Note: Descriptions are shown in the official language in which they were submitted.
3~(JIC~
The present invention relates to 411-1,4 benzothiazine
der.ivatives and novel intermediates used in the preparation
thereof. More particularly, this invention provides chemi-
cal compounds of the formula:
~;' ~C
wherein R and R' each represents hydrogen or lower alkyl con-
taining l to 4 carbon atoms; M ~nd N each represents hydro-
gen, halogen, nitrv, amino or alkoxy containing l to 4 car-
bon atoms; Z represents sulfur, sulfinyl or sulfonyl and Ar
represents phenyl or mono- or di-substituted phenyl wherein
the substituents may be halogen, hydroxy, trifluoromethyl,
methoxy, cyano or lower alkyl having l to 4 carbon atoms; and
pharmaceutically acceptable acid addition salts of the com-
pounds of the above formula.
When R of Formula I is hydrogen, the benzothiazine
derivatives of the invention exist in tautomeric form. When
R is other than hydrogen, tautomerism, however, is not pos-
sible. One form of the tautomeric mixture has the pyridone
structure shown by formul.a I while the other form of the
tautomeric mixture has an hydroxide pyridine structure of
the formula III:
~ ~bH
.. , ~,
~33,6~Q
This type of tautomerism :is well-known in the lite-
rature, see for example Mason, et al. Tetrahedron Letters 5,
5129, et. seq. (1969~.
In solution and in solid state, the free base benzo-
thiazine derivatives of the invention actually exist as a
tautomeric mixture of these two forms, with the tautomer
shown by formula I predominating. Formati.on of an acid
addition salt such as the hydrochloride salt will cause a
shift of the tautomeric equilibrium toward the tauto~er
shown by formula III. Consequently, the solid acid addition
salts will predominately contain the hydroxy pryidine form
of formula III.
It will be understood that the invention contemplates
both forms of this tautomeric mixture in any proportion as
well as eithex the pyridone I form or the hydroxy pyridine
III form in a substantially pure state when produced by chem-
ical manipulation of the tautomeric equilibrium.
Preferred compounds of this invention are those com-
pounds of the formula I or III:
M ~ ~ ~ or ~ ~
N i ~ N ~ ~ OH
Rl Ar R' Ar
I III
wherein R and Rl each represents hydrogen or lower alkyl con-
taining 1 ~o 4 carbon atoms; M and N represent hydrogen, halo-
gen, nitro, amino, or alkoxy containing 1 to 4 carbon atoms;
provided that when M is other than alkoxy, N represents hydro-
gen and when M is an alkoxy group, N is hydrogen or the same
alkoxy group; Z represents sulfur, sulfinyl or sulfonyl; Ar is
phenyl, mono- or di-substituted phenyl, wherein the substituents
2a
may be halogen, hydroxy, trifluoromethyl, rnethoxy, cyano or
lower alkyl having 1 to 4 carbon atoms; and pharmaceutically
acceptable acid addition salts o the compounds of the abo~e
formulae.
Among the substituents represented by R and R' hydro-
gen is preferred. However, R and/or ~' may represent lower
alkyl, methyl, ethyl, l-methyl ethyl, or propyl (i.e., alkyl
containing less than 4 carbon atoms).
2b
Positioning of the substituents on the phenyl xelative to the
point of attachment of the phenyl, or where two ~re present,
to each other is not critical. Thus, within the scope of this
invention are o-, m-, or p-monosubstituted phenyls of the type
described above, such as o-fluorophenyl, o-chlorophenyl, m-
trifluoromethylphenyl, p-bromophenyl and p-hydroxyphenyl and
2, 4-, 2,6-, and 3,4- disubstituted phenyls of the type des-
cribed above, such as 2 t 4 dichlorophenyl, 2,6-dichlorophenyl
and 3,4-dichlorophPnyl. The preferred substituents of the
substituted phenyl representing Ar are halogens.
The intermediates of this invention are represented by
formula II:
M ~ ~ C ~ ~ II
wherein W is CN, CONH2 or CON=CHNXY, wherein Xr and Y, are
lower alkyl havi.ng 1 to 4 carbon atoms; ~herein M and N each
represents hydrogen, halogen, nitro, amino or alkoxy contain-
ing 1 to 4 carbon atoms; and R" represents hydrogen, methoxy,
trifluoromethyl or lower alkyl having 1 to 4 carbon atoms when
R"' is hydrogen, and when R" is halogen, R"' is halogen or hy-
dxogenO
Preferred acid addition salts of this invention are
those which are pharmacologically acceptable, that is i.e.,
relatively non-toxic and effective for the purposes set forth
here and below.
Equivalent to the foregoing compounds, includin~
3~
salts, for the purposes of this invention are solYates
thereof in which pharmacologically insignificant amount of
solvates are present~
The final product compounds to which this invention
relate are useful because of their valuable pharmacological
properties. Thus, for example, they are anorectic. The
anorectic utility of the instant compounds is evident from
results of a test showing a dose responsive decrease in food
intake and subsequent weight loss upon administration of the
compounds of the present invention. The procedure i5 as
follows:
Male Sprague Dawley derived, COBS rats from Charles
River Breeaing Laboratoriess(Portage, Michigan) weighed
between 215 and 235 grams at the start of the experiment.
All the ani~als were housed in indi~idual cages ana
maintained on a 12 hour light-dark cycle with the light being
on between 6 a.mO to 6 p.m. They were given access to .
powdered rat feed (Ralston Purina Rat Chow~ #5012) for onl~
4 hours a day from 10 a.m. to 2 p.m. Water was given at ad
libitum. Food intake stabili~ed after about one week. On
the eleventh day, the rats were divided into 4 groups of 13
rats each. The groups were matchea for avera~e food intake
and body weight, based on the means of the previous 4 days.
