CA1051427A - 6-h-pyrimido- (1,2-c) (1,3,5) benzoxadiazepines - Google Patents

Abstract

Abstract This invention relates to compounds of the formula X

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; T 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, I, alkyl of from 1 to 4 carbons, alkylsulfonyl wherein the alkyl radical has from 1 to 4 carbons, dialkylamidosulfonyl wherein each alkyl radical has from 1 to 4 carbons, trifluoro-methyl; n is 0 or 1; and R" is hydrogen or alkyl of from 1 to 4 carbons; and pharmaceutically acceptable acid-addition salts thereof, a process for preparing them and to intermediates therefor. These compounds exhibit central nervous system stimulating properties and act as muscle relaxants.

Description

~051~'~7 This invention relates to novel pyrimidoben~oxadiazepines and pyrimidobenzoxadiazocines, a process for preparing them and intermediates therefor.
The compounds of the present invention have the following formulae ~"

~ , Cll ( CH2~

~ I
.
wherein m is 1 or 27 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 i8 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, I, alkyl of from 1 to 4 carbons, alkylsulfonyl whereih the alkyl radical has from 1 to 4 carbons, dialkylamidosulfonyl wherein each alkyl radical has from 1 to 4 carbons, trifluoromethyl; n is 0 or 1; and R" is hydrogen or alkyl of from 1 to 4 carbons;
and pharmaceutically acceptable acid-addition salts thereof.
- The ~oregoing compounds possess central nervous system stimulating propertieg and act as muscle relaxants.

.. , , . . . . . . ~ , . . . .
.

105~4'~7 Compound30f Formula I may be prepared by reacting a 2-aminopyrimidine II wherein R is as previously defined with an o-bromophenoxyalkylene halide III wherein R" is 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 diethylene glycol, dimethyl ether of diethylene glycol (diglyme), monomethyl ether of ethylene glycol or dimethyl ether of ethylene glycol (glyme) are examples of suitable ethers.
n-Amyl alcohol i5 an example of a suitable aliphatic alcohol, while benzyl alcohol is an example of a suitable aryl-sub-stituted aliphatic alcohol. Heating compounds II and III in a solvent as described above, or a mixture thereof, at tempera-tures from about 100 to about 140C for 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 an alkali metal carbonate.
The reaction takes place at room temperature ~ver a period ~; of from about 1 to about 4 hours.~ Compound V may be converted ; ~ " ' , '' , ~ ' ' ' ' ' 1~514'~7 MR36 to the final compound I by treating with a water miscible alcohol and an alkali metal alkoxide of up to 3 carbons in the presence of copper at a temperature of from about 60 to about 120 for about 4 to 10 days, typically from about 6 to about 8 days. Alternatively, IV may be converted directly to I by heating at a temperature of from about 60 to about 120C for about 4 to 10 days, typically from about 6 to about 8 days in the presence of potassium carbonate and copper in a solvent such as dimethylformamide, dimethylacetamide, dichlorobenzene, trichloroben~ene, or diethylbenzene. Alternatively, however, IV may be converted directly to I by heating at a temperature of from about 60 to about 120C for about 4 to 10 days, typically from about 6 to about 8 days in the presence of an alkaii metal hydroxide, alkali metal carbonate, tris-alkali metal phosphate, aIkali metal metaborate or alkali metal tetra-borate in a solvent comprising a mixture of water and a water miscible alcohol in the presence of copper. Specific examples of suitable compounds include LioH, NaOH, KOH, RbOH, CsOH, Na2CO3, ~2CO3~ Rb2CO3~ Cs2 3 3 4 3 4 3 4 3 4' Na2B24' Na2B4O7~ K2B2o4, and K2B4O7.
~he ratios of water and alcohol in the mixture of water and a water miscible alcohol are such that a homogeneous single phase system result~.
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, and R' occupies only the ; ~ 5-po3ition of III, two isomers, Ia and Ib are formed via the intermediates IVa or Va and IVb and Vb, respectively. When m .

