CA1051429A

CA1051429A - Certain 6h-pyrimido (1,2-c) (1,3,5) benzothiadiazo compounds

Info

Publication number: CA1051429A
Application number: CA203,661A
Authority: CA
Inventors: Harry L. Yale; Ramesh B. Petigara
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1973-07-26
Filing date: 1974-06-28
Publication date: 1979-03-27
Also published as: US3875162A; FR2238491B1; FR2238491A1; GB1476684A; JPS5041892A; DE2435382A1

Abstract

ABSTRACT

This invention relates to compounds of the formula I

wherein m is 1 or 2; when m is 1, R occupies either position-4 or -5 of the starting 2-aminopyrimidine, but when R is halogen, it occupies only position-5; when m is 2, the two R's occupy the 4- and 5-positions of the starting 2-aminopyrimidine, but only one of the two R-substituents can be halogen and it must occupy the 5-position; R is the same or different and is hydrogen, F, C1, Br, alkyl of from 1 to 4 carbons, benzyl, phenyl or mono-substituted phenyl wherein the substituent is F, Cl, Br, I, alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, or trifluoromethyl; R' is hydrogen, F, Cl, Br, CF3, alkyl of from 1 to 4 carbons, or dialkylamidosulfonyl wherein each alkyl radical has from 1 to 4 carbons; n is 0 or 1; R" is hydrogen or alkyl of from 1 to 4 carbons; Z is S or SO2, and pharmaceutically acceptable acid-addition salts thereof and a process for preparing them and to intermediates therefor. These compounds exhibit central nervous system stimulating properties and act as muscle relaxants.

Description

lOSl~Z9 MR37 This invention relates to novel pyrimidobenzothiadiazepines, pyrimidothiadiazocines and dioxides thereof, a process for preparing them and intermediates therefor.
The compounds of the present invention have the following formula ~ ~ (CH ~ R' wherein m is 1 or 2; when m is 1, R occupies either position-4 of -5 of the starting 2-aminopyrimidinej but when R is halogen it occupies only position-5; when m is 2, the two R's occupy the 4- and 5-positions of the starting 2-aminopyrimidine, but only one of the two R-substituents can be halogen and it must occupy the 5-position; R is the same or different and is hydrogen, F, Cl, Br, alkyl of from 1 to 4 carbons, benzyl, phenyl or mono-substituted phenyl wherein the substituent is F, Cl, Br, I, alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, or trifluoromethyl; R' is hydrogen, F, Cl, Br, CF3, alkyl of from 1 to 4 carbons, or dialkylamidosulfonyl wherein each alkyl radical has from 1 to 4 carbons n is 0 or 1; R" is hydrogen or alkyl of from 1 to 4 carbons; ~ is S or SO2, and pharmaceutically acceptable acid-addition salts thereof.
The foregoing compounds possess central nervous system stimulating properties and act as muscle relaxants.

~37 lOS1429 Compounds of Formula I may be prepared by reacting a 2-aminopyrimidine II wherein R is as previously defined with an o-bromophenyl-Z-alkylene halide III wherein R" i9 as previously defined and X is chlorine or bromine. This reaction takes place in any solvent or solvent mixture in which the reactants can be dissolved and which has a boiling point of at least about 100C. Typical solvents are aromatic hydrocarbons, ethers, aliphatic alcohols or aryl-substituted aliphatic alcohols.
Toluene and xylene are examples of suitable aromatic hydrocarbons.
Monomethyl ether of ~iethylene glycol, dimethyl ether of di-diethylene glycol (diglyme), monomethyl ether of ethylene glycol or dimethyl ether of ethylene glycol (glyme) are examples of suitable ethers. n-Amyl alcohol is an example of a suitable aliphatic alcohol, while benzyl alcohol i5 an example of a suitable aryl-substituted aliphatic alcohol. Heating compounds II and III in a solvent as described above, or a mixture thereof, at temperatures from about 500a tQ abo,ut 14QC

" iO5~429 ~or a period of several hours, typically from about 3 to about 24 hours produces a pyrimidinium compound IV.
The latter is converted to an imino compound V by treating with a water miscible alcohol and an alkali metal alkoxide of up to 3 carbon atoms, or with an alkali metal carbonate, e.g-, K2CO3~ Na2C3~ RbCO3, etc-The reaction takes place at room temperature over a period of from about l to about 4 hours, or at from about 50C
to about 80C in about l hour. Compound V may be converted to the final compound I by treating with a water miscible alcohol and an alkali alkoxide of up to 3 carbons in the presence of copper at a temperature of from about 60C to about 120C for a period, typically from about 4 to about 10 days. Alternatively, IV may be converted directly to I by heating at a temperature of from about 60C to about 120C for a period, typically from about 4 to about 10 days~ in the presence of potassium carbonate and copper in a solvent such as dimethylformamide, dimethylacetamide, dichlorobenzene, trichlorobenzene, or diethylbenzene. Alternatively, IV may be converted directly to I by heating at a temperature of from about 60C to a~out 120C ~or about 4 to 10 days, typically from about 6 to about 8 days in the presence of an alkali metal hydroxIde, alkali metal carbonate, tris~alkali metal phosphate, alkali metal metaborate or alkali metal tetra~
borate in an anhydrous alcohol solvent, e.g., ethanol, propanol, butanol, pentanol in the presence of copper. Specific examples of suitable compounds include LioH, NaOH, KOH, ~OH, CsOH, Na2CO3K2cO3~ Rb2C3' CS2C3' Na3 4, 3 4 iO51~29 3 4 3 4' Na2B24' Na2B4o7~ K2B2o4, and K2B4O7, When m is 1, and when R occupies only the 5-position of II, only one isomer, I, is formed. When m is 1, and when R occupies only the 4-position of IIa, two isomers, Ia and Ib are formed via the intermediates IVa or Va and IVb and Vb, respectively. When m is 2, and since the two R's occupy only the 4-, 5-positions, two isomeric products, Ic and Id are formed. The isomers in all instances, can be separated by conventional procedures, e.g., fractional recrystallization or column chromatography.

