CA1051885A - Therapeutic compounds and intermediates therefor - Google Patents

Abstract

Abstract This invention relates to compounds of the formula I

wherein m is 1 or 2, when m is 1, R occupies either the 4-or 5-positions of the starting 2-aminopyrimidine, but when R is halogen it occupies only position-5; whem m is 2, the two R-substituents occupy the 4- and 5-positions of the starting 2-aminopyrimidine, but only one of the two R-sub-stituents can be halogen and it must occupy the 5-position;
R is the same of 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 tri-fluoromethyl; provided that when R is halogen, and m is 1, R occupies only the 5-position in the starting 2-aminopyrimidine;
R' is hydrogen, F, Cl, Br, I, alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, alkylthio of from 1 to 4 carbons, alkylsulfonyl wherein the alkyl radical has from 1 to 4 carbons, phenyl, phenyloxy, sulfamoyl, dialkylamidosulfonyl wherein each alkyl radical has from 1 to 4 carbons, trifluoromethyl, mono-substituted phenyl or mono-substituted phenyloxy wherein the substituent is F, Cl, Br, I, alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons or trifluoromethyl; n is 2 or 3, and pharmaceutically acceptable acid addition salts thereof, a process for preparing them and intermediates therefor. These compounds exhibit central nervous system stimulating properties and act as muscle relaxants.

Description

~5~Z~38~
This invention relates to novel dihydropyrimidobenzo-diazepines and dihydropyrimidobenzodiazocines t a process for preparing them and intermediates therefor~
The compounds of the present invention have the following formula (CH `
N

wherein m is 1 or 2; when m i.s 1., ~ occupies either the 4-or 5-positions of the starting 2-aminopyrimidine, but when R is halogen it occupies only position-5; when m is 2, the two R-substituents occupy the 4- and 5-positions of the starting 2-aminopyrimidine, but only one of the two R-sub-stituents can be halogen and it must occupy the 5-position;
R is the same or different and is hydrogen, F, C1, ~r, alkyl of from 1 to 4 carbons, benzyl, phenyl, or mono-substituted phenyl wherein the substituent is F, C1, Br, I, alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, or tri-fluoromethyl, provided that when R is halogen, and m is 1, R occupies only the 5-position in the starting 2-aminopyrimidine;
R' is hydrogen, F, Cl, Br, I alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, alkylthio of from 1 to 4 carbons, alkylsulfonyl wherein the alkyl radical has from 1 to ~ carbons, phenyl, phenyloxy, sulfamoyl, dialkylamidosulfonyl wherein each alkyl radical has from 1 to 4 carbons, trifluoromethyl, mono-substituted phenyl Or mono-substituted pheny~oxy wherein the substituen-t is F, Cl, Br, I, alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons or trifluoromethyl; n is 2 or 3, and pharmaceutically acceptable acid addition salts thereof.

_ 1--1~35 88~i The foregoing compounds possess central nervous system stimulating properties and act as muscle relaxants.
Compounds of Formula I may be prepared by reacting a

2-aminopyrimidine II with an o-bromophenalkylene halide III.
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 is an example of a suitable aliphatic alcohol, while benzyl alcohol is an example of a suitable aryl-substituted aliphatic alcohol. Heating com-pounds II and III in a solvent as descri~ed above, or a mixture thereof, at temperatures 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. The reaction takes place at room temperature over a period of from about 1 to about 4 hours.
Compound V may be converted 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 several days, 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 about 4 to 10 days, typically 105~8~5 MR35 from about 6 to about 8 days in t;he presence of potassium carbonate and copper in a solvent such as dimethylformamide, dimethylacetamide, dichlorobenzene, trichlorobenzene, or diethylben~ene. Preferably, however, IV may be conver-ted directly to I by heating at a ternperature 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 alkali metal hydroxide, alkali metal carbonate, tris-alkali metal phosphate, alkali metal metaborate or alkali metal tetraborate 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, KOHo RbOH~ CsOH~ Na2CO3 ~ K2CO3, Rb CO , Cs2C03, Na3P04, K3PO4, Rb3PO4~ 3 4 2 2 4 Na2B4O7, K2B2O4, and K2B4O7. The ratios of water and alcohol in the mixture of water and a water miscible alcohol are such that a homogeneous single phase system results.
When m is 1, and ~hen R occupies only the 5-position of II and R' occupies only the 5-position ~ to the bromine atom) of III, only one isomer, I, is formed. When m is l, and when R occupies only the 4-position of IIa, and R' occupies only the 5-position of III, two isomers, Ia and Ib are formed via the intermediates ~Va or Va and IVb and Vb, respectively.
~hen m is 2, and since the two R's occupy only the 4-, 5-positions and R' occupies only the 5-position of III, two isomeric products, Ia and Ib are formed. These isomers,in all instances, can be separated by conventional procedures, e.g., fractional recrystallization or column chromatography.

