Compounds of the following formula are disclosed: Compounds of Formula I are the topic of this invention: ##STR1## Wherein G, J and the two atoms of the thiophene ring to which they are attached form a six-membered ring chosen from ##STR2## The compounds are useful as carbonic anhydrase inhibitors.

BACKGROUND OF THE INVENTION 
The disease state referred to as glaucoma is characterized by a permanent 
loss of visual function due to irreversible damage to the optic nerve. The 
several morphologically or functionally distinct types of glaucoma are 
typically characterized by elevated intraocular pressure (IOP), which is 
considered to be causally related to the pathological course of the 
disease. 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. If glaucoma or ocular hypertension 
is detected early and treated promptly with medications which effectively 
reduce elevated intraocular pressure, loss of visual function or its 
progressive deterioration can generally be ameliorated. 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 detrimental, 
systemic (extraocular) side effects. The most serious, but rare, side 
effects are life-threatening blood dyscrasia and the formation of renal 
calculi. The more common side effects are nausea, dyspepsia, fatigue, 
impotence, depression, metabolic acidosis, and others which, although not 
generally life threatening, are sufficiently debilitating that patients 
frequently choose to discontinue therapy. 
There is, therefore, a clear need for an inhibitor of carbonic anhydrase 
which would be topically effective, thereby eliminating, or significantly 
reducing, the detrimental side effects associated with oral 
administration. 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. 
Compounds of commonly assigned U.S. Pat. No. 5,240,923 possess a chiral 
center within the 3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine ring. It has 
been demonstrated that, in general, one of the two possible stereochemical 
representations about this center is more active in binding to the target 
enzyme, carbonic anhydrase. Therefore, for those compounds it is most 
advantageous to obtain the preferred enantiomer in optically pure form. 
This can be accomplished by procedures known in the art, such as 
resolution or synthesis; however, obtaining an optically pure compound can 
be laborious. Therefore, it is advantageous to employ compounds with no 
chiral centers, or with as few chiral centers as possible if such 
alternatives are available. Surprisingly, it was discovered that compounds 
of the present invention, which do not possess a chiral center within the 
heterocycle, 2H-thieno[3,2-e]-1,2-thiazine, are in general more potent 
inhibitors of carbonic anhydrase than the corresponding reduced compounds. 
The class of non-steroidal antiinflammatory agents generally referred to as 
oxicams (e.g. piroxicam) can be considered to be structurally related to 
the compounds of present interest. Specifically, 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. However, 
there have been no disclosures wherein a sulfamoyl (SO.sub.2 NH.sub.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. Replacement of the fused benzene ring of 
piroxicam with a thiophene and further structural variations are disclosed 
in German Patent No. 2,537,070 and Swiss Patent No. 617,705 (and their 
related U.S. Pat. Nos. 4,230,873; 4,224,445 and 4,177,193); and European 
Patent No. 103,142 and U.S. Pat. Nos. 4,180,662 and 4,187,303. 
U.S. Pat. No. 5,093,332 discloses 
2,3-dihydro-1H-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. Pat. 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. 
SUMMARY OF THE INVENTION 
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.

DETAILED DESCRIPTION OF THE INVENTION 
Compounds consistent with Formula I are the topic of this invention: 
##STR3## 
Wherein G, J and the two atoms of the thiophene ring to which they are 
attached form a six-membered ring chosen from 
##STR4## 
wherein if Z is Z.sup.1, Z.sup.1 is C.sub.1-8 alkyl; 
C.sub.1-3 alkyl-C.sub.3-6 cycloalkyl; 
CH.sub.2 C(.dbd.O)R.sup.7 ; CH.sub.2 C(.dbd.O)NR.sup.2 R.sup.3 ; CH.sub.2 
CN; 
C.sub.2-8 alkyl substituted with one or more of hydroxyl, C.sub.1-4 alkoxy, 
C.sub.2-4 alkoxy-C.sub.1-4 alkoxy, OC(.dbd.O)R.sup.1, 
N(R.sup.2)C(.dbd.O)R.sup.1, halogen, CN, NR.sup.2 R.sup.3, SO.sub.n 
R.sup.4 or C(.dbd.O)R.sup.5 ; 
C.sub.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.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halogen, nitrile, NR.sup.2 
R.sup.3, SO.sub.n R.sup.4, C(.dbd.O)R.sup.5 or C.sub.1-4 alkyl which is 
substituted with hydroxy, NR.sup.2 R.sup.3, halogen, CO.sub.2 R.sup.1 or 
C.sub.1-3 alkoxy; 
C.sub.3-8 alkenyl unsubstituted or substituted with hydroxyl, C.sub.1-4 
alkoxy or NR.sup.2 R.sup.3 ; 
C.sub.3-8 alkynyl unsubstituted or substituted with hydroxyl, C.sub.1-4 
alkoxy or NR.sup.2 R.sup.3 ; 
and if Z is Z.sup.2, Z.sup.2 is an aromatic group chosen from phenyl or Q 
either of which can be unsubstituted or substituted with one or more of 
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy halogen, nitrile, NR.sup.2 
R.sup.3, SO.sub.n R.sup.4, C(.dbd.O)R.sup.5, or C.sub.1-4 alkyl which is 
substituted with hydroxy, NR.sup.2 R.sup.3, halogen or C.sub.1-3 alkoxy; 
Y is hydrogen; 
C.sub.1-8 alkyl; 
C.sub.1-6 alkyl substituted with one or more of hydroxyl, C.sub.1-4 alkoxy, 
C.sub.2-4 alkoxy-C.sub.1-4 alkoxy, OC(.dbd.O)R.sup.1, 
N(R.sup.2)C(.dbd.O)R.sup.1, halogen, CN, NR.sup.2 R.sup.3, SO.sub.n 
R.sup.4, or C(.dbd.O)R.sup.5 ; 
C.sub.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.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halogen, nitrile, NR.sup.2 
R.sup.3, SO.sub.n R.sup.4, C(.dbd.O)R.sup.5 or C.sub.1-4 alkyl which is 
substituted with hydroxy, NR.sup.2 R.sup.3, halogen, CO.sub.2 R.sup.1 or 
C.sub.1-3 alkoxy; 
C.sub.3-8 alkenyl unsubstituted or substituted with hydroxyl, C.sub.1-4 
alkoxy or NR.sup.2 R.sup.3 ; 
C.sub.3-8 alkynyl unsubstituted or substituted with hydroxyl, C.sub.1-4 
alkoxy or NR.sup.2 R.sup.3 ; 
R.sup.1 is C.sub.1-6 alkyl; 
C.sub.1-6 alkyl substituted with hydroxyl, halogen, C.sub.1-4 alkoxy, 
NR.sup.2 R.sup.3 or C(.dbd.O)R.sup.5 ; 
phenyl which can be unsubstituted or substituted with one or more of 
C.sub.1-4 alkyl, alkoxy, hydroxy or halogen; 
R.sup.2 and R.sup.3 are independently chosen from hydrogen; 
C.sub.1-4 alkyl; CH.sub.2 CN; 
C.sub.1-3 alkyl-C.sub.3-6 cycloalkyl; 
C.sub.3-8 cycloalkyl; 
C.sub.2-4 alkyl substituted with hydroxyl, halogen, CN, C.sub.1-4 alkoxy or 
C(.dbd.O)R.sup.5 ; 
hydroxyl; 
C.sub.1-4 alkoxy; 
C.sub.2-4 alkoxy substituted with hydroxyl, NR.sup.2 R.sup.3, halogen or 
C.sub.1-4 alkoxy; 
C.sub.3-8 alkenyl unsubstituted or substituted with hydroxy, or C.sub.1-4 
alkoxy; 
C.sub.3-8 alkynyl unsubstituted or substituted with hydroxyl, or C.sub.1-4 
alkoxy; 
or further R.sup.2 and R.sup.3 together with the nitrogen atom to which 
they are attached can be incorporated into a saturated heterocyclic ring 
of 5 to 8 atoms which may include a second heteroatom selected from O, S 
or N, such as pyrrolidine, oxazolidine, morpholine, thiomorpholine, 
thiomorpholine 1,1-dioxide, piperazine, 2-oxa-5-azabicyclo[2.2.1]heptane, 
2-oxa-5-azabicyclo[3.2.1]octane, thiazolidine, or thiazolidine 
1,1-dioxide, which can be unsubstituted or substituted on carbon with 
hydroxyl, (=O), halogen, C.sub.1-4 alkoxy, C(.dbd.O)R.sup.5, C.sub.1-4 
alkyl, C.sub.1-4 alkyl substituted with hydroxyl, halogen, C.sub.1-4 
alkoxy, C(.dbd.O)R.sup.5, or on nitrogen with C.sub.1-4 alkoxy, 
C(.dbd.O)R.sup.5, SO.sub.n R.sup.4, C.sub.1-4 alkyl or C.sub.1-4 alkyl 
substituted with hydroxyl, halogen, C.sub.1-4 alkoxy or C(.dbd.O)R.sup.5. 
R.sup.4 is C.sub.1-4 alkyl; 
C.sub.2-4 alkyl substituted with hydroxyl, halogen, NR.sup.2 R.sup.3 or 
C.sub.1-3 alkoxy; 
R.sup.5 is C.sub.1-6 alkyl; 
C.sub.1-6 alkyl substituted with hydroxyl, halogen, SO.sub.n R.sup.4, 
C.sub.1-4 alkoxy, NR.sup.2 R.sup.3 or C(.dbd.O)R.sup.6 ; 
C.sub.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.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halogen, nitrile, NR.sup.2 
R.sup.3, SO.sub.n R.sup.4 or C.sub.1-4 alkyl which is substituted with 
hydroxy, NR.sup.2 R.sup.3, halogen or C.sub.1-3 alkoxy; 
hydroxyl; 
C.sub.1-4 alkoxy; 
C.sub.2-4 alkoxy substituted with hydroxyl, NR.sup.2 R.sup.3, halogen or 
C.sub.1-4 alkoxy; 
NR.sup.2 R.sup.3 ; 
R.sup.6 is C.sub.1-4 alkyl; 
C.sub.1-4 alkoxy; 
amino; 
C.sub.1-3 alkylamino; 
(C.sub.1-3 alkyl).sub.2 amino; 
R.sup.7 is hydroxyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxy substituted with 
hydroxyl, NR.sup.2 R.sup.3 or C.sub.1-4 alkoxy; 
n is 0, 1, or 2; and 
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. 
In compounds of Structure I 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. 
In the above definitions, the total number of carbon atoms in a substituent 
group is indicated by the C.sub.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. 
For example, the substituent halogen, which means fluorine, chlorine, 
bromine or iodine, would indicate that 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. 
SYNTHESIS 
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. Subsequent amination of these intermediates with either 
ammonia, in the first case, or with an electrophilic aminating reagent, 
for example, hydroxylamine-O-sulfonic acid, in the second provides the 
desired sulfonamides of Formula I. Alternately, conversion of the 
sulfinate salt to the sulfonyl chloride with, for example, 
N-chlorosuccinimide, chlorine or sulfuryl chloride followed by reaction 
with ammonia gives compounds of Formula I. 
##STR5## 
Intermediate 1 can be prepared by the methods shown in Equations 2-4. 
Alkylation of compound 2, which can be prepared as described in U.S. Pat. 
No. 5,153,192 and U.S. Pat. No. 5,240,923, using any of a variety of 
conditions known in the art, which in general involve the use of a base, 
such as sodium hydride or potassium carbonate, in an inert solvent, such 
as DMF, DMSO or ethanol, provides selectively alkylation at nitrogen, ring 
position two. 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). 
##STR6## 
Alternately, 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.degree. C. and 
300.degree. C. under vacuum, provide the desired olefin compound 1 
(Equation 3). 
##STR7## 
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). 
##STR8## 
Furthermore, it can be advantageous to prepare certain intermediates 3 from 
compounds such as 6, prepared by alkylation of compound 2 with a suitable 
dibromoalkane in the manner analogous to that previously described for 
Equation 2. The hydroxyl group of 6 can be activated toward subsequent 
elimination by formation of a sulfonate ester, e.g. methanesulfonyl; 
treatment of such sulfonate esters under generally basic conditions 
results in formation of olefin 7. Reaction of olefin 7 with the desired 
nucleophile, e.g. amines or alcohols, using conditions well known in the 
art, provides intermediates 1 wherein Z is a substituted alkyl group such 
as aminoalkyl, i.e. R.sup.2 R.sup.3 N-alkyl-, or alkoxyalkyl, i.e. R.sup.1 
-O-alkyl- (Equation 5). 
##STR9## 
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.sup.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 accomplished in a manner analogous 
to Equation 1, but in this case reacting the intermediate sulfonyl 
chloride with the appropriate arylamine to give intermediate 9. The 
conversion of these thiophenesulfonamides into the desired cyclic 
compounds of Formula I can be accomplished using a variety of procedures 
well known in the art; e.g. acid hydrolysis of the ketal followed by 
bromination of the ketone and subsequent base catalyzed cyclization of the 
.alpha.-haloketone provides intermediates of structure 3. Furthermore, the 
groups Z of intermediate 1 introduced according to Equations 2-6 can in 
many instances be further modified to furnish yet other novel compounds of 
Formula I using methods known to one skilled in the art. 
##STR10## 
Alternately, it can be advantageous in certain cases to incorporate the 
sulfonamide group into the molecule prior to formation of the olefin. In 
these cases it may also be advantageous to protect the primary sulfonamide 
group from undergoing potentially undesirable reactions by incorporating a 
protecting group such as t-butylamine, a formamidine, or an imidate ester. 
Therefore, certain compounds of Formula I can best be prepared according 
to Equation 7. Alkylation of compound 11, which can be prepared as 
described in U.S. Pat. No. 5,240,923, with a haloalkylester, such as 
2-bromoethyl acetate, using any of a variety of conditions known to the 
art provides intermediate 12. Transformation of the secondary hydroxyl 
group of 12 to a sulfonate ester, for example, by treatment with 
methanesulfonic anhydride, and subsequent treatment under basic conditions 
to effect elimination, provides, after cleavage of the ester, intermediate 
alcohol 13. The primary hydroxyl group of 13 can be transformed into 
groups (Z.sup.1) of interest in the context of the present invention by a 
variety of functional group transformations. For example, 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 Mitsunobu reaction, diethyl 
azodicarbo-xylate-triphenylphosphine-amine. Deprotection of the 
sulfonamide group provides compounds of Formula I. 
##STR11## 
Other desirable compounds of Formula I can be prepared according to 
Equation 8 where R.sup.2, R.sup.3, T and Z are as described previously. 
Incorporation of the desired substituted sulfonamide at position two of 
the thiophene acetal 14 to give 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 .alpha.-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. For example, reduction of the ester group, 
with for example DIBAL, provides a primary alcohol (18) which can be 
readily converted to a sulfonate ester by known procedures; treatment of 
this sulfonate ester with the desired primary or secondary amine gives 
intermediate 19. 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. 
It can be advantageous in certain cases to introduce the primary 
sulfonamide prior to incorporating the amino group. In such cases direct 
sulfamoylation of 18 can be accomplished to give intermediate 20 by 
employing a procedure similar to that used for the sulfamoylation of 19. 
Amination of 20 by the same method used for the conversion of 18 to 19 
provides compounds of Formula I. 
##STR12## 
It can be desirable in certain cases to modify the substituent Z of Formula 
I (see Equation 9) to provide yet other compounds of Formula I. For 
example, where Z is Z.sup.1 and Z.sup.1 is alkoxyalkyl (e.g. 21), 
treatment under conditions suitable for ether cleavage, for example with a 
Lewis acid, such as borontribromide or bromodimethylborane, provides the 
.omega.-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.sup.1 is an acylated co-hydroxyalkyl 
group (23). Oxidation of the primary alcohol group of 22 with, for 
example, Jones reagent, provides the compound of Formula I where Z.sup.1 
is an alkylcarboxylic acid substituent, such as butanoic acid (24). 
Esterification of this carboxylic acid moiety can be readily accomplished 
by any of a variety of procedures known in the art, such as treatment with 
the desired alcohol in the presence of a suitable acid catalyst, such as 
sulfuric acid, to provide 25. Other 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. 
##STR13## 
Yet other desirable compounds of Formula I, namely 2,3-disubstituted 
2H-thieno[2,3-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides, can be prepared 
in a manner analogous to that already described for 2,3-disubstituted 
2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides in Equation 8, 
but using instead acetal 27 as the starting material (Equation 10). 
Selective metallation of 2,3-dibromothiophene with an organolithium base 
and subsequent treatment with an N, N-dialkylformamide, such as 
N,N-dimethylformamide or N-formylpiperidine, provides 
3-bromo-2-thiophenecarboxaldehyde which can be protected as the acetal 
(27). Introduction of the desired substituted sulfonamide at position 
three of acetal 27 to give intermediate 28 can be accomplished in a manner 
analogous to that already described for thiophene acetals in Equation 8. 
It can be advantageous in certain cases to react the intermediate sulfonyl 
chloride prepared from 27 directly with an N-substituted glycine ester to 
provide intermediate 29. Cyclization of intermediate 29 and the subsequent 
transformation to compounds of Formula I proceeds as described in Equation 
8. 
##STR14## 
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.sub.2 O.sub.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. 
##STR15## 
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. 
##STR16## 
The compounds of this invention, Formula I, can be incorporated into 
various types of ophthalmic formulations for delivery to the eye. For 
example, 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. In order to prepare sterile ophthalmic 
ointment formulations, the active ingredient is combined with a 
preservative in an appropriate vehicle, such as, mineral oil, liquid 
lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be 
prepared by suspending the active ingredient in a hydrophilic base 
prepared from the combination of, for example, Carbopol-940 or the like 
(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, 
polyvinylpyrrolidone, or the like to improve the retention of the 
medicament in the conjunctival sac. 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. 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. 