. .

lOS14Z9 The foregoing reaction sequence is illustrated by the following equations: `

:Dx' ~.

~ N--~

~O~ ~ æ Hl -^N //~ \æ ~
~1 ~
P~U~ æ

~ ' ~ \

~ N h :~ . ~ m ~: . X
U
o~--c~z ~æ

~ P~
:

. . . -5-.

~ / ~
p:: N~ a~

~3 N~ U~
~ 3~

T ~ ~b ~

:
.

iO51'~9 ~:
.

P

N~
N
\ U I

.. ~ -.

-- m ~
u I m i~l ¦

~ \ ~ '~) J `

-- C) H

<'OZ ' ~
' ~ Z

, .
~Z-'. ~

.

~ ~ S 1 ~ ~9 MR37 The intermediates of formula III wherein n is O and Z is S may be prepared by refluxing about equimolar amounts of a l,l-dibromoalkane or a l-bromo-l-chloroalkane of 1 to 4 carbons VI with a saturated solution of Na2SO3 for a period of from about 40 to about 120 hours. The resulting l-bromoalkane-l-sodium sulfonate VII is then reacted by heating with about equimolar amounts of an o-bromothiophenol VIII in the presence of aqueous alkali to yield a sodium o-bromophenylthioalkylene-sulfonate IX. Treatment of the latter with PC15 or PBr5 at ambient temperature yields the corresponding o-bromophenylthioalkyl chloride or bromide X. The foregoing reaction sequence is illustrated by the ~ollowing equations.

Br~ H-X Na2S3 Br~CH--S03Na X=Cl or Br YI VII
VII

HS R~ /

B ~
VIII /

NaO3S-~H~ R~ ~ X ~ H~S R~

~3r~J X=Cl or 13r !3r IX X

~8~

105i~'~9 The intermediates of formula III wherein n is 1 and Z is S may be prepared by reacting a l-bromo-2-chloro-alkane of formula XI with about equimolar amounts of a compound of formula VIII in the presence of aqueous alkali.
Alternatively, a compound of formula XII may be prepared by reacting an o-bromophenylthioalkanol XIII with PC15 or PBr5. The foregoing reaction sequence is illustrated by the following equations R"

Rl" HS ~ X-CHCH2-S R' Cl-CH-CH2-Br Br VIII Br XI XII
PC13 or PBr3 ~R"
HO-~HCH2-S R' Br XIII
Compounds of formula VIII wherein R~ is H, halogen, alkyl of from 1 to 4 carbons, phenyl, dialkyl-amidosulfon~l or trifluoromethyl may be prepared by reacting an ~'~substituted aniline XXIV with N~bromosuccinimide in CC14 according to the procedure of Arcoria et al., Ann. Chim.
~Rome~, 54 139~155 ~1964) to yield an o-bromo-R'-substituted aniline XXV. The latter is treated with NaN02 in HCl and then with S02 according to the procedure of Meerwein et al., lOS~ 9 J. ~rakt. Chem. 152, 237 (1939) to yield the corresponding sulfonyl chloride XXVI. The latter is treated with Zn in H2SO4 according to the procedure of Organic Syntheses, Collective Volume I, pp. 504-506 to yield the desired o-~romo-R'-substituted thiophenol VIII. The reaction sequence is as followsc H2N ~ ~ N-bromo- 2 ~ ~ l)NaNO2- ClSO ~ ~' ~J mlde ~ ~

XXIV XXV XXVI

~2S04 HS ~ ' Br VIII

Compounds of the formula III wherein Z is SO2 may be prepared by converting a compound of formula XXV to the 2Q diazonium chloride XXVIII following the procedure of Meerwein, et al. supra, and converting the latter to the sulfonyl chloride XXIX following the procedure of Meerwein et al., supra. The sulfonyl chloride is then converted to the sodium sul~inate XXX by reduction wi~th zinc following the procedure of ~rg~nic $yntheses, Coll. Vol. 1, pp~ 492 (1941~. Reacting the sodi~um sulfinate XXX with a 1,l-dihaloalkane following the procedure o~ Michael et al., J.A.C.S., 6, p. 253 (1884) gives the compound of formula III wherein Z is S02 and n is O.
Reacting the sodium sulfinate XXX with a l-bromo-2-chloroalkane following the procedure of Michael et al., supra, gives the lQ514'~9 compound of formula III wherein Z is S02 and n is 1. The foregoing reaction sequence is illustrated by the following equations:

