CA1234809A - Fused aromatic oxazepinones and sulfur analogs thereof in a method of counteracting histamine - Google Patents

Abstract

FUSED AROMATIC OXAZEPINONES AND
SULFUR ANALOGS THEREOF

ABSTRACT OF THE INVENTION

Aromatic-2,3-dihydro-1,4-oxazepin-5(4H)-ones and sulfur analogs thereof having the formula

Description

~2~09 ~ACXGROUND OF ~HE I~VE~TIO~
1. Field of Inven~ion.
The pre~ent invention relate3 to noYel ~romatic

2,3-dihydro-1,4-oxazepin-5~(4~)-ones ~nd sulfur ~nalog~
~hereof and i~ particularly ~onoerned with aromatic-2,3-dihydro-1,4-oxazepin-5(48)-ones and ~ulfur analogs thereo~
which have the aromatic component ~us~d into the oxazepine or ~hiazepine ring and ~re ~ub~titu~ed i~ ~he 2-position with ~hort ~ha ~ amino~lkyl ~adicals, having ~ntihistaminic and anti-allerg~ utili~y and a novel process and novel intermed'iates fo~ the pr6paration thereof.
2. Information Discl~sure Statement ~-Aryl-1,4-benzoxazepin-5~4~)-ones sub~tituted on the oxazepin3 nitrogen ~y an a~inoalkyl Eadical have bsen di~clo~ed by SchenXer, X. in swi83 Patent 505.850 (C.A. I~, 986009~.
Conver~ion of flav2nones into ~enzoxazepinones sub~titut~d in the 2-poQition by a phenyl ~aaical has be~n di~closed ~y L~vai, ~. and Bognar, R., ~op. Flavanoid Chem. Bioch~m. Proc. ~ung. Bio~lavonoi~ Symp. 4th Ed. 1973 (Pu):~. 1975) 119-23 (~.A. ~,, 79098n). Thione derivatives were obtained ~y treating with pho~phon~s pentasul~ide.
Certain chemical inte~nediates, t~ ub~t itute!d-

3-~ub~tituted phenoxypyrrolidine3 illu~tr2ted by 1-methyI-~-(2-car~amoylp2~noxy)pyrrolidine~ ~ ~
l~benzyl-3-(2-c~r~Dylphenoxy~pyrrolidine, ~nd l-m~thyl-3-(2-car~oxyph*noxy)pyrrolidine n ~n otherwi8e novel ~ 8 ~re ~ ai~closed in U . S . ~atent ~;,577,415 -; ~

O~JECTS AND SllMM~Y OF ~ TIO~I
The oxazepine and thiazepine derivative3 of the pre~ent invention which exhibit antihistaminic activity have ~he ~ormula: .

~ (C~n~z t ~ A ~ ~ Formula I

wherein;
A repre3ent~ an aromatic ring having two of it~
earbon atom~ held mutually with the oxazepine or thiazepine moiety selected from the group consi ting of benzene, naphthalene or a pyridine in any o~ it~ four po~itions, any of the rings option~lly substitu~ed by ona or two Y
radical~ selected ~rom the group con isting o~ halo, lower-alkyl, loweralkoxy, ~itro or trifluoromethyl:
B and E are selected from oxygen or sul~ur and may be the same or di~erent:
R is selected from the group conQi~ting of hydrogen~
loweralkyl, cycloalkyl or phenyl-loweralkyl, of which phenyl may be optionally sub~tituted by one or two radicals selected ~rom haloJ loweralkyl, loweralkoxy, nitr~ or trifluoromethyl:
n i8 1, 2 or 3:
Z i~ selscted f~om the ~roup ~onsisting o~ -~RlR2, lH-pyr3zol-l-yl or lH-imidazol-l-yl:
~1 and R2 are selected from the group con~i~ting of hydro~n, loweralXyl, cycloalkyl and phenyl-loweralkyl, o~::
which ph~nyl may be optionally sub~tituted by 1 or 2 . :
~0 radical~ s~lected ~rom h~lo, loweralkyl, lower~lkoxy, ~itro, trif}uorom~hyl or cyano, or Rl and R2 ~ken together with the adjac~nt nitrogen ~to~ ~ay form ~ h~terocyclic se~idue s~locted from th~ group con i~ing o l-pyrroli~inyl, 2,5-dimethylpyrrolidin-1-yl, 2-methylpyrrol~dinloyl, l-piperidinyl, 4-~ubstituted piperidine l-yl, 4-morpholinyI, l-piperaziny~, 4-0ub~ituted piper~zin-l-yl and },8,3,6-_ 419A-CIP
~L23~0~