EXAMPLE 1 
##STR17## 
2-(2-Methoxyethyl)-2H-thieno[3,2-e]-1, 2-thiazine-6-sulfonamide 1,1-dioxide 
Sodium Salt 
Step A: 3-(2,5,5-Trimethyl-1,3-dioxan-2-yl)-2-thiophenesulfonamide 
To a solution of 3-(2,5,5-trimethyl-1,3-dioxan-2-yl)thiophene (106 g, 0.5 
mol) in hexane (1200 mL) at -60.degree. C. was added a 2.5M solution of 
n-butyllithium in hexane (240 mL, 0.6 mmol) over 40 min. The mixture was 
allowed to warm to room temperature (approximately 1.5 hr) and then once 
again cooled to -60.degree. 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.sub.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.degree. C. and hydroxylamine-O-sulfonic acid (107 g, 0.95 
mol) was slowly added. The mixture was stirred at room temperature for 18 
hr and then extracted with ethyl acetate. The combined extracts were 
washed with a saturated aqueous sodium bicarbonate solution, brine, dried 
(Na.sub.2 SO.sub.4) and evaporated to give a viscous brown oil (174.05 g); 
this product was used in the next step without further purification. 
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 1N HCl (1000 mL) and heated at reflux temperature for 1.5 
hr. The THF was evaporated and the aqueous solution made basic by the 
addition of a saturated aqueous sodium bicarbonate solution. The mixture 
was cooled and the precipitate collected by filtration, washed with cold 
water and dried in vacuo to give the crude product (109.1 g,). 
Recrystallization from acetonitrile gave the desired product (81.5 g, 
79%): mp 193.degree.-196.degree. C. 
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.degree. C. and the addition of pyridinium bromide 
perbromide (183 g, 0.515 mol) commenced and continued as the temperature 
continued to drop to 0.degree. C. After the addition was completed, the 
reaction mixture was allowed to warm to 14.degree. C. (approximately 3 
hr). The solvent was evaporated and the residue mixed with water; 
filtration provided the crude intermediate which was washed with cold 
water and dried in vacuo overnight to give 149.5 g of solid which was 
dissolved in ethanol (3000 mL) at room temperature and then chilled with 
ice; this solution was treated with NaBH.sub.4 (19 g, 0.5 mol) and the 
mixture, which turned clear in about 15 min, was heated at 50.degree. C. 
for 2 hr, and then stirred at room temperature for an additional 18 hr. 
The ethanol was evaporated and the residue dissolved in water; this 
aqueous solution was adjusted to a pH of 6 and then extracted with ethyl 
acetate. The extracts were washed with brine, dried and evaporated to give 
a residue which was triturated with cold ethyl acetate. The solid (crude 
product) was collected by filtration and the ethyl acetate soluble 
material was purified by column chromatography (silica, 20% to 50% ethyl 
acetate/hexane). These two batches of product were combined and 
recrystallized from ethyl acetate (59.6 g, 58%): mp 
138.degree.-140.degree. C. 
Step D: 
4-(1-Ethoxyethoxy)-2-(1-ethoxyethyl)-3,4-dihydro-2H-thieno[3,2-e]-1,2-thia 
zine 1,1-dioxide 
A solution of the product from Step C (106.9 g, 0.521 mol) in THF (360 mL) 
was cooled to 0.degree. C. and para-toluenesulfonic acid (3.6 g) was 
added. 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.degree. C. The yellow solution was stirred at 0.degree. C. for 1 hr, a 
saturated aqueous sodium bicarbonate solution (400 mL) was added and this 
mixture was extracted with ethyl acetate (3.times.250 ml). The combined 
extracts were dried (Na.sub.2 SO.sub.4) and evaporated to give a residue 
which was purified by column chromatography (silica, hexane to 20% 
hexane/ethyl acetate) to give the desired product (78%) as a light yellow 
oil. This material was used in the next step. 
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 
The product from Step D (125.6 g, 0.359 mol) was dissolved in THF (1200 mL, 
dry) and the solution cooled to -70.degree. C. n-Butyllithium (2.5M in 
hexanes, 215 mL, 0.538 mol) was added slowly, after stirring at 
-70.degree. C. for 1 hr sulfur dioxide was bubbled into the mixture until 
the pH reached 4. The 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.degree. C., N-chlorosuccinimide (62.3 g, 0.467 mol) was added 
in portions while maintaining the temperature of the reaction mixture at 
0.degree. C. The mixture was allowed to warm to room temperature and 
stirred at this temperature for 2 hr. Saturated aqueous sodium bicarbonate 
(500 mL) and brine (500 mL) were added and the organic layer was separated 
and washed with saturated aqueous sodium bicarbonate (250 mL) and brine 
(250 mL), dried (MgSO.sub.4) and evaporated to give the sulfonyl chloride 
intermediate as a brown oil (132 g, 82%). The sulfonyl chloride (147 g, 
0.327 mol) was dissolved in THF (900 mL) and cooled to 5.degree. C. 
t-Butylamine (350 mL) was slowly added and the mixture was allowed to warm 
to room temperature, stirring continued for 20 hr. The solvent and excess 
amine were removed by evaporation to give a dark oil which was stirred 
with ethyl acetate (500 mL) and saturated aqueous sodium bicarbonate (250 
mL). The organic layer was removed and the aqueous layer was washed with 
ethyl acetate (2.times.250 mL). The combined organic layers were dried 
(MgSO.sub.4), filtered through silica gel, and evaporated to give the 
desired product as an oil (159 g, 99%). 
Step F: 
3,4-Dihydro-4-hydroxy-N-(1,1-dimethylethyl)-2H-thieno[3,2-e]-1,2-thiazine- 
6-sulfonamide 1,1-dioxide 
A mixture of the product from Step E (158 g, 0.325 mol), THF (700 mL) and 
2N HCl (180 mL) were stirred at room temperature for 20 hr. After 
evaporating the THF, the aqueous mixture was cooled to 0.degree. C. and 
sodium bicarbonate (50 g) was carefully added followed by water (400 mL) 
and ethyl acetate (500 mL). The two layers were separated and the aqueous 
layer was extracted with ethyl acetate (250 mL). The combined organic 
extracts were washed with brine, dried (MgSO.sub.4) and evaporated to give 
a foam which was triturated with methylene chloride (200 mL) to give a 
solid (81.7 g, 75%): mp 144.degree.-147.degree. C. Recrystallization of 
this solid from methylene chloride gave an off-white solid: mp 
163.degree.-165.degree. C. 
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.degree. C. The cooling bath was 
removed and the mixture was stirred for one hour at which point 
2-bromoethyl methyl ether (0.09 mL, 0.97 mmol) was added. The mixture was 
stirred for 18 hr at room temperature, water was added and the mixture 
extracted with ethyl acetate (3.times.3 mL). The combined extracts were 
washed with water (10 mL), dried (MgSO.sub.4) and evaporated to provide an 
oil which was purified by column chromatography (silica, hexane/ethyl 
acetate gradient) to give the desired product as an oil (0.35 g, 100%) 
which was used in the next reaction. 
Step H: 
2-(2-Methoxyethyl)-N-(1,1-dimethylethyl)-2H-thieno[3,2-e]-1,2-thiazine-6-s 
ulfonamide 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. After three hours the mixture was washed with 2N HCl (15 mL), 
water (15 mL), saturated aqueous sodium chloride (20 mL), dried 
(MgSO.sub.4) and evaporated to a residue which was purified by column 
chromatography (silica, hexane/ethyl acetate) to provide the desired 
product (2.14 g, 39%) as an oil. This oil was heated under vacuum 
(200.degree. C./5 mm Hg) for approximately 5 minutes (until no more 
condensate collected) and then purified by column chromatography (silica, 
hexane/ethyl acetate) to provide the desired product (1.48 g, 97%) which 
was used in the next step. 
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. Evaporation 
provided a residue which was dissolved in dichloromethane (15 mL) and 
washed with water (3.times.10 mL), saturated aqueous sodium chloride (15 
mL), dried (MgSO.sub.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 give the desired product (0.7 g, 55%) as 
an oil. To a solution of this oil in ethanol (2 mL) was added 2N NaOH 
(1.08 mL, 2.16 mmol). Ethyl ether was added to the cloud point and the 
product that precipitated was collected by filtration, washed with ether 
and dried under nitrogen to give the desired product (0.3 g) as a white 
solid: mp 95.degree.-97.degree. C. Analysis. Calculated for C.sub.9 
H.sub.11 N.sub.2 O.sub.5 S.sub.3 Na-2.0 H.sub.2 O: C, 28.27; H, 3.95; N, 
7.33. Found: C, 27.90; H, 3.64; N, 7.19. 
EXAMPLE 2 
##STR18## 
2-(3-Methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1, 
1-dioxide Sodium Salt 
Step A: 
6-Chloro-3,4-dihydro-2-(3-methoxypropyl)-4-O-phenoxythiocarbonyl-2H-thieno 
[3,2-e]-1,2-thiazine 1,1-dioxide 
Sodium hydride (1.1 g of a 60% suspension in mineral oil, 27.53 mmol) was 
added in portions to a solution of 
6-chloro-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide 
(6.0 g, 25.03 mmol) in dry DMF (100 mL) under nitrogen. The mixture was 
stirred for 1 hr, cooled to 0.degree. C. in an ice bath and 3-bromopropyl 
methyl ether (3.83 g, 25.03 mmol) was added The mixture was stirred 
overnight at room temperature and evaporated to a residue which was mixed 
with water (100 mL) and extracted with ethyl acetate (5.times.20 mL). The 
extracts were combined, washed with saturated aqueous sodium chloride, 
dried (MgSO.sub.4) and evaporated to provide an oil. A solution of this 
oil and 4-dimethylaminopyridine (4.58 g, 37.5 mmol) in 1,2-dichloroethane 
(100 mL) was cooled by means of an ice bath and phenyl chlorothionoformate 
(4.15 mL, 37.5 mmol) was added slowly. The cooling bath was removed and 
the mixture stirred at room temperature for 18 hr, diluted with a 3:1 
mixture of hexane/ethyl acetate (200 mL) and filtered through silica gel. 
The filtrate was evaporated to a residue which was purified by column 
chromatography (silica, hexane to 3:1 hexane/ethyl acetate) to give the 
desired compound as an oil (5.1 g, 46%). 
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.degree. C./0.5 mm Hg) until no more condensate formed (approximately 
5 min). The flask was cooled to room temperature and the residue purified 
by column chromatography (silica, hexane to 3:1 hexane/ethyl acetate) to 
give the desired product as an oil (2.33 g, 70%) which was used in the 
next reaction. 
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.degree. C.) under 
nitrogen. n-Butyllithium (4.1 mL of a 2.1M 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.times.8 mL). The combined extracts were 
washed with a saturated aqueous sodium chloride solution, dried 
(MgSO.sub.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 give the desired product as an oil (0.91 g, 34%). 
This oil was converted to the sodium salt by dissolving it in ethanol (1.5 
mL) and adding 2N NaOH (1.26 mL). Ethyl ether was added to the cloud point 
and the product which precipitated was isolated by filtration under 
nitrogen to give the desired salt (0.81 g, 90%): mp 90.degree.-92.degree. 
C. Analysis. Calculated for C.sub.10 H.sub.13 N.sub.2 O.sub.2 S.sub.3 
Na-H.sub.2 O: C, 30.30; H, 4.32; N, 7.07. Found: C, 30.29; H, 4.13; N, 
6.97. 
EXAMPLE 3 
##STR19## 
2-(3-Ethoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide 
Step A: 3-Bromopropyl Ethyl Ether 
To a solution of 3-ethoxypropanol (5.0 g, 48 mmol) in carbon tetrachloride 
(19.1 g, 57.6 mmol) cooled to 0.degree. C. was added triphenylphosphine 
(15.1 g, 57.6 mmol); this mixture was stirred for 3 hr, filtered through 
silica gel and evaporated to a residue which was distilled to give and oil 
(10.98 g). Redistillation of the oil from phosphorous pentoxide gave 
3-bromopropyl ethyl ether (8.0 g, 100%): bp 142.degree.-144.degree. C. 
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.degree. 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 temperature. The reaction 
mixture was diluted with cold water (300 mL) and extracted with ethyl 
acetate (5.times.10 mL). The combined extracts were washed with water 
(3.times.10 mL), saturated aqueous sodium chloride (20 mL), dried 
(MgSO.sub.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-thi 
azine 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. Sodium bicarbonate (2.0 g) was 
added and the mixture stirred for 30 min, washed with water (3.times.75 
mL), saturated aqueous sodium chloride (100 mL) and dried (MgSO.sub.4). 
The mixture was evaporated to a residue which was filtered through silica 
gel with 3:1 hexane/ethyl acetate to give a pale yellow oil (7.53 g, 46%) 
which was used in the next reaction. 
Step D: 
2-(3-Ethoxypropyl)-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine-6-s 
ulfonamide 1,1-dioxide 
A solution of the product from Step C (13.25 g, 36.5 mmol) in THF (250 mL) 
was degassed under nitrogen and cooled to -60.degree. C. in a 
dry-ice/isopropanol bath. n-Butyllithium (16.0 mL of a 2.5M solution, 40 
mmol) was added slowly over 5 min and the mixture was stirred at 
-60.degree. C. for 45 min followed by the introduction of excess sulfur 
dioxide gas into the flask. The mixture was allowed to warm to room 
temperature over two hours and the solvent was removed by evaporation. The 
residue was mixed with water (200 mL) and sodium acetate trihydrate (13.91 
g, 102.2 mmol) followed by the addition of hydroxylamine-O-sulfonic acid 
(6,9 g, 61.32 mmol). The mixture was stirred at room temperature for 18 hr 
and then extracted with ethyl acetate (5.times.15 mL). The combined 
extracts were evaporated and the residue dissolved in THF (150 mL), mixed 
with 2N HCl (10 mL), warmed gently for 1 hr and then evaporated to a 
residue. The residue was mixed with ethyl acetate (100 mL) and water (100 
mL). The organic layer was separated, washed with saturated aqueous sodium 
chloride, dried (MgSO.sub.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 pale yellow solid 
(11.6 g, 86%): mp 140.degree.-145.degree. C. dec. Analysis. Calculated for 
C.sub.11 H.sub.18 N.sub.2 O.sub.6 S.sub.3 : C, 35.66; H, 4.90; N, 7.56. 
Found: C, 35.79; H, 4.80; N, 7.47. 
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) was slowly added and the mixture allowed to 
warm to room temperature. 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 
chromatography (silica, gradient elution hexane to 3:1 hexane/ethyl 
acetate) to give the desired product (0.79 g, 33%) and a secondary product 
wherein the protecting group had been removed (0.35 g, 16%). 
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.degree. C./0.5 mm Hg) until no more 
condensate formed (approximately 5 min). The flask was cooled to room 
temperature and the residue was dissolved in methanol (5 mL); 2N HCl (1.0 
mL) was added. The mixture was heated at 50.degree. C. for 2 hr and 
evaporated to a residue which was mixed with saturated aqueous sodium 
chloride and extracted with ethyl acetate (5.times.2 mL). The combined 
extracts were dried (MgSO.sub.4) and evaporated to a residue which was 
purified by column chromatography (silica, 3:1 hexane/ethyl acetate to 7:3 
methylene chloride/methanol) to give the desired product (0.42 g, 57%) as 
a white solid: mp 131.degree.-132.degree. C. Analysis. Calculated for 
C.sub.11 H.sub.16 N.sub.2 O.sub.5 S.sub.3 : C, 37.49; H, 4.58; N, 7.95. 
Found: C, 37.82; H, 4.56; N, 7.82. 
EXAMPLE 4 
##STR20## 
2-(4-Methoxyphenyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide 
Step A: 3-Acetyl-2-[(phenylmethyl)thio]-5-chlorothiophene 
A mixture consisting of thiourea (858.4 g, 11.28 mol), benzyl bromide 
(1,930 g, 11.28 mol), THF (9000 ml), and water (3000 ml) was heated at 
reflux temperature for 2 hr followed by cooling to 50.degree. C. To this 
solution was added 3-acetyl-2,5-dichlorothiophene (2000 g, 10.25 mol) and 
an aqueous solution of sodium hydroxide (2,200 g of 50% NaOH diluted to 
3000 ml); this mixture was heated at reflux temperature for 4 hr, cooled 
to room temperature, and the two layers separated. The organic layer was 
diluted with ethyl acetate (6000 ml) and washed with water (3.times.2000 
ml) and saturated aqueous sodium chloride, dried (MgSO.sub.4) and the 
solvent evaporated to give a residue which was triturated with hexane. 
This solid was collected by filtration and dried to give the desired 
product (2,550 g, 88%): mp 86.degree.-88.degree. C. 
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.degree. C. Chlorine gas was slowly passed through the solution until the 
temperature reached 15.degree. C. at which point the mixture was cooled to 
5.degree. 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.times.200 mL). The 
combined extracts were washed with cold 2N NaOH (2.times.200 mL), brine 
(150 mL) and dried (MgSO.sub.4). One half of this solution of sulfonyl 
chloride was evaporated to an oil which was dissolved in DMF, cooled 
(3.degree. C.), and a solution of p-anisidine (7.14 g) in DMF (50 mL) was 
added. After stirring for 0.5 hr, the mixture was evaporated to a residue 
which was suspended in water and extracted with methylene chloride 
(2.times.70 mL). The combined extracts were dried (MgSO.sub.4) and 
evaporated to a syrup which crystallized to give a yellow solid (3.15 g). 
The mother liquor was chromatographed (silica, 20% ethyl acetate/hexane) 
to give an additional quantity (1.66 g) of the desired product (total 
yield, 48%). 