H2N ~ ~ R HONo ClN ~ R' ClSO ~ R' B ~ Br Br XXV XXVIII XXIX

\
X-CH-S02 R' X-Cl,Br ~ ~aSO ~ R' XXX

2 ~:.r~

i 2~
Br The compounds of the present invention may be aldministered to mammalian species as central nervous system stimulants and as muscle relaxants. In the rat, responses to the stimulant activity of the compounds of the present invention include increased activity and body tremors~ The muscle relaxant properties manifest themselves by responses that include decreased limb tone, decreased grip strength, and limb paralysis. In both the stimulant and muscle relaxant activities, the onset of activity is rapid, i.e., within about 15 minutes; the activity persists for about 2 hours or longer. In~the rat the dosage range varies from-about 6.25 to about 50 mg/kg for both activities, while in humans the dosage range varies from about 40 to about 2000 mg.
daily in about four divided dose~ for both activities.
In addition to serving as intermediates for the preparation of compounds of formula I, the pyrimidinium compounds of formula IV are themselves effective bactericides.
Microbial bioassays, as described in "The Microbial World," by R. Y Stanier, M. Doudoroff and E. A. Adelberg, ? Prent~ce-Hall, Inc., Englewood Cliffs, N.J., 3rd Ed., p. 858, are employed to determine the bactericidal properties of the pyrLmidinium compounds IV of this invention. The bacteria employed include Staphylococcus aureus, 1, Strepto-coccus pyogenes, 2, Salmonella schottmuelleri, 3, Salmonella gallinarum, 4, Pseudomonas aeruginosa, 5, Proteus vulgaris, 6, Escherichia coli, ~, Pasturella multocida, 8, and Mycobacterium tuberculosis, 9.
- In the procedure, a sterile agar plate is seeded with the test organism, and then a number of glass cylinders are iO514'~9 placed on its surface, forming a series of little cups.
A known dilution o~ the compounds of this invention is added to each cup and the entire plate is then incubated until significant bacterial growth has occurred. The compounds of this invention diffuse out of the cup into the surrounding agar and produce a zone of inhibition. In this fashion it i~ possible to find the minimum inhibiting concentration (mic), of the compound that produces a recognizable zone of inhibition. The following summarizes the data.

Micro- mic of Pyrimidinium Compound, orqanism Microqrams, (mcq)/ml Compound CompoundCompound Compound of Ex 1 of Ex. 27of Ex. 29 of Ex. 38 .
1 3.13 12.5 6.25 6.25 2 12.5 50.0 50,0 25.0

3 12.5 50.0 12.5 12.5

4 6.25 25.0 12.5 12.5 12.5 25.0 25.0 25.0 6 12.5 25.0 25.0 25.0 7 3.13 25.0 12.5 6.25 8~ 6.2S 12.5 25.0 12.5 9 0.39 6.25 1.57 0.78 ' ~ .

1~51429 MR37 The compounds of the present invention in the described dosages may be administered orally; however, other routes such as intraperitoneally, subcutaneously, intramuscularly or intravenously may be employed.
The active compounds of the present inventlorl are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic adminis-`tration, the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, cap~ules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like;
a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, i~ may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the ph~sical form of the dosage unit, for instance, tablets, pills or i()Sl~Z9 capsules may be coated with shellac, sugar, or both. A
syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
As to the pharmaceutically acceptable salts, those coming within the purview of this invention include the pharmaceutically acceptable acid-addition salts. Acids useful for preparing these acid-addition salts include, inter alia, inorganic acids, such a~ the hydrohalic acids (e.g., hydrochloric and Hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as maleic, fumaric, tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicylic, succinic acid, theophylline, 8-chlorotheophylline, p-aminobenzoic, p-acetamidobenzoic, or methanesulfonic.

~14Z~ MR37 The following examples illustrate the invention.
All temperatures given are in degrees Centigrade.

Example 1 ~(o-Bromo~henyl)thio]methanesulfonic acid, sodium salt To a solution of 40.0 g of o-bromobenzenethiol in aqueous sodium hydroxide ~10.0 g of sodium hydroxide in 40 ml of water) is added 60.0 g of bromomethanesulfonic acid, sodium salt and the mixture is heated so that the water distills~ To the dry residue is added a second portion of 40 ml of water and the distillation to dryness ~s~repeated, The dry residue is heated for three hours, cooled, and dissol~ea in 600 ml of hot water. The pH
is adJustea to 5~0 and cooled to give abou~ 63.3 g of the n~ed compound, mp~31a~

`Exa~le 2 1. chl.or.ome.th~l..sulf~de .... ~
A mL~xture of 60.4 g of I(o~bromophenyl)thio]methane-sul~onic acid, sodium salt and 98.0 g of phosphorus pentachlor~de is blended until liquified, diluted with 6aa ml of ether, and then poured on 1.2 kg of crushed ice~
The~ether layer is separated, washed, dried, and concen-t~ated to ~i~e aBout 43~7 g of the named compound, bp ~: ~b-out 86 C~.6 mmI, mp a~out 28 30.