Three of the groups were administered the compound
~n Example 39. Each group was assigned a specific dose. The
doses were 5.6, 17.B and 56.2 milligra~s per kilogram of b~dy
weight. The compound was suspended in a normal saline
vehicle (of which less than 1% of it contained a 50/50
mixture of propylene .glycol and "TWEEN " ~ 80). Concentrations
of the compound were adjusted s'~ that each rat received a
volume of 2 milliliter per kilogram of body weight. The
fourth group receive~ 2 milliliter per kiligram of body
weight of the vehicle only. The compound and vehicle
preparations were given intraperitoneal one hour before the
rats were given access to food.
Table 1 shows the results of the tests. A student t
test was used for ~aking statistical comparisons, and the p-
values are based upon two-tailed comparisons,
~Table 1
Mean Weight
Difference 24 hrs
after compound
Mean Food Intake administered Grams
Condition n Grams (+ S. D.) (~ S. D. )
Normal Saline 13 21.2 (1.2) ~2.9 (4.6)
Compound - 5.6 ~g/kg 13 17.4 (2.9) -2.6b (3.8)
(Ex. 39) 17.8 mg/kg 13 16.5 (4-7) _5.2c (5.1)
205602 mg/kg 13 12.1a (3.0) _9.5 (2-9
a p ~ .002 compared wi~h normal saline control group
b p < .05 between pre and post weight change
p < .005 between pre and post weight change
The compound prepared in accordance with the --
procedure of Exa~ple 39 produced a statistically significant
dose responsive decrease in food intake when compared to the
~ormal saline control groups. The drug groups showed a
~tatistically significant (as compared with their previous
day's weight~ dose responsive weight loss after 24 hours,
whereas the normal saline group gained an average of 2.9
36~(~
. .
grams. ~he compound produced a decrease in food intake and a
~ubsequent los~ in weight~ i ¦
The anorectic utility of other compounds described
her~in can also be shown in the following procedure.
Six qroups of 12 each male Sprague Dawley derived,
COBS rats from Charles River Breeding Laboratories, (Portage,
Michigan) were housed in individual cages, maintained on a 12
hour light-dark cycle with the liqht being on from 6 a.m. to
6.p.m. and given ad libitum access to water and rat feed
(Ralston Purina Rat Chow~ #5001). Twenty-four hours prior
to drug testing all ~o~ w~s removed from the cages. Groups
of 12 rats each were matched on the basis of body weight.
Forty-five minutes before they were again given access to
food t~e rats were given, intraperitoneally, either one of
the five experimental compounds or its vehicle ~the control
group). A single dose of 32 milligrams per kilogram of body
weight of the compounds was administered. All animals
received an injection volume of 2 milliliters per kilogram of
body weight. The amount of ood consumed after two hours of
access to food was measured. The mean food intake for each
test compound group is presented as a percentage of its
vehicle control group in Table 2.
Table 2
Compound
Described in Food Intake % Statistical
Example Dose ~ of Control Significance
28 32 mg/kg 12 51% p ~.001
2~3 32 mg/kg 12 76% p = .06
32 mg/kg 12 61~ p C .002
33 32 mg/kg 12 70% p ~ ,02
41 32 mg/kg 12 53% p < .01
~3~
Each of the giverl compounds o the present invention
produced a decrease in food intake as compared with the control
group. The p-values derived from statistical comparisons are
presented in the last column. Only the results of the co~pound
from Example 29 marginally missed the conventionally acceptable
p-value of p=.05. This could indicate that a somewhat higher dose
o~ this compound would be required for a statistically significant
reduction in food intake.
Compounds of formula II are useful as intermediates for
the benzothiazine derivatves presently being disclosed and claimed.
Those skilled ;in the art will appreciate that the
characterizing pharmacological responses to embodiments o this
invention specified above are intended merely for purposes of
illustration and, accordingly, are not to be construed as either
delimiting or exclusionary.
For therapeutic purposes, the compounds of this in~ention
are ordinarily combined with one or more adjuvants appropriate to
the ;ndicative route of administration. If per os, they ~ay be
mixed with lactose, sucrose, starch powder, cellulose esters of
~o alkanoic acids, cellulose alkyl ethers, talc, stearic acid,
magnesium stearate, magnesium oxide, sodium and calcium salts of
phosphoric and sulfuric acids, gelatin, acacia, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alchohol, and thus tableted
or encapusulated for convenient administration; alternatively,
they may be dissolved or suspended in water or a comparably
innoduous liquid. Parenteral administration may be effected via
~terile fluid and ad mixture with water, polye'hylene glycol,
propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil,
.
6esame oil, benzyl alcohol, so~ium chloride and/or Yarious
buffers. O~her adjuvants and modes of adminstration are well and
widely known in the pharmaceutical arts; see for example, F~Wo
~Sartin et. al., "Remington's Pharmaceutical Sciences", 14th
edition, Merck Publishing Co., Eaton Pennsylvania, 1965.
Appropriate dosages in any given instance, of course,
depend upon the nature and severity of the condition treated, the
route of administration, and the species of ma~mal involved,
including its size and any individual idiosyncrasies which
obtained.