Step C: 
6-Chloro-3,4-dihydro-4-hydroxy-2-(4-methoxyphenyl)-2H-thieno[3,2-e]-1,2-th 
iazine 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.degree. C. A solution of pyridinium bromide perbromide (4.32 g, 13.52 
mmol) in THF (20 mL) was added and the reaction mixture allowed to warm to 
room temperature. The THF was evaporated and the residue dissolved in 
ethanol (40 mL); this solution was cooled (3.degree. C.), sodium 
borohydride (pellets, 3.25 g, 86.03 mmol) added and the reaction mixture 
stirred at 5.degree. C. for 1 hr followed by heating at reflux temperature 
for 1 hr. The reaction mixture was evaporated to a residue which was 
suspended in water and the pH of this suspension was adjusted to 7 with 
saturated aqueous ammonium chloride. This mixture was extracted with ethyl 
acetate (3.times.50 mL) and the combined extracts were dried (MgSO.sub.4). 
The products from two such reactions were purified by column 
chromatography (silica gel, 1:1 ethyl acetate/hexane) to give the desired 
product (3.6 g), mp 127.degree.-132.degree. C.; this material was used in 
the next reaction. 
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 (200.degree. C./0.5 mm Hg) approximately 5 min followed by 
cooling the mixture to room temperature. The residue was purified by 
column chromatography (silica gel, 3:1 hexane/ethyl acetate to 7:3 
methylene chloride/methanol) which gave 0.91 g (65%) of the desired 
product as an oil which was not purified further. 
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. The solution was cooled in a 
dry-ice/isopropanol bath (-78.degree. C.) followed by the slow addition of 
n-butyllithium (2.2 ml of a 1.54M solution, 3.44 mmol). After stirring for 
1 hr, sulfur dioxide gas was passed through the flask until the solution 
tested acidic to moist litmus paper at which point the cooling bath was 
removed. After stirring for 1 hr the solvent was evaporated and the 
residue mixed with water (10 mL). Sodium acetate trihydrate (1.87 g, 13.75 
mmol) and hydroxylamine-O-sulfonic acid (0.94 g, 8.25 mmol) were added and 
this aqueous mixture stirred for 3 hr and then extracted with ethyl 
acetate (5.times.3 mL). The combined extracts were washed with a saturated 
aqueous solution of sodium chloride (10 mL), dried (MgSO.sub.4) and 
evaporated to a residue which was partially purified by column 
chromatography (silica, 3:1 hexane/ethyl acetate to 7:3 methylene 
chloride/methanol) to give 0.19 g of a dark oil. To a solution of this oil 
in ethanol (2 mL) was added sodium hydroxide (0.3 mL of a 2N solution) 
followed by sufficient diethyl ether to precipitate the disodium salt 
which was collected by filtration: mp 98.degree.-100.degree. C. A solution 
of the sodium salt in water (3 mL) was acidified (pH 4) with 2N HCl and 
the precipitate collected by filtration to give the desired compound (67 
mg, 6%) as a tan solid: mp 90.degree.-92.degree. C. Analysis. Calculated: 
C, 41.92; H, 3.25; N, 7.52. Found: C, 42.02; H, 3.31; N, 7.53. 
EXAMPLE 5 
##STR21## 
2-[2-(4-Morpholinyl)ethyl]-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 
1,1-dioxide Hydrochloride 
Step A: 
2-(2-Bromoethyl)-6-chloro-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiaz 
ine 1,1-dioxide 
To a solution of 
6-chloro-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide 
(2.0 g, 8.37 mmol) in DMF (50 mL) was added sodium hydride (0.37 g, 9.2 
mmol), after stirring for 30 min 1,2-dibromoethane (2.36 g, 16.7 mmol) was 
added and this mixture was stirred at room temperature for 72 hr. The 
reaction mixture was poured into water and the aqueous mixture was 
extracted with ether. The combined extracts were dried (MgSO.sub.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 
To a solution of the product from Step A (0.76 g, 2.20 mmol) in 
tetrahydrofuran (30 mL) containing triethylamine (0.56 g, 5.5 mmol) was 
added methanesulfonic anhydride (0.75 g, 4.3 mmol); this mixture was 
stirred at room temperature for 1 hr and evaporated to dryness. The 
residue was dissolved in DMF (30 mL), triethylamine (1 mL) was added and 
the mixture heated at 150.degree. C. for 45 min. Morpholine (3 mL, 34 
mmol) was added to the reaction mixture and heating continued at the same 
temperature for 1 hr followed by heating at 100.degree. C. for an 
additional hour. The volatiles were evaporated and the residue mixed with 
ethyl acetate; this mixture was washed with saturated aqueous sodium 
bicarbonate, dried (MgSO.sub.4) and evaporated to an oil which was 
purified by column chromatography (silica, 50% ethyl acetate/hexane to 
ethyl acetate) to give a viscous oil (0.42 g, 58%) which was used in the 
next step. 
Step C: 
2-[2-(4-Morpholinyl)ethyl]-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 
1,1-dioxide hydrochloride 
The product from Step B (1.00 g, 2.99 mmol) was dissolved in dry THF (30 
mL) and cooled to -65.degree. C. under nitrogen. n-Butyllithium (1.44 mL 
of a 2.5M solution in hexanes, 3.59 mmol) was added dropwise and the 
mixture stirred for 20 min during which time the temperature was allowed 
to increase to -45.degree. C. The reaction mixture was cooled to 
-70.degree. C. and sulfur dioxide was introduced into the flask for 5 min 
and the mixture was allowed to warm to room temperature. Evaporation of 
the reaction mixture provided a residue which was dissolved in water to 
which was added sodium acetate trihydrate (1.63 g, 12 mmol); this solution 
was cooled to 0.degree. C. and hydroxylamine-O-sulfonic acid (0.676 g, 
5.98 mmol) was added followed by stirring for 18 hr. The reaction mixture 
was extracted with ethyl acetate. The combined extracts were dried 
(MgSO.sub.4) and evaporated to a crude oil which was purified by column 
chromatography (silica, 5% methanol/methylene chloride) to give a viscous 
oil (0.115 g). This oil was dissolved in ethyl acetate (2 mL) and treated 
with ethanolic hydrogen chloride (2 mL). The suspension which formed was 
evaporated to a solid which was triturated with ethyl acetate, filtered 
and dried (vacuum) to give the desired product (105 mg, 17%): mp 
234.degree.-236.degree. C. Analysis. Calculated for C.sub.12 H.sub.18 
ClN.sub.3 O.sub.5 S.sub.3 : C, 34.65; H, 4.36; N, 10.10. Found: C, 34.69; 
H, 4.41; N, 10.04. 
EXAMPLE 6 
##STR22## 
2-Methyl-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamid 
e 1,1-dioxide hydrochloride 
Step A: N-[[3-(1,3-dioxolan-2-yl)-2-thienyl]sulfonyl]-N-methyl-glycine 
Ethyl Ester 
To a solution of thiophene-3-carboxaldehyde ethylene acetal (5.82 g, 37.3 
mmol) in anhydrous THF (50 mL) at -70.degree. C. was added 2.5M 
n-butyllithium (16.4 mL, 41 mmol) over 10 min. The solution was stirred at 
-50.degree. C. for 10 min, cooled to -70.degree. C. for 30 min and sulfur 
dioxide was passed over the reaction mixture for 5 min. The mixture was 
allowed to warm to ambient temperature, the volatiles were evaporated and 
methylene chloride (200 mL) was added. The suspension was cooled (ice 
bath) and N-chlorosuccinimide (6.47 g, 48.5 mmol) was added. This mixture 
was stirred at ambient temperature for 2 h, filtered and the filter pad 
was washed with ethyl acetate (200 mL). The combined filtrates were added 
to a solution of sarcosine ethyl ester hydrochloride (15.0 g, 97.6 mmol) 
in saturated aqueous sodium bicarbonate (100 mL) and the mixture stirred 
for 4 h at ambient temperature. After the organic layer was separated, the 
aqueous layer was extracted with ethyl acetate (2.times.100 mL), the 
combined extracts were dried (MgSO.sub.4) and evaporated to dryness. 
Purification by column chromatography (silica, 30 to 50% ethyl 
acetate/hexane) gave an oil (8.95 g, 72%). 
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. Water (0.5 mL) was added and this mixture was 
stirred for 4 h followed by addition of a saturated aqueous solution of 
sodium bicarbonate (50 mL) and evaporation of the acetone. The aqueous 
mixture was extracted with ethyl acetate (2.times.200 mL) and the combined 
extracts were dried (MgSO.sub.4) and evaporated to give crude aldehyde 
which was dissolved in ethyl acetate (150 mL). DBN (0.5 g) was added and 
the mixture heated at reflux temperature for 2 h, cooled and washed with a 
saturated aqueous solution of sodium bicarbonate (50 mL). The ethyl 
acetate solution was dried (MgSO.sub.4) and evaporated to a residue which 
was purified by column chromatography (silica, 30 to 50% ethyl 
acetate/hexane) to give the desired product as a white solid (5.05 g, 
70%). 
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.degree. C. was added DIBAL (1.0M, 7.69 mL, 7.69 mmol). 
The mixture was warmed to ambient temperature and stirred for 2 h, 
additional DIBAL (20 mmol) was added and the reaction was stirred for 18 
h. Methanol (100 mL) was added and the reaction mixture was evaporated to 
a residue which was suspended in 2N HCl (50 mL) and extracted with ethyl 
acetate (2.times.80 ml). The combined extracts were dried (MgSO.sub.4) and 
evaporated to give a solid which was recrystallized from ethyl 
acetate/hexane to give the desired product (0.80 g, 95%): mp 
128.degree.-130.degree. C. 
Step D: 2-Methyl-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazine 
To 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. After 30 min morpholine (2 mL) was added and the mixture stirred 
for 1 h at ambient temperature and then heated at reflux temperature for 1 
h. The volatiles were evaporated and a saturated aqueous solution of 
sodium bicarbonate (80 mL) was added. This mixture was extracted with 
ethyl acetate (2.times.100 mL) and the combined extracts were dried 
(MgSO.sub.4) and evaporated to give a viscous oil which was purified by 
column chromatography (silica, 30 to 50% ethyl acetate/hexane) to give a 
white solid (0.82 g, 84%): mp 104.degree.-106.degree. C. 
Step E: 
2-Methyl-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonami 
de 1,1-dioxide Hydrochloride 
To a mixture of the product from Step D (0.30 g, 1.04 mmol) in anhydrous 
THF (30 mL) under nitrogen at -65.degree. C. was added 2.5N n-butyllithium 
(0.63 mL, 1.56 mmol) over 5 min. The mixture was stirred at -50.degree. C. 
for 10 min and at -65.degree. 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. Ice water (50 mL) and a 
saturated aqueous solution of sodium bicarbonate (50 mL) were added and 
this mixture was extracted with ethyl acetate (100 mL). 
Hydroxylamine-O-sulfonic acid (0.294 g, 2.60 mmol) was added to the 
aqueous mixture and stirring continued for 3 h. The mixture was extracted 
with ethyl acetate (2.times.100 mL) and the combined extracts were dried 
(MgSO.sub.4) and evaporated to give the free base (0.098 g, 26%) which was 
converted to the hydrochloride salt by treatment with 1.5N HCl in ethanol: 
mp 231.degree.-233.degree. C. Analysis: Calculated for C.sub.12 H.sub.18 
ClN.sub.3 O.sub.5 S.sub.3 -0.5 H.sub.2 O: C, 33.91; H, 4.51; N, 9.89. 
Found: C, 33.95; H. 4.58; N, 9.75. 
EXAMPLE 7 
##STR23## 
2-[2-[Bis(2-methoxyethyl)amino]ethyl]-2H-thieno[3,2-e]-1,2-thiazine-6-sulfo 
namide 1,1-dioxide Hydrochloride 
Step A: 
2-[2-(Acetyloxy)ethyl]-3,4-dihydro-4-hydroxy-N-(1,1-dimethyl)ethyl-2H-thie 
no[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide 
To a solution of the product of Example 1, Step F (3.00 g, 8.82 mmol) in 
anhydrous DMF (50 mL) at ambient temperature under nitrogen was added 
sodium hydride (60% dispersion in mineral oil, 0.424 g, 10.59 mmol). The 
mixture was stirred for 20 min, cooled (ice bath) and 2-bromoethyl acetate 
(2.21 g, 13.2 mmol) was added. Stirring continued at this temperature for 
2 h followed by warming the reaction mixture to ambient temperature and 
stirring at this temperature for 18 h. The mixture was poured into an 
ice/sodium bicarbonate mixture (100 mL) and extracted with ethyl acetate 
(2.times.200 mL). The combined extracts were dried (MgSO.sub.4) and 
evaporated to a residue which was purified by column chromatography 
(silica, 50% ethyl acetate/hexane) to give a foamy residue (3.36 g, 89%). 
Step B: 
2-(2-Hydroxyethyl)-N-(1,1-dimethylethyl)-2H-thieno[3,2-e]-1,2-thiazine-6-s 
ulfonamide 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.degree. C. (bath temperature) for 20 
min and evaporated to dryness. Methanol (50 mL) and 2N 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.times.100 mL). The combined extracts were dried 
(MgSO.sub.4) and evaporated to give the desired product as an oil (2.78 g, 
96%). 
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 
To a solution of the product of 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) under nitrogen. This mixture 
was stirred at ambient temperature for 30 min followed by evaporation to a 
residue which was dissolved in ethyl acetate (80 mL) and washed with a 
saturated aqueous solution of sodium bicarbonate (50 mL). The organic 
phase was dried (MgSO.sub.4) and evaporated to give a solid (1.06 g) which 
was dissolved in anhydrous DMF (50 mL) and bis-(2-methoxyethyl)amine (5 
mL) was added and the mixture heated at reflux temperature for 1 h, cooled 
and poured into a saturated solution of sodium bicarbonate (100 mL). The 
solution was extracted with ethyl acetate (2.times.100 mL) and the 
combined extracts were dried (MgSO.sub.4) and evaporated to give a crude 
oil which was purified by column chromatography (silica, 50 to 100% ethyl 
acetate/hexane) to give a viscous oil (0.89 g, 66%). 
Step D: 
2-[2-[Bis(2-methoxyethyl)]amino]ethyl]-2H-thieno[3,2-e]-1,2-thiazine-6-sul 
fonamide 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. Evaporation gave a residue which was mixed 
with a saturated aqueous solution of sodium bicarbonate (50 mL) and 
extracted with ethyl acetate (2.times.80 mL). The combined extracts were 
dried (MgSO.sub.4) and evaporated to a residue which was purified by 
column chromatography (silica, 3 to 5% methanol/methylene chloride) to 
give an oil (0.74 g) which was converted to the hydrochloride salt by 
treatment with 2N HCl in ethanol (0.63 g, 79%): mp 60.degree.-65.degree. 
C. Analysis. Calculated for C.sub.14 H.sub.24 ClN.sub.3 O.sub.3 : C, 
36.39; H, 5.24; N, 9.10. Found: C, 36.46; H, 5.28; N, 9.01. 
EXAMPLE 8 
##STR24## 
2-[2-(Propylamino)ethyl]-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 
1,1-dioxide Hydrochloride 
Step A: 
2-[2-(Propylamino)ethyl]-N-(1,1-dimethylethyl)-2H-thieno[3,2-e]-1,2-thiazi 
ne-6-sulfonamide 1,1-dioxide 
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. The volatiles were evaporated after 30 min and the residue 
dissolved in ethyl acetate (80 mL). This mixture was washed with a 
saturated aqueous solution of sodium bicarbonate (50 mL), dried 
(MgSO.sub.4) and evaporated to give a solid. The solid (1.55 g from two 
batches) was dissolved in a mixture of anhydrous DMF (40 mL) and 
1-propylamine (6 mL) and heated at reflux temperature for 1 h followed by 
evaporation to a residue which was added to a saturated aqueous solution 
of sodium bicarbonate (100 mL). This mixture was extracted with ethyl 
acetate (2.times.100 mL) and the combined extracts were dried (MgSO.sub.4) 
and evaporated to an oil which was purified by column chromatography 
(silica, 6% methanol/methylene chloride) to give a viscous oil (1.17 g, 
84%). 
Step B: 
2-[2-(Propylamino)ethyl]-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-d 
ioxide Hydrochloride 
The product from Step A (0.37 g, 0.90 mmol) was dissolved in 
trifluoroacetic acid (5 mL) and the solution was stirred at ambient 
temperature for 18 h. Evaporation gave a residue which was mixed with a 
saturated aqueous solution of sodium bicarbonate (50 mL) and this mixture 
was extracted with ethyl acetate (2.times.80 mL). The combined extracts 
were dried (MgSO.sub.4) and evaporated to a residue which was purified by 
column chromatography (silica, 10% methanol/methylene chloride) to give an 
oil (0.19 g). Treatment with 1.5N HCl in ethanol gave the hydrochloride 
salt (0.18 g, 50%): mp 208.degree.-210.degree. C. Analysis. Calculated for 
C.sub.11 H.sub.18 ClN.sub.3 O.sub.4 S.sub.3 : C, 34.06; H, 4.68; N, 10.83. 
Found: C, 34.13; H, 4.67; N, 10.78. 