tetrahydropyridin-l-yl and the ph~rmaceutically acceptable salt~ thereof with the previso that when R = H, z i8 never a primary or ~econdary amine, and ~ further provi~o that when n = 3, Z i~ not lH-pyrazol-l-yl, lH-imidazol-l-yl, 2,5-dimethylpyrrolidin-l-yl, 2-methylpyrrolidin-l-yl or 1,2,3,6-tetrahydropyridin-l-yl.
~ he novel oxazepine and thiazepine precursor~
leadiny to ~ompounds o~ Formula I have the forTnula:
E~(CP~ ~ n_X

Formula II
wherein A, B, ~, R and Y are as defined undex Formula I
15 above except R i~ not hydrogen, n is 1 or 2 J and X i8 chlorine, bromine or cyano, and the acid addition salts thereof.
Other chemical intermediates in the preparation of compounds of Formula II are novel ~nd have the ~ormula:

~ ~
Formula III
wherein A, E, R, n and Y are as de~ined under Formula ~I
above and X i~ chlorine or bromine.
Still oth~r chemical intermediates leading to 0 compound~ of Fonnul~ IVb have the formula:
n O~'C R
3~ 3~o~ul~
wherein A, E, R, n and Y are aa de:Eined under Formula II9

4~9A-CIP
-4 ~23 o and Q is selected from -C-NH2, -C~ or -C-oR3 where R3 is H, alkali metal ion or an esterifying radical. Compounds o~
Formula IVa are novel except wherein A is phenyl or substituted phenyl and E i9 oxygen.
In the further definition of symbols in the ormulas hereof and where they appear elsewhere throughout thi~
~pecification and the claims, the te~ms have the fol~owing significanc2.
The term l'loweralkyl" a3 used hexein include~ straight and branched chain radicals of up to eight caxbons inclusive and i~ exemplified by ~uch groups a~ methyl, ethyl, propyl, i~opropyl, ~utyl, ~ec. butyl, tart.butyl, amyl, isoamyl, hexyl, heptyl and octyl radical3 and the like. The term "loweralkoxy" has the formula -0-loweralkyl.
The term "cycloalkyl" as used herein inclu~es primarily cyclic alXyl raaical~ containing 3-9 carbon atoms inclusive and includes such groups as cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cyclo-heptyl and the like.
~he term "halo" or "halogen" when referred to herein include fluorine, chlorine, bromine and iodine unless other-wise ~tated.
"Pharmaceutically acceptable ~alt~" include acid addition salts, hydrate~, alcoho~ate3 and quaternary ~alt~
o~ the compounds of Formula I, which are phy~iologically compatible in warm-blooded animals. ~he acid addition salts may be formed by either strong or waak acids. R~prescntative o~ strong acid~ are hydrochloric, sul~uric and phosphoric acid~. RepresentatiYe of weak acids are fumaric, maleic, succinic, oxalic, ~itric, tartaric, cyclohexamic and the like.
Suitable quaten-ary salt~ include the loweralXyl halide~ and loweralkyl sul~ate3.
By "sulfurizing agent" i8 meant any agent or mixture 35 of agents which will cDnvert ox- and thiazepinone~. to ox-and thiazepine-thione~, uch as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithi0dipho~phetane-2,4- disulfide or a mixture o~