~16~

10514~ MR37 Example 3 2-Amino~ (o-bromophenyl)thio]methyl]pyrimidinium chloride To a solution of 14.1 g of 2~aminopyrimidine in 180 ml of xylene is added a solution of 24.0 g of o-bromophenyl chloromethyl sulfide in 40 ml of xylene.
The mixture is heated at 90-95 for about fifteen hours to give about 27.3 g^of the named compound.

Example 4 [(2-Bromo-4-chlorophenyl)thio]methanesulfonic acid, sodium salt To a solution of 49.2 g of 2-bromo-4-chlorobenzene-thiol in 40 ml of 25% aqueotls sodium hydroxide is added 60.0 g of b~omomethanesulfonic acid, sodium salt, and the procedure of example 1 is reproduced. The yield of the named product, mp>310, is 69.2 g.
The 2-bromo-4-chlorobenzenethiol is prepared from 2~b~omo~4-chloroaniline via the procedure described in Organic Syntheses, Collective Volume 3, pp. 809-811.

Example 5 C2~B~ ~o-4~tolyl)thio]methane-sulfonic acid, sodium salt When 44,7 g of 2-bromo-4-toluenethiol replaces the 2~bromobenzeneth~ol in Example 1, there is obtained about 65.7 g of the named product, mp>300.
The 2-bromo-4-toluenethiol is prepared from 2-bromo-~tolutdine by the procedure reported in Organic Syntheses y~de s~p~a~.

1 ~5 ~ MR37 Example 6 [(2-Bromo~ -trifluoro-p-tolyl)thio]methanesulfonic a d, sodium salt A. To 161.0 g of p-aminobenzotrifluoride and 10.0 g of iron filings is added, dropwise, with agitation at 35-40, 160.0 g of bromine, using a slow stream of nitrogen to sweep out the evolved hydrogen bromide. Subsequently, the mixture is agitated for an additional two hours and then distilled in vacuo to give 3-bromo-4-aminobenzotri-fluoride.
B. The product from (A) is subjected to the procedure of Organic Syntheses (vide supra) to give 2-bromo-4-a,~,~-trifluoro-p-toluenethiol.
C. By substituting 56.6 g of ~ -trifluoro-p-toluenethiol for the o-bromobenzenethiol in example 1, there is obtained about 70.2 g of 2-bromo-4-(~
trifluoro-p-tolyl)thio]methanesulfonic acid, sodium salt, mp~300.
Example 7 6H-~yrimido~1~2-c][1~3~5]benzothiadiazepine ~ mixture of 33.2 g of 2-amino-1-[[(o-bromophenyl)-thio]methyl]pyrimidinium chloride, 27.7 g of anhydrous potassium carbonate, 0.8 g of copper bronze, and 750 ml of n-propanol is heated and stirred, under reflux, for ~ days, filtered hot, and the filtrate concentrated to dryness in vacuo. The residue is dissolved in 600 ml of ___ ether, and the ether solution is washed, dried, decolorized with *Darco, and concentrated to give about * Trade Mark lOS14Z9 MR37 23.7 g of a yellow solid. Recrystallization from cyclo-hexane-benzene gives about 17.4 g of the name~ compound.

ExamPles-8-- 12 By employing the procedure described in Organic Syntheses, Collective Volume 3, pp. 809-811, the aniline derivatives in Column 1 are converted to the thiol derivatives in Column 2, and the latter derivatives, following the procedure of examples 1 and 2, give the chloromethyl sulfides in Column 3.

Example Aniline Thio Chloromethyl No. DerivativeDerivative Sulfide 8. CH ~ ~2 ~ Br ~ CH2 (CH3)3 ~ NH2(CH3)3C ~ ~

Br Br Br Br Br Br 10~
CF3 NH2 CF3 SH CF3 SCH2Cl lOSi429 MR37 Example Aniline Thiol Chloromethyl No. Derivative Derivative Sulfide NH2 ~H SCH2Cl 2 5 r ~Br ~Br (C~3)2~S2 (C~3)2'X52 ( 3)217S2 Br NH2 H ~ CH2 Examples 13_- 21 By ~ubstituting an equivalent amount of the chloro-methyl sulfides of Column 3, examples 8 - 12, for the : o-bromophenyl chloromethyl sulfide in example 3, and an equivalent amount of the substituted aminopyri~idine in .
Column 2 for the aminopyrimidine in example 3 and employing the procedure of that example,- the pyrimidinium chlorides shown in Column 3 are obtained.

_, ~
~ m~

a~ p:~ m~

S~ ~U
c~ m 1 .
~ m P:

_~

o tq ,C P~

: , a _I .
~ ,~
~ .

.

MR3.7 ~0514Z9 ~D
~D
t~l ~) ~ h ~ m~ m~, E ~_~ n + ~ N

$
- 10 e~

.