:, .

~0514'27 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.
The foregoing reaction sequences are illustrated by the following equations:

~X )~
- ~
_~ \
~Q ~//~ -- ;

- 51 ~

t~: .
~-mN ~T ~ I

C~ m Hl . ~ .

m ~ .
C~

S~' H¦
P~

i()514'Z7 MR36 c Z ~1 ~ ~Z;

1~ ~ m v~
o~<s~
~ ~ m ~ ;~
- 1: rl H _ >
~z ~

+

0~ ~
~ m c~
~1

2 0 U ~I > P--P~ i H¦

Z

O

~5 H ¦ C~ ~¦
- :~ m P~--U

~OSl~'~7 ^~\ ~
~: ul ~
U Z Hl m \ ~1 ZjH

1` 1`

N
, z ~

~X -~ X ~

m~ Hl + ^ m ~1 U H
z~ m Z
. <OZ ~<
~ ~ P~
'~, ~ . N

~Q~;
~<
,.

~514~,7 MR36 The intermediates of formula III wherein n is 0 may be prepared by refluxing about e~uimolar 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 equi-molar amounts of an o-bromophenol VIII in the presence of aqueous alkali to yield a sodium o-bromophenoxyalkylene-sulfonate IX. Treatment of the latter with PC15 or PBr5 at ambient temperature yields the corresponding o-bromophenoxy-alkyl chloride or bromide X. The foregoing reaction sequence is illus-trated by the follo~ing equations R" R"
B_-CH-X 2 3 > Br-CH-SO3Na X-Cl or Br VI VII

Br ~

VIII /
.

R " R "
NaO -C ,o . X-CH-O ~ ~R' . X=Cl or Br IX X

0 S ~ 4f~ MR36 The intermediates of formula III wherein n is 1 may be prepared by reacting a l-bromo-2-chloroalkane 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-bromophenoxyalkanol XIII with PC15 or PBr5. The foregoing reaction sequence is illustrated by the following equations:

R"

~' HO ~ X ~H E12 Cl-CH-CEl2-Br Br Br~_~
VIII
XI XII
~ . -PC13 o~ /
PBr3 R"
~0-CHCH2-0 ~ R' ' XIII

Compounds of Formula VIII wherein R' is fluorine, trifluoromethyl, alkylsulfonyl, or dialkylamidosulfonyl may be prepared by the following sequence of reactions iO514Z'7 Hcl HNO Zn-Hcl HONO
R' ~ Br ~ R' ~ Br - ~ R ~ r 0O >

R ~ Br Heat > R' ~ Br 2+Cl OH

all of which are conventional and can be effected by procedures 10well-known in the art.

HO ~ Fe catalyut ~ R' Br R' = -F, -CF3 or -S-alXyl : 30 _9_, ... . . . . . .

105~4'Z7 The compounds of the present invention may be administered 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 doses 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 de~cribed in "The Microbial World," by R~ Y. Stanier, M. Doudoroff and E. A. Adelberg, Prentice-Hall, Inc., Englewood Cliffs, N.J., 3rd Ed~, p. 858, are employed to determine the bactericidal properties of tha pyrimidinium 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, 7, Pasturella multocida, 8, and Mycobac$srium tuberculosis, 9.
In the procedure, a sterile agar plate is seeded with the test organism, and then a number of glass cylinders are 105i4~Z7 placed on its surface, forming a series of little cups.
A known dilution of 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 is 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 Micrograms, (m~g)/ml Compound CompoundCompound Compound of Ex. 1 of Ex. 4of Ex. 5 of Ex.ll 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.~
7 3.13 25.0 12.5 6.25 6.25 12.5 25.0 12.5 9 0.39 6.25 1.57 0.78 10514~7 MR36 - The compounds of the present inven-tion 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 invention 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, capsules, 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, it 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 physical form of the dosage unit, for instance, tablets, pills or iO5~ 7 capsules may be coated with shellac, su~ar, 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 prepdring any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
As to the pharmaceutically acceptabl~ salts, those coming within the purview of the invention include the pharmaceutically acceptable acid-addition salts~ Acids useful for preparing these acid-addition salts include, inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and pho~phoric 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 methan~sulfonic.