EXAMPLE 9 
##STR25## 
2-[2-[4-Acetyl-(1-piperazinyl)]ethyl]-2H-thieno[3,2-e]-1, 
2-thiazine-6-sulfonamide 1,1-dioxide 
Step A: 
2-[2-[4-Acetyl-(1-piperazinyl)]ethyl]-N-(1,1-dimethyl)ethyl-2H-thieno[3,2- 
e]-1,2-thiazine-6-sulfonamide 1,1-dioxide 
To a solution of Example 7, Step B (2.78 g, 7.60 mmol) and triethylamine 
(2.30 g, 22.8 mmol) in anhydrous THF (50 mL) was added methanesulfonic 
anhydride (2.17 g, 11.4 mmol); this mixture was stirred at ambient 
temperature for 30 min followed by evaporation to give a residue which was 
dissolved in EtOAc (200 mL); this solution was washed with a saturated 
aqueous solution of sodium bicarbonate (80 mL), dried (MgSO.sub.4) and 
evaporated to give a solid (3.45 g). A portion of this solid (1.70 g) was 
dissolved in anhydrous DMF (50 mL), 1-acetylpiperazine (2.40 g, 18.7 mmol) 
was added and the mixture was heated at reflux temperature for 1 h, 
cooled, poured into ice water (150 mL) and this mixture was extracted with 
ethyl acetate (2.times.100 mL). The combined extracts were dried 
(MgSO.sub.4) and evaporated to a residue which was purified by column 
chromatography (silica, ethyl acetate to 10% methanol/ethyl acetate) to 
give a viscous oil (1.30 g, 73%) which solidified upon standing: mp 
135.degree.-138.degree. C. 
Step B: 
2-[2-[4-Acetyl-(1-piperazinyl)]ethyl]-2H-thieno[3,2-e]-1,2-thiazine-6-sulf 
onamide 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.times.100 mL). The combined extracts were dried (MgSO.sub.4) and 
evaporated to a residue that was purified by column chromatography 
(silica, ethyl acetate to 10% ethanol/ethyl acetate) to give a solid which 
was recrystallized from methanol/methylene chloride to give the desired 
product (0.59 g, 52%): mp 180.degree.-183.degree. C. Analysis. Calculated 
for C.sub.14 H.sub.20 N.sub.4 O.sub.5 S.sub.3 : C, 39.98; H, 4.79; N, 
13.32. Found: C, 40.02; H, 4.78; N, 13.23. 
EXAMPLE 10 
##STR26## 
2-(3-Methoxypropyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazine-6 
-sulfonamide 1,1-dioxide Hydrochloride 
Step A: N-[[3-(1,3-Dioxolan-2-yl)-2-thienyl]sulfonyl]-glycine Ethyl Ester 
A solution of 3-(1,3-dioxolan-2-yl)-thiophene-2-sulfonyl chloride, prepared 
from thiophene-3-carboxaldehyde ethylene acetal (13.27 g, 85.1 mmol) as 
described in Example 6, Step A, was combined with glycine ethyl ester 
hydrochloride (33.99 g, 221 mmol) and a saturated aqueous solution of 
sodium bicarbonate (250 mL). After stirring for 18 hr at ambient 
temperature, the organic layer was separated, dried (MgSO.sub.4) and 
evaporated to a residue which was purified by column chromatography 
(silica, 40% ethyl acetate/hexane) to give an oil (16.55 g, 61%). 
Step B: Ethyl 
2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-3-carboxylate 
1,1-dioxide 
A solution of potassium t-butoxide in t-butanol (1M, 15.7 mL, 15.7 mmol) 
was added to a solution of the product of Step A (4.80 g, 14.95 mmol) in 
anhydrous DMF (50 mL) at 0.degree. C. followed by 1-bromo-3-methoxypropane 
(3.43 g, 22.4 mmol) and sodium iodide (0.2 g). The mixture was stirred for 
5 h at ambient temperature, poured into ice water (300 mL) and extracted 
with ethyl acetate (2.times.200 mL). The combined extracts were dried 
(MgSO.sub.4), filtered and evaporated to give a viscous liquid which was 
dissolved in acetone (300 mL); p-toluenesulfonic acid (0.4 g) was added 
and this mixture was heated at reflux temperature for 4.5 h. A saturated 
aqueous solution of sodium bicarbonate (100 mL) was added to the reaction 
mixture and acetone was evaporated. The aqueous mixture was extracted with 
ethyl acetate (2.times.200 mL) and the combined extracts were dried 
(MgSO.sub.4), filtered and evaporated to give crude aldehyde which was 
dissolved in ethyl acetate (100 mL). DBN (0.2 g) was added and the mixture 
heated at reflux temperature for 2 h under nitrogen. The mixture was 
cooled, quenched with a 2N HCl (50 mL) and extracted with ethyl acetate 
(2.times.150 mL). The combined extracts were dried (MgSO.sub.4) and 
evaporated to a syrup which was purified by column chromatography (silica, 
30% ethyl acetate/hexane) to give a white solid (2.68 g, 54%): mp 
82.degree.-83.degree. C. 
Step C: 2-(3-Methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-3-methanol 
1,1-dioxide 
To a solution of the product from Step B (3.70 g, 11.18 mmol) in anhydrous 
THF (50 mL) at ambient temperature under nitrogen was added DIBAL (50 mL 
of a 1.0 M solution, 50.0 mmol). After stirring for 4 h the reaction 
mixture was cooled (ice bath) and 2N HCl (100 mL) was added over a 10 min 
period. THF was evaporated and the aqueous mixture was extracted with 
ethyl acetate (2.times.100 mL). The combined extracts were dried 
(MgSO.sub.4), filtered and evaporated to give a viscous oil (3.23 g), 
which was used in the next step without further purification. 
Step D: 
2-(3-Methoxypropyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazine- 
1,1-dioxide 
To a solution of the product from Step C (1.30 g, 4.50 mmol) and 
triethylamine (1.36 g, 13.5 mmol) in anhydrous THF (30 mL) at ambient 
temperature was added methanesulfonic anhydride (1.18 g, 6.75 mmol). After 
stirring for 30 min, morpholine (5 mL) was added; this mixture was stirred 
at ambient temperature for 18 h and then heated at reflux for 1 h. The 
volatiles were evaporated and a saturated aqueous solution of sodium 
bicarbonate (100 mL) was added. The mixture was extracted with ethyl 
acetate (2.times.100 mL) and the combined extracts were dried (MgSO.sub.4) 
and evaporated to give a viscous oil which was purified by column 
chromatography (silica, 30 to 50% ethyl acetate/hexane) to give a viscous 
oil (1.51 g, 94%). 
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 2.5M 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.degree. 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. A saturated aqueous solution of sodium 
bicarbonate (150 mL) was added to the residue and this mixture was 
extracted with ethyl acetate (100 mL). The aqueous mixture was cooled (ice 
bath) and hydroxylamine-O-sulfonic acid (1.42 g, 12.6 mmol) was added; 
this mixture was stirred for 15 h and extracted with ethyl acetate 
(2.times.100 mL). The combined extracts were dried (MgSO.sub.4) and 
evaporated to a residue which was purified by column chromatography 
(silica, 80 to 100% ethyl acetate/hexane) to give an oil (0.81 g) which 
was dissolved in ethyl acetate, treated with 1.5M HCl/EtOH (1 mL) and 
evaporated to give the hydrochloride salt (0.69 g, 35%): mp 
145.degree.-149.degree. C. Analysis. Calculated for C.sub.15 H.sub.24 
ClN.sub.3 O.sub.6 S.sub.3 : C, 38.00; H, 5.10; N, 8.86. Found: C, 37.90; 
H, 5.15; N, 8.78. 
By following the above procedure but using instead n-propylbromide, 
i-butylbromide or cyclopropylmethylbromide in Step B the following 
compounds were prepared: 
1. 
3-(4-Morpholinylmethyl)-2-propyl-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonami 
de 1,1-dioxide hydrochloride, mp 233.degree. C. 
2. 
2-(2-Methylpropyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazine-6 
-sulfonamide 1,1-dioxide, mp 180.degree.-181.degree. C. 
3. 
2-(Cyclopropylmethyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazin 
e-6-sulfonamide 1,1-dioxide hydrochloride, mp 110.degree. C. 
By following the above procedure but using the appropriate alkylbromide 
instead of 1-bromo-3-methoxypropane in Step B the following compounds were 
prepared: 
4. 
3-(4-Morpholinylmethyl)-2-(2-propenyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sul 
fonamide 1,1-dioxide, mp 136.degree.-138.degree. C. 
5. 
2-Ethyl-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamid 
e 1,1-dioxide hydrochloride, mp 239.degree.-241 .degree. C. 
By following the above procedure but using propylbromide in Step B and 
propargylamine in Step D the following compound was prepared: 
6. 
2-Propyl-3-[(2-propynylamino)methyl]-2H-thieno[3,2-e]-1,2-thiazine-6-sulfo 
namide 1,1-dioxide, mp 136.degree.-138.degree. C. 
EXAMPLE 11 
##STR27## 
3-[[Bis(2-methoxyethyl)amino]methyl]-2-(4-methoxyphenylmethyl)-2H-thieno[3, 
2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide 
Step A: 
N-[[3-(1,3-Dioxolan-2-yl)-2-thienyl]sulfonyl]-N-(4-methoxyphenylmethyl) 
glycine Ethyl Ester 
To a solution of the product from Example 10, Step A (2.80 g, 8.72 mmol) in 
anhydrous DMF (40 mL) at 0.degree. C. was added a solution of potassium 
t-butoxide in t-butanol (1M, 9.16 mL, 9.16 mmol) followed by 
4-methoxybenzyl chloride (1.78 g, 11.34 mmol). The solution was stirred at 
ambient temperature for 4 h, poured into 2N HCl (50 mL), diluted with 
water (150 mL) and extracted with ethyl acetate (2.times.120 mL). The 
combined extracts were dried (MgSO.sub.4), filtered and evaporated to give 
a viscous oil (3.91 g) which was used in the next step. 
Step B: Ethyl 
2-(4-methoxyphenylmethyl)-2H-thieno[3,2-e]-1,2-thiazine-3-carboxylate 
1,1-dioxide 
A mixture of the product from Step A (3.91 g) and p-toluenesulfonic acid 
(0.2 g) in acetone (150 mL) was heated at reflux temperature for 3 h, 
cooled and a saturated solution of sodium bicarbonate (50 mL) was added 
and acetone evaporated. The aqueous mixture was extracted with ethyl 
acetate (2.times.10 mL) and the combined extracts were dried (MgSO.sub.4) 
and filtered. DBU (0.3 g) was added to the filtrate and this mixture was 
heated at reflux temperature for 2 h, cooled and acidified by the addition 
of 1N HCl. The organic layer was separated, dried (MgSO.sub.4) and 
evaporated to a residue which was purified by column chromatography 
(silica, 30% ethyl acetate/hexane) to give a viscous oil (1.80 g, 55%). 
Step C: 
3-Hydroxymethyl-2-(4-methoxyphenylmethyl)-2H-thieno[3,2-e]-1,2-thiazine-3- 
methanol 1,1-dioxide 
To a solution of the product from Step B (1.80 g, 4.75 mmol) in anhydrous 
THF (40 mL) at ambient temperature was added DIBAL (1.0M, 11.87 mL, 11.87 
mmol) and the mixture was stirred for 1 h. Additional DIBAL (1M, 15 mL,15 
mmol) was added (TLC showed starting material remained) and the reaction 
mixture was stirred for 20 h, cooled (ice bath) and the reaction was 
quenched by the slow addition of 1N HCl (100 mL). THF was evaporated and 
the aqueous mixture was extracted with ethyl acetate (2.times.100 mL). The 
combined extracts were dried (MgSO.sub.4), filtered and evaporated to give 
an oil (1.60 g) which was used in the next step without further 
purification. 
Step D: 
3-[[Bis(2-methoxyethyl)amino]methyl]-2-(4-methoxyphenylmethyl)-2H-thieno[3 
,2-e]-1,2-thiazine 1,1-dioxide 
To 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). The mixture was 
stirred for 72 h, evaporated to dryness and the residue extracted with 
ethyl acetate (2.times.100 mL). The combined extracts were dried 
(MgSO.sub.4), filtered and evaporated to a residue which was purified by 
column chromatography (silica, 20-30% ethyl acetate/hexane) to give an oil 
(0.71 g) which solidified upon standing: mp 75.degree.-77.degree. C. 
Step E: 
3-[[Bis(2-methoxyethyl)amino]methyl]-2-(4-methoxyphenylmethyl)-2H-thieno[3 
,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide 
To a mixture of the product of Step D (1.08 g, 2.39 mmol) in anhydrous THF 
(40 mL) under nitrogen at -70.degree. C. was added n-butyllithium (2.5M, 
1.91 mL, 4.78 mmol) over 5 min. The mixture was stirred for 30 min and 
then sulfur dioxide was passed over the reaction mixture for about 5 min 
followed by allowing the reaction mixture to warm to ambient temperature, 
and finally the mixture was evaporated to dryness. A saturated aqueous 
solution of sodium bicarbonate (100 mL) was added to the residue; this 
mixture was cooled (ice bath) and hydroxylamine-O-sulfonic acid (1.00 g, 
8.84 g) was added. The mixture was stirred for 18 h at ambient temperature 
and extracted with ethyl acetate (2.times.100 mL). The combined extracts 
were dried (MgSO.sub.4) and evaporated to a residue which was purified by 
column chromatography (silica, first column 50% ethyl acetate/hexane; 
second column 5% methanol/methylene chloride) to give a solid which was 
triturated with methylene chloride/hexane, filtered and dried under vacuum 
at 65.degree. C. to give a solid (0.29 g, 23%): mp 104.degree.-105.degree. 
C. (dec). Analysis. Calculated for C.sub.21 H.sub.29 N.sub.3 O.sub.7 
S.sub.3 : C, 47.44; H, 5.50; N, 7.90. Found: C, 47.50; H, 5.49; N, 7.95. 
By using the procedure described above but using instead the appropriate 
alkylhalide in Step A the following compounds were prepared: 
1. 
3-[[Bis(2-methoxyethyl)amino]methyl]-2-ethyl-2H-thieno[3,2-e]-1,2-thiazine 
-6-sulfonamide 1,1-dioxide hydrochloride, mp 185.degree.-186.degree. C. 
2. 3-[[Bis 
(2-methoxyethyl)amino]methyl]-2-propyl-2H-thieno[3,2-e]-1,2-6-sulfonamide 
1,1-dioxide hydrochloride, mp 201.degree.-203.degree. C. 
3. 3-[Bis 
(2-methoxyethyl)amino]methyl]-2-(2-methoxyethyl)-2H-thieno[3,2-e]-1,2-thia 
zine-6-sulfonamide 1,1-dioxide hydrochloride, mp 200.degree.-202.degree. C. 
By using the procedure described above but using instead methyl iodide as 
the alkylhalide in Step A and 2-methoxyethyl(3-methoxypropyl)amine as the 
alkylamine in Step D the following compound was prepared: 
4. 
3-[[(2-methoxyethyl)(3-methoxypropyl)amino]methyl]-2-methyl-2H-thieno[3,2- 
e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride, mp 
173.degree.-175.degree. C. 
EXAMPLE 12 
##STR28## 
2-[4-(4-Morpholinyl)-2-butenyl]-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 
1,1-dioxide Hydrochloride 
Step A: 
3,4-Dihydro-4-hydroxy-N-(1,1-dimethylethyl)-2-[4-(4-morpholinyl)-2-butenyl 
]-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide 
Sodium hydride (60% dispersion in mineral oil, 0.113 g, 2.82 mmol) was 
added to a solution of the product from Example 1, Step F (0.80 g, 2.35 
mmol) in anhydrous DMF (50 mL) under nitrogen. After 20 min, the reaction 
mixture was cooled (ice bath), 1,4-dibromo-2-butene (0.754 g, 3.53 mmol) 
was added and the mixture stirred for 2 h. Morpholine (5 mL) was added and 
the reaction mixture was stirred at ambient temperature for 18 h. DMF was 
evaporated under reduced pressure and the residue was mixed with a 
saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl 
acetate (2.times.100 mL). The combined extracts were dried (MgSO.sub.4), 
filtered and evaporated to dryness. Chromatography on silica (ethyl 
acetate) gave the desired product as a viscous oil (0.65 g, 58%). 
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 
To a solution of the product from Step A (0.64 g, 1.34 mmol) in anhydrous 
THF (30 mL) under nitrogen were added methanesulfonic anhydride (0.349 g, 
2.00 mmol) and 2,6-lutidine (0.431 g, 4.02 mmol). After 30 min, an 
additional quantity of methanesulfonic anhydride (0.349 g, 2.00 mmol) and 
2,6-lutidine (0.431 g, 4.02 mmol) was added and the reaction continued for 
30 min. Evaporation of the solvent provided a residue which was dissolved 
in anhydrous DMF (50 mL) and DBN (1 mL) was added. This mixture was heated 
at reflux temperature for 1 h, cooled, poured into a saturated solution of 
sodium bicarbonate (100 mL) and extracted with ethyl acetate (2.times.100 
mL). The combined extracts were dried over (MgSO.sub.4), filtered and 
evaporated to a residue which was purified by column chromatography 
(silica, 5% methanol/methylene chloride) to give a viscous oil (0.35 g, 
57%). 
Step C: 
2-[4-(4-Morpholinyl)-2-butenyl]-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamid 
e 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. The residue was mixed with a saturated solution of sodium 
bicarbonate (50 mL) and this mixture was extracted with ethyl acetate 
(2.times.80 mL). The combined extracts were dried (MgSO.sub.4) and 
evaporated to a residue which was purified by column chromatography 
(silica, 6% methanol/methylene chloride to give a viscous oil (0.21 g, 
68%). The free base was converted to the hydrochloride salt by treating a 
methanol solution (5 mL) of the free base with 2N HCl/ethanol. The residue 
was dissolved in methanol and evaporated under high vacuum at 65.degree. 
