CA1193600A - 4h-1,4-benzothiazine derivatives and intermediates - Google Patents
4h-1,4-benzothiazine derivatives and intermediatesInfo
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- CA1193600A CA1193600A CA000465592A CA465592A CA1193600A CA 1193600 A CA1193600 A CA 1193600A CA 000465592 A CA000465592 A CA 000465592A CA 465592 A CA465592 A CA 465592A CA 1193600 A CA1193600 A CA 1193600A
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Abstract
ABSTRACT OF THE DISCLOSURE
4H-1,4 benzothiazine derivatives having anorectic activity and their preparation including intermediate compounds are disclosed.
4H-1,4 benzothiazine derivatives having anorectic activity and their preparation including intermediate compounds are disclosed.
Description
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
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~
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~
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
~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 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:
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~ -~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 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.
__ .
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~.
.
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 36~
I
detailed, (2H-1,4-benzothiazin 3(4H~-ylid~ne [3~(trifluoro-methyl) phenyl3 acetonitrile melting in the range 142-145.
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.
._ 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.
= == .... = =
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~
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.
_ .
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.
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.
.
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 (2-36~
. .
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
'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.
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 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.
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.
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.
To 10 parts pyridine hydrochloride heated to 170 under a stream.of nitrogen is added 0.5 parts of 4-(4-3~
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.
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.
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.
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, ~;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.
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
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
~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 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:
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~ -~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 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.
__ .
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~.
.
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 36~
I
detailed, (2H-1,4-benzothiazin 3(4H~-ylid~ne [3~(trifluoro-methyl) phenyl3 acetonitrile melting in the range 142-145.
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.
._ 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.
= == .... = =
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~
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.
_ .
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.
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.
.
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 (2-36~
. .
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
'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.
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 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.
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.
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.
To 10 parts pyridine hydrochloride heated to 170 under a stream.of nitrogen is added 0.5 parts of 4-(4-3~
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.
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.
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.
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, ~;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.
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.
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)~
.
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.
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
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~
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.
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)~
.
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.
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
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~
Claims (17)
1. A process for the preparation of a compound of the formula:
wherein W represents CN, CONH2 or CON=CHNXY, wherein X repre-sents a lower alkyl of 1 to 4 carbon atoms; Y represents a lower alkyl of 1 to 4 carbon atoms; M and N each represents hydrogen, halogen, nitro, amino or alkoxy containing 1 to 4 carbon atoms; and R" represents hydrogen, methoxy, trifluoro-methyl or lower alkyl having 1 to 4 carbon atoms when R''' rep-resents hydrogen, and when R" represents halogen, R''' represents hydrogen or halogen which comprises either:
a) heating a methylthio compound of the formula:
with a 2-phenylacetonitrile of the formula:
to provide a compound of the formula:
wherein M, N, R" and R''' have the meaning stated above; or b) hydrolyzing a nitrile of the formula:
to the corresponding amide of the formula:
wherein M, N, R" and R''' have the meaning stated above; or c) reacting an amide of the formula:
with a dimethyl- or diethyl-ketal of the formula:
wherein R represents methyl or ethyl, to provide a compound of the formula:
wherein M, N, R, R'' and R''' have the meaning stated above.
wherein W represents CN, CONH2 or CON=CHNXY, wherein X repre-sents a lower alkyl of 1 to 4 carbon atoms; Y represents a lower alkyl of 1 to 4 carbon atoms; M and N each represents hydrogen, halogen, nitro, amino or alkoxy containing 1 to 4 carbon atoms; and R" represents hydrogen, methoxy, trifluoro-methyl or lower alkyl having 1 to 4 carbon atoms when R''' rep-resents hydrogen, and when R" represents halogen, R''' represents hydrogen or halogen which comprises either:
a) heating a methylthio compound of the formula:
with a 2-phenylacetonitrile of the formula:
to provide a compound of the formula:
wherein M, N, R" and R''' have the meaning stated above; or b) hydrolyzing a nitrile of the formula:
to the corresponding amide of the formula:
wherein M, N, R" and R''' have the meaning stated above; or c) reacting an amide of the formula:
with a dimethyl- or diethyl-ketal of the formula:
wherein R represents methyl or ethyl, to provide a compound of the formula:
wherein M, N, R, R'' and R''' have the meaning stated above.