11 C~mpounds of this inven~ion when M is not an amino group
can be prepared as follows: a 2H-1, 4-ben~othiazin-
3-(4H)-one of the formula
N~N~
!~wherein M is hydrogen, halogen, nitro and/or alkoxy containin~ 1
''! to 4 carbon atoms and, when M is other t~an alkoxy, ~ i9 hydrogen,
whe~ M is alko~y, N is hydrogen or the same alkoxy, i5 heated in
1, 4-dioxane with diphosphorus pentasulfide to obtain a
corresponding thione comprehended by the formula
O M- ~ ~
Such a thione is contacted with sodium hydride in
~iL9;36(~
. .
tetrahydrofura~ u~der nitrogen,',and the resultant sodio derivative
i~ contacted in situ with ;odomethane to obtain a corresponding
3-methylthio~2 H-l, 4-benzothiazine comprehended by the formul~
N
Such a methythio compQund is heated in N,
~-dimethylformamide under nitrogen with the sodio deri~ative of an
optionally substituted 2-phenylacetonitrile prepared in situ by
oontacting the nitri e with sodium hydride, whexeby a
correspondingly optionally substituted ~-phenyl-2-t2, 3-dihydro-4
H-l, 4-benzothiazin-3-ylidene] acetonitrile is obtained which is
comprehended by the formula
~ ~ 1 C(CN)~r
_ .
~936~
. .
The~e nitrile~ are hy~rolyzed in sulfuric acid/water
601utions to afford 'he corresponding amides
M ~`lc ~CONH2 ) Ar
/) ' ~ ~,
Such an amide is contacted in N, ~-dimethylforma~ide
under nitrogen with a aimethyl or diethyl ketal of the formula
(C1~3~C2H5)
N (CH3) 2
O ~CH3/C2H5 ~ .
.
to give the corresponding adduct
,
C (~r) C~=C~N ((~113~C2l~5) 2 (A~
- . - ,
1~
6~
. .
These adducts are converted to the corresponding
tricyclic systems by two methods: method A, wherein
intermediate compound A is treated with bis (dimethylamino)
methoxy methane in DMF at 55 degrees to 60 degrees C for 3 to
18 hours; method B, wherein the af~,rementioned adducts
represented by intermediate compound A are converted to
tricyclic pyrimidones by heating this adduct at 80 to 140
degrees centigrade
(~
~5
~ ' ' .
in DMF from 1 to 6 ho~rs. These systems are treated with bis
(dimethylamino~ m~thoxymethane for 2 to 24 hours at 50 to 80
degrees centigrade and the resultant products
.3~
. .
.
are then heated in aqueou~ DMF ~or 2 to lE~ hour~ to afford
the desired tricyclic pyridones
~5
H Ar
(>' ~ ~ ,
A 4-phenyl-5~-pyrido [3,4-b] [1,4] benzothiazin-3~2H)-
one of the - formula
. .
)1N~
H
7 wherein M=N=EI
12
~9,.~.6q~
"
i~ contacted in N, N-dimethylform~mide with an iodoalkane, in
the presence of potassium carbonate to obtain a corresponding
2-alkyl-4-phenyl-5H-pyrido [3,4-b~[1,4~ benzothiazin-
3(2H)-one comprehended by the formula
1) !
ALKYL
H ~ ~ A~' .
and which in turn is heated in N,N-dimethylformamide with an
iodoalkane in the presence of potassium carbonate to obtain a
corresponding 2,5-dialkyl-4-p~enyl-5H-pyrido [3,4-b] C1,4
~enzothiazin 3(2H)-one comprehended by the formuia
~ ~ -ALKYL
N I ~ ~ O
AL~YL Ar
- 13
Such a 2~5 dialkyl-4-~hcnyl-5H-pyrido [3, 4-b~ ~1,4~
benzothiazin-3(2H)-one is contacted with ethaneperoxoic acid
in acetic acid to obtain a 10-oxide comprehended by the
formula
N~'rO
, v 3R ~ Ar
and such a 10-oxide or its im~ediate precursor is heated with
ethaneperoxoic acid in acetic acid to obtain a corresponding
10,10-dioxide comprehended by the formula
Op I
N~ N3~o
. R' Ar
Alternatively, a 4-phenyl-SH-pyrido L 3, 4~b] [1, 4]
benzothiazin-3(2H~-one of the formula .
~ R
~ R' ~F l
. , ~4
~93~
.
iB (1~ heated with bromine in a mixture of carbon
tetrachloride and acetic acid to obtain a corresponding
8-bromo compound comprehended by the formula
Br ~--,~R
R' Ar
or (2) contacted with a cold mixture of nitric and sulfuric
acids to obtain a corresponding 8-nitro 10-oxide comprehended
by the formula
, . . l
02N~-R
R~ Ar
which in turn is (1) heated with triphenylphosphine in a .
mixture of tetrachloromethane and acetonitrile to obtain a .
corresponding 10-desoxidic compound comprehended by the
formula
R' ~r .
and (2~ heated with stannous chloride dihydra~e in a mixture
of hydr~chloric and ~cetic acid~ to obtain -- upon
neutralizatisn -- a corresponding ~-amino 10-desoxidic
compound compxehended by the formula
ll2N ~ -R
l`J. -~ Ar .
.
Finally, an acid addition salt of the invention is obtained
by contacting -- ordinarily in a solvent medium -- an amino
compound of the preceding formula with an inor~anic or strong
organic acid such as hydrochloric, hydrobromic, hydriodic,
nitric, phosphoric, sulfuric or the methyl or ethyl ester
thereof, sulfamic, benzenesulfonic, methylbenzenesulfonic,
acetic, 2-hydroxy~propanoic, 3-phenyl-2-propanoic, butanedioic,
2, 3-dihydroxy-butanedioic, 2 butenedioic, 2-hydroxy-1,2,3-pro
panetricarboxylic~ gluconic, ascorbict benzoic, or the like,
the relative amount of amino compound contacted being
determined by the basicity of the acid and the stoich;ometry
elected where options ar~ presented. Those substituted
p~enyl acetonitriles which are appropriate for Method A may
include but should not be limited to:
16
3~
~-chlorophenylacetonitrile, o-çhlorophenylacetonitrile~
~-fluorophenylacetonitrile, m-trifluoromethylphenyl
acetoni trile, phenylacetonitrile. Those subs~ituted
phenylacetonitriles appropriate for Method B may include but
should not ke limited to ~-bromophrjnylacetonitrile,
p-fluorophenylacetonitrile, ~-methoxyphenylacetonitrile.