~ ~5~
The foregoing reaction sequence is illustrated by the following equations:

~X ~

_~ m " / \p;

~) H I

~\
~Z ' \

\
_~ ~ \
~:~
~ h ~)Hl ~h m ~ I

H I <~/~

M~3 5 1~5~8~

C) ~i H

P~; /
_ ~
~ m -- N ~ 1 > p:~ ,g ¦

+

^~6~
2 o u H¦ u ~ H¦

\

~ ~ m <~0_~ H I m ~1 3 0 ~P~

10518g~5 MR:~ 5 -N ~

~ ~Z
lo T ~

~ m ~ ¦ + N H ¦
z \ Z
0~
P;

~j ~Z
<OZ

18~5 The in-termediates of formula III ~herein n is 2 may be prepared by treating an o-bromobenzyl alcohol VI with PBr3 at temperatures of from about 0 o about 100C for a period OL from about 1 to about 6 hours.
The resulting o-bromobenzyl bromide VII is then -treated with sodium cyanide in the presence of water and a water miscible alcohol to yield an o-bromophenylace~onitrile VIII~ Treatment of the latter with an alcohol in the presence of concentrated sulfuric acid yields the li~ corresponding ester IX. Treatment of the latter ~ith lithium aluminum hydride yields an o-bromophenethanol . -Treatment of the latter with PBr3 at temperatures wi~hin the range of from a~out 0 to about 100 for a period of from about 1 to about 6 hours yields the correspondi~g o-bromophenethyl bromide XI. The foregoing reaction -~equence is illustrated ~y the following equations.

R ~ CH2H PBr3 ~ 2 VI VII
~MaC~ !

R' ~ H2COOR ~ R ~ -IX VIII
~ LiA1~4 R-~H2CH20H PE~r ~H2CH2Br X XI
?,0 1~5~B~5 The intermediates of formula III wherein n is 3 may be prepared by trea-ting a compound of formula XI
with sodium cyanide in the prese~ce of water ~nd a water misci~le alcohol to yield an o-~romophenylpropionitrile XII.
Treatment of the latter with an alcohol in the presence of concentrated sulfuric aci~ yields the correspondilLg ester XIII~ Txeaiment of the latter with lithi~m aluminum hydride yields an o-bromophenpropanol~ Txeatment of the latter with PBr3 at temperatures within -the range of from about O to lJ about 100C for a period of from about 1 to about 6 hours yields the correspon~ng o~bromophenpropyl bromide XV.
The foregoing reaction sequence is illustrated by the following equations R ~ H2 2 ~ R ~ CB2cH2cN

XI XII
I
ROH
.
RL~CH2CH2CH20~1 ~ ~CH2CH2COOR

XIV XIII

1 PBr3 R' Br XV

3l35 ~ hen R' is alkylthio tne compounds of formuLa XI or XV may be prepared by nitrating an o-bromobenzyl alcohol XVI at 0C using a mixture of nitric and sulfuri~ acids.
The resulting isomeric mi~ture of nitrated 2--bromobenzyl alcohols is separated by conventiorlal techni~ues Each separated isorner XVII may then be reduced to the corres-ponding amine XVIII by means of zinc and hy~rochloric acid Treatment of the amino derivative XVIII wi-th ni-tr~

and then ~ith sodium alkylmercaptide yields the corres-ponding alkylthio-2 bromobenzyl alcohol XIX.