2. The process as in claim 1a) wherein the heating is carried out in the presence of N,N-dimethylformamide under nitrogen.
3. The process as in claim 1a) wherein the 2-phenyl-acetonitrile reactant is used in the form of a sodio deriva-tive.
4. The process as in claim 3 wherein the sodio deriv-ative is generated in situ from the 2-phenylacetonitrile and sodium hydride.
5. The process as in claim 1a) wherein the methylthio compound is heated in N,N-dimethylformamide under nitrogen with the sodio derivative of the 2-phenylacetonitrile, said sodio derivative being generated in situ from said 2-phenyl-acetonitrile and sodium hydride.
6. The process as in claim 1b) wherein the hydrolysis is carried out by means of a sulfuric acid/water solution.
7. The process as in claim 1c) wherein the amide is contacted in N,N-dimethylformamide under nitrogen with the dimethyl- or diethyl-ketal.
8. The process as in claim 1 wherein the compound thus prepared is a nitrile of the formula:
wherein M, N, R" and R''' have the meaning stated in claim 1.
wherein M, N, R" and R''' have the meaning stated in claim 1.
9. The process as in claim 1 wherein R''' is hydrogen and the compound thus prepared is of the formula:
wherein M, N and R" have the meaning stated above.
wherein M, N and R" have the meaning stated above.
10. The process as in claim 1 wherein R''' is halogen and the compound thus prepared is of the formula:
wherein M and N have the meaning stated in claim 1 and R" and R''' both represent halogen.
wherein M and N have the meaning stated in claim 1 and R" and R''' both represent halogen.
11. The process as in claim 1 wherein the compound thus prepared is an amide of the formula:
wherein M, N, R" and R''' have the meaning stated in claim 1.
wherein M, N, R" and R''' have the meaning stated in claim 1.
12. The process as in claim 1 wherein R''' is hydrogen and the compound thus prepared is of the formula:
wherein M, N and R" have the meaning stated in claim 1.
wherein M, N and R" have the meaning stated in claim 1.
13. The process as in claim 1 wherein R''' is halogen and the compound thus prepared is of the formula:
wherein M and N have the meaning stated in claim 1 and R'' and R''' both represent halogen.
wherein M and N have the meaning stated in claim 1 and R'' and R''' both represent halogen.
14. The process as in claim 1 wherein the compound thus prepared is a compound of the formula:
wherein M, N, R'' and R''' have the meaning stated in claim 1 and R is methyl or ethyl.
wherein M, N, R'' and R''' have the meaning stated in claim 1 and R is methyl or ethyl.
15. The process as in claim 1 wherein R is methyl and the compound thus prepared is of the formula:
wherein M, N, R'' and R''' have the meaning stated in claim 1.
wherein M, N, R'' and R''' have the meaning stated in claim 1.
16. The process as in claim 1 wherein R''' is hydrogen and the compound thus prepared is of the formula:
wherein M, N, R and R" have the meaning stated in claim 1.
17. The process as in claim 1 wherein R''' is halogen and the compound thus prepared is of the formula:
wherein M, N and R have the meaning stated in claim 1 and R"
and R''' both represent halogen.
18. A compound of the formula:
wherein W represents CN, CONH2 or CON=CHNXY, wherein X repre-sents a lower alkyl of 1 to 4 carbon atoms; Y represents a lower alkyl of 1 to 4 carbon atoms; M and N each represents hydrogen, halogen, nitro, amino or alkoxy containing 1 to 4 carbon atoms; and R" represents hydrogen, methoxy, trifluoro-methyl or lower alkyl having 1 to 4 carbon atoms when R''' rep-resents hydrogen, and when R" represents halogen, R''' repre-sents hydrogen or halogen, when prepared by the process of claim 1.
19. A compound, as defined in claim 18, when prepared by the process of claim 2 or 3.
20. A compound, as defined in claim 18, when prepared by the process of claim 4 or 5.
21. A compound, as defined in claim 18, when prepared by the process of claim 6 or 7.
22. A compound, as defined in claim 18, wherein W rep-resents CN, when prepared by the process of claim 8.
23. A compound, as defined in claim 18, wherein W rep-resents CN and R''' is hydrogen, when prepared by the process of claim 9.