Use of the appropriately substituted 2H-l,
4-benzothiazin-3-(4H)-one such as those halogenated at the 5,
6, or 7-position, or the 5-nitro derivative or the 6,
7-dimethoxy derivative in the previously described sequence
and various substituted phenylacetonitriles as described will
produce the desired pyridones with this corresponding
substitution patterns on both the fused aroma~ic ring and the
phenyl substitutent of the pyridone ring.
In addition use of various disubstituted
phenylacetonitriles such as 3,4-dichloro-or 2,6-dichloro- or
2,4~dichloxo-for the monosubstituted phenylacetonitriles in
either Method A or Method B will result in disubs~itute~
phenyl groups on the pyridone ring. The fused aromatic ring
of these tricycles pyriaones may be unsubstituted, mono- or
di~iubstituted.
Throughout the foregoing preparative disclosure, R,
R', R", R''',M, No X, Y, and Z retain the meanings originally
assigned~ -
17
~JI9~3~
The following examples~describe in detail compound~illustrative of the present invention and methods which have
been devised for their preparation. It will be apparent to
those skilled in the art that many modifications, both o~
materials and of methods, may be practiced without departing
from the purpose and intent of this disclosure. Throughout
the examples hereinafter set forth, temperatures are giv~n in
degrees Centigrade and relative amounts of materials in part
by weight, except as otherwise noted.
!) ~ LE 1
In a one liter flask is placed 10.8 parts of pre-
washed sodium hydride in 150 parts of N,N-dimethyl-formamide
~DMF) at room temperature. After stirring for five minutes
under nitrogen atmosphere, 30 parts of 2H-l,
4-benzothiazine-3~4H~-thione~J. Mea. Chem., 12, 290(1969)] is
added in portions over a period of 30 minutes and
continuously stirred at room temp~rature for 20 minutes. To
the reaction mixture is then added 15 parts of methyl iodide
and the mixture stirred at room temperature for 20 minutes
under nitrogen. Remsval of solvent by vacuum distillation
under nitrogen affords 3-methylthio-2~-1,4-benzothiazine as
the residue. Since the product is subject to spontaneous
hydrolytic decomposition, it is not usually isolated for the
purposes of this invention but instead employed as the
solution in DMF preparable via the foregoing procedure.
EX~MPLE 2
A mixture of 12 parts 50% sodium hydride/mineral oil
dispersion previously washed with hexane to remove the oil is
18
36~
~uspend~d in 300 ml of DMF und¢r a nitrogen atmosphere and is
treated with 32 parts of p-chlorophenylacetonitrile. After
the mixture is stirr~d at room temperature for 15 minutes to
2 hours, 30 parts of 3-methylthio-2H-1,4-benzothiazine from
~xample 1 is added to the mixture and the reaction mixture
stirred at room temperature for one hour.
The mixture is neutralized with acetic acid and
diluted with one to two volumes of water. The mixture is
stirr~d at room temperature for 30 minutes during which time
th2 product which preciFitated from the reaction mixture is
filtered and dried to yield (2H-1~4-benzothiazin-3(4H)-
ylidene)(4-chlorophenyl)acetonitrile melting at approximately
137-133.
EXAMPLE ?
_ .
Substitution of 32 parts of o-flurophenylacetonitrile
for the 32 parts of p-chlorophenylacetonitrile in Example 2
affords by the procedure therein detailed, (2H-1,4-benzothiazin
-3(4H)-ylidene~(2-EIuorophenyl) acetonitrile.
EXAMPLE 4
__ .
Substitution of 32 parts of o-chlorophenylacetonitrile
for 32 parts of p-chlorop~enylacetonitrile in Examp3e 2
affords~ by the procedure therein detailed; (2H-1,4-
benzoth;azin-3(4H)-ylidene)(2-chlorophenyl) acetonitrile
melting at about 155-158~.
EXAMPLE 5
.
Substitution of 32 parts of m-trifluoromethyl-
phenylacetonitrile for 32 parts of p-chlorophenylacetonitrile
c~lled ~or in Example 2 affords, by the procedure therein
19
36~
I
detailed, (2H-1,4-benzothiazin 3(4H~-ylid~ne [3~(trifluoro-
methyl) phenyl3 acetonitrile melting in the range 142-145.
EXAMPLE 6
Substitution of 32 parts of phenylacetonitrile for
32 parts of p-chlorophenylacetonitrile in Example 2 affords,
by the procedure therein described, (2H-1,4-benzothia~in-3(4H)-
ylidene) phenylacetontrile.
EXAMPLE 7
._
Substitutîon of 32 parts of either
o-methylphenylacetonitril~e/~;m-methylphenylacetonitrile/ or
p-methylphenylacetonitrile for 32 parts of
p-chlorophenylacetonitrile in Example 2 affords, by the
procedure therein described respectively, ~2H-1,4-
benzothiazin-3(4H3-ylidene)(2-methylphenyl) acetonitrile,
(2H-1,4-benzothiazin-3~4H)-ylidene)(3-methylphenyl)acetonitrile
and (2H-1,4-benzothiazin-3(4H)-ylidene)l4-methylphenyl)
acetonitrile.