C. to give 0.152 g of a powder (50%): mp 108.degree.-112.degree. C. 
Analysis. Calculated for C.sub.12 H.sub.20 ClN.sub.3 O.sub.5 S.sub.3 -0.5 
H.sub.2 O: C, 37.28; H, 4.69: N, 9.31. Found: C, 37.35; H, 4.68; N, 9.25. 
EXAMPLE 13 
##STR29## 
2-(4-Methoxyphenylmethyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1, 2- 
thiazine-6-sulfonamide 1,1-dioxide Hydrochloride 
Step A: 
2-(4-Methoxyphenylmethyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thi 
azine 1,1-dioxide 
Methanesulfonic anhydride (1.24 g, 7.13 mmol) was added to a solution of 
the product of Example 11, Step C (1.3 g, 3.86 mmol) and triethylamine 
(1.17 g, 11.6 mmol) in anhydrous THF (50 mL) at ambient temperature. After 
stirring for 1 h, morpholine (3 mL) was added and the reaction mixture was 
heated at reflux temperature for 1 h followed by removal of solvent. A 
saturated aqueous solution of sodium bicarbonate was added and the mixture 
was extracted with ethyl acetate (2.times.100 mL). The combined extracts 
were dried (MgSO.sub.4) and evaporated to an oil which was purified by 
column chromatography (silica, 30% to 60% ethyl acetate/hexane) to give a 
solid (1.39 g, 88%): mp 112.degree.-114.degree. C. 
Step B: 
2-(4-Methoxyphenylmethyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thi 
azine-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). Treatment of this oil with 2N HCl in ethanol provided the 
hydrochloride salt (0.342 g, 20%): mp 212.degree.-214.degree. C. Analysis. 
Calculated for C.sub.19 H.sub.24 ClN.sub.3 O.sub.6 S.sub.3 ; C, 43.71; H, 
4.63; N, 8.05. Found: C, 43.88; H, 4.73; N, 7.97. 
EXAMPLE 14 
##STR30## 
3-[[Bis(2-methoxyethyl)amino]methyl]-2-(4-methoxyphenyl)-2H-thieno[3,2-e]-1 
,2-thiazine-6-sulfonamide 1,1-dioxide 
Step A: 3-(1,3-Dioxolan-2-yl)-N-(4-methoxyphenyl)-thiophene-2-sulfonamide 
A solution of 3-(1,3-dioxolan-2-yl)-thiophene-2-sulfonyl chloride (11.16 
g), prepared from thiophene-3-carboxaldehyde ethylene acetal as described 
in Example 6, Step A, in THF (100 mL) at 0.degree. C. was combined with 
p-anisidine (7.87 g, 63.9 mmol) and triethylamine (4.04 g, 40 mmol). After 
stirring for 4 hr at ambient temperature, the mixture was evaporated to a 
residue which was extracted with ethyl acetate (2.times.150 mL). The 
combined extracts were dried (MgSO.sub.4) and evaporated to a residue 
which was purified by column chromatography (silica, 40% ethyl 
acetate/hexane) to give an oil (10.21 g, 75%). 
Step B: N-[(3-formyl-2-thienyl)sulfonyl]-N-(4-methoxyphenyl)-glycine Methyl 
Ester 
To a solution of the product of Step A (10.21 g, 29.9 mmol) in anhydrous 
THF (100 mL) and DMF (15 mL) at 0.degree. C. was added sodium hydride (60% 
dispersion in mineral oil, 1.32 g, 32.9 mmol). After stirring for 30 min, 
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 bicarbonate (150 mL) and extracted with ethyl 
acetate (2.times.100 mL). The combined extracts was dried (MgSO.sub.4) and 
evaporated to give an oil which was dissolved in acetone (150 mL) and 
p-toluenesulfonic acid (2.5 g) was added. This solution was stirred at 
ambient temperature for 2 h, heated at reflux temperature for 5 h, cooled 
and mixed with water (100 mL) and sodium carbonate (1.0 g). Acetone was 
evaporated and the aqueous was extracted with ethyl acetate (2.times.100 
mL). The combined extracts were dried (MgSO.sub.4) and evaporated to a 
residue which was purified by column chromatography (silica, 40% ethyl 
acetate/hexane) to give an oil (3.67 g, 33%). 
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 2N HCl (50 
mL) and brine (50 mL), and dried (MgSO.sub.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 1M 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 1N HCl (100 mL). This 
mixture was extracted with ethyl acetate (2.times.100 mL) and the combined 
extracts were dried (MgSO.sub.4) and evaporated to a residue which was 
purified by column chromatography (silica, 50% ethyl acetate/hexane) to 
give a viscous oil (1.19 g, 41%). 
Step E: 
3-[[Bis(2-methoxyethyl)amino]methyl]-2-(4-methoxyphenyl)-2H-thieno[3,2-e]- 
1,2-thiazine 1,1-dioxide 
To 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. The reaction mixture was heated at reflux 
temperature for 1 h, cooled, poured into a saturated solution of sodium 
bicarbonate (100 mL) and this mixture was extracted with ethyl acetate 
(2.times.100 mL). The combined extracts were dried (MgSO.sub.4) and 
evaporated to a residue which was purified by column chromatography 
(silica, 40% ethyl acetate/hexane) to give a viscous oil (1.16 g, 72%). 
Step F: 
3-[[Bis(2-methoxyethyl)amino]methyl]-2-(4-methoxyphenyl)-2H-thieno[3,2-e]- 
1,2-thiazine-6-sulfonamide 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%): mp48.degree.-51.degree. C. Analysis. 
Calculated for C.sub.20 H.sub.27 N.sub.3 O.sub.7 S.sub.3 : C, 46.40; H, 
5.26; N, 8.11. Found: C, 46.34; H, 5.30; N, 8.04. 
By following the procedure described above but replacing para-anisidine 
with 4-(4-morpholinyl)-aniline in Step A, and further replacing 
bis(2-methoxyethyl)amine with morpholine in Step E the following compound 
was prepared: 
1. 
3-(4-Morpholinylmethyl)-2-[4-(4-morpholinyl)phenyl]-2H-thieno[3,2-e]-1,2-t 
hiazine-6-sulfonamide 1,1-dioxide hydrochloride, mp 230.degree.-235.degree. 
C. 
EXAMPLE 15 
##STR31## 
2-(1-Methylethyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazine-6-s 
ulfonamide 1,1-dioxide 
Step A: 3-(1,3-Dioxolan-2-yl)-N-(1-methylethyl)-2-thiophenesulfonamide 
By following the procedure described in Example 14, Step A, but using 
isopropylamine in place of para-anisidine the desired compound was 
obtained, following column chromatography (silica, 30% ethyl 
acetate/hexane), as a colorless oil (62%). 
Step B: 
N-[[3-(1,3-Dioxolan-2-yl)-2-thienyl]sulfonyl]-N-(1-methylethyl)-glycine 
Ethyl Ester 
To a solution of the product from Step A (25.0 g, 90.3 mmol) in anhydrous 
DMF (350 mL) at 0.degree. C. was added a 1M solution of potassium 
t-butyloxide in t-butanol (99.3 mL, 99.3 mmol) followed by ethyl 
bromoacetate (12.0 mL, 18.1 g, 108.4 mmol). The solution, which 
immediately turned cloudy, was maintained at 0.degree. C. for 18 h. The 
reaction mixture was poured into a saturated aqueous solution of sodium 
bicarbonate (600 mL) and this mixture was extracted with ether 
(3.times.300 mL). The combined extracts were dried (MgSO.sub.4) and 
evaporated to give an viscous oil (36.25 g) which was used in the next 
reaction without further purification. 
Step C: Ethyl 2-(1-methylethyl)-2H-thieno[3,2-e]-1,2-thiazine-3-carboxylate 
1,1-dioxide 
A solution of the product from Step B (36.25 g) and p-toluenesulfonic acid 
hydrate (2.0 g) in acetone (300 mL) was heated at reflux temperature for 6 
h, cooled and a saturated aqueous solution of sodium bicarbonate (100 mL) 
was added. Acetone was evaporated and the aqueous mixture was extracted 
with ether (2.times.100 mL). The combined extracts were dried (MgSO.sub.4) 
and evaporated to give a dark brown oil which was dissolved in ethyl 
acetate (200 mL). DBU (2 mL) was added to this solution and after 1 h the 
reaction mixture was washed with 2N HCl and brine, dried (MgSO.sub.4), and 
evaporated to give a solid which was recrystallized from 25% ethyl 
acetate/hexane to give 9.95 g of product. The mother liquor was 
chromatographed (silica, 25% ethyl acetate/hexane) to give an additional 
3.57 g of product (total 13.52 g, 50%): mp 97.degree.-99.degree. C. 
Step D: 2-(1-Methylethyl)-2H-thieno[3,2-e]-1,2-thiazine-3-methanol 
1,1-dioxide 
To a solution of the product from Step C (13.80 g, 45.85 mmol) in anhydrous 
THF (50 mL) at ambient temperature was added DIBAL (1.0M, 145 mL, 145 
mmol) under nitrogen. After stirring for 5 h, the reaction mixture was 
evaporated to dryness and mixed with ethyl acetate (200 mL), water was 
slowly added over 20 min. The mixture was acidified with 2N HCl and 
extracted with ethyl acetate (2.times.200 mL). The combined extracts were 
dried (MgSO.sub.4) and evaporated to a residue which was purified by 
column chromatography (silica, 40% ethyl acetate/hexane) to give a viscous 
oil. Crystallization from ethyl acetate/hexane gave the desired product 
(7.51 g, 63%): mp 67.degree.-69.degree. C. 
Step E: 
3-Hydroxymethyl-2-(1-methylethyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonam 
ide 1,1-dioxide 
To a solution of the product from Step D (3.25 g, 12.5 mmol) in anhydrous 
THF (60 mL) under nitrogen at -70.degree. C. was added n-butyllithium 
(2.5M, 12.5 mL, 31.4 mmol) over 5 min. 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.times.200 mL). The combined extracts were dried 
(MgSO.sub.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 
To a solution of the product from Step E (2.16 g, 6.39 mmol) and 
triethylamine (2.58 g, 25.6 mmol) in anhydrous THF (100 mL) at 0.degree. 
C. was added p-toluenesulfonyl chloride (2.44 g, 12.8 mmol) with stirring. 
After 1 h the reaction mixture was warmed to ambient temperature and 
maintained at this temperature for 4 h. Half of the reaction mixture was 
removed, cooled on an ice bath and morpholine (3 mL) was added with 
stirring. The reaction mixture was stirred for 18 h and evaporated to a 
residue which was mixed with ethyl acetate (200 mL); this solution was 
washed with a saturated solution of sodium bicarbonate (100 mL), dried 
(MgSO.sub.4), filtered and evaporated to a residue which was purified by 
colunmn chromatography (silica, 4% methanol/methylene chloride) to give a 
viscous oil which crystalized from methylene chloride/hexane to afford a 
yellowish solid (0.41 g, 32%): mp 196.degree.-198.degree. C. Analysis: 
Calculated for C.sub.14 H.sub.21 N.sub.3 O.sub.5 S.sub.3 : C, 41.26; H, 
5.19 N, 10.31. Found: C, 41.35; H, 5.10; N, 10.28. 
EXAMPLE 16 
##STR32## 
2-(1-Methylethyl)-3-[(2-propynylamino)methyl]-2H-thieno[3,2-e]-1,2-thiazine 
-6-sulfonamide 1,1-dioxide 
To a solution of the product from Example 15, Step E (1.40 g, 4.14 mmol) 
and triethylamine (1.26 g, 12.4 mmol) in anhydrous THF (80 mL) at 
0.degree. C. was added p-toluenesulfonyl chloride (1.18 g, 6.21 mmol) and 
the mixture was maintained at this temperature for 20 h. Propargylamine (3 
mL) was added to the reaction mixture which was stirred for an additional 
18 h. The reaction mixture was evaporated to a residue which was mixed 
with 2N HCl (60 mL) and this mixture was extracted with ethyl acetate 
(2.times.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.times.60 mL). The 
combined extracts were dried (MgSO.sub.4), filtered, and evaporated to a 
residue which was purified by column chromatography (silica, 50% to 75% 
ethyl acetate/hexane) to give an oil which crystallized from methylene 
chloride/hexane to provided an off-white solid (0.61 g, 39%): mp 
133.degree.-135.degree. C. Analysis: Calculated for C.sub.13 H.sub.17 
N.sub.3 O.sub.4 S.sub.3 : C, 41.58; H, 4.60; N, 11.11. Found: C, 41.42; H, 
4.60;0N, 11.11. 
EXAMPLE 17 
##STR33## 
2-(1-Methylethyl)-3-[[(2-methoxyethyl)(3-methoxypropyl)amino]methyl]-2H-thi 
eno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide Hydrochloride 
By following the procedure described in Example 16 but using 
(2-methoxyethyl)(3-methoxypropyl)amine instead of propargylamine, 
2-(1-methylethyl)-3-[[(2-methoxyethyl)(3-methoxypropyl)amino]methyl]-2H-th 
ieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide was obtained as an oil 
following purification by column chromatography (silica, column one: 3% to 
5% methanol/methylene chloride; column two: gradient, 60% ethyl 
acetate/hexane to ethyl acetate). Treatment of this oil with ethanolic 
hydrogen chloride provided the title compound as a white solid (26%): mp 
56.degree.-60.degree. C. Analysis: Calculated for C.sub.13 H.sub.17 
N.sub.3 O.sub.4 S.sub.3 -0.5H.sub.2 O: C, 39.79; H, 6.09; N, 8.19. Found: 
C, 39.50; H, 6.14; N, 8.12. 
EXAMPLE 18 
##STR34## 
2-(3-Methoxyphenyl)-3-[(2-propynylamino)methyl]-2H-thieno[3,2-e]-1,2-thiazi 
ne-6-sulfonamide 1,1-dioxide 
Step A: 3-(1,3-Dioxolan-2-yl)-N-(3-methoxyphenyl)-2-thiophenesulfonamide 
By following the procedure described in Example 14, Step A, but using 
meta-anisidine in place of para-anisidine the desired compound was 
obtained, following column chromatography (silica, 30% ethyl 
acetate/hexane), as a solid (62%): mp 112.degree.-114.degree. C. 
Step B: 
N-[[3-(1,3-Dioxolan-2-yl)-2-thienyl]sulfonyl]-N-(3-methoxyphenyl)glycine 
Ethyl Ester 
A solution of the product from Step A (10.0 g, 29.3 mmol) in anhydrous DMF 
(100 mL) was treated in a manner essentially analogous to that described 
in Example 15, Step B to give a viscous oil (12.52 g) which was used in 
the next step without further purification. 
Step C: Ethyl 
2-(3-methoxyphenyl)-2H-thieno[3,2-e]-1,2-thiazine-3-carboxylate 
1,1-dioxide 
A solution of the product from Step B (33.78 g) and p-toluenesulfonic acid 
hydrate (3.0 g) in acetone (300 mL) were treated in a manner essentially 
analogous to that described in Example 15, Step C to give a total of 13.41 
g (46%) of the desired product: mp 107.degree.-109.degree. C. 
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.degree.-143.degree. C. 
Step E: 
3-Hydroxymethyl-2-(3-methoxyphenyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfon 
amide 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.degree.-182.degree. C. 
Step F: 
2-(3-Methoxyphenyl)-3-[(2-propynylamino)methyl]-2H-thieno[3,2-e]-1,2-thiaz 
ine-6-sulfonamide 1,1-dioxide 
To a solution of the product from Step E (0.766 g, 1.89 mmol) and 
triethylamine (0.57 g, 5.67 mmol) in anhydrous THF (50 mL) at 0.degree. C. 
was added p-toluenesulfonyl chloride (0.54 g, 2.84 mmol). The reaction 
mixture was stirred for 18 h maintaining a temperature below 15.degree. C. 
Propargylamine (2 mL) was added and this mixture was stirred for 18 h, 
evaporation of the solvent provided a residue which was acidified to pH 1 
with 2N HCl and extracted with ethyl acetate (200 mL). The aqueous layer 
was separated, adjusted to pH 7.5 with a saturated aqueous solution of 
sodium bicarbonate (50 mL) and this mixture was extracted with ethyl 
acetate (2.times.80 mL). The combined extracts were dried (MgSO.sub.4) and 
evaporated to give a solid which was recrystallized from methylene 
chloride/hexane to give a cream colored solid (0.26 g, 31%): mp 
174.degree.-176.degree. C. Analysis: Calculated for C.sub.17 H.sub.17 
N.sub.3 O.sub.5 S.sub.3 -0.5H.sub.2 O: C, 45.52; H, 4.05; N, 9.36. Found: 
C, 45.53; H, 3.85; N, 9.12. 
By following the procedure described above but replacing propargylamine 
with morpholine in step F the following compound was prepared: 
1. 
2-(3-Methoxyphenyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazine- 
6-sulfonamide 1,1-dioxide hydrochloride mp 170.degree.-174.degree. C. 
By following the procedure described above but replacing meta-anisidine 
with the appropriate substituted aniline in Step A the following compounds 
were prepared: 
2. 
2-(3,4-Dimethoxyphenyl)-3-[(2-propynylamino)methyl]-2H-thieno[3,2-e]-1,2-t 
hiazine-6-sulfonamide 1,1-dioxide hydrochloride, mp 154.degree.-156.degree. 
C. 
3. 
2-(3,5-Dimethoxyphenyl)-3-[(2-propynylamino)methyl]-2H-thieno[3,2-e]-1,2-t 
hiazine-6-sulfonamide 1,1-dioxide hydrochloride, mp 236.degree.-237.degree. 
C. 
By following the procedure described above using 3,5-dimethoxyaniline in 
Step A and replacing propargylamine with-morpholine in Step F the 
following compound was prepared: 
4. 