CH2~H 2 ~ CH2H 2 ~ CH2H

O . HNO3 1 0 I HCl ~_~ ~Br > ~ Br ~_~'~Br XV~ XVII XVI I

1 ) HN02 ~ 2) AlkylSNa Alkyl-S_~ CH2H

XIX

Treatment of the compound of formula XIX with PBr3 as shown in the sequence proceeding from X to XI, and from XIV to XV yields the compound of formula XI or XV wherein R' is alkylthio.

When R' is trifluoromethyl, the intermediate of formula VII may be prepared by reacting a trifluoromethyl-phenyl magnesium bromide XX with methyl iodide to obtain a trifluoromethyl toluene XXI. Treatment of the latter with bromine in the presence oF iron powder at 20C yields a 8~
bromo-substituted trifluoromethyl toluene XXII. Treatment of the latter with bromine in the presence o-f ligh-t and a peroxide catalyst yields the correspondony bromo-trifl~loro-methylbenzyl bromide XXIII.

3C ~ ~ > ~ ~ Br MgBr C~I3 CH3 XX XXI XXII

/ Br2/hV
. O
~/ (~C 320 Br XXIII

~5~ 5 Compounds o for~ III wherein R' is phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, alkoxy-su~stituted phenyl, or trifluoromethyl~subs~ituted phenyl may be prepared by treating an amino-subs-tituted o-bromobenzoic acid XXVI~I with acetic anhydride and then with nit~cns acid. The resulting N=acetamido-N-nitroso-o-bromobenzoic acid XXIX is then treated with benzene or an R-substituted b~nzene wherein R is halogen, alkyl, alkoxy cr trifluoromethyl according to the procedure 1~ of Haworth et al, supra. The aryl-substituted o bromo benzoic acid is then treated with Li~lH4 or AlH3 accoraing to known techniques to yield the corresponding aryl-substituted o-~romo~enzyl alcohol XXXI. The reaction sequence is as follows:

COOH COOH

B ~ 1) (CH3C)2 ~
2) HNO2 ~ ~ /NO
~H2 XXVIII XXIX O

. R

R=halo, alXyl, ~ alkoxy or CF3 Br ~ LiAlH4 ' <l' ~ 3 ~ R

3 0XXXI X~X

-Ll-' MR35 ~5~35 - The compounds of the presen-t invention may ~e administered to mammalian species as cen-tral nervous system stimulants and as muscle relaxants. In the rat, responses to the stimulant activity of the ~ompounds o~ the prese~t invention include increased activity ana body tremors. The muscle relaxant properties ~ani~est themselves by responses that include decreased limb tone, decreased yrip strength, and limb paxalysis. 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 a~out 6~2~ to about S0 mg/~g for both activities, while in humans - the dosage range varies from a~out 40 to about 2000 mg.
daily in about four divided doses for both activities.
In addition to serving as intermedia~es 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. Ya Stanier, M. Doudoroff and E. A. AdelbergD
Prentice-Hall, Inc., Englewood Cliffs, ~.J., 3rd Ed., p. 858, are employed to determine the bactericidal properties of the pyrimidlnium 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 Mycobacterium tuberculosis, 9.
In the procedure, a sterile agar plate is seeded with the test organism, and then a number of glass cylinders are 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 yrowth 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 possihle to find the minimum inhibiting concentration ~mic), of the compound that produces a recognizable zone of inhibition. The following summarizes 10the data.
Microorqanism mic of Compound, Microqrams, (mcq)/ml Compound Compound Compound Compound of Ex. 3, of Ex. 10, of Ex. 12, of Ex. 16 col. 3 col. 3_ col. 3 col. 3 1 12.5 6.25 6.25 3.13 2 50.0 50.0 25.0 12.5 3 50.0 12.5 12.5 12.5