EXAMPLE 8
= == .... = =
A mixture of 30 parts of (2H-1,4-benzothiazin-3(4H)-
ylidene)~4-chlorophenyl)acetonitrile, 180 parts concentrated
sulfuric acid and 18 parts watex i5 stirred at room
temperature for 1 1/2 hours. The mixture i~ cooled to 0-5
and diluted with 1 to 2 volumes of water which results in a
crystalline solid which is-filtered, dried and crystallized
from methanol to afford crystalline 2-~2H-1,4-
benzothiazin-3(4H~-ylidene)-2-(4-chlorophenyl9acetamide
melting at about 188-191D.
;3~
XAMPLE 9
Substitution of 30 part~ of (2H-1,4-benzothiazin-3
(4H)-ylidene) phenyl acetonitrile for 30 parts of
(2H-1,4 benzothiazin-3(4H)-ylidene)(q-chlorophenyl)
acetonitrile in Example 8 affords, by the procedure therein
described, 2-(2H-1~4-benzothiazin-3(4H)-ylidene3-2-phenyl-
acetamide melting at about 149-151.
EXAMPLE 10
_ .
Substitution of 30 parts of (2H-1, 4-benzothiazin-3
(4H)-ylidene)(2-chlorop~.~ny~) acet~nitrile for 30 parts of
~2H-1,4-benzothiazin-3(4H)-ylidene)(4-chlorophenyl)
ac~tonitrile in Example 8 affords, by the procedure therein
described, 2-~2H-1,4-benzothiazin-3(4H)-ylidene-2-(2-
chlorophenyl) acetamide melting in the range of 167-169.
EXAMPLE 11
Substitution of 30 parts of(2H-1, 4-benzothiazin-3
(4H)-ylidene)~3-trifl~oromethylphenyl)-acetvnitrile ~or 30
parts of (2H-1,4-benzothiazin-3~4H)~ylidene)(4-chlorophenyl)
acetonitrile in Example a affords, by the procedure therein
20 described, 2-(2~-1, 4-benzothiazin-3(4H~ylidene)-2 [3-
(trifluoromethyl)phenyl] acetamide melting in the range of
167-168.
EXAMPLE 12
.
Substitution of 30 parts of 2H-1, 4-benzothiazin-3(4H)
-ylidene)(2~fluorophenyl~ acetonitrile for 30 parts of
(2H-1,4-benzothiazin-3(4H)-ylidene)~4 chlorophenyl~
acetonitrile in Example 8 affords, by the procedure therein
described, 2-(2H-1,4-benzothiazin-3(4H)-ylidene-2 (2-
21
36~
. .
fluorophenyl) acetamide melting in the range of 156-158.
EX~PLE 13
Substitution of 30 parts of either
2H-1,4-benzothiazin-3(4~)-ylidene (2-methylphenyl)
acetonitrile, 2H-1,4-benzothiazin-3(4H)-ylidene
~3-methylphenyl) acetonitrile or 2H-1, 4-benzothiazin-3~4H)-
ylidene (4-methylphenyl) acetonitrile in Example 8 affords,
by the procedure therein described respectively, 2-(2H-1,4-
benzothiazin-3(4H)-ylidene~2-(2-methylphenyl) acetamide,
10 2-(2H-1,4-benzothiazin-3~4H)-ylidene-2-(3-methylphPnyl)
acetamide and 2-(2~-1,4-benzothiazin-3(4H)-ylidene-2-~4
methylphenyl) acetamide.
EXAMPLE 14 (MFTHOD A)
In a one ~iter flask equipped with a magnetic
stirrer are placed 35 parts of 2-(2H-1,4-benzothiazin-3(4H)-
ylidene-2-(4-chlorophenyl) acetamide, 300 parts of DMF and 20
parts of dimethylformamide diethyl acetal reagent. The
~ixt~re is stirred at room temperature overnight, and 42
parts of methoxy(dimethylamino) methane is then added. The
mixture is heated to 50 for six hours, cooled to room
temperature, and poured onto about 400 parts of water and
stirred at room temperature. The oily semi-solid which
forme~ is collected, triturated with methanol, filtered and
dried.
The yellow material is further triturated with about
500 p~rts of methanol with heating then cooled~ and the solid
is collected, washed with ethyl acetate followed by ether and
dried. The yellow crystalline ~olid is recrystallized
~`
f~om aqueous DMF to yield 4~(4-chlorophenyl)~5H-pyrido[3,4-b~
[1,4] benzothiazin-3~2H)-one which melts above 330.
EXAMPLE 15
Substitution of 35 parts of 2-(2H-1, 4-benzothiazin-
3(4H~-ylidene-2-(phenyl) acetamide called for in Example 14
affords, by the procedure there detailed, 4-phenyl-5H-pyrido
[3,4-b][1,4] benzothiazin-3(2H)-one melting at about 266-271.
EXAMPLE 16
Substitution of 35 parts of 2-(2H-1, 4-benzothiazin-3
(4H)-ylidene-2-(2-chlorophenyl) ace-tamide called for in
Example 14 affords, by the procedure there detailed~
4-(2-chlorophenyl)-5H-pyrido[3,4-b][1,4] benzothiazin-312H)-one
melting at about 320-323.
EXAMPLE 17
Substitution of 35 parts of 2-(2H-1, 4-benzothiazin-
3(4H)-ylidene)-2-[3-(trifluoromethyl)phenyl] acetamide called for
in Example 14 affords, by the procedure therein described,
4-[(3-trifluoromethyl)phenyl]-5H-pyrido [3,4-b][1,4] benzothia-
zin-3(2H)-one melting at about 268-270C.
