
saturated NaHCO.sub.3, water, dried over anhydrous Na.sub.2 SO.sub.4, 
filtered and concentrated in vacuo. This gave 4.0 g of a viscous amber 
oil. The crude oil was chromatographed on silica gel (150 ml) eluting with 
5% methanol/chloroform to give 1.96 g of colorless oil which showed a 
single spot by TLC. Trituration of the oil in n-butyl chloride gave a 
white solid (1.69 g, 49%), m.p. 126-128.5.degree. C. NMR supported the 
structure. 
EXAMPLE 15 
4-(1-(ethylamino)ethyl)-5-ethylsulfonylthiophene-2-sulfonamide 
Step A: Preparation of 
4-(1-Acetamidoethyl)-5-ethylsulfonylthiophene-2-sulfonamide 
To acetonitrile (40 ml) was added concentrated sulfuric acid (8.1 g, 0.0828 
mol). Then 5-ethylsulfonyl-4-(1-hydroxyethyl)thiophene-2-sulfonamide (4.14 
g, 0.0138 mol) was added and the solution was stirred at room temperature 
until no starting material remained (48 hours). The solution was 
neutralized by adding solid NaHCO.sub.3 along with water (5 ml). The 
mixture was filtered and the solids were washed with acetonitrile. The 
filtrate and washings were concentrated in vacuo to an oil. This residual 
oil was taken up in ethyl acetate (125 ml). The extract was washed with 
saturated NaCl, dried over anhydrous Na.sub.2 SO.sub.4, filtered and 
concentrated in vacuo at room temperature, to give 2.74 g (58%) of white 
solid which was a single product by TLC, m.p. 213-220.degree. C. NMR 
supported the structure. 
Step B: Preparation of 
4-[1-(Ethylamino)ethyl]-5-ethylsulfonylthiophene-2-sulfonamide 
To a stirred, refluxing suspension of 
4-(1-acetamidoethyl)-5-ethylsulfonylthiophene-2-sulfonamide (2.61 g, 
0.0077 mol) in dry tetrahydrofuran under nitrogen atmosphere was added 
dropwise over 1/2 hour a solution of dimethylsulfide borane complex (2.3 
ml of a 10 M solution, 0.023 mol) in dry THF (10 ml). The cloudy solution 
which formed was stirred at reflux for 11/2 hours. The mixture was cooled 
in ice and acidified by the dropwise addition of 6N HCl (10 ml), and 
concentrated in vacuo at room temperature. The moist solid residue was 
basified with saturated NaHCO.sub.3 and was extracted with ethyl acetate 
(4.times.50 ml). The amino product was extracted into 3N HCl (4.times.25 
ml). The combined HCl extracts were neutralized with NaHCO.sub.3 and 
extracted with ethyl acetate (4.times.50 ml). The ethyl acetate extract 
was dried over anhydrous Na.sub.2 SO.sub.4, filtered and concentrated in 
vacuo at room temperature. A colorless oil was obtained which solidified 
to a white solid upon trituration in ethyl acetate. The crude yield was 
1.99 g or 80%. The solid after recrystallization from ethyl acetate had 
m.p. 135-137.5.degree. C. NMR supported the structure and HPLC confirmed 
the purity. 
EXAMPLE 16 
______________________________________ 
4-(1-Hydroxyethyl)-5-ethyl- 
1 mg. 15 mg. 
sulfonylthiophene-2- 
sulfonamide 
Monobasic sodium phosphate .2H.sub.2 O 
9.38 mg. 6.10 mg. 
Dibasic sodium phosphate .12H.sub.2 O 
28.48 mg. 16.80 
mg. 
Benzalkonium chloride 
0.10 mg. 0.10 mg. 
Water for injection q.s. ad. 
1.0 ml. 1.0 ml. 
______________________________________ 
The title Compound, phosphate buffer salts, and benzalkonium chloride are 
added to and dissolved in water. The pH of the composition is adjusted to 
6.8 and diluted to volume. The composition is rendered sterile by ionizing 
radiation. 