4 25.0 12.5 12.5 6.25 25.0 25.0 25.0 12.5 6 25.0 25.0 2500 12.5 7 25.0 12.5 6.25 3.13 8 12.5 25.0 12.5 6.25 9 6.25 1.57 0.78 0.39 The compounds of the present invention in the described dosages may be administered orally; ho~,/ever, other routes such as intraperitoneally, su~cutaneously, intram~scul2rly or intravenously may be employed.
The active compo~nds of -the present invention are orally administered, for exar~ple, wi~h an iner~ 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 foo~ of ~he diet. For oral therapeutic administra~ion, the active compounds of this invention may be incorporated ~ith excipients and used in the form o tablets, troches, capsules, elixirs, sus~ensions~ syrups, wafers, chewing gum, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage in the compo-sitions and preparations may, of course, be varied and mzy aon~eniently be between a~out 5% to about 75% or more of the weight of the unit. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage wil' be obtained. Pre.erred co~osi-tions or preparations according to the present invention are prepared so that an oral dosage uni. form contains bet~2en about 10 and 200 milligrams of active compound.
- The tablets, troches, pills, capsules and the liXo - may also contain the follo~ing: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phospha-~; a disintegrating agent such as corn starch, potato starch, alginic acid and the li~e; a lubricant such as magnesium stearate; and a sweetening a~ent 3C such as sucrose, l~ctose or saccharin may be added or a ~ 5~ MR35 flavoring agent such a5 peD~ermint~ oil of wintergreen, or cherry flavoring. ~Jhen the dosage unit form is a capsule, it may contain in addition to materials of the absve type a liquid carrier such as a fatty oil. Various other ma~erials may be present as coatings or to otherwise modify the physical fonn ~f the dosage unit, for insta~ce, table-ts, pills or capsules may ~e coa.ed with shellac, sugar or both A syrup or elixir may contain the active compounds, sucrosP as a sweetening agent, methyl and propyl parabens as preserva-tives, a dve and a flavorin~ 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 the invention include the pharmaceutically acceptable acid-addition salts. Acids - useful for preparing these acid-addition salts include, inter alla, inorganic acids, such as 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.

-15- . :

~S1~8S
The following examples illustrate the following invention without, howe~er, limitiny the same thereto.

All temperatures are e~pressed in degrees Centigrade.

Example 1 11,12-Dihydropyrimido~2,1-b][1,3]benzodiazepine A. o-sromobenzyl sromide _ . _ To 187.0 g o-E o-bromobenzyl alcohol at room temperature, with stirring, is added dropwise, 271 0 g of phosphorus tribromide. After the addi-tion is 1~ complete, stirring is continued for three hours at room temperature. The mixture is then heated at 90-100 for three hours and poured into 6 kg of crushed ice.
The hydrolysis mixture is extracted with three 600 ml portions of ether, the ether extracts are washed, dried, and concentxated to give o-bromobenzyl bromide, bp a~out 130-132(15mm).

B. o-Bromophenylacetonitrile To a suspension of 220.0 g of sodium cyanide in 265 ml of water and 380 ml of absolute ethanol, is added~ ~
while stirring, a solution of 911.0 g of o-bromobenzyl bromide in 911 ml of ethanol. The reaction proceeds exothermally, but is eventually heated under reflux for about O.S hour, then cooled in an ice-bath, and fi~tered.

The solid is washed with ether, the filtrate is concen-trated, the residue is suspended in 300 ml of water and extrac.ed with three 500 ml portions of ether The ether extracts are washed, dried, and the sol~ent is removed. The residue is distilled to give 730 g of the named ~roduct, bp 141-142(12mm~.

` ~51~5 MR35 C. Eth~ bromophenylacetate To a cooled solution o~ 730.0 g of o-bromophenyl-acetonitrile in 2.9 1 of absolute ethanol is added, drop~ise, while stirring, 7~0 ml of concentrated sulphuric acid. The addition requires about two hours.
The reaction m;xture is heated under reflux for nine hours, poured into ice water, and extracted with 2.5 of ether. The ether extracts are washed, dried, and concentrated. The residue is distilled to give 780.0 g of e~thyl o-bromophenylacetate, bp. abcut 115-117(4mm),n26 1,5434.

D~ o-Bromophenethyl alcohol To a stirred suspension of 106.0 g of lithium aluminum hydride in 3.7 1 of anhydrous ether, is added, dropwise, a solution of 780.0 g of ethyl o-bromophenyl-acetate in 3.1 1 of anhydrous ether. The reaction mixture is stirred for about three hours and then heated under reflux for about five hours. The mixture i~ cooled, then treated dropwise with 800 ml of water, and 1.5 1 of 1~/~ aqueous hydrochloric acid The ether eolution is washed, dried, concentrated, and the residue is distilled to give 554.0 g of o-bromophenethyl alcohol, bp. about 130-132 (8mm~, n20 1,5760.