24. A compound, as defined in claim 18, wherein W rep-resents CN and R" and R''' are both halogen, when prepared by the process of claim 10.
25. A compound, as defined in claim 18, wherein W rep-resents CONH2, when prepared by the process of claim 11.
26. A compound, as defined in claim 18, wherein W rep-resents CONH2 and R''' is hydrogen, when prepared by the process of claim 12.
27. A compound, as defined in claim 18, wherein W rep-resents CONH2 and R" and R''' both represent halogen, when pre-pared by the process of claim 13.
28. A compound, as defined in claim 18, wherein W rep-resents wherein R is methyl or ethyl, when prepared by the process of claim 14.
29. A compound, as defined in claim 18, wherein W rep-resents when prepared by the process of claim 15.
30. A compound, as defined in claim 18, wherein W rep-resents wherein R is methyl or ethyl and R''' is hydrogen, when prepared by the process of claim 16.
31. A compound, as defined in claim 18, wherein W rep-resents wherein R is methyl or ethyl and R" and R''' both represent halogen, when prepared by the process of
wherein M, N, R and R" have the meaning stated in claim 1.
17. The process as in claim 1 wherein R''' is halogen and the compound thus prepared is of the formula:
wherein M, N and R have the meaning stated in claim 1 and R"
and R''' both represent halogen.
18. A compound of the formula:
wherein W represents CN, CONH2 or CON=CHNXY, wherein X repre-sents a lower alkyl of 1 to 4 carbon atoms; Y represents a lower alkyl of 1 to 4 carbon atoms; M and N each represents hydrogen, halogen, nitro, amino or alkoxy containing 1 to 4 carbon atoms; and R" represents hydrogen, methoxy, trifluoro-methyl or lower alkyl having 1 to 4 carbon atoms when R''' rep-resents hydrogen, and when R" represents halogen, R''' repre-sents hydrogen or halogen, when prepared by the process of claim 1.
19. A compound, as defined in claim 18, when prepared by the process of claim 2 or 3.
20. A compound, as defined in claim 18, when prepared by the process of claim 4 or 5.
21. A compound, as defined in claim 18, when prepared by the process of claim 6 or 7.
22. A compound, as defined in claim 18, wherein W rep-resents CN, when prepared by the process of claim 8.
23. A compound, as defined in claim 18, wherein W rep-resents CN and R''' is hydrogen, when prepared by the process of claim 9.
24. A compound, as defined in claim 18, wherein W rep-resents CN and R" and R''' are both halogen, when prepared by the process of claim 10.
25. A compound, as defined in claim 18, wherein W rep-resents CONH2, when prepared by the process of claim 11.
26. A compound, as defined in claim 18, wherein W rep-resents CONH2 and R''' is hydrogen, when prepared by the process of claim 12.
27. A compound, as defined in claim 18, wherein W rep-resents CONH2 and R" and R''' both represent halogen, when pre-pared by the process of claim 13.
28. A compound, as defined in claim 18, wherein W rep-resents wherein R is methyl or ethyl, when prepared by the process of claim 14.
29. A compound, as defined in claim 18, wherein W rep-resents when prepared by the process of claim 15.
30. A compound, as defined in claim 18, wherein W rep-resents wherein R is methyl or ethyl and R''' is hydrogen, when prepared by the process of claim 16.
31. A compound, as defined in claim 18, wherein W rep-resents wherein R is methyl or ethyl and R" and R''' both represent halogen, when prepared by the process of
claim 17.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US241,984 | 1981-03-09 | ||
| US06/241,984 US4356302A (en) | 1981-03-09 | 1981-03-09 | 4H-1,4-Benzothiazine derivatives |
| CA000397878A CA1180702A (en) | 1981-03-09 | 1982-03-09 | 4h-1,4-benzothiazine derivatives and intermediates |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000397878A Division CA1180702A (en) | 1981-03-09 | 1982-03-09 | 4h-1,4-benzothiazine derivatives and intermediates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1193600A true CA1193600A (en) | 1985-09-17 |
Family
ID=25669604
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000465592A Expired CA1193600A (en) | 1981-03-09 | 1984-10-16 | 4h-1,4-benzothiazine derivatives and intermediates |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1193600A (en) |
-
1984
- 1984-10-16 CA CA000465592A patent/CA1193600A/en not_active Expired
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| MKEX | Expiry | ||
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