~ :' ~ ~ ' .

a ~ N

.
_l 0 S a~ h ~ m c~

C~ ~

~ -.. X

a~
_I
~ ~ ~ ~9 30 . ~ .

.

~ a S

~3 ~ ~rl h~
o~

_I ~
.
V ~ ,~, .

a) _~ .

~ _, OD
, .

~05~4Z9 " ~ m U~ m ~o o ~ o~ ~ <O~m + P:
e~l ~u ~ ~:

~ 3 m~

o~ N

O U~ /
m :~

:

a~
~ o~ o 30 c:

--2~--lOS14Z9 m~
~u ~D --u u u N
. ~ O
.,, ., m u~
a~ ~ \~m m m u u~ ~L~

U~

~.~

~ U~

O ~N

O
_I O
~ V~
U

C~

.

~ _l . .
~ .

l~Si4~ MR37 Example 22 [(2-Bromo-5-chlorophenyl)thio]methanesulfonic acid, sodium s~lt.
By substituting 49.2 g of 2-bromo-5-chlorobenzene-thiol for the 2-bromo-4-chlorobenzenethiol in example 4, there is obtained 68.7 g of the named product, mp>300.

Example 23 2-Imino-l-[[(o-bromophenyl)thio]methyl]pyrimidine To a suspension of 13.8 g of anhydrous potassium carbonate in 150 ml of anhydrous n-propanol is added 33.1 g of 2-amino-1-l~(o-bromophenyl)thio]methyl]pyrimidinium chloride, portionwise, under nitrogen, at room temperature, with stirring. Subsequently, the mixture is stirred and heated under re~lux for two hours, filtered hot, and the filtrate concentrated in vacuo. The residue is parti-tioned between 200 ml each of water and ether, the ether layer is separated, dried, and concentrated to give about 28~7 g of the named compound, after recrystallization from pentane.

Example 24 6H-Pyr~imidol1,2-c]~1,3,5]benzthiadiazepine Hydrochloride-H2O
.
A mixture of 14.8 g of 2-imino-1-~[(_-bromophenyl)-tR~o~methyl]pyridine, 13.8 g of anhydrous potassium ca~bonate, 0.5 g of copper bronze, and 400 ml of anhydrous n~propanol is stirred and heated under nitxogen for about ei~hty hours, filtered hot, and the filtrate concentrated t~ dryness in ~acuo. The residue is distributed between :

.. .. . . . .. . . . . . . .

105~42~
250 ml of water and ether, the ether layer is separated, dried, and concentrated to give about 7.2 g of the base product. By the usual methods, the base gives a hydrochloride, monohydrate.

Example 25 2-Bromo-4-chlorophenyl chloromethyl sulfide A mixture of 68.2 g of the product from example 4 and 98.0 g of phosphorus pentachloride is blended until liquefaction occurs, diluted with 600 ml of ether and then poured on 1.3 kg of crushed ice. Workup of the ether layer yields about 47.3 g of the named compound, bp about 98 (0.5 mm).

Example 26 2-Amino-1-[[(2-bromo-5-chlorophenyl)thio]methyl]pyrimldinium chloride To a solution of 18.8 g of 2-aminopyrimidine in 180 ml of benzene is added 54.6 g of the product from example 30, and the mixture stirred and heated under reflux for about twelve hours. The cooled mixture is filtered to give about 62.8 g of the named compound, mp about 240-242.

Example 27 20 3-Chloro-6H-pyrimido[1,2-c][1,3,5]benzothiadiazepine hydrochlor-ide H2O

A mixture of 7.4 g of the product from example 26, 2.8 g of anhydrous potassium carbonate, 0.1 g of copper bronze, and 100 ml of anhydrous _-butanol is heated at 110 for about fifteen hours. Workup as in example 7 . .,.,~
~ ~ -27-yields about 3.6 g of the named compound.

Examples 28 - 41 By substituting equivalent amounts of the pyrimidinium chlorides in column 2 for the 2-amino-1-[(o-bromophenyl)-thio]methyl]pyrimidinium chloride in example 7, the corres-pondingly substituted 6H-pyrimido~1,2-c][1,3,5]benzothiadia-zepines shown in column 3 are obtained.

~ .

In ,, ,_ ~g ~
U ~ . ~ .

~ O

\~ N \~
~ ~ m ~n .
o ~ m~

2 0 ~ ~ cn `
~ .

., ~
a~ ~ .
~ co ~ ' X t`~ N
1~

~0 ,_ In ~0 ,_ ~
y .~
, C~
~I N

-- .

_, ~ :D
'~5 C~
20 ~ ~

~ C~
~, : -~ .
~ o ~ .

~

lOS~4Z9 In ~1 '--bq y .~ U~
N C4 ~C
` a) N
N ~.) z~
10C4 N ~ J ~SZ ;-ca ~U
~ _I
rl O ~D
~1 1~
~ m~

~N / ~ l / m ~N ~z; N

~ ' -~ .
~;
_l C
.
r~ .
x . ~ ' .