E. o~Bromophenethyl bromide To 550.0 g of o-bromophenethyl alcohol, while stirring, is added, drop~ise, 375~0 g o~ phosphorus tribromide. After stirring for three hours at room temperature, the reaction mixture is heated on a steam bath for three hours and then poured into 6 kg of crushed ~5~ 5 ice. The mixture is extracted with three 600 and ts~o 200 ml portions of ether. The ether extracts are ~rashed, dried, concentrated, and the residue is distilled to give 531.0 g ofo-bromophenethyl bromide, bp about 86-88(0.9mm), nD 1.5922.

F. 2-Amino-l-(o-bromophenethyl)pyrimidinium Bromide .. .. . ...
- To a solution of 212.0 g of o-~romophenethyl bromide in 4 on ml of dry xylene is added a solution of 121.0 g of 2-aminopyrimidine in 400 ml of dry xylene. The mixture is heated under re~lux for about three hours, ~oolPd, and the xylene solution is decanted from the crystalline solid. The solid is triturated with 300 ml o~ 2-propanol, filtered, and dried to give 138.0 g of the product. The xylene solution is again heated under r~flux for 16 hours and by the same procedure, an additional 43.0 g of product is recovered. The total - of about 181.0 g of product is recrystallized from 2-propanol to give 170.0 g of the title compound, ~0 mp. about 231-232.

G. 11,12-Dihydropyrimldo~2,1-b]Ll,3]benzodiazepine To a solution or 9.0 g of 2-amino-1-(o-bromo-phenethyl)pyridinium bromide in 55 ml of dimethylformamide is added 10.3 g of micronized, anhydrous potassium carbonate and 0.5 g of copper bronze. The mixture is heated at 100 for about seven days under nitrogen while stirring~ and then is filtered while hot. The filtrate is conce~trated to dryness in vacuo to give about 8.6 g of residue. This is extracted with two 125 ml portions of boiling diisopropyl ether~ The diiso~
propyl ether solution is treated with Darco, filtered, and concentrated to about 40 ml to give on cooling, about 7.2 g of 11,12~dihydropyrimido~2,1-b]~1,3~benzo-diazepine, mp about 45-~6.

~ .
12, 13 -Dihydro-3~methylthio- llH-pyrimido [ 2, l-b ] ~1, 3 ~ -.
benzodiazQcine A. 2~Bromo 5-methylthiobenzyl Bromide 2-Bromo-5-methylthiobenæyl alcohol is prepared by the following s~quence of reactions 2-bromo-5-nitrobenzoic acid is reduced to 2-~romo-5-aminobenzoic acid by means of iron and hydrochloric acid in aqueous ethanol. The 2-bromo-5-aminobenzoic acid is diazotized with sodium nitrite in aqueous sulfuric acid, and the diazonium compound treated with sodium methylmercaptide to give 2-bromo-5-methylthiobenzoic acid. The 2rbromo-

5-methylthiobenzoic acid is conver~ed to its methyl ester by heating under reflux with methanol-concentrated sulfuric acid, the methyl ester is isolated by ether extraction from the esterification mixture, recovered from the ether solution, distilled for purification, and reduced with lithium aluminum hydri~e to yield 2-bromo-5-methylthiobenzyl alcohol. Treatment of the preceding compound with PBr3 as described in part A of example 1 gives 2-bromo-5-methylthiobenzyl bromide.

~ 5~ MR35 B 3-(2-~romo-5 (methylthio)phenyl)-l-propanol ~ o a suspension of 25.0 g of magnesium ribbon in a solution of 0.~ g of iodine in 550 ml o~ anhydrous ether is added 5 ml of a solutio~ of 296.0 g of 2-~romo-5-(methylthio)benzyl bromide in 250 ml of anhydrous ether. The reaction is initiated by gentle heating, and the remainder of the solution is then added dropwise so as to ~aintain a reflux. Subsequently, the mixture is heated and stirred under reflux for one hour, and then cooled to 10.
A stream of nitrogen gas that has been bubbled through a reservoir containing 48.0 g of ethylene oxide is introduced into the reaction mixtur~. The addition of the ethylene oxide requires two hours. The mixture is subsequently stirred as it warms to room temperature, is stirred for four hours at room temperature, and then hydrolyzed by pouring on a mixture of 1 kg of ice and 55.0 g of ammonium chloride.
Extraction with ether, followed by conventional workup of the ether solution, yield 210.0 g of 3-(2-bromo-5-(methylthio)phenyl)-l-propanol, bp, about 125-127(0.6mm3.