~34809 phosphorus penta~ulfide and alkalimetal ~ulfide or a mixture of phosphorus penta~ulfid~ in pyridine.
~ he compound~ of the pre~ent i~vention ~xhibit antl-hi~taminic activity in guinea pig~. ~he method of testing is a modification of the procedure o~ Tozzi st al.(Agent~
and Action3, Vol. ~/4, 264-270, 1974) as follow~: Guinea pigs are fast~d 18-24 hrs in individual cages. Water i8 available ad libitum. On the tést day, animal~ in groups o~ ~ are injected intraperitoneally with ~0 mg ~ g of the teQt compound prepared in an appropriate vehicle. Thirty minuts~ later hi3tamin~ a~ ~ dosage level of 1.2 mg ~g (= 2 x the XD~9) iS injected into B marginal ear vein.
Survival of the guinea pigs for 24 hrs is positive evidence of ant~histami~e activity. If the vehicle used for the test ~ompound i~ other than water, its effect is established by teQting an a~u~l amount as a control. ~he dose pro-tecting ~0% of the animals (PDso) from death may be establi~hed fxom dose-response curves.
The novel process of this inven~ion comprises the following ~teps:
Step 1) Halogenating a compound of ~he formula ,..,~ ~ E ~ (C~n ~ A I I /
( ~o-2 `~~ o~OR ~ N IVb wherein:
A repre~nts an ~romatic ring ~el~ted from benzene, naphthalene, or a pyridiale in any one of it3 four po~itions, 30 optionally ~ub~titutea by on~ or two Y-radicals selected ~rom halo, loworalkyl, low~ralkoxy, nitro, ox trifluoro-m~thyl;
E i~ oxygen o~ ~ulfur;
R i~ uelected f~o~ ~he group con~i~ting o loweralkyl, cy~loalkyl or phenyl-lGwer~lkyl, of which ph~nyl may be op~ionally 3ubstitutad ~y one or ~wo ~adical~ ~eloctod from halo, lower~lkyl, low~ralkoxy, nitro or trifluoromethyl;

~ ~l9~-C~P

~23 R~ is hydr~gen or an a~id neutralizing ion, and n i~ ~ne or ~wo, to give a compound of the formula ~ j A ~ A~ X~

or it~ ~ree ba~e wherein X i8 chlorine or bromine and A, E, R, Y and n are the sam~ a~ the ~tartin~ values.
Amon~ ~uitable halogenating agent~ are a) ~hionyl halid~s b) triphenylphosph~ne and a car~on tet~ahalide c) phosphoru~ pentahalide~
d) pho~phoru3 trihalides, and e) triphenylphosphin2 dih31ide, with the thionyl hali~es being preferred.
Step 2) ~eutralizing, if neces3ary, and u iny the carboxylic acid halide der~va~ive pr~pared in step 1 to give an oxaz~pln~n~ or a thiazepinone of th~ formula , ~ E~t CH2 ~ n~X
~Y~

. ~Ia wherein A, E, R, X, Y and n nre as defined above in step 1, and A now ha3 two of its c~r~on atom~ held mutually with the oxazepine or thiaz~pine mo-iety. ~ :
Stop 3) Option~lly reacting the compound prepar~a in ~t~p 2 with a sul~uriz~ng ag~nt to obtain an ox æ ~pine-thion~ or a thi~epinethione o~ ~h- fonmula :
.

, ' :

:

` 419A-CIP

7 ~ 309 E ~ ( C~ ) n-X
~ A ~ ) (Y~
S R IIb wherein A9 E, R, X, Y ~nd n a~e a~ defined abov2 in s~ep 2.
Step 4) When required, Eeacting a compound prepared in st~p 2 with an alkali-metal cyanide to obtain a compound o~ ~h~ fonmula " ~ E ~ ~CX~ CN