_AMPLE 18
Substitution of 35 parts of 2-(2H-1, 4-benzothiazin-
3(4H)-ylidene-2(2-fluorophenyl3 acetamide called for in
Example 14 affords, by the procedure therein described, 4-
(2-fluorophenyl)~5H-pyrido[3,4-b][1,4] benzothiazin-3(2H)-
one, which melts above 300.
EXAMPLE_l9
Substitution of 35 parts of either 2-(2H-1,4-
benzothiazin-3(4H)-ylidene-2-(2-methylphenyl)
~ - 23 -
acetamide, 2-(2~3-1,4-benzothiazin-3(4E~ ylidene-2~(3-
methylphenyl) acetamide or 2-(2H-1,4-benzothiazin-3(4H)-ylidene
-2--(4 methylphenyl) acetamide called for in Exa~ple 15
affords by the procedure therein detailed respectively 4-(2-
methylphenyl)-5H-pyrido [3~4-b~cl~4] benzothiazin-3(2H)-one, 4-
(3-methylphenyl-5H-pyrido ~3,4-b~[l/4] benzothiazin-3(2H)-one
and 4-(4-methylphenyl)-pyrido ~3,4-b~[1,4] benzothiazin-3(2H)
-one. D
EXAMPLE 20
Substitution 6f~3~ par!ts of p-fluorophenylacetonitrile
for the 32 parts of ~-chlorophenylacetonitrile in example 2
affords by the procedure therein detailed (2H-1, 4-benzothiazin
-3(4H)-ylidene)(4-fluorophenyl) a~etonitrile melting at about
120-122C.
EXAMPLE 21
Substitution of 32 parts of p methoxyphenylacetonitrile
for the 32 parts of p-chlorophenylacetonitrile in example 2
affords by the procedure therein described (2H-l,
4-benzothiazin-3(4H~-ylidene)(4-methoxyphenyl)acetonitrile
melting at about 1~1-153C.
EXAMPLE 22
Substitution of 32 parts of p-bromophenylacetonitrile
for the 32 parts of p-chlorophenylacetonitrile in example 2
affords by the procedure therein described (2H-1,
4-benzothiazin-3(4H)-ylidene~(4-bromophenyl) acetonitrile
melting at about 155-157C.
EXAMPLE 23
Substitution of 32 parts of either 3,4-
dicholorophenylacetonitrile, 2,4-dichlorophenylacetonitrile or
. .
2,6-dichlorophenylacetonitrile in Example 2 affords by the
procedure therein descrihed respectively (2H-1 4-benzothiazin-
3(4H)-ylidene)(3,4-dichlorophenyl) acetonitrile, (2H-l,
4-benzothiazin-3(4H)-ylidene~(2,4-dichlorophenyl)
acetonitrile, or ~2H-1,4-benzothiazin-3(4H)-ylidene3(2,6-
dichlorophenyl) acetonitrile.
EXAMPLE 24
S~bstitution of 30 parts of (2H-1, 4-benzothiazin-3(4H)
ylidene)(4-fluorophenyl) a~etonitrile for the 30 parts of
,0 substrate of example 8 affords by the procedure therein
described 2-(2H-1,4-bellzvth~,dzin-3(4H)-ylidene)-2-(4-
fluorophenyl) acetamide melting at about 190-192~C.
EXAMPLE 25
Substitution of 30 parts of (2H-1, 4-benzothiazin-3
t4H)-ylidene)(4-methoxyphenyl) acetonitrile or the 30 parts
of substrate of Example 8 affords by the procedure therein
described 2 (2H-l, 4-benzothiazin-3(4H)-ylidene)-2-(4-
methoxyphenyl) acetamide melting at about 183-184C.
EXAMPLE 26
'0 Substitution of 30 parts of (2H-1, 4-benzothiazin-3
~4H)-ylidene)(4-bromophenyl) acetonitrile for the 30 parts of
substrate of example 8 affords by the procedure therein
described 2-(2H--1, 4-benzothiazin-3(4H)-ylidene)-2-(4-
bromophenyl) acetamide melting at about 209-210C.
EXAMPLE 27
Substitution of 30 parts of either
(2H-1,4-benzothiazin-3(4H)-ylidene)(3,4-dichlorophenyl)
acetonitrile, (2H-1),4-benzothiazin-3~4H)-ylidene)(2,4-
3~
dichlorophenyl~ acetonitrile, or ~2H-1,4~benzothiazin-3(4H)-
ylidene)(2,6-dichlorophenyl~ acetonitrile fox the substrates
of exa~ple 8 affords by the procedure therein d~scribed
respectively 2-~2H-1,4-benzothiazin-3(4H)-ylid ne)-2-(3,4-
dichlorophenyl) acetamide, 2-(2~1,J4-ben~othiazin-3(4H)-
ylidene)-2-(2,4-dichlorophenyl) acetamide and 2-(2H-1,4-
benzothiazin-3(4H)-ylidene)-2-(2,6-dichlorophenyl acetamide.