~os~ 7 The following examples illustrate the present invention. All temperatures given are expressed in degrees Centigrade.

Example 1 6H-Pyrimidorl,2-c~rl,3,5}benzoxadiazepine, hydrochloride .. . .
A. Sodiumbromomethanesulfonate A mixture of 372.0 g of dibromomethane and a saturat~d ~o solution of 261.0 g of sodium sulfite in 750 ml of water is refluxed with stirring for about 80 hours. ~he reaction mixture is concentrated by distillation (600 ml of ~ater is removed); the residue solidifies on standing. The solid, 608 g, is recrystallized from 200 ml of water to give a~out 380.0 g of the product, mp about 277-281.
. B. (o-Bromophenoxy)methanesulfonic acid, sodium salt To a solution of 61.3 g of o-bromophenol in aqueous : NaOH solution [15.5 g of sodium hydroxide in 61 ml of water], is added 68.0 g of sodium bromomethanesulfonate.
While stirring, the reaction mixture is slowly heated to 150~, in an oil bath, with s.imultaneous removal of water~.
In about 3 hours of heatin~, 61 ml of water is distilled, and the residue solidifies; this is further heated at 200 for abou-t 2.5 hours. The solid is dissolved in 800 ml of warm water, the solution filtered and the fiItrate adjusted to pH 5 and washed with 2 x 200 ml of ether. The aqueous phase is concentrated to 600 ml and cooled. The crystalline solid is filtered and dried in vacuo to give 63.3 g of the product, which is recrystal-lized from 600 ml of 9~/c aqueous ethanol to furnish about 1051'?~;~7 s7.5 g of the titleproduct, mp about 282-2840.
C. o-Bromo-~-chloroanisole A mixture of 29.0 g of (o-bromophenoxy)methane sulfonic acid, sodium salt and 50.0 g of PC15 are thoroughly blended in a mortar.
After about 10 minutes of continuous mixing, the mixture partly melts, a vigorous reaction occurs, and the whole turns to a lic~uid. The mixture is kep~ 15 minutes with occasional stirring, 700 ml of ether is added (a white solid separates) and the mixture is poured into 750 g of crushed ice.
The ether solution is separated, washed, dried, and concen-trated in vacuo to give about 21.0 g of a liquid residue.
This is distilled under reduced pressure to give about 19.5 g of the colorless lic3uid product, b2 o 74~75~ n24 5 1.5799.
D. 2-Amino-l-r(o-bromophenoxY)methyllPYrimidinium chloride To a solution of 7.1 g of 2-aminopyrimidine in 35 ml of xylene iq added, dropwise, a solution of 11.1 g of b-bromo-a-chloroanisole in 45 ml of xylene. The mixture is warmed at 50 for 5 minutes and allowed to stir for 40 hours at room temperature. The solid is filtered and dried to give about 16.0 g of the product. This is recrystallized from 2-propanol to give about 14.0 g of the title product.
E. 6H-Pyrimido[1,2-c][1,3,5]benzoxadiazepine A mixture of 9.5 g of 2-amino-1-[(o-bromophenoxy)-methyl]pyrimidinium chloride, 8.3 g of potassium carbonate, and 0.4 g of copper-bronze in 150 ml of n-propanol, under N2, is heated under reflux for about 7 days while stirring. The mixture is filtered hot and the deep yellow filtrate is concentrated to dryness. The residue is dissolved in 400 ml of ether, the ether solution is washecl, dried and lOSi427 the solvent removed to give about 6.4 g of the crude yellow product. This is recrystallized from cyclohexane to give about 3.6 g of the title product.
F. 6H-Pyrimido[1,2-c]rl,3,5]benzoxadiazepine, hydro-chloride To a solution of 1.0 g of 6H-pyrimido[1,2-c]rl,3,5]-benzoxadiazepine in 20 ml of 2-propanol is added 5.0 ml of 4.2N 2-propanolic hydrogen chloride. To the clear solution is added anhydrous ether until a turbidity forms.
The pale yellow crystalline solid is filtered and recrystal-lized from acetonitrile to give about 1.0 g of the title compound.