C. 3-(2-Bromo-5-methylthiophenyl)propyl Bromide To 49.0 g of the product from (A), with stirring, is ~dded, dropwise, 27.1 g of phosphorus tribromide.
The mixture is stirred subsequently for three hours at room temperature, then heated at 90-100 for three hours, and then poured into 1 kg of crushed ice.
Workup via ether extraction yields 52.7 g o~ 3-(2-bromo-5-rnethylthiop~enyl)propyl bromide, bp. about 100-102(0.8mm).

-2~-D. 2-Amino-1-[3-(2-bxomo-5-methylthiophenyl)propyl3-pyrimidinium bromide To a solutio~ of 154 0 g of 3--(2-bromo-5~methylthio-phenyl)propyl bromide in 400 ml of dry xylene, is added a solution of 70.0 g of 2~aminopyrimidine in 300 ml of dry xylene and the mixture is heated under reflux for about eighteen hours. The cooled xylene solution is decanted from the crystalline solid, the solid is triturated with 200 ml of 2-propanol and filtered to give 117.0 g of crude product~ Recrystallizatio~ o the latter from 2-propanol gives about 98.0 g of 2-amino-1-[3-(2~bromo-5-methylthiophenyl)propyl]-pyrimidinium bromide.

E. 12,13-Dihydro-3-methylthio-llH-pyrimido~2,1-~][1,3]-benzodiazocine To a solution of 8.1 g of 2-amino-1- L 3-(2-bromo-5-methylthiophenyl)propyl pyrimidinium bromide in,50 ml of dimethylformamide is added 10.3 g of micronized, anhydrous potassium carbonate and 0.5 g of copper bronze.
The mixture is heated at 100 for about three hours under nitrogen while stirring, and then it is filtered hot~ The filtrate is concentrated to dryness in vacuo to give about 9.0 g of residue. This is extracted with two 120 ml portions of boiling diisopropyl ether.
The solution is treated with*Darco, filtered, and concen-trated to about 35 ml. This on cooling gives about 4 3 g of 12,13-dihydro-3-methylthio~llH-pyrimido[2,1-b3[1,33-benzodiazocine.

*Trade Mark -21 .

.

Examples 3-~7 Following the procedure of example 1 (A) but substituting an equi~7alent amount of the substituted o-bromobenzyl alcohol in column 1 for o-bromobenzyl alcohol, there is obtained respectively, the corresponding o-bromo-phenethyl bromide indicated in column 2. Reaction of the latter with 2-aminopyrimidine following the procedure of example 1 (F) yields, respectively, the pyrimidinium compound indicated in column 3. Treating the latter with K2CO3 and copper bronze following the procedure of example 1 (G) yields, respectively, the final product of column 4.

88~ MR35 r~

U X ~ ~
~; U \ ~4.\ U
Y

-~D
~D ~ a) $
C) m 0 " ~ m ~ a ~, m ~ ~
~: m ~ 5~ m V
Y I V
~ ~ V
V

s~
h h ~1 - ~1 N ~ U 5~

u m U U
m -, - m -- ' ~ ON ON

t~ O X - N
~ V O
o U tl:
~; V
~ , X

~3 U N
' O ~ ~., m m_ 7 CD ~
h ~ 1 5~ h h m ~J u m m .
.
~ ~ ~ u--u ~

m ~ m V ~
U\~Z; Z N

U
m ~ ~1 . , m m O U 1~ ~ r. ~1 O
r~ Z
~ U ~ _ ~ 5: ' ~ ~ O

m J~( mr~ m~ Or' r~) IL1 o _ c.) _ 3 0 r~ O
rLl --~4-- -~51885 M~3 5 ~) N ~.) ,_1 m m N N ~N~

Z C) /1 1 Z I Z ~ ~i u~ ~ m ~ u\~!