2-(3,5-Dimethoxyphenyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiaz 
ine-6-sulfonamide 1,1-dioxide hydrochloride, mp 236.degree.-237.degree. C. 
EXAMPLE 19 
##STR35## 
2-(3-Hydroxyphenyl)-3-[(2-propynylamino)methyl]-2H-thieno[3,2-e]-1,2-thiazi 
ne-6-sulfonamide 1,1-dioxide Hydrochloride 
Step A: 
3-Chloromethyl-N-(1,1-dimethylethyl)-2-(3-methoxyphenyl)-2H-thieno[3,2-e]- 
1,2-thiazine-6-sulfonamide 1,1-dioxide 
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.degree. C. was added 
n-butyllithium (2.5M, 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. The 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.times.200 mL). The combined 
extracts were dried (MgSO.sub.4) and evaporated to give a residue which 
was purified by column chromatography (silica, 40% ethyl acetate/hexane) 
to give an oil (4.41 g, 62%): 
Step B: 
2-(3-Hydroxyphenyl)-3-[(2-propynylamino)methyl]-2H-thieno[3,2-e]-1,2-thiaz 
ine-6-sulfonamide 1,1-dioxide Hydrochloride 
To 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 mixture was 
stirred at ambient temperature for 30 min, heated at 80.degree. C. for 2 h 
and evaporated to dryness. The residue was mixed with a saturated aqueous 
solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate 
(2.times.100 mL). The combined extracts were dried (MgSO.sub.4) and 
evaporated to a residue which was purified by column chromatography 
(silica, 50 % ethyl acetate/hexane) to give a viscous oil (0.53 g, 51%). 
The oil was dissolved in methylene chloride (50 mL), cooled to 0.degree. 
C., and a 1M solution of BBr.sub.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.times.100 mL). The combined extracts 
were dried (MgSO.sub.4) and evaporated to an oil which was purified by 
column chromatography (silica, 70% ethyl acetate/hexane) to give an oil 
which was dissolved in ethyl acetate and treated with HCl/EtOH. After 
evaporating the solvent, the salt was recrystallized from 
ethanol/methylene chloride to give a yellowish solid (0.278 g, 57%): mp 
195.degree.-198.degree..degree. C. Analysis. Calculated. for C.sub.16 
H.sub.16 ClN.sub.3 O.sub.5 S.sub.3 : C, 41.60; H, 3.49; N, 9.09. Found: C, 
41.69; H, 3.51;N, 9.04. 
By following the procedure described above but replacing propargylamine 
with morpholine in Step B the following compound was prepared: 
1. 
2-(3-Hydroxyphenyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazine- 
6-sulfonamide 1,1-dioxide mp 220.degree.-222.degree. C. 
EXAMPLE 20 
##STR36## 
N-[[6-(Aminosulfonyl)-2-methyl-2H-thieno[3,2-e]-1,2-thiazin-3-yl]methyl]-N- 
methyl-glycine Ethyl Ester S.sup.1, S.sup.1 -dioxide 
Step A: 
3-Hydroxymethyl-2-methyl-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-d 
ioxide 
To a solution of the product from Example 6, Step C (3.20 g, 13.85 mmol) in 
anhydrous THF (50 mL) under nitrogen at -70.degree. C. was added 
n-butyllithium (2.5M, 12.74 mL, 31.86 mmol) via syringe over 3 min. The 
suspension was stirred for 10 min before a stream of sulfur dioxide was 
passed over the surface of the reaction mixture for about 5 min. The 
reaction mixture was warmed to ambient temperature and solvent was 
evaporated to give a residue which was mixed with ice-water (200 mL). 
Hydroxylamine-O-sulfonic acid (4.70 g, 41.6 mmol) and sodium acetate (7.53 
g, 55.4 mmol) were added and this aqueous mixture was stirred at ambient 
temperature for 16 h followed by extraction with ethyl acetate 
(2.times.200 mL). The combined extracts were dried (MgSO.sub.4) and 
evaporated to a solid which was recrystallized from ethyl acetate/hexane 
(3.55 g, 83%): mp 144.degree.-146.degree. C. 
Step B: 
N-[[6-(Aminosulfonyl)-2-methyl-2H-thieno[3,2-e]-1,2-thiazin-3-yl]methyl]-N 
-methyl-glycine Ethyl Ester S.sup.1, S.sup.1 -dioxide 
To a solution of the product from Step A (1.00 g, 3.23 mmol) and 
triethylamine (0.652 g, 6.45 mmol) in anhydrous THF (30 mL) at ambient 
temperature was added methanesulfonic anhydride (0.844 g, 4.85 mmol). 
After 30 min sacosine ethyl ester (freshly prepared from 3.00 g of the 
hydrochloride salt, 7.9 mmol) was added and the mixture stirred for 3 h, 
evaporated to dryness, mixed with a saturated aqueous solution of sodium 
bicarbonate (100 mL) and extracted with ethyl acetate (2.times.100 mL). 
The combined extracts were dried (MgSO.sub.4) and evaporated to a residue 
which was purified by column chromatography (silica, 50% ethyl 
acetate/hexane) to give an oil (0.94 g, 71%). The oil was dissolved in 
ethyl acetate (10 mL) and treated with 2N ethanolic HCl. The volatiles 
were evaporated and the residue was recrystallized from a water/methanol 
mixture to give a white solid which analyzed as the free base (0.396 g, 
30%): mp 106.degree.-108.degree. C. Analysis. Calculated for C.sub.13 
H.sub.19 N.sub.3 O.sub.6 S.sub.3 : C, 38.13; H, 4.68; N, 10.26. Found: C, 
38.16; H, 4.63; N, 10.31. 
EXAMPLE 21 
##STR37## 
N-[[6-(Aminosulfonyl)-2-methyl-2H-thieno[3,2-e]-1,2-thiazin-3-yl]methyl]-gl 
ycine 2-methylethyl Ester S.sup.1, S.sup.1 -dioxide Hydrochloride 
To a solution of the product from Example 20, Step A (1.00 g, 3.23 mmol) 
and triethylamine (0.65 g, 6.45 mmol) in anhydrous THF (30 mL) at ambient 
temperature was added methanesulfonic anhydride (0.843 g, 4.84 mmol). 
After 5 min glycine isopropyl ester (1.20 g, 10.3 mmol) was added and the 
mixture stirred for 2 h, evaporated to dryness, mixed with a saturated 
aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl 
acetate (2.times.100 mL). The combined extracts was washed with 2N HCl 
(2.times.50 mL). The aqueous was separated, adjusted to about pH 8 and 
extracted with ethyl acetate (2.times.80 mL). The combined extracts were 
dried (MgSO.sup.4) and evaporated to give an oil (0.51 g) which was 
dissolved in ethyl acetate (10 mL) and treated with 2N ethanolic HCl. 
Evaporation of the solvent provided a residue which was recrystallized 
from isopropanol to give a white solid (0.37 g, 26%): mp 
202.degree.-205.degree. C. Analysis calculated for C.sub.13 H.sub.19 
N.sub.3 O.sub.6 S.sub.3 -HCl-H.sub.2 O: C, 33.65; H, 4.78; N, 9.06. Found: 
C, 33.69; H, 4.76; N, 8.85. 
EXAMPLE 22 
##STR38## 
3-[[(2-methoxyethyl)methylamino]methyl]-2-methyl-2H-thieno[3,2-e]-1, 
2-thiazine-6-sulfonamide 1,1-dioxide 
To a stirred solution of the product from Example 20, Step A (0.80 g, 2.58 
mmol) and triethylamine (0.52 g, 5.16 mmol) in anhydrous THF (30 mL) was 
added methanesulfonic anhydride (0.674 g, 3.87 mmol) under nitrogen. After 
30 min the reaction mixture was cooled on an ice bath and 
(2-methoxyethyl)methylamine (1 mL) was added, warmed to ambient 
temperature and maintained at this temperature for 2 h followed by heating 
at reflux temperature for 10 min and evaporated to dryness. The residue 
was mixed with 2N HCl (50 mL) and extracted with ethyl acetate (100 mL) to 
remove unreacted starting material. The aqueous layer was separated, mixed 
with a saturated aqueous solution of sodium bicarbonate (150 mL) and 
extracted with ethyl acetate (2.times.100 mL). The combined extracts were 
dried (MgSO.sub.4) and evaporated to dryness. Column chromatography on 
silica (4% methanol/methylene chloride) gave a viscous oil which was 
recrystallized from ethyl acetate/chlorobutane to give a yellowish solid 
(0.635 g, 66%): mp 127.degree.-129.degree. C. Analysis. Calculated for 
C.sub.12 H.sub.19 N.sub.3 O.sub.5 S.sub.3 : C, 37.78; H, 5.02; N, 11.01. 
Found: C, 37.77; H, 4.99; N, 10.98. 
EXAMPLE 23 
##STR39## 
3-[(Acetyloxy)methyl]-2-[2-(4-morpholinyl)ethyl]-2H-thieno[3,2-e]-1,2-thiaz 
ine-6-sulfonamide 1,1-dioxide Hydrochloride 
Step A: 3-(2-Dioxolanyl)-N-[2-(4-morpholinyl)]ethyl]-2-thiophenesulfonamide 
To a solution of thiophene-3-carboxaldehyde ethylene acetal (10.0 g, 64.1 
mmol) in anhydrous THF (200 mL) at -70.degree. C. was added n-butyllithium 
(2.5M, 28.2 mL, 70.5 mmol) over 10 min with stirring under nitrogen. The 
solution was stirred at -50.degree. C. for 10 min and -70.degree. C. for 1 
h. Sulfur dioxide gas was passed over the reaction mixture for about 10 
min followed by warming to room temperature and then evaporating to 
dryness. The residue was mixed with methylene chloride (200 mL) and 
N-chlorosuccinimide (11.13 g, 83.3 mmol) was added to the suspension. 
After 2 h, the mixture was filtered through a celite pad. The filtrate was 
cooled (ice bath) and 2-(4-morpholinyl)ethylamine (11.6 g, 89.1 mmol) and 
a saturated aqueous solution of sodium bicarbonate (100 mL) were added. 
The mixture was stirred at room temperature for 2 h and the organic layer 
was separated, washed with brine, dried over magnesium sulfate and 
evaporated to give a crude oil. Chromatography on silica (50% ethyl 
acetate/hexane) gave a viscous oil (20.15 g, 90%). 
Step B: N-[(3-Formyl-2-thienyl)sulfonyl]-N-[2-(4-morpholinyl)ethyl]-glycine 
Methyl Ester 
To a solution of the product from Step A (6.34 g, 18.2 mmol) in anhydrous 
DMF (40 mL) at ambient temperature was added sodium hydride (60% 
dispersion in mineral oil, 0.80 g, 20.0 mmol) with stirring under 
nitrogen. After 20 min, methyl 2-bromoacetate (3.62 g, 23.7 mmol) was 
added and the resulting mixture was stirred at ambient temperature for 40 
min; a 2N HCl aqueous solution (50 mL) was added and the mixture was 
stirred overnight. The reaction mixture was poured into a saturated 
aqueous solution of sodium bicarbonate (150 mL) and extracted with ethyl 
acetate (2.times.100 mL). The combined extracts were dried over magnesium 
sulfate and evaporated to give a crude oil (6.53 g, 95%). 
Step C: 
2-[2-(4-Morpholinyl)ethyl]-2H-thieno[3,2-e]-1,2-thiazine-2-carboxylic Acid 
Methyl Ester 1,1-dioxide 
A mixture of the product from Step B (6.53 g, 1.74 mmol), DBU (0.8 mL) and 
molecular sieves (4.0 g) in ethyl acetate (100 mL) was stirred at ambient 
temperature overnight and mixed with a saturated aqueous solution of 
sodium bicarbonate (80 mL). The organic layer was separated, washed with 
brine (100 mL), dried over magnesium sulfate and evaporated to give a 
crude oil. Chromatography on silica (66% ethyl acetate/hexane) gave a 
white solid (4.15 g, 67%): mp 103.degree.-106.degree. C. 
Step D: 2-[2-(4-Morpholinyl)ethyl]-2H-thieno[3,2-e]-1,2-thiazine-3-methanol 
1,1-dioxide 
To a stirred solution of the product from Step C (3.80 g, 10.6 mmol) in 
anhydrous THF (50 mL) at 0.degree. C. was added a 1M solution of 
diisobutylaluminium hydride in THF (31.8 mL, 31.8 mmol). The mixture was 
stirred for 1 h and then warmed to ambient temperature and stirred for an 
additional 30 min, cooled (ice bath) and the reaction was quenched by the 
addition of a aqueous solution of potassium sodium tartrate (15.0 g in 50 
mL of water). This mixture was stirred at ambient temperature for 1 h and 
extracted with ethyl acetate (22.times.100 mL). The combined extracts were 
dried over magnesium sulfate and evaporated to give a solid (3.26 g, 93%): 
mp 119.degree.-121.degree. C. 
Step E: 
3-Hydroxymethyl-2-[2-(4-morpholinyl)ethyl]-2H-thieno[3,2-e]-1,2-thiazine-6 
-sulfonamide 1,1-dioxide 
To a mixture of the product from Step D (3.25 g, 9.85 mmol) in anhydrous 
THF (40 mL) under nitrogen at -70.degree. C. was added n-butyllithium 
(2.5M in hexanes, 9.06 mL, 22.7 mmol). The mixture was stirred for 7 min 
before sulfur dioxide gas was passed over the solution for about 5 min. 
The resulting mixture was warmed to ambient temperature and evaporated to 
a residue which was mixed with ice-water (150 mL), 
hydroxylamine-O-sulfonic acid (3.34 g, 29.6 mmol) and sodium acetate (6.20 
g, 45.6 g) and stirred for 4 h at ambient temperature. The reaction 
mixture was extracted with ethyl acetate (2.times.100 mL) and the combined 
extracts were dried over magnesium sulfate and evaporated to a residue 
which was purified by column chromatography (silica, 5% to 10% 
methanol/methylene chloride) to give a glass (3.10 g, 77%). 
Step F: 
3-(Acetyloxymethyl)-2-[2-(4-morpholinyl)ethyl]-2H-thieno[3,2-e]-1,2-thiazi 
ne-6-sulfonamide 1,1-dioxide Hydrochloride 
The product from Step E (0.80 g, 1.96 mmol) was mixed with acetic acid (20 
mL) and acetic anhydride (0.45 g, 4.41 mmol), stirred at ambient 
temperature for 2 h, heated at reflux temperature for 2 h and evaporated 
to give an oil. A solution of the oil in ethyl acetate (100 mL) was washed 
with a saturated aqueous solution of sodium bicarbonate (100 mL), dried 
over magnesium sulfate and evaporated to give a viscous oil. Purification 
of this oil by column chromatography (silica, 50% ethyl acetate/hexane to 
ethyl acetate gradient) gave a foamy solid (0.61 g) which was dissolved in 
ethyl acetate and treated with ethanolic HCl. Evaporation and 
recrystallization from acetonitrile/isopropanol gave a colorless solid 
(0.57 g, 55%): mp 135.degree.-140.degree. C. Analysis. Calculated for 
C.sub.15 H.sub.21 N.sub.3 O.sub.7 S.sub.3 -HCl-0.8 i-PrOH: C, 38.90; H, 
5.51; N, 7.82. Found: C, 38.85; H, 5.48; N, 7.72. 
By following the procedure described above but using trimethylacetyl 
chloride and trifluoroacetic acid in Step F the following compound was 
prepared. 
1. 
3-[(2,2-Dimethyl-1-oxopropoxy)methyl]-2-[2-(4-morpholinyl)ethyl]-2H-thieno 
[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride, mp 
156.degree.-159.degree. C. 
EXAMPLE 24 
##STR40## 
Ethyl 
4-[(2-methoxyethyl)[[6-(aminosulfonyl)-2-(2-methoxyethyl)-2H-thieno[3,2-e] 
-1,2-thiazin-2-yl]methyl]amino]butanoate S.sup.1, S.sup.1 -dioxide 
Hydrochloride 
Step A: 4-[(2-Methoxyethyl)amino]butyronitrile 
To a stirred mixture of 2-methoxyethylamine (20.3 g, 270 mmol) and 
potassium carbonate (11.2 g, 81.1 mmol) was added 4-bromobutyronitrile 
(10.0 g, 67.6 mmol) over 20 minutes. This mixture was heated at reflux 
temperature for 1 h, mixed with ethyl acetate (100 mL) and filtered. The 
filtrate was concentrated and distilled at 109.degree.-115.degree. C. (0.1 
mmHg) to give a clear liquid (9.78 g, quantitative). 
Step B: 
4-[(2-methoxyethyl)[[6-(aminosulfonyl)-2-(2-methoxyethyl)-2H-thieno[3,2-e] 
-1,2-thiazin-2-yl]methyl]amino]butyronitrile S.sup.1, S.sup.1 -dioxide 
To a solution of 
3-hydroxymethyl-2-(2-methoxyethyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfona 
mide 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.degree. 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. 
The mixture was again cooled (ice bath) and the product of Step A (2 mL) 
was added and the mixture stirred for 2 h followed by heating at 
50.degree. C. for 5 min and evaporation to dryness. This crude product was 
mixed with a saturated aqueous solution of sodium bicarbonate (100 mL) and 
extracted with ethyl acetate (2.times.100 mL). The combined extracts were 
dried (MgSO.sub.4) and evaporated to a residue which was purified by 
column chromatography (silica, 70% ethyl acetate/hexane) to give two 
compounds; 1.16 g and 0.57 g, respectively. NMR showed the first compound 
to be unreacted mesylate intermediate, which was again treated with 
4-[(2-methoxyethyl)amino]butyronitrile (2 mL) but at refluxing temperature 
for 2 h to effect conversion to the desired compound (total 1.42 g, 41%). 