ExamPle 2 6H-Pyrimido[1,2-c][1,3,5]benzoxadiazepine A. l-(o-Bromophenoxymethyl)-1,2-dihydro-2-iminopyrimidine A suspension of 7.0 g of the product from Example lD,

5.6 g of micronized, anhydrou~ potassium carbonate, and 175 ml of anhydrous n-propanol is stirred and heated under reflux for ; 20 about eight hours, filtered hot, and the filtrate concentrated to dryness in vacuo. The residue, about 6.3 g, is dissolved in 150 ml of ether, the ether solution is washed with water, ~aturated aqueous sodium chloride, dried and concentrated to give l-(o-bromophenoxymethyl)-1,2-dihydro-2-iminopyrimidine.
Recrystallization from pentane gives about 5.8 g of the pure product.
B. 6H-Pyrimido[1,2-c]~1,3,5]benzoxadiazepine To a solution of 4.65 g of the product from A in 150 ml of n-propanol is added 0.20 g of copper bronze and 5.6 g of micronized, anhydrous, potassium carbonate, and the stirred .

1()~14Z7 suspension is heated under reflux for about ten hours.
Workup as in Example lE gives about 2.78 g of the title compound.

Examples3 - 13 Following the procedure of example lD, but substituting for 2-aminopyrimidine in part D the substituted pyrimidine listed below, there is obtained the correspondingly substi-tuted compound of formulas IV, IVa, IVb, IVc or IVd wherein R' and R" are hydrogen and n=o which compound, following the procedure of Example 2, Part A, is then converted to the correspondingly substituted compound of formula V, Va, Vb, Vc and Y~ which is then converted to the correspondingly 3ubstituted compound of formula I, Ia, Ib, Ic and Id, by following the procedure of Example 2, part B.

~051~'~7 o~ /~\ ~;
U_~ ~Z; LN~ ~3 N

m ~ ~
~

o o~ ~

v m ~_ ~

C~ cC~ K ~, X
N L,~

m ~ J

v m ~ o X~

'-18---il0514'~:7 .

o~
m / w ~ ~ -m~ m mNm . ~ ~

W
C~ _ d~m c~m ~m ; ~ ~ ~ m~

$ W $_$
C~ C~C) O
.

mN N .r ~ N

~W~ <~

m m "~ I N

3 0 ~1 ~(~51427 a~

~/ m~ ~
~'~

c~h )/~m //~m o o N

P~
, c~m O~m o~m .. , ~' g Y

Q) - ~ IOSi~'z'7 ,_ o~
Z ~,K

C)~

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~2m ~ ~m c~ $
~ ~ t~
$

~æ

.
:C
u a~
~, , 3Q ~

~0514'Z7 ~ ' U~

m ~ C~

~ o~m ~ Z
~4 U~;4~

~ ,............. .
m $

a~m O~m ~ _ $ N

$

a~

-~22--.

~()5i4'~7 Examples 14 - 23 Following the procedure of example LA through lD
but substituting for 2-aminopyrimidine the substituted pyrimidine listed below, there i~ obtained the correspondingly substituted compound of formula IV, which following the procedure of example 1, part E, is converted to the correspondingly sub-stituted compound of formula I.

:

~05~4'~7 o~ o~ ~
m ~ N

p~ . O

~N ~N mN
~0~

m m~ mN

m ~d ~05~4'~7 N~ ~ U~ 4 lo ~ mr ~ J

~m ~m o~m o C~ u ~ ~ u ~N ~N
m~ P~ mN

, ~ .