~D
D h h m ~ m 0 ~m oN 1U4~h ~\m y ~ C~ N
~ U U C~
U ~ ~ ~ N ~`1 ~3~;m~,WzN .. U~ m\~-SZ

_ . m--u~
mN--~ ~, ~ m v--u ~ ~ o 1 m~ m c~
_ . . _ _ . . _ . _ . . . _ _ ~
:q o o o ~ ~ ~c :~ ~ o u s~
v ~ q m u e o N ~ d' X ~1 ~ ~1 885 M~ 3 5 ~ ^
5~ N N ~) O'` ~ ~7.

m m N N ~, h m ~ h 5:
$(~ ~ y C~ mN mN

N ~,m _ .

~N )~ ~
h o c ) ,~,m m ~,m ~ o X

~05~885 MR35 Examples 18-30 Following the procedure of example ls but substituting for 2-aminopyrimidine an equivalent amount of the substituted 2-aminopyrimidine in column 1, there is obtained, respectively, the quaternary derivative shown in column 2. Treatment of the latter as described in example 1 yields, respectively, the final compound indicated in column 3.

s \ ~; + ~ æ

\~ m~ ~ ~

_ c) ~

v (D a ~ ' t~) 7 ~
U

r~

.
~ ~i X

1053L8~35 MR35 ~r~ z X~
~ ~ r~
m m m ,~, o V :~
_V

æ

~z ~
h m v 5:~

_I
. . .
~o ~Z ~ ~ r~
X

105~. ~3t351 MR35 IN
Y

N ~ h~ ~
C) ~ C~ ~

X ,_ ~, c) . .

:D
m ~ h 1:~1 ~ h ~ol tmqN m , ~ ¦

X ~
V 5~ r~
~1 r~) 5:
r~, ~ C,~
~ p~
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~l B~ 35 Example 31 11,12-D.ihydropyrimido[2,1-b][1,3]benzodiazepine -To a solution of 18.0 g of 2-amino-1-(o-bromo-phenethyl)pyrimidinium bromide and 14.7 g of potassium carbonate in 100 ml of _-propanol and 200 ml of water is added 0.5 g of copper bronze and the mixture is heated under nitrogen, with stirring, at 90~ for 2.5 hours.
The mixture is cooled and extracted with three 100 ml portions of ether, the ether e~tracts are wasned, dried, and concentrated to give about 10.0 g of product, mp about 45-46, after recrystallization from diisopropyl ether.

Example 32 A. 1,2-Dihydro-2-imino-1-(_-bromophenethyl)pyrimidine To a solution of 3.3 g of sodium methoxide in 120 ml of anhydrous methanol is added 10.8 g of 2-amino-1-(o-bromophenethyl)pyrimidinium bromide, prepared as described in example 1 (G). The solution is stirred under nitro-gen for 2 hours and then heated under reflux for 5 hours. The solvent is rem~ved _ vacuo and the residue is -~reated with 200 ml of anhydrous ether. The ether solution is washed, dried, and concentrated _ vacuo to give about 6.8 g of yellow solid. This is recrystallized from hexane to give the name product, mp about 97-9~.
B. 11,12~Dihydropyrimido~2,1-b~1,3]benzodiazepine To a solution of 5.6 g of 1,2-d.ihydro~2-imino-1-(o-bromophenethyl)pyrimidine in 100 ml of xylene is added 2.8 g of potassium carbonate and 0.5 g of copper bronze and the mixture is heated under reflux for 3 hours, and filtered. The filtrate is conc~entrated ln vacuo and the residue recrystallized fro~n diisopropyl ether to give about 2.3 g of the title product, mp about 45-46.

Examples 33-35 Following the procedure of example 1 (B) through 1 (G) but substituting the o-bromophenethylbromide in column I below for the o-bromobenzyl bromideinpart B, and substituting for 2-aminopyrimidine in part F, the compound listed in column II, there is obtained (from part F) the pyrimidinium compound listed in column III
and (from part G) the benzodiazocine compound listed in column IV.