~Y~_2`~
IIc wherein AJ E~ Y~ and R are ~8 defined in ~tep 2.
Step 5) Rea~ting a halogen ~ompo~nd prepared in step 2 or 3 with a compound of ~he formula wherein Z i8 ~elected from -~RlR2 9 lH-pyrazol-l-yl or lH-~midazol-l-yl, and wherein Rl and R~ ar~ selected from hydrogen, loweralkyl, cycloalkyl and phenyl-loweralkyl, o~
25 whic~ phe~yl may be optionally 3u~stitu~ed with 1 or 2 radicals selected from halo, low~ralkyl, low~ralkoxy, nitro, tri:Eluoromethyl or cyano, or Rl and R2 taken toge~her with the adjacent nitrogen ato~ may for~ a het~rocyclic residue s~lect~d from th~ group consi~ting o l-pyrrolidinyl, 2,5-dime~hylpy~rolidin-1-yl~-2-methylpyrrolidin-1-yl, l-pip~ri~inyl, 4-~ubstitut~d-piperidine-1-yl, 4-morphelinyl5 l-piperazinyl, 4-substituted-piperazin-1-yl and 1,2,39-6-t~trahydropyridine-l-yl, to give n compound of the ~ormul~
3~ "~ C~ Z

(Y~
I~. .

8 ~3~ 9 wherein A, E, R9 n and Y are a~ defined above in ~tep 2, Z i8 the 3ame ns in the ZH compound, and B i8 an oxygen or ~ulfur atom.
Step 6) Optionally reacting a c~mpound prepared in 8tep 5 wh~rein B i8 an oxygen ~tom with a sul~urizing agent~ preferably phosphorus pentasul~ide in pyridine to obtain a conSpound of the formula E_~( CH2 ~ n ~Z

(Y~_2 (~--R Ib wherein A, E, R, n, Y and Z are as defined in step 5~
Step 7) Re~ucing a cyano compound (Formula IIc) prepared in step 4 to a primary ~mine of the formula E- ~ (CH4)~_9XH4 ~ A
(Y)Q-2``--~ ~7 R IC-la wherein A, E, Y an~ R are de~ined in steps 2 and 4.
Step 8) When required, reactlng a primary amine prepared in steps 5 or 7 of the formula ~ / E-~_ (C~2~- ~
_,A ¦ ) :
~ R Ic-l wherein A, E, Y and R are ~B de~ined in 3tep 2 ~R i8 not hydrogen) with one of the following reactant~ or set~ o~
reactants ~) form~ldehyde and formic acid to give a tortiary dime~ylamine~, b) ~ dih~lide to~give ~ heterocyclic amine, 419~-CIP
,_ ~:3~30~

c) a dialdehyde and sodium cyanoborohydride to give a heterocyclic amine, d) equal molar amountq o aldehyde or ketone, -qodium cyanoborohydride with large exce~s of above primary amine to give a ~econdary amine, e) equal molar amount~ of the primary amine and ~odium cyanoborcihydride with at lea~t two equivalents of aldehyde or ketone, ~) in se~uence tri~luoroacetyl ~hloride, alkyl or phenyl-alkyl halide, potas~ium hydride and potaq~ium hydroxide, all products being encompassed by ~he formula , _~ E (CH~)-Z
A ~ 1-3 y~_" ~
R Id wherein A, E, Y and R are aq de~ined in qtep 2 (note~
not hydrogen) and z is -~RlR~ wherein Rl and R2 are lower-alkyl, cycloalkyl and phenyl-loweralkyl with phenyl being optionally substituted by halo, loweralkyl, loweralkoxy, nitro, trifluoromethyl or cyano or Rl and R~ taken together with the adjacent nitrogen may fonm a heterocyclic residue selected ~rom l-pyrrolidinyl, l-piporidinyl, 4-~ubstituted:
piperidin-1-yl, 4-morpholinyl, l-piperazinyl-l-yl or~
1,2,~,6-tetrahydropyridin-1-yl and optionally;sulfurizing;
th azepinone or thiazepinone ~o give the::corresponding :~
thione as in step 6.
Step 9) wh~n:required, reacting a benzyl or ~ub~tituted~
benzyl compound obtained in 4tep~5, 6 or 8 wherein~2 i~
~: tertiary am1no, pyrazolyl or imid~zolyl of the ~onmula :

:: : :

419A_CIP

- ~234