;

lOS14'~7 o~ o~ o~ ~
N N O

N
$ N ~
U U $ $ U
m m m~ U mU
~~ ~

c~m O~?m / m N N N N
m N m ~ m m N N
$~ ~ ~ U~;

U--U U ~ $

Z N
2 (:) ~ Z

: . $N $ m 5:~ m u~ u $~
.

,. .
o Ç~

10514'~7 -o~ o~
z; ~ \ m z ~ z ~ N ~) `

c~m o~m ~DX O~m O~m ~X

~C) ON ~) _-- =
" ~ ~
P~

m m~

,. _ ~ 0 ~, .
;~i Z ~ N
3 0 1i3 ~>~ 10514Z7 ~ Z
m ~
/

5:

~S~
a~

k~
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.",, . ~, :' , :
i` ~0 ,. ~

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.: ,, .~ . : . .

iO514'~7 Example 24 2-Chloro-6H-pyrimido[1,2-c][1,3,5]benzoxadiazepine hydrochloride -A. 2-Bromo-4-chlorophenoxymethanesulfonic acid, sodium salt To a solution of 75.0 g of 2-bromo-4-chlorophenol in 65 ml of water is added 16.0 g of sodium hydroxide and lOOg of bromomethanesulfonic acid, sodium salt. The procedure of Example 1, part B, is followed to give about 74.5 g of 2-bromo-4-chlorophenoxymethanesulfonic acid, sodium salt, m.p. above 315.
B. 2-Bromo-4-chlorophenyl chlo omethyl ether A mixture of 71.0 g of the product from A and 110.0 g of phosphorus pentachloride is reacted as in Example 1, part C, to give about 55.7 g of 2-bromo-4-chlorophenyl chloromethyl ether, m.p. about 56.0 - 57.5.
C. 2-Amino-1-[(2-bromo-4-chlorophenoxy)methyl]-, . .
yrimidinium chloride To a solution of 14.1 g of 2-aminopyrimidine in 180 ml of warm, anhydrous xylene is added 25.6 g of the product from ; 20 B in 70 ml of anhydrous xylene and the mixture is stirred for about four hours at room temperature and then at 100 for .. ;~, about two hours to give about 33.0 g of 2-amino-1-[(2-bromo--, 4-chlorophenoxy)methyl]pyrimidinium chloride.

D. 2-Chloro-6H-pyrimido[1,2-c][1,3,5]benzoxadiazepine hYdrochloride A mixture of 14.0 g of 2-amino-1-[(2-bromo-4-chloro-phenoxy~methyl]pyrimidinium chloride, 11.1 g of micronized, anhydrous potassium carbonate, 0.4 g of copper bronze, and 350 ml of anhydrous n-propanol is stirred and heated under ' 30 ' ' :

lOS~4~7 MR36 reflux for about eight hours, filtered hot, and the deep yellow filtrate is concentrated to dryness in vacuo. workup gives about 6.8 g of 2-chloro-6~-pyrimido[1,2-c][1,3,5~-benzoxadiazepine.
To the above base, 2.0 g in 50 ml of warm 2-propanol, is added about 5.0 ml of 4.8N 2-propanolic hydrogen chloride.
The solid that separates is filtered to give about 2.2 g of product. This is recrystallized from a mixture of acetonitrile and absolute ethanol to give about 1.9 g of the title compound, m.p. about 303 - 305 (dec.).

ExamPles 25 -_40 Following the procedure of example 24 but substituting for 2-bromo-4-chlorophenol the substituted 2-bromophenol listed in column I, there is obtained the correspondingly substituted compound from parts B and C, and finally the compound of the following formula wherein R' and the position it occupies are indicated in column II.