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.sup.1, S.sup.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.degree. 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.degree. 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 bicarbonate 
(100 mL) and extracted with ethyl acetate (2.times.80 mL). The combined 
extracts were dried (MgSO.sub.4) and evaporated to a residue which was 
purified by column chromatography (silica, 80% ethyl acetate/hexane) to 
give an oil (0.76 g, 49%). The oil was dissolved in methylene chloride and 
treated with 2N HCl/EtOH to give the hydrochloride salt as an amorphous 
solid (0.72 g, 44%): mp 67.degree.-72.degree. C.; Analysis. Calculated for 
C.sub.19 H.sub.31 N.sub.3 O.sub.8 S.sub.3 -HCl: C, 40.59; H, 5.74; N, 
7.48. Found: C, 40.48; H, 5.78; N, 7.41; 
EXAMPLE 25 
##STR41## 
6-(Aminosulfonyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazine-2-b 
utanoic Acid 1,1-dioxide Ethyl Ester 
Step A: 3-(1,3-Dioxolan-2-yl)-N-(4-hydroxybutyl)-2-thiophenesulfonamide 
A solution of 3-(1,3-dioxolan-2-yl)-thiophene-2-sulfonyl chloride, prepared 
from thiophene-3-carboxaldehyde ethylene acetal (20.0 g, 128 mmol) as 
described in Example 6, Step A, was combined with 4-amino-1-butanol (17.1 
g, 192 mmol) and triethylamine (15 g, 148 mmol). The reaction was stirred 
for 1 h, a saturated aqueous solution of sodium bicarbonate (200 mL) was 
added and this mixture was stirred for 1 h. The organic layer was 
separated, dried (MgSO.sub.4), and evaporated to a residue which was 
purified by column chromatography (silica, 50% ethyl acetate/hexane to 
ethyl acetate, gradient) to give an oil (26.45 g, 62%). 
Step B: 2-(4-Hydroxybutyl)-2H-thieno[3,2-e]-1,2-thiazine-3-carboxylic Acid 
1,1-dioxide Methyl Ester 
To a solution of the product from Step A (10.6 g, 34.5 mmol) in anhydrous 
DMF (200 mL) at 0.degree. C. was added NaH (60% dispersion in mineral oil, 
1.45 g, 36.3 mmol). After 30 min methyl bromoacetate (3.92 mL, 6.33 g, 
41.4 mmol) was added and the solution was stirred for 40 min. A 2N HCl 
solution (100 mL) was added and this mixture was stirred at ambient 
temperature for 1 h, poured into ice-water (300 mL) and extracted with 
ethyl acetate (2.times.300 mL). The combined extracts were dried 
(MgSO.sub.4), and evaporated to give a viscous oil (13.42 g). The crude 
oil was dissolved in ethyl acetate (200 mL), mixed with DBU (1 mL) and 
molecular sieves (8.0 g) and stirred for 2 h followed by quenching the 
reaction by the addition of 2N HCl (100 mL). The organic layer was 
separated, dried (MgSO.sub.4), and evaporated to a residue which was 
purified by column chromatography (silica, 70% ethyl acetate/hexane) to 
give a viscous oil (7.44 g, 68%). 
Step C: 
2-[4-(1-Ethoxyethoxy)butyl]-2H-thieno[3,2-e]-1,2-thiazine-3-methanol 1,1-d 
ioxide 
To a solution of the product from Step B (1.01 g, 3.19 mmol) and 
p-toluenesulfonic acid (0.05 g) in anhydrous THF (30 mL) at 0.degree. C. 
was added ethyl vinyl ether (0.5 mL, 5.23 mmol) and stirred for 15 min. To 
this solution was added via syringe DIBAL-H (1M solution in hexanes, 12 
mmol); this mixture was stirred for 20 min at which point a solution of 
potassium sodium tartrate (8.0 g in 30 mL water) was added over 5 min. The 
resulting mixture was stirred overnight and extracted with ethyl acetate 
(2.times.50 mL). The combined extracts were dried (MgSO.sub.4) and 
evaporated to give an oil. 
Step D: 
2-[4-(1-Ethoxyethoxy)butyl]-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-t 
hiazine 1,1-dioxide 
To a solution of the product from Step C (2.52 g, 6.98 mmol) and 
triethylamine (1.41 g, 13.9 mmol) in anhydrous THF (20 mL) at 0.degree. C. 
was added methanesulfonic anhydride (1.58 g, 9.07 mmol). The ice bath was 
removed and the reaction mixture was allowed to proceed for 20 min; the 
reaction mixture was again cooled on ice and morpholine (5 mL) was added. 
This mixture was stirred for 3 h at ambient temperature, evaporated to 
dryness and extracted with ethyl acetate (2.times.100). The combined 
extracts were dried (MgSO.sub.4), evaporated to dryness and purified by 
column chromatography (silica, 50% ethyl acetate/hexane) to give an oil 
(2.52 g, 84%). 
Step E: 
2-(4-Hydroxybutyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazine-6 
-sulfonamide 1,1-dioxide 
To a solution of the product from Step D (3.22 g, 7.49 mmol) in anhydrous 
THF (30 mL) under nitrogen at -70.degree. C. was added n-butyllithium 
(2.5M in hexanes, 3.30 mL, 8.24 mmol) via syringe over 5 min. The mixture 
was stirred for 30 min at which point 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, evaporated to dryness and the 
residue was mixed with water (100 mL), cooled on an ice bath at which 
point hydroxylamine-O-sulfonic acid (1.69 g, 14.9 mmol) and NaOAc (4.07 g, 
29.9 mmol) were added; after stirring for 5 min, a saturated solution of 
sodium bicarbonate (20 mL) was added. The reaction mixture was allowed to 
warm to ambient temperature and stirred for 16 hr followed by mixing with 
a saturated solution of sodium bicarbonate (50 mL) and extraction with 
ethyl acetate (2.times.200 mL). The combined extracts were washed with 2N 
HCl (100 mL). The aqueous layer was separated, stirred for 30 min, 
adjusted to pH 7 by the addition of potassium carbonate, and extracted 
with ethyl acetate (2.times.100 mL). The combined extracts were dried 
(MgSO.sub.4), evaporated to dryness and purified by column chromatography 
(silica, ethyl acetate to 10% ethanol/ethyl acetate, gradient) to give an 
oil (2.25 g, 69%). 
Step F: 
3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-2-buta 
noic Acid 1,1-dioxide Ethyl Ester Hydrochloride 
To a solution of the product from Step E (1.48 g, 3.39 mmol) in acetone 
(100 mL) at 0.degree. C. was added Jones reagent (1.1M, 10 mL, 11 mmol). 
The reaction mixture was stirred at ambient temperature for 2 h and then 
maintained at a temperature of 5.degree. C. for 16 hr followed by 
quenching the reaction with an excess of isopropanol and sodium 
bicarbonate. This suspension was filtered and the filtrate was evaporated 
to dryness and dissolved in ethanol (15 mL). To this solution was added 
thionyl chloride (1 mL) and the mixture heated at 50.degree. C. for 1 h 
and evaporated to dryness. Purification by column chromatography (silica, 
50% ethyl acetate/hexane) gave an oil (0.42 g) which was dissolved in 
ethanol, treated with a 2N ethanolic hydrogen chloride and evaporated to 
dryness. The residue was triturated with ethyl acetate and dried to give a 
white solid (0.353 g, 20%): mp 130.degree.-134.degree. C. Analysis. 
Calculated for C.sub.17 H.sub.26 N.sub.3 O.sub.7 S.sub.3 Cl: C, 39.56: H, 
5.08; N, 8.14. Found: C, 39.41; H, 5.15; N, 7.96. 
EXAMPLE 26 
##STR42## 
2-(2-Hydroxyethyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1, 
2-thiazine-6-sulfonamide 1,1-dioxide 
Step A: 
2-(2-Methoxyethyl)-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiazine-6 
-sulfonamide 1,1-dioxide 
To a solution of 
3-hydroxymethyl-2-(2-methoxyethyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfona 
mide 1,1-dioxide (prepared as described in Example 11.3) (3.40 g, 9.60 
mmol) and TEA (1.94 g, 19.2 mmol) in anhydrous THF (40 mL) at 0.degree. C. 
was added methanesulfonic anhydride (2.17 g, 12.5 mmol). After the 
addition was completed, the ice bath was removed and the mixture was 
warmed to ambient temperature, stirred for 30 min, again cooled on an ice 
bath and morpholine (10 mL) was added. The reaction mixture was stirred 
for 16 hr and evaporated to dryness. The crude product was mixed with a 
saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl 
acetate (2.times.100 mL). The combined extracts were dried (MgSO.sub.4) 
and evaporated to a residue which was purified by column chromatography 
(silica, 7% methanol/methylene chloride) to give an oil (1.57 g). 
Step B: 
2-(2-Hydroxyethyl)-3-(4-morpholinylmethyl)-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.times.80 mL). The combined extracts were 
dried (MgSO.sub.4) and evaporated to a residue which was purified by 
column chromatography (silica, 5% methanol/methylene chloride) to give a 
firm foam (0.85 g, 56%): mp 104.degree.-108.degree. C. Analysis. 
Calculated for C.sub.13 H.sub.19 N.sub.3 O.sub.6 S.sub.3 - 0.3H.sub.2 O: 
C, 37.63; H, 4.76; N, 10.13. Found: C, 37.61; H, 4.60; N, 10.00. 
EXAMPLE 27 
##STR43## 
2-[2-(Acetyloxy)ethyl]-3-(4-morpholinylmethyl)-2H-thieno[3,2-e ]-1, 
2-thiazine-6-sulfonamide 1,1-dioxide Hydrochloride 
A solution of the product from Example 26 (0.41 g, 1.00 mmol), acetic 
anhydride (0.167 g, 1.60 mmol) in acetic acid (4 mL) was heated at reflux 
temperature for 1 h, evaporated to dryness, mixed with a saturated 
solution of sodium bicarbonate (60 mL) and extracted with ethyl acetate 
(2.times.80 mL). The combined extracts were dried (MgSO.sub.4) and 
evaporated to a residue which was purified by column chromatography 
(silica, 80% ethyl acetate/hexane) to give a foam (0.42 g). The foam was 
dissolved in ethanol, treated with 2N ethanolic hydrogen chloride and 
evaporated to dryness. Recrystallization from 2-propanol gave a solid 
(0.185 g, 36%): mp 152.degree.-156.degree. C. Analysis. Calculated for 
C.sub.15 H.sub.22 N.sub.3 O.sub.7 S.sub.3 Cl - 0.33 2-PrOH: C, 37.82; H, 
4.89; N, 8.27. Found: C, 37.74; H, 4.91; N, 8.28. 
By following the procedures described above and in Example 26, Step B but 
using instead the product of Example 10 in Example 26, Step B the 
following compound was prepared: 
1. 
2-[3-(Acetyloxy)propyl]-3-(4-morpholinylmethyl)-2H-thieno[3,2-e]-1,2-thiaz 
ine-6-sulfonamide 1,1-dioxide, mp 54.degree.-55.degree. C. (foam). 
EXAMPLE 28 
##STR44## 
2-Methyl-3-(4-morpholinylmethyl)-2H-thieno[2,3-e]-1,2-thiazine-6-sulfonamid 
e 1,1-dioxide 
Step A: 3,5-Dibromo-2-thiophenecarboxaldehyde 
To a solution of 2,5-dibromothiophene (20.0 g, 82.7 mmol) in anhydrous THF 
(200 mL) at -70.degree. C. was added a 1.5M solution of LDA in cyclohexane 
(60.6 mL, 90.9 mmol) over 10 min. The mixture was stirred for 1 h before 
anhydrous DMF (18.1 g, 248 mmol) was added. The resulting mixture was 
stirred overnight, solvent evaporated, the residual oil poured into 2N HCl 
(200mL), and this mixture was extracted with ethyl acetate (2.times.200 
mL). The combined extracts were dried (MgSO.sub.4) and evaporated to give 
a brown solid (20.21 g, 91%) which was used in the next step without 
further purification. 
Step B: 3,5-Dibromo-2-(1,3-dioxolan-2-yl)-thiophene 
A mixture consisting of the product from Step A (11.0 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 (100 mL). The organic layer was separated, 
dried (MgSO.sub.4), and evaporated to dryness. Purification of this crude 
material by column chromatography (silica, 6% ethyl acetate/hexane) gave 
10.33 g of an oil (81%). 
Step C: N-[[2-(1,3-dioxolan-2-yl)-3-thienyl]sulfonyl]-N-methyl-glycine 
Ethyl Ester 
To a solution of the product from Step B (10.00 g, 31.85 mmol) in anhydrous 
ether (150 mL) at -75.degree. C. butyllithium (2.5M in hexanes, 13.37 mL, 
33.43 mmol) was slowly added over 10 min, maintaining the temperature 
below -65.degree. C.; a precipitate formed during the addition. After the 
addition was complete, n-propanol (1.91 g, 31.85 mmol) was added and the 
solution turned homogenous. A solution of n-butyllithium (2.5M 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.degree. C., and 
N-chlorosuccinimide was added with stirring. After 40 min a saturated 
aqueous solution of sodium bicarbonate (100 mL) was added to the mixture 
followed by sacorsine ethyl ester hydrochloride (7.34 g, 47.8 mmol). The 
organic layer was separated after 30 min, dried (MgSO.sub.4), and 
evaporated to dryness. Column chromatography (silica, 30% ethyl 
acetate/hexane) gave 5.96 g of a viscous oil (53%). 
Step D: Ethyl 2-methyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxylate 
1,1-dioxide 
A mixture of the product from Step C (5.86 g, 16.5 mmol) and 
trifluoroacetic acid (8 mL) in acetone (50 mL) was heated at reflux 
temperature for 1 h, cooled, and poured into water (100 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.times.150 mL). The combined extracts were dried (MgSO.sub.4) 
and evaporated to give a crude aldehyde which was dissolved in ethyl 
acetate (100 mL) followed by the addition of DBN (1 mL) and molecular 
sieves (5 g). This mixture was heated at reflux temperature for 15 min, 
cooled, and poured into 2N HCl (50 mL). The organic layer was separated, 
dried (MgSO.sub.4), and evaporated to dryness. Column chromatography 
(silica, 30% ethyl acetate/hexane) gave 3.60 g (79%) of an off-white 
solid: mp 87.degree.-89.degree. C. 
Step E: 2-Methyl-2H-thieno[2,3-e]-1,2-thiazine-3-methanol 1,1-dioxide 
To a solution of the product from Step D (3.16 g, 11.6 mmol) in anhydrous 
THF (30 mL) at 0.degree. C. was added DIBAL (1.0M, 29.0 mL, 29.0 mmol). 
This mixture was stirred for 30 min, warmed to ambient temperature, and 
stirred for an additional 30 min. The mixture was evaporated to dryness 
and the residue mixed with ethyl acetate (100 mL) and poured into 2N HCl 
(50 mL). The organic layer was seperated, washed with brine, dried 
(MgSO.sub.4) and evaporated to dryness. Column chromatography (silica, 
ethyl aectate/hexane) gave a viscous oil which solidified on standing: mp 
78.degree.-80.degree. C. 
Step F: 
3-Hydroxymethyl-2-methyl-2H-thieno[2,3-e]-1,2-thiazine-6-sulfonamide 1,1-d 
ioxide 
To a solution of the the product from Step E (1.00 g, 4,33 mmol) in 
anhydrous THF (30 mL) at -70.degree. C. was added n-butyllithium (2.5M in 
hexanes, 3.81 mL, 9.52 mmol) over 5 min (solution turned cloudy). After an 
additional 10 min, sulfur dioxide was passed over the reaction for about 
10 min, the resulting mixture was warmed to ambient temperature and 
evaporated to dryness. The residue was dissolved in a mixture of sodium 
acetate (2.94 g, 21.7 mmol) and water (50 mL) and extracted with ethyl 
acetate (50 mL) to remove unreacted starting material. The aqueous was 
cooled on an ice bath and hydroxylamine-O-sulfonic acid (1.47 g, 12.99 ml) 
was added with stirring. After stirring for 18 hr the reaction mixture was 
extracted with ethyl acetate (100 mL.times.2). The combined extracts were 
dried (MgSO.sub.4) and evaporated to dryness. Column chromatography 
(silica, 50% to 80% ethyl acetate/hexane) gave 0.80 g of a viscous oil 
(60%). 
Step G: 
2-Methyl-3-(4-morpholinylmethyl)-2H-thieno[2,3-e]-1,2-thiazine-5-sulfonami 
de 1,1-dioxide 
To 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). After stirring 
for 4.5 h, morpholine (2 mL) was added and the mixture was stirred for 1 h 
followed by heating at reflux temperature for 10 min. The volatiles were 
evaporated and a saturated solution of sodium bicarbonate (80 mL) was 
added. This mixture was extracted with ethyl acetate (2.times.100 mL) and 
the combined extracts were dried (MgSO.sub.4) and evaporated to a viscous 
oil which was purified by column chromatography (silica, 5% to 10% 
methanol/methylene chloride) to give a solid (0.41 g 43%). 
Recrystallization from ethyl acetate/methylene chloride gave a yellowish 
solid: mp 192.degree.-194.degree. C. Analysis. Calculated for C.sub.12 
H.sub.17 N.sub.3 O.sub.5 S.sub.3 : C, 37.98; H, 4.52; N, 11.07. Found: C, 
38.09; H, 4.53; N, 11.09. 
The following formulations are exemplary and not limiting. They can be 
administered 1-4 times daily for the control of intraocular pressure 
according to the discretion of a skilled clinician. 