. .

lOS~Z9 U~

'--bq ,_ U ~ ,~
1 ,, ~m J Z)~Z~
Ijll N .~

o . .
~n , '~

~-0 ~ ~ ~

U~,~

: ~

:::
:: ~

'::

X
: ~ 30 ~:~
:,~ . . ' .
-i2-- lOSi4~9 N
U~
~ U
~1 ~
I, ~_ ~ N
O ~ O
U~
~I O
,, ~ A
o ~ ~ O
~ ~ >~
1 o ~ N

1~ I~
~n u .~

N
~ ' ' .

<~_m . m ~ U
.~ ~

;~

.

~D
~C

.

Example 37 6H-Pyrimido~1,2-c]~1,3,5]benzothiadiazepine, hydrochloride To a solution of 1.0 g of 6H-pyrimido[1,2-c][1,3,5]- - -benzothiadiazepine in 20 ml of anhydrous 2-propanol is added about 5.0 ml of 4.2 N 2-propanolic hydrogen chloride.
The clear solution that is formed is diluted with anhydrous ether until a turbidity persists and is then cooled to give the pale yellow crystalline product. Recrystalliza-tion from acetonitrile gives about 1.0 g of the named product.

Example 38 ,6,,,7-Dihydro-7-n-propylpyrimido[1,2-d][1,4,6]benzothiadia-zo'c'ine, hy~rochloride A. o-Bromophenyl, 2-chloro-1-pentyl sulfide To a solution of 23.0 g of sodium metal in 500 ml of absolute ethanol is added, in about 0.5 hour, a solution of 173.Q g of o-bromothiophenol in 250 ml of absolute et~anol. T~e mixture is stirred and heated under reflux for about 0.5 hour, cooled to 0, and treated, dropwise, with 185.5 g of 1-bromo-2-chloropentane. The addition requires about 1 hour. The mixture is stirred for about 2 hours at 0, warmed slowly to reflux, and then heated under reflux for two hours. The mixture is fil~ered and the filtrate concentrated in vacuo at 40 to give about 255,7 g of o-bromophenyl 2-chloro-1-pentyl sulfide as a pale yellow oil.

- . . .

~ O S 1 ~ 2 g MR37 B. 2-Amino-1-[2'-(o-bromophenylthio-1-pentyl)]-pyrimidini_m_c~lor_de To a solution of 58.7 g of the product from A
and 18.4 g of 2-aminopyrimidine in 200 ml of anhydrous toluene is heated under reflux for about 6 hours, cooled, and the crystalline product filtered to give about 67.2 g of the title compound as a pale yellow crystalline solid.
C. 1-[2'-(o-Bromophenylthio-l-pentyl~-1,2-dihydro-2-iminopyrimidine To a solution of 7.7 g of the product from B in `
100 ml of 95% ethanol is added 2.8 g of potassium carbonate and the mixture is stirred at about 40 for 1 hour, filtered and the filtrate concentrated in vacuo. The residue is recrystallized from cyclohexane to give 6.3 g of 1-~2'-(o-bromophenylthio)-1-pentyl)-1,2-dihydro-2-iminopyridine as a pale yellow crystalline solid.
D. 6,7-Dihydro-7-n-propylpyrimido[1,2-d]~1,4,6]-benzothiadiazocine, hydrochloride The product from B, 15.4 g, 13.8 g of anhydrous ~icron~zed potassium carbonate, 0.5 g of copper bronze and 100 ml of anhydrous n-butanol are stirred and heated under reflux for about 6 days, filtered, and the filtrate concentrated, in vacuo, to give the product as a deep yellow-colored viscous oil. The oil, 12.7 g, in 120 ml of anhydrous ether, is cooled to 0 and treated slowly, ~th stirring with 10 ml of 1.5 N ethereal hydrogen chloride. The solid that separates is filtered, and ~ecrystallized from 2-propanol to give the title compound, as a pale yellow crystalline product.

~35~

lOS~429 ExamPles 39 - 41 Following the procedure of examples 1 - 7 but substituting for bromomethanesulfonic acid, sodium salt in example 1 the bromoalkylsulfonic acid, sodium salt listed in column I, there is obtained the compound of formula I R"
~ N~ CH-S ~

wherein R" is the radical indicated in column II.
I II
39. l-bromoethane-l-sulfonic acid, -CH3 'v sodium salt 40. l-bromobutane-l-sulfonic acid, -CH2CH2CH3 so~ium salt 41. 1-bromo-2-methylpropane-1- -CH(CH3)2 sulfonic acid, sodium salt ' - . - . . - . , .

lOSl~Z9 MR37 Example 42 3-Trifluoromethyl-6H-pyrimido[1,2-c][1,3,5]benzothiadiazepine--