~ / CH ~ R' Exam~le I II

25.2,5-dibromophenol 3-bromo 26.2-bromo-5-iodophenol 3-iodo 27.2-bromo-5-methylp~enol 3-methyl 2~romo-5-ethylphenol 3-ethyl 2~2-bromo-5-chlorophenol 3-chloro -:30-~` MR36 iO5il(~
Example I II
30. 2-bromo-5-n-butylphenol 3-n-butyl :31. 2-bromo-5-isobutylphenol 3-_-butyl 32. 2-bromo-5-fluorophenol 3-fluoro 33. 6-bromo_a,a,a-trifluoro-_-cresol 3-trifluoromethyl 34. 2-bromo-5-sulfamoylphenol 3-sulfamoyl 35. 2-bromo-5-dimethylamidosul- 3-dimethylamido-fonylphenol sulfonyl 36. 2-bromo-4-dibutylamidosulfonyl- 2-dibutylamidosulfonyl phenol 37. 2-bromo-5-(methylsulfonyl)- 3-methylsulfonyl phenol 38. 2-bromo-5-(n-butylsulfonyl)- 3-n-butylsulfonyl phenol 39. 2-bromo-5-ethylsulfonylphenol 3-ethylsulfonyl 40. 2~bromo-5-propylsulfonylphenol 3-propylsulfonyl Examples 41 - 46 Following the procedure of example 1 but substituting ~20 for dibromoethane the compound listed in column I, there is obtained the compound of the following formula R"

wherein R" is as indicated in column II.

~.1 lOS14'c:7 Example I II
41. l,l-dibromoethane -CH3 42. l,l-dibromoisobutane ~ ~3 CE~H3 43. l,l-dibromopropane CH2CH3 44. 1,1-dibromopentane -(CH2)3CH3 45. 1,1-dibromobutane -CH2CH2CH3 46. l,1-dibromoisopentane -CH2CH~CH3)CH3 .

Example 47

6,7-Dihydro-7-methyl-10-phenylpyri~ido[1,2-d~[1,4,6~-benzoxadiazocine A. _-Bromophenyl 2-chloropropyl ether To a ~olution of 23.0 g of sodium metal in 500 ml of absolute ethanol is added in about 0.5 hour a solution of 173.0 g of o-bromophenol in 250 ml of absolute ethanol. The mixture is stirred and heated under reflux for about 0.5 hours, cooled to 0, and treated, dropwise, with 157.5 g of 1-bromo-2-chloropropane. The last addition requires about 1 hour. The mixture is stirred at 0 for about 2 hours and slowly warmed to re~lux during about 2 hours, heated under reflux for about 2 hours, filtered from the precipitated sodium bromide, and the filtrate is concentrated in vacuo at 40 to give about ; 240.2 g of o-bromophenyl 2-chloropropyl ether as a mobile, colorless liquidO
B. 2-Amino-1-[2'-(o-bromophenoxy-1'-methylethyl)]-5-phenylpyrimidinium ~hloride A solution of 29.4 g of 2-amino-5-phenylpyrimidine and 50.0 g of o-bxomophenyl 2-chloropropyl ether and 200 ml of anhydrous toluene is heated under reflux for about 6 hours, -3~-105~4~ MR36 cooled, and the crystalline product filtered to give about 60.2 g of 2-amino-1-[2'-(o-bromophenoxy-1'-methylethyl)]-5-phenylpyrimidinium chloride as a colorless, crystalline solid.
C. 1-[2'-(o-Bromophenoxy-l'-methylethyl)]-1,2-dihydro-2-imino-5-phenYlpyrimidine To a solution of 8.5 g of the product from B in 100 ml of anhydrous n-propanol is added 2.8 g of anhydrous, micronized potassium carbonate and the mixture stirred and heated under reflux for about 1 hour. The hot suspension is filtered and the filtrate concentrated to give a pale yellow solid.
This is recrystallized from cyclohexane to give about 5.8 g of 1-[2'-(o-bromophenoxy-1'-methylethyl)]-1,2-dihydro-2-imino-5-phenylpyrimidine as a pale yellow crystalline solid.
D. 6,7-DihYdro-7-methYl-lO-phenYlPyrimid ~1,2-d]~1,4,6]benzoxadiazocine The product from C, 3.39 g, S0 ml of anhydrous n-propanol, 2.8 g or anhydrous, micronized potassium carbonate, and 0.25 g of copper bronze are stirred and heated under reflux for about 6 hours, filtered hot, and ; 20 the deep, yellow colored filtrate is concentrated to `~ dryness in vacuo at 40. The deep yellow-colored solid is recrystallized from ligroin to give about 2.22 g of 6,7-dihydro-7-methyl-10-phenylpyrimido~1,2-d]~1,4,6]-ben oxadia7ocine.