EXAMPLE 28 (~ethod B~
To 4 parts of 2-(2H-1,4-benzothiazin-3(4H)-
ylidene)-2-(4-fluorophenyl3 acetamide in 80 parts of DMF is
added 6 parts dimethylformamide diethyl acetal and the
reaction mixture was stirred at room temperature for 2 to 6
hours then heated at 80-140C for 1 to 6 hours. After
cooling 6 parts of methoxy-bis-(dimethylamino) methane is
added and the reaction mixture then heated at 50 to 80C for
2 to 24 hrs. The cooled reaction mixture is then ailuted
with 40 parts of water and refluxed for 2 to 18 hr~ Upon
cooling the precipitate present was collected and
recrystallizea from aqueous DMF to give 4-~4-fluorophenyl)-5~-
pyrido [3,4-b] Cl,4] benzothiazin-3(~H~-one which melts above
3000
EXAMPLE 29
Substitution of 4 parts of 2-(2H--1,4-benzothiazin-3
(4H3-ylidene)-2-(4-methoxyphenyl) acetamide for the substrate
in example 28 affords by the procedure therein described
4-(4-methoxyphenyl)-5H-pyrido [3, 4-b~l, 43
ben~othiazin-3(2H~one melting above 300C.
EXAMPLE 30
Substitution of 4 parts of 2-(2H-1, 4-benzoth;azin-3
~a
~6
36~)~3
. .
(4H)-ylidene~-2-(4-bro~ophenyl~ acetamide for the substrate
o~ example 28 affords by the p~ocedure therein described
4-(4-bromophenyl)-5H-pyrido ~3,4-b]~l, 4] benzothiazin-3(2~-
one melting above 300~C.
EXAMPLE 31
Substitution of 4 parts of either 2-(2H-1,4-
benzothiazin-3(4H~-ylidene)-2-(3,4-dicnlorophenyl) acetamide,
2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(2,4-dichlorophenyl)
acetamide or 2-(2H-1,4-ben~othiazin-3(4H) ylidene~-2-(2,6-
dichlorophenyl) acetamide for the substrate o example ~8affords by the proce~'ur~ ~`erein aescribed respectively
4-t3,4-dichlorophenyl)-SH-pyrido [3,4-b][1,4] benzothiazin-3
(2H)-one, 4-(2,4-dichlorophenyl)-5H-[3,4 b]~l,4] benzothiazin-3
(2P)-one and 4-(2,6-dichlorophenyl)-SH-pyrido ~3,4-b~[1,4]
benzothiazin-3-(2H)-one.
. EXAMPLE 32
To 10 parts of 4-(4-bromophenyl)-5~-pyrido [3,4-b3
tl,4] benzothiazin-3(2~ one suspended in 300 parts of ~MF is
added 4 parts of cuprous cyanide and the reaction mixture is
refluxed for 2 to 12 hours. After cooling, water is added
and the solution extracted with ethyl ac~tateO The combined
extracts are washed with saturated NaCl solution and dried.
Solvent removal gives a residue which upon recrystallization
from aqueous DMF gives 4-(4-cyanophenyl)-5H-pyrido C3,4-b]
[1,4] benzothiazin-3(2H)-one, which melts above 290C.
EXAMPLE 33
To 10 parts pyridine hydrochloride heated to 170
under a stream.of nitrogen is added 0.5 parts of 4-(4-
27
3~
methoxyphenyl)-5H-pyrido~3, 4-b~{1,4] benzothiazin-3~2H)- one
~n one portion. The reaction mixture is refluxed for 45
minutes, cooled, water is added and the solid which forms is
collected and dried to yield 4-(4-hydroxyphenyl)-5H-pyrido[3,4-
b][l,4] benzothiazin -3(2H)-one, m.p. greater than 300.
EXAMPLE 34
To 3 parts of the product of the process described
in Example 14, 4-(4-chlorophenyl)-5H-pyrido~3,4-b]~1,4]
benzothiazin-3(2H)-one, suspended in 5 parts acetic acid is
added and 1 part 40% per`)cet~ic aci~. After ten mi~utes
reaction time, water is added to the now homogeneous reaction
mixture and the precipitate which forms is collected and
recrystallized from aqueous DMF to yield white needles of
4-(4-chlorophenyl)-5H-pyrido t3,4-b] [1~43 benzothiazin-3(2H)-
one 10 oxide, melting above 310.
EXAMPLE 35
Suhstîtution of the products-from examples 15, 16,
17, 18, 19, 28~ 29, 30, 31, 32 and 33 for the 4-(4-
chlorophenyl)-5H-pyrido ~3, 4-b~ Cl,4] benzothiazin-3(2H)-one
in example 34 affords the corresponding 4-(aryl)-5H-pyrido
C3,4-b3[1, 4] benzothiazin-3~2H)-one 10 oxide.
EXAMPLE 36
A mixture of 1 part of 4-(4~chlorophenyl)-5~-pyrido
[3, 4-b]~l, 4] benzothiazin-3(2H7-one, 10 parts of
ethaneperoxoic acid, and 10 parts of glacial acetic acid is
~tirred and heated at 25c to 60 for 1 to 20 hours, whereupon
insoluble solids are filtered, washed with ethyl acetate,
28
~;36~
. .
and dried in vacuo at 110 to give 4-(4-chlorophenyl3-5H-pyrido
t3.4-b~ benzothiazin-3(2H~-one 10,10-dioxide melting
above 300~.
EX~MPLE 37
-
Substitution of the products from example 35 for the
starting material in example 36 will give the corresponding
4-(aryl)-5H-pyrido [3, 4-b~l, 4~ benzothiazin-3(2H)-one lU,
10-dioxide.
XAMPLE 38
Substitution of the corresponding substituted 2H-l,
4 ben~othiazine-3(4H)-thione, derived from the appropriate
2H-1, 4-ben~othiazin-3(4H)-ones such as the
5-chloro-deri~ative [J. Chem. Soc., 893 (1945)] or the
6-chloro-deriva~ive [Can. J. Chem., 44, 1733 (1965)~ or the
7-chloro-derivative [Can. J. Chem., 48, 1859 (1970)] or the
6-1uoro-derivative ~J. Chem. Soc., 787 (1952) or the
6-bromo-derivative [J. Chem. Soc., 2624 ~1957) or the
5-nitro-derivative [Ann. Chem. ~Rome) 588, 1226 (1968)~ or
the 6, 7 dimethoxy aerivative ~J. Proc. RoyO Soc., ~. S.