5,5-dioxide A. _,a,a-Trifluoro-m-acetoluidide_ To a solution of 161.0 g of a,a,a-trifluoro-m-toluidine in 500 ml of 2N hydrochloric acid, at room temperature, with vigorous agitation, is added rapidly 102.0 g of acetic anhydride. An exothermic r`eaction occurs and the temperature is allowed to rise spontaneously to about 50. Subsequently, the mixture is allowed to cool to room temperature, and then cooled in ice. The crystalline solid is filtered to give 189.3 g of a,a,a-trifluoro-_-acetotoluidide.
B. a,a,_-Trifluoro-_-N,N-diacetotoluidide The product from A, 102.0 g, and 500 ml of acetic anhydride are heated under reflux for about 18 hours.
The~ixture is then concentrated in vacuo to remove the excess of acetic anhydride. The residual solid crystallizes and is recrystallized from heptane to give 136.7 g of a,a,_-trifluoro- -N,N-diacetotoluidide.
C. 2-Bromo_~,a,a-trifluoro-m-N,N-diacetotoluidide To a solution of 50.6 g of the product from B in 120 ml of carbon tetrachloride is added 35.6 g of N-bromosuccinimide and the mixture is stirred and heated under reflux for about 0.25 hours. Workup according to the procedure of Arcoria and Scarlata [Ann. Chim. (Rome), 54, 139 (1964)~ yields about 58.7 g of 2-bromo-a,a,a-trifluoro-_-N,N-diacetotoluidide.

3~

M~37 lOS14'~9 D . 2-Bromo-~ -trifluoro-m-toluidine Hydrochloride The product from C, 58.0 g, 250 ml of 95% ethanol, and 10.0 ml of concentrated hydrochloric acid are heated under reflux for about one hour and then concentrated to dryness in vacuo. The residue crystallizes on cooling to give about .
45.3 g of 2-bromo-~ -trifluoro-m-toluidine hydrochloride.
E. 2-Bromo-~ -trifluoro-m-toluenesulfonyl chloride Following the procedure of Meerwein, et al, J. prakt.
Chem., 152, 237 (1939), 27.8 g of the product from D in 100 ml of 25% hydrochloric acid, at 0, is treated dropwise, with a solution of 6.9 g of sodium nitrite in 14 ml of water.
Subsequent to the addition, the mixture is stirred at 0 for 0.5 hour, Q.5 g of cupric chloride is added and while kept at 0, a rapld stream of sulfur dioxide is introduced into the reaction mixture for 0.5 hour. Subsequently, the m;xture is slowly warmed to 50 while the introduction of sulfur dioxide continues. Workup of the reaction mixture gi~es 25~6 g of 2~bromo~ -trifluoro-m-toluenesulfonyl chloride.
F. Sodium 2-bromo-a,~,~-trifluoro-m-toluenesulfonate Into a suspension of 15.6 g of zinc dust in 115 ml of water is introduced dry steam! until the internal tempera-ture reaches 70. The steam~ is shut off, and 32.4 g of the product ~rom E is added in small portions during about ten minutes. Stirring is maintained throughout the addition and for akout ten minutes afterwards. Steam is again introduced ~nto the mixture, with stirring, until the internal tempera-ture rea~hes 90 at which time the steam is shut off and lQ ml ~f 12N aqueous sodium hydroxide is added followed by 2.~ g portions of solid sodium carbonate until the mixture l~Si4Z9 MR37 is strongly alkaline. Following this, the procedure of Org. Syntheses, Coll. Vol 1, 492 (1941) is followed to give about 24.7 g of sodium 2-bromo-a,a,a-trifluoro-~-toluenesulfonate.
G. 2-Bromo-a,a,a-trifluoro-m-tolyl Bromomethyl Sulfone A mixture of 31.1 g of the product from F,34.8 g of l,l-dibromomethane, 500 ml of absolute ethanol, 13.8 g of anhydrous, micronized potassium carbonate, and 0.5 g of copper bronze is stirred and heated under reflux for about 9.5 hours.
The hot solution is filtered and the filtrate concentrated to a volume of about 100 ml and cooled. The product that crystallizes is filtered to give about 30.6 g of 2-bromo-~,a,a-trifluoro-m-tolyl bromomethyl sulfone.
H. 3-Trifluoromethyl-6H-pyrimidoll,2-c]~1,3,5]benzo-thiadiazepine-5,5-dioxide Following the procedure of example 3 but substituting for o-bromophenyl chloromethyl sulfide an equivalent amount of the product from part G, there is obtained 2-amino-1-[[(2-bromo~5~a,a,a-trifluoro-m-tolyl)sulfonyl]methyl]pyrimidinium b`romide~ Following the procedure of example 7 but substituting the above pyrimidinium bromide for 2-amino-1-[~o-bromophenyl)-th~o]methyl~pyrimidinium chloride, the title compound is obtained.

, .. . . . . . . . .. ..
: . .

loSl Y~9 MR37 Exampl~s 4-~ ~4 Following the procedure of example 42 but substituting for l,l-dibromomethane in part G the dihaloalkane listed ~:-below in column I, there is obtained the compound of formula I
of the formula .
~" ' , ~N ~ N ~ CF3 10 ' ' `'' wherein R" and n are as indicated in columns II and III:
I II III .
43. 1-bromo-2-chloroethane H
44. l,1-dibromoethane -CH3 0 .
45. 1,1-dibromo-2-methylpropane -CH(CH3)2 0 46. 1-bromo-2-chloropentane C3H7 . , .

, ' ''.