EXAMPLE 17 
______________________________________ 
4-(1-Hydroxypropyl)-5-ethyl- 
5 mg. 
sulfonylthiophene-2-sulfonamide 
petrolatum q.s. ad. 1 gram 
______________________________________ 
The title compound and the petrolatum are aseptically combined. 
EXAMPLE 18 
______________________________________ 
4-(1-Hydroxyethyl)-5-ethylsulfonyl- 
1 mg. 
thiophene-2-sulfonamide 
Hydroxypropylcellulose q.s. 
12 mg. 
______________________________________ 
Ophthalmic inserts are manufactured from compression molded films which are 
prepared on a Carver Press by subjecting the powdered mixture of the above 
ingredients to a compressional force of 12,000 lbs. (gauge) at 300.degree. 
F. for one to four minutes. The film is cooled under pressure by having 
cold water circulate in the platen. Ophthalmic inserts are then 
individually cut from the film with a rod-shaped punch. Each insert is 
placed into a vial, which is then placed in a humidity cabinet (88% R.H. 
at 30.degree. C.) for two to four days. After removal from the humidity 
cabinet, the vials are stopped and then capped. The vials containing the 
hydrate insert are then autoclaved at 250.degree. F. for 1/2 hour. 
EXAMPLE 19 
______________________________________ 
4-(2-Hydroxyethyl)-5-methylsulfonyl- 
1 mg. 
thiophene-2-sulfonamide 
Hydroxypropyl cellulose q.s. ad. 
12 mg. 
______________________________________ 
Ophthalmic inserts are manufactured from a solvent cast film prepared by 
making a viscous solution of the powdered ingredients listed above using 
methanol as the solvent. The solution is placed on a Teflon plate and 
allowed to dry at ambient conditions. After drying, the film is placed in 
an 88% R. H. cabinet until it is pliable. Appropriately sized inserts are 
cut from the film. 
EXAMPLE 20 
______________________________________ 
4-[1-(Ethylamino)ethyl]-5-methyl- 
1 mg. 
sulfonylthiophene-2-sulfonamide 
Hydroxypropylmethyl cellulose q.s. ad. 
12 mg. 
______________________________________ 
Ophthalmic inserts are manufactured from a solvent cast film which is 
prepared by making a viscous solution of the powdered blend of the above 
ingredients using a methanol/water solvent system (10 ml. methanol is 
added to 2.5 g. of the powdered blend, to which 11 ml. of water (in three 
divided portions) is added. The solution is placed on a Teflon plate and 
allowed to dry at ambient conditions. After drying, the film is placed in 
an 88% R. H. cabinet until it is pliable. Appropriately sized inserts are 
then cut from the film. 
EXAMPLE 21 
______________________________________ 
5-(2-Hydroxyethylsulfonyl)-4-methyl- 
1 mg. 
thiophene-2-sulfonamide 
Hydroxypropylmethyl cellulose q.s. ad. 
12 mg. 
______________________________________ 
Ophthalmic inserts are manufactured from compression molded films which are 
prepared on a Carver Press by subjecting the powdered mixture of the above 
ingredients to a compressional force of 12,000 lbs. (gauge) at 350.degree. 
F. for one minute. The film is cooled under pressure by having cold water 
circulate in the platen. Ophthalmic inserts are then individually cut from 
the film with a punch. Each insert is placed into a vial, which is then 
placed in a humidity cabinet (88% R. H. at 30.degree. C.) for two to four 
days. After removal from the humidity cabinet, the vials are stopped and 
then capped. The vials containing the hydrated insert are then autoclaved 
at 250.degree. F. for one-half hour. 
It is highly preferred that the solid inserts of this invention are 
available for use by the patient in a pathogen free condition. Thus, it is 
preferred to sterilize the inserts and to insure against recontamination, 
the sterilization is preferably conducted after packaging. The best mode 
of sterilizing is to employ ionizing radiation including radiation 
emanating from Cobalt 60 or high energy electron beams.