EXAMPLE 29 
Ophthalmic Suspension 
______________________________________ 
Concentra- 
Ingredient tion (wt %) 
______________________________________ 
2-(2-Methoxyethyl)-3-(4-morpholinylmethyl)- 
3.0% 
2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1, 
1-dioxide hydrochloride (Compound) 
Hydroxypropylmethylcelluose 
0.5% 
Dibasic Sodium Phosphate 
0.2% 
Disodium Edetate 0.01% 
Sodium Chloride 0.8% 
Purified Water q.s. 
Benzalkonium Chloride 0.01% 
Polysorbate 80 0.1% 
NaOH/HCl pH 7.02 
______________________________________ 
The Compound (0.09 g), benzalkonium chloride (0.03 g), and polysorbate 80 
(0.15 g) can be mixed together in water (1.23 g) and ball milled for 
approximately 4 hr. 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 1N HCl (250 .mu.L). A portion of this vehicle (1.5 
mL) can be added to the mixture containing the Compound to furnish the 
desired suspension. 
EXAMPLE 30 
Ophthalmic Solution 
______________________________________ 
Concentra- 
Ingredient tion (wt %) 
______________________________________ 
3-[[(2-methoxyethyl)(3-methoxypropyl) 
2.0% 
amino]methyl]-2-methyl-2H-thieno [3,2-e]-1,2- 
thiazine-6-sulfonamide 1,1-dioxide 
hydrochloride (Compound) 
Hydroxyethylcellulose 0.5% 
Monobasic Sodium Phosphate 
0.13% 
Dibasic Sodium Phosphate 
0.01% 
Benzalkonium Chloride 0.01% 
Disodium Edetate 0.01% 
Purified Water q.s. 
NaCl (Osmolality = 282 mOsm) 
0.4% 
HCl/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 1N NaOH (10 .mu.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 1N HCl (100 
.mu.L). A portion of this vehicle (1.5 g) was added to the solution 
containing the compound and the pH was adjusted to 5.03 by the addition of 
1N NaOH (10 .mu.L). 
EXAMPLE 31 
Ophthalmic Gel 
______________________________________ 
Concentra- 
Ingredient tion (wt %) 
______________________________________ 
3-[[Bis(2-methoxyethyl)amino]methyl]-2-ethyl-2H- 
1.0% 
thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1, 1-dioxide 
hydrochloride (Compound) 
Mannitol 3.6% 
Benzalkonium Chloride 0.01% 
Carbopol 3.0% 
HCl/NaOH pH 5.0 
Purified Water q.s. 
______________________________________ 
The mannitol (0.18 g), benzalkonium chloride (0.05 g), Compound (0.1 g) and 
carbopol (0.15 g) can all be added to water (4.3 mL) and mixed well. The 
pH can be adjusted to pH 5.0 and purified water (q.s. to 5 mL) can be 
added and mixed well to form a gel. 
Using the procedures described in Equations 1-12, the Examples 1-28 and 
well known procedures, one skilled in the art can prepare the compounds 
disclosed herein and those in the Tables. In the Tables the following 
abbreviations correspond to the indicated structural elements: Me is 
methyl; Et is ethyl; Pr is propyl; iPr is isopropyl; iBu is isobutyl; Ac 
is acetyl; OABH is 2-oxa-5-azabicyclo[2.2.1]heptanyl; OABO is 
2-oxa-5-azabicyclo[3.2.1]octanyl. 
TABLE 1 
______________________________________ 
##STR45## 
Z Y 
______________________________________ 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
H 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-Me 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
4-Me 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-iBu 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
4-iBu 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 OEt 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
4-CH.sub.2 OEt 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
3-CH.sub.2 OEt 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
4-CH.sub.2 OEt 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 SO.sub.2 
3-CH.sub.2 OEt 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 SO.sub.2 
4-CH.sub.2 OEt 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 OCO-iPr 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
4-CH.sub.2 OCO-iPr 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CO.sub.2 -iPr 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
3-CO.sub.2 -iPr 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CONHMe 
(CH.sub.2).sub.2 -(5-OABO) 
H 
CH.sub.2 CCCH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
H 
CH.sub.2 CCCH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 OMe 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 O(CH.sub.2).sub.2 OMe 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 C.sub.6 H.sub.4 -(4-OMe) 
(CH.sub.2).sub.2 N(CH.sub.3)CH.sub.2 CH.sub.2 F 
H 
(CH.sub.2).sub.2 N(CH.sub.3)CH.sub.2 CH.sub.2 F 
3-CH.sub.2 OEt 
(CH.sub.2).sub.2 N(CH.sub.3)CH.sub.2 CH.sub.2 F 
4-CH.sub.2 OEt 
C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
H 
C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
3-Me 
C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
4-Me 
C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
3-CH.sub.2 OEt 
C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
4-CH.sub.2 OEt 
C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
3-CH.sub.2 OCH.sub.2 C.sub.6 H.sub.5 
C.sub.6 H.sub.4 -(4-OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(4-OMe) 
4-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(3-OH) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(4-CH.sub.2 OH) 
3-CHhd 2N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(3-CH.sub.2 OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(4-CH.sub.2 CH.sub.2 OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(3-CH.sub.2 CH.sub.2 OH) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.3 -(3,4-OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(4-CONMe.sub.2) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(4-SO.sub.2 Me) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -NHCOMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.4 -(4-OH) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.4 -(4-OH) 
4-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.4 -(3-OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.4 -(4-CH.sub.2 OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.4 -(4-CH.sub.2 OMe) 
4-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.4 -(3-CH.sub.2 OH) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.3 -(3,4-OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.3 -(3,4-OH) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
H 
CH.sub.2 C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
3-CH.sub.2 OMe 
CH.sub.2 C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
4-CH.sub.2 OMe 
CH.sub.2 C.sub.6 H.sub.3(4-OH)-(3-CH.sub.2 NMe.sub.2) 
3-CO.sub.2 -iPr 
Me 3-CH.sub.2(5-PABH) 
(CH.sub.2).sub.2 OMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 SMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 SO.sub.2 Me 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
Pr 4-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.4 OH 3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2C.sub.3 H.sub.5 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2C.sub.3 H.sub.5 
4-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
iBu 3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 CHCHCH.sub.2 OMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 CO.sub.2 -iPr 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.2 CONH(CH.sub.2)OH 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 CCCH.sub.2 OMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 -(pyridin-4-yl) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
CH.sub.2 -(pyridin-3-yl) 
4-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
CH.sub.2 -[(2-CO.sub.2 Et)-pyridin-4-yl] 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
2-(4-morpholinyl)-thiazol-4-yl 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
5-(4-morpholinyl)methyl-thiadiazol-2- 
3-CH.sub.2 OEt 
yl 
CH.sub.2 -(thien-2-yl) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
CH.sub.2 [(5-CO.sub.2 -iPr)-thien-2-yl] 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
CH.sub.2 -(thiazol-2-yl) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
pyridin-3-yl-(5-OCH.sub.3) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.2 -(4-Ac-piperazinyl) 
3-CH.sub.2 OEt 
(CH.sub.2).sub.3 OMe 
3-CH.sub.2 N(Me)CH.sub.2 CCCH.sub.2 
(CH.sub.2).sub.3 OMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 S 
(CH.sub.2).sub.3 OMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 SO.sub.2 
C}hd 6 H.sub.4 -(4-OMe) 
3-CH.sub.2 N(Me)CH.sub.2 CH.sub.2 F 
C.sub.6 H.sub.4 -(4-OMe) 
4-CH.sub.2 N(Me)CH.sub.2 CH.sub.2 F 
CH.sub.2 C}hd 6H.sub.4 -[4-N(CH.sub.2 CH.sub.2).sub.2 O] 
3-CH.sub.2 N(Me)CH.sub.2 CH.sub.2 F 
C.sub.6 H.sub.4 -[4-N(CH.sub.2 CH.sub.2).sub.2 O] 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
C.sub.6 H.sub.4 -[3-N(CH.sub.2 CH.sub.2).sub.2 O] 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
C.sub.6 H.sub.4 -(4-OMe) 
3-CH.sub.2 NHCH.sub.2 CCH 
(CH.sub.2).sub.3 OMe 
3-CH.sub.2 NHCH.sub.2 CCH 
C.sub.6 H.sub.4 -(3-OH) 
3-CH.sub.2 NHCH.sub.2 CCH 
C.sub.6 H.sub.4 -(4-OMe) 
4-CH.sub.2 N(Me)CH.sub.2 CCH 
CH.sub.2 C.sub.6 H.sub.4 -(3-OMe) 
4-CH.sub.2 N(Me)CH.sub.2 CCH 
C.sub.6 H.sub.3 -(3,5-OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 CO.sub.2 Et 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
(CH.sub.2).sub.3 CO.sub.2 CH(CH.sub.3).sub.2 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 C(O)NHMe 
3-CH.sub.2 N(Me)CH.sub.2 CH.sub.2 OMe 
(CH.sub.2).sub.2 C(O)NHC.sub.3 H.sub.5 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 C(O)NHCH.sub.2 CH.sub.2 OH) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 O(CO)Me 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 O(CO)CH.sub.2 CH.sub.2 OH 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
(CH.sub.2).sub.2 O(CO)CH(Me).sub.2 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.2 O(CO)C.sub.3 H.sub.5 
3-CH.sub.2 N(Me)CH.sub.2 CH.sub.2 OMe 
(CH.sub.2).sub.2 NH(CO)Me 
3-CH.sub.2 N(Me)CH.sub.2 CH.sub.2 OMe 
(CH.sub.2).sub.2 NH(CO)CH.sub.2 CH.sub.2 OH 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.2 OMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe) 
(CH.sub.2).sub.3 CO.sub.2 Et 
(CH.sub.2).sub.2 OMe 
3-(CH.sub.2).sub.2 N(Me)CH.sub.2 CO.sub.2 Et 
(CH.sub.2).sub.2 OMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
(CH.sub.2).sub.2 OH 3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe) 
(CH.sub.2).sub.3 OMe 
(CH.sub.2).sub.2 OH 3-CH.sub.2 NHCH.sub.2 CO.sub.2 iPr 
(CH.sub.2).sub.2 OH 3-CH.sub.2 NHOH 
(CH.sub.2).sub.2 OH 3-(CH.sub.2).sub.2 N(OH)Et 
(CH.sub.2).sub.2 O(CO)CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 CH.sub.2 CH.sub.2 OH 
(CH.sub.2).sub.3 OH 3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
______________________________________ 
TABLE 2 
______________________________________ 
##STR46## 
Z Y 
______________________________________ 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
H 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-Me 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
4-Me 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-iBu 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
4-iBu 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 OEt 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
4-CH.sub.2 OEt 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
3-CH.sub.2 OEt 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
4-CH.sub.2 OEt 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 SO.sub.2 
3-CH.sub.2 OEt 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 SO.sub.2 
4-CH.sub.2 OEt 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 OCO-iPr 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
4-CH.sub.2 OCO-iPr 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CO.sub.2 -iPr 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
3-CO.sub.2 -iPr 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CONHMe 
(CH.sub.2).sub.2 -(5-OABO) 
H 
CH.sub.2 CCCH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
H 
CH.sub.2 CCCH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 OMe 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 O(CH.sub.2).sub.2 OMe 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 C.sub.6 H.sub.4 -(4-OMe) 
(CH.sub.2).sub.2 N(CH.sub.3)CH.sub.2 CH.sub.2 F 
H 
(CH.sub.2).sub.2 N(CH.sub.3)CH.sub.2 CH.sub.2 F 
3-CH.sub.2 OEt 
(CH.sub.2).sub.2 N(CH.sub.3)CH.sub.2 CH.sub.2 F 
4-CH.sub.2 OEt 
C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
H 
C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
3-Me 
C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
4-Me 
C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
3-CH.sub.2 OEt 
C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
4-CH.sub.2 OEt 
C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
3-CH.sub.2 OCH.sub.2 C.sub.6 H.sub.5 
C.sub.6 H.sub.4 -(4-OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(4-OMe) 
4-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(3-OH) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(4-CH.sub.2 OH) 
3-CHhd 2N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(3-CH.sub.2 OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(4-CH.sub.2 CH.sub.2 OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(3-CH.sub.2 CH.sub.2 OH) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.3 -(3,4-OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(4-CONMe.sub.2) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -(4-SO.sub.2 Me) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
C.sub.6 H.sub.4 -NHCOMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.4 -(4-OH) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.4 -(4-OH) 
4-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.4 -(3-OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.4 -(4-CH.sub.2 OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.4 -(4-CH.sub.2 OMe) 
4-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.4 -(3-CH.sub.2 OH) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.3 -(3,4-OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.3 -(3,4-OH) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
H 
CH.sub.2 C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
3-CH.sub.2 OMe 
CH.sub.2 C.sub.6 H.sub.3 -(4-OH)-(3-CH.sub.2 NMe.sub.2) 
4-CH.sub.2 OMe 
CH.sub.2 C.sub.6 H.sub.3(4-OH)-(3-CH.sub.2 NMe.sub.2) 
3-CO.sub.2 -iPr 
Me 3-CH.sub.2(5-PABH) 
(CH.sub.2).sub.2 OMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 SMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 SO.sub.2 Me 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
Pr 4-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.4 OH 3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2C.sub.3 H.sub.5 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2C.sub.3 H.sub.5 
4-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
iBu 3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 CHCHCH.sub.2 OMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 CO.sub.2 -iPr 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.2 CONH(CH.sub.2)OH 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 CCCH.sub.2 OMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
CH.sub.2 -(pyridin-4-yl) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
CH.sub.2 -(pyridin-3-yl) 
4-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
CH.sub.2 -[(2-CO.sub.2 Et)-pyridin-4-yl] 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
2-(4-morpholinyl)-thiazol-4-yl 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
5-(4-morpholinyl)methyl-thiadiazol-2- 
3-CH.sub.2 OEt 
yl 
CH.sub.2 -(thien-2-yl) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
CH.sub.2 [(5-CO.sub.2 -iPr)-thien-2-yl] 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
CH.sub.2 -(thiazol-2-yl) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
pyridin-3-yl-(5-OCH.sub.3) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.2 -(4-Ac-piperazinyl) 
3-CH.sub.2 OEt 
(CH.sub.2).sub.3 OMe 
3-CH.sub.2 N(Me)CH.sub.2 CCCH.sub.2 
(CH.sub.2).sub.3 OMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 S 
(CH.sub.2).sub.3 OMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 SO.sub.2 
C}hd 6 H.sub.4 -(4-OMe) 
3-CH.sub.2 N(Me)CH.sub.2 CH.sub.2 F 
C.sub.6 H.sub.4 -(4-OMe) 
4-CH.sub.2 N(Me)CH.sub.2 CH.sub.2 F 
CH.sub.2 C}hd 6H.sub.4 -[4-N(CH.sub.2 CH.sub.2).sub.2 O] 
3-CH.sub.2 N(Me)CH.sub.2 CH.sub.2 F 
C.sub.6 H.sub.4 -[4-N(CH.sub.2 CH.sub.2).sub.2 O] 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
C.sub.6 H.sub.4 -[3-N(CH.sub.2 CH.sub.2).sub.2 O] 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
C.sub.6 H.sub.4 -(4-OMe) 
3-CH.sub.2 NHCH.sub.2 CCH 
(CH.sub.2).sub.3 OMe 
3-CH.sub.2 NHCH.sub.2 CCH 
C.sub.6 H.sub.4 -(3-OH) 
3-CH.sub.2 NHCH.sub.2 CCH 
C.sub.6 H.sub.4 -(4-OMe) 
4-CH.sub.2 N(Me)CH.sub.2 CCH 
CH.sub.2 C.sub.6 H.sub.4 -(3-OMe) 
4-CH.sub.2 N(Me)CH.sub.2 CCH 
C.sub.6 H.sub.3 -(3,5-OMe) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 CO.sub.2 Et 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
(CH.sub.2).sub.3 CO.sub.2 CH(CH.sub.3).sub.2 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 C(O)NHMe 
3-CH.sub.2 N(Me)CH.sub.2 CH.sub.2 OMe 
(CH.sub.2).sub.2 C(O)NHC.sub.3 H.sub.5 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 C(O)NHCH.sub.2 CH.sub.2 OH) 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 O(CO)Me 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.3 O(CO)CH.sub.2 CH.sub.2 OH 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
(CH.sub.2).sub.2 O(CO)CH(Me).sub.2 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.2 O(CO)C.sub.3 H.sub.5 
3-CH.sub.2 N(Me)CH.sub.2 CH.sub.2 OMe 
(CH.sub.2).sub.2 NH(CO)Me 
3-CH.sub.2 N(Me)CH.sub.2 CH.sub.2 OMe 
(CH.sub.2).sub.2 NH(CO)CH.sub.2 CH.sub.2 OH 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.2 OMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe) 
(CH.sub.2).sub.3 CO.sub.2 Et 
(CH.sub.2).sub.2 OMe 
3-(CH.sub.2).sub.2 N(Me)CH.sub.2 CO.sub.2 Et 
(CH.sub.2).sub.2 OMe 
3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe).sub.2 
(CH.sub.2).sub.2 OH 3-CH.sub.2 N(CH.sub.2 CH.sub.2 OMe) 
(CH.sub.2).sub.3 OMe 
(CH.sub.2).sub.2 OH 3-CH.sub.2 NHCH.sub.2 CO.sub.2 iPr 
(CH.sub.2).sub.2 OH 3-CH.sub.2 NHOH 
(CH.sub.2).sub.2 OH 3-(CH.sub.2).sub.2 N(OH)Et 
(CH.sub.2).sub.2 O(CO)CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3 
(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
3-CH.sub.2 CH.sub.2 CH.sub.2 OH 
(CH.sub.2).sub.3 OH 3-CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O 
______________________________________