Wales, 71, 112 (1938)~ according to the procedure described
in J. Med. Chem., 12, 290 (1969), in example 1 will afford
the corresponding 3-methylthio derivatives. These in turn
when substituted in examples 2, 3, 4, 5, 6, 7, 20, 21, 22 or
23 will give the corresponding acetonitrile derivatives.
These turn when treated wîth aqueous sulfuric acid as
described in example 8, 9, 10, 11, 12, 13, 24, 25, 26, or 27
will give the corresponding acetamide derivatives. These in
turn when treated with DMF diethyl acetal then methoxy bis
(dimethylamino) methane a~
^
6~
. .
described in examples 14 thru l~jwill give the corresponding
4-(4-chlorophenyl~-5~-pyrido [3,4-b~[194] benæothiazin-3(2H~
one or 4-phenyl-5H-pyrido t3,4-b~ [1,4] benzothiazin-3(2H)-one
or 4-(2-chlorophenyl~-SH-pyrido E3, 4-b3 tl,4] benzothiazin-3(2
H)-one or 4-(3-trifluoromethylphenyl) 5H-pyrido [3,4-b] [1,4
benzothiazin-3(2H~-one ox 4(2-fluorophenyl)-SH-pyrid~
[3,4-b ] tl,4] benzothiazin-3(2H)-one with the respective
substitution on the benzene ring. Alternatively, when these
acetamides are treated with DMF diethyl acetal, methoxy bi~
(dimethylamino) methane and water as described in examples 28
thru 31, they will give the correspondin~ 4-(4-fluorophenyl)-5H
-pyrido [3, 4-b] [1, 4~ benzothiazin-3(2H)-one or 4-(4-
methoxyphenyl)-5H- pyrido [3, 4-b] Cl, 4] benzothiazin-3(2H)-
one or 4(4-bromophenyl)-5H~pyrido [3, 4-b] Cl, 4~ benzothiazin
-3(2H) one with the respective substituents on the benzene
ring.
EXAMPLE 39
To a solution of l part 4-(4-chlorophenyl)-5H-pyrido
t3,4-b3tl,4~ benzothiazin-3(2~) one in 25 parts of
concentrated hydrochloric acid is added ~S parts methanol.
The solution is warmed to the mean boiling point of the
alcohol. Another 5~ parts of methanol is added and heating
continued until nearly all the solid material is dissolved.
The hot solution is filtered to remove undissolved solids and
upon concentrating the solution volume of filtrate in a
suction flask, yellow needles of 4-(4-chlorophenyl~ 5H-pyrido
t3,4-b]tl,4] benzothiazin-3-ol hydrochloride result, melting
above ~OO~C.
. 30
., .
6t)~
.
EXAMPLE 40
Substitution of the products from examples 15, 16,
17, 18, 19, 28, 29, 30, 31, 32 and 33 for the 4-(4-
chlorophenyl)-5H-pyrido L3, 4-b~ [1,4] benzothiazin-3(2H)
one, in example 39 affords the corresponding 4-(aryl)-5H-pyrido
~3, 4-b~tl,4~ benzothiazin-3-ol hydrochlorides.
XAMPLE 41
To a ~olution of 1 part of ~-[(3-trifluoromethyl)
phenyl]~5H-pyrido [3, 4-b~l, 4~ benzothiazin-3(2H3-one in 20
10 parts hydrochloric aci~ i~ a~ded 60 part6 methanol in 10
pa~t~ portions with swirling and heating on a steam bath~
Near the boiling point of the alcohol, the hot solution is
filtered through a scintered glass funnel. Then the filtrate
i~ concentrated with vacuum while keeping the liquid warm.
After 3 portions of hydrochloric acid, the liquid is
es~entially finished crystallizing as short, fluffy needles.
These are collected, washed, dried in air and ground u~ing
~ortar and pe~tle to a flour consi~tency to yield
4-[(3-tri~luoromethyl~phenyl]-5H-pyrido t3, 4-b~[1,4
benzothiazin~3-ol, hydrochloride as a yellow powder.
~XAMP~E ~2
To 0.5 parts ~-(2-chlorophenyl)-5H-pyrido
[3,~-b~[1,4~ benzothiazin-3(2H)-one suspended in 10 part~
concentrated hydrochloric acid i~ added 10 part~ methanol
while gently warming the solution on a steam bath. A brown
gum i6 formed and the second 10 part portion of methanol is
added to substantially solubilize the gumq Near the boiling
point of the alcohol, the solution i8 iltered. The filtrate
iB
31
119~6~
. .
concentrated on a ~team bath using a nitrogen stream. A gold
precipitate formed which was air dried and pulverized to
yield a bright yellow powder, 4-52-chlorophenyl)-5H-pyrido 3,
4-b~ benzothiazin-3-ol, hydrochloride.
_AMPLE 43
Substitution of 0.25 parts of 4-~2-fluorophenyl)-5H-
pyrido[3,4-b]~1,4] benzothiazin-3(2H)-one for the 4-(2-
chlorophenyl)-5H-pyrido t3,4 b~[l,4~ benzothiazin-3(2H)-one
called foz in example 42, using 10 parts concentrated
hydrochloric acid with 25 parts methanol, affords by the
procedure detailed thereln 4-~2-fluorophenyl)-5H-pyrido 3,
4-b3 [1, 4] benzothiazin-3-ol, hydrochloride.
3~