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Examples 36-.39 Following the procedure of example 1 but substituting for 2-aminopyrimidine an equiva:lent amount of the substituted 2-aminopyrimidine in column 1, there is obtained, respectively, the quaternary derivative shown in column 2. Treatment of the latter as described in example 1 yields, respectively, the final compound indicated in colun~ 3.

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xam~les 40-51 Following the procedure of example 1 tB~ through 1 (G) but substituting for o-bromobenzyl bromide in part B, the compound listed in column I below, and suhstituting for 2-aminopyrimidine in part F, the compound listed in column II, there is obtained (from part F) the pyrimidinium compound listed in column III and from part G the benzo-diazepine compound l.isted in column IV.

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~5~3~ 35 Preparation of capsule formula-tio Ingr dient Milligrams per Capsule 11,12-Dihydropyrimido-[2,1-b][1,3]benzodiazepine . . . . . . . . 400 Starch . . . . . . . . . . . . . . . O . . 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 53 Preparation of tablet formulation Inqredient Milliqrams per Tablet 12,13-Dihydro-2-methylthio-llH-pyrimido~2,1-b~[1,3]benzodiazocine. . . . 300 Lactose . . . . . . . . . . . . . . . . . 200 Corn starch (for mix~ . . . . . . . . . . 50 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 watPr at a ratio of 10 grams of corn starch per 80 milliliters of wat,er 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 stearate and compressed into tablets in a suitable tableting machine. Each tablet contains 300 milligrams of active ingredient.

Example 54 Preparation of oral syru~formulation Ingredient Amount 11,12-Dihydropyrimido[2,1-b]-[1,3]benzodiazepine. . . . . . O . . . . . . 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 . . . . lOO 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 dissolved in the above solution. The volume is adjusted to lOO milliliters with distilled water.
Other ingredients may replace those listed in the above formulation. For example, a suspending agent such as bentonite magma, tragacanth, 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 (10)

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

1. A process for preparing a compound of the formula I

wherein R' is hydrogen or alkylthio of from 1 to 4 carbons;
n is 2 or 3; or a pharmaceutically acceptable acid addition salt thereof which comprises heating a compound of the formula IV or V

wherein 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, an alkali metal carbonate, a tris-alkali metal phosphate, an alkali metal metaborate or alkali metal tetraborate.

2. The process of claim 1 which comprises heating a compound of the formula wherein R' and n are defined as in claim 1 to a temperature of from about 60°C to about 120°C in the presence of copper catalyst and at least 2 molar equivalents of an alkali metal hydroxide, an alkali metal carbonate, a tris-alkali metal phosphate, an alkali metal metaborate or alkali metal tetraborate in a solvent comprising water and a water-miscible alcohol.

3. The process of claim 1 which comprises contacting a compound of the formula V

wherein R' and n are defined as in claim 1 with a water miscible alcohol and at least one molar equivalent of an alkali metal hydroxide, an alkali metal carbonate, a tris-alkali metal phosphate, an alkali metal metaborate or alkali metal tetra-borate and a copper catalyst.

4. The process of claim 1 which comprises contacting a compound of the formula IV

wherein R' and n are defined as in claim 1 with at least 2 molar equivalents of K2C03 and copper catalyst in a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, dichlorobenzene, trichlorobenzene and diethylbenzene.

5. The process of claim 1 wherein R' is hydrogen and n is 2 and there is thus prepared 11,12-dihydropyrimido[2,1-b][1,3]benzodiazepine.

6. The process of claim 1 wherein R' is methylthio and n is 3 and there is thus prepared 12,13-dihydro-2-methylthio-11H-pyrimido[2,1-b][1,3]-benzodiazocine.

7. A compound of the formula I

wherein R1 is hydrogen or alkylthio of from 1 to 4 carbons;
n is 2 or 3; or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of claim 1.

8. A compound of the formula I

wherein R' is hydrogen or alkylthio of from 1 to 4 carbons;
n is 2 or 3; or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of claims 2, 3, or 4.

9. The compound having the name 11, 12-dihydropyrimido [2,1-b][1,3]benzodiazepine, whenever prepared by the process of claim 5.

10. The compound having the name 12, 13-dihydro-2-methylthio-11H-pyrimido[2,1-b][1,3]-benzodiazocine, whenever prepared by the process of claim 6.