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105~ 7 Example 48 Preparation of capsule formulation Inqredient Milligrams per Capsule 6H-~yrimido[l~2-cJ[l~3~5]benzoxadia-zepine, 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.

Example 4~
Preparation of tablet f_rmulation Inqredient Milligrams per Tablet 2-Chloro-6H-pyrimido[1,2-c]~1,3,5]benzoxa-diazepine hydrochloride . . . . . . . . . 300 Lactose . . . . . . . . . . . . . . . . . 200 Corn starch (for mix) . . . . . . . . . . 50 - 20 Corn starch (for paste) . . . . . . . . . 50 Magnesium stearate . . . . . . . . . . . 6 The active ingredient, 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 ~o. 16 screen. The mixture i5 lubricated with magnesium ~34-~ '7 ~36 stearate and compressed into tablets in a suitable tableting machine. Each tablet contains 300 milligrams of active ingredient.

Example 50 Preparation of oral syrup formulation Inqredient Amount 6,7-Dihydro-7-methyl-10-phenylpyrimido-[1,2-d~[1,4,6]benzodiazocine . . . . . . . . 500 mg.
Sorbitol solution (7~/c N.F.) . . . . . . . . 40 ml.
Sodium benzoate . . . . . . . . . . . . . . 150 mg.
Sucaryl . . . . . . . . . . . . . . . . . . 90 mg.
Saccharin . . . . . . . . . . . . . . . . . 10 mg.
Red Dye (F.D. & Co. No. 2) . . . . . . . . . 10 mg.
Cherry flavor . . . . . . . . . . . . . . . 50 mg.
Distilled 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, flavor and dye are added and di5solved in the above solution. The volume is adjusted to 100 milliliters with distilled water.
Other ingredients may replace those listed in the above foxmulation. For example, a suspending agent such as ~entonite magma, txagacanth, carboxymethylcellulose, or methylcellulose 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.

Claims (8)

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 R is hydrogen or phenyl; R' occupies either position-2or-3 and is hydrogen or Cl; n is 0 or 1; and R" is hydrogen or alkyl of from 1 to 4 carbons; or a pharmaceutically acceptable acid-addition salt thereof, which comprises heating a compound of formula or IV V

wherein R, R', R", 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 is such that the compound so prepared is a compound having the name 6-H-pyrimido[1,2-c][1,3,5]benzoxadiazepine.

3. The process of claim 1 wherein the starting material is such that the compound so prepared is a compound having the name2-chloro-6H-pyrimido[1,2-c][1,3,5]benzoxadiazepinee.

4. The process of claim 1 wherein the starting material is such that the compound so prepared is a compound having the name6,7-dihydro-7-methyl-10-phenylpyrimido[1,2-d][1,4,,61-benzoxadiazocine.

5. A compound of the formula I

R is hydrogen or phenyl; R' occupies either position-2or-3 and is hydrogen or Cl;
n is 0 or 1;
and R" is hydrogen or alkyl of from 1 to 4 carbons; or a pharmaceutically acceptable acid-addition salt thereof, whenever prepared by the process of claim 1.

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

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

8. A compound having the name 6,7-dihydro-7-methyl-10-phenylpyrimido[1,2-d] [1,4,6]benzoxadiazocine, whenever prepared by the process of claim 4.