105:14;~9 Example 47 Preparation of capsule formulation Inqredient Milliqrams Per Capsule 6H-Pyrimido[1,2-c][1,3,5]benzo-thiadiazepine, hydrochloride . . . . . . . 400 Starch . . . . . . . . . . . . . . . . . . 80 Magnesium stearate . . . . . . . . . . . . 5 The active ingredient, starch and magnesium stearate are blended together. The mixture is used to fill hard shell capsules of a suitable size at a fill weight of 485 milli-grams per capsule.

Exam~le 48 Preparation of tablet formulation Inqredient Milliqrams per Tablet 6H-Pyrimido[1,2-c]rl,3,5~benzo-thladiazepine-5,5-dioxide . . . . . . . . 300 Lactose . . . . . . . . . . . . . . . . . 200 Corn starch (for mix) . . . . . . . . . . 50 Corn starch (for paste) . . . . . . . . . 50 Magnesium stearate . . . . . . . . . . . 6 The active lngredient, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in water at a ratio of 10 grams of corn starch per 80 milliliters of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders. The wet granules are passed through a No. 8 screen and dried at 120F. The dry granules are passed through a No~ 16 screen. The mixture is lubricated with magnesium l()S14~9 stearate and compressed into tablets in a suitable tableting machine. Each tablet contains 300 milligrams of active ingredient.

ExamPle 49 Pre~aration of oral syrup formulation Ingredient Amount

6,7-Dihydro-7-n-propylpyrimido-~1,2-d]-~1,4,6]benzothiadiazocine, hydrochloride . . 500 mg.
Sorbitol solution (70~/O N.F.) . . . . . . . . 40 ml.
Sodium benzoate . . . . . . . . . . . . . . 150 mg.
Sucaryl . . . . . . . . . . . . . . . . . . 90 mg.
Saccharin . . . . . . . . . . . . . . . . . 10 mg.
Red Dye (F.D. & Co. ~o. 2) . . . . . . . . . 10 mg.
Cherry flavor . . . . . . . . . . . . . . . 50 mg.
Distill~d water . . . . . . qs to . . . . 100 ml.
The sorbitol solution is added to 40 milliliters of distilled water and the active ingredient is suspended therein. The sucaryl, saccharin, sodium benzoate, fiavor and dye are added and dissolved in the above solution. The volume is adjusted to 100 milliliters with distilled water.
Other ingredients mày replace those listed in the above formulation. For example, a suspending agent such as , ~, bentonite magma, tragacanth, carboxymethylcellulose, or methylaellulose may be used. Phosphates, citrates or tartrates may be added as buffers. Preservatives may include the - :
parabens, sorbic acid and the like and other flavors and dyes may be used in place of those listed above.
.

~ ' ' , ~ -42-,., , . ~,, ... . ,.. :.. , '.' ' ' ' '":

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for preparing a compound of the formula I

wherein R' is hydrogen, Cl, or CF3: n is 0 or 1; R" is hydro-gen or alkyl of from 1 to 4 carbons; Z is S or SO2; or a pharmaceutically acceptable acid-addition salt thereof, which comprises heating a compound of the formula IV

or V

wherein R', R", Z, and n are defined as above and X is chlorine or bromine in the presence of a copper catalyst and an alkali metal hydroxide, alkali metal carbonate, tris-alkali metal phosphate, alkali metal metaborate or alkali metal tetraborate.

2. The process of claim 1 wherein the starting material IV or V is such that the compound so obtained is the compound named 6-H-pyrimido-[1,2-c] [1,3,5]benzothiadia-zepine.

3. The process of claim 1 wherein the starting material IV or V is such that the compound so obtained is the compound named 3-chloro-6H-pyrimido[1,2-c] [1,3,5]benzothia-diazepine.

4. The process of claim 1 wherein the starting material IV or V is such that the compound so obtained is the compound named 6,7-dihydro-7-n-propylpyrimido[1,2-d] [1,4,6]
benzothiadiazocine.

5. The process of claim 1 wherein the starting material IV or V is such that the compound so obtained is the compound named 3-trifluoromethyl-6H-pyrimido[1,2-c]
[1,3,5]benzothiadiazepine-5,5-dioxide.

6. A compound of the formula I
wherein R' is hydrogen, Cl or CF3; or n is 0 or 1;
R" is hydrogen or alkyl of from 1 to 4 carbons; Z is S or SO2, or a pharmaceutically acceptable acid-addition salt thereof, whenever prepared by the process of claim 1.

7. A compound having the name 6H-pyrimido-[1,2-c]
[1,3,5]benzothiadiazepine, whenever prepared by the process of claim 2.

8. A compound having the name 3-chloro-6H-pyrimido-[1,.2-c][1,3,5]benzothiadiazepine, whenever prepared by the process of claim 3.

9. A compound having the name 6,7-dihydro-7-n-propylpyrimido[1,2-d][1,4,6]benzothiadiazocine, whenever prepared by the process of claim 4.

10. A compound having the name 3-trifluoromethyl-6H-pyrimido[1,2-c][1,3,5]benzothiadiazepine-5,5-dioxide, whenever prepared by the process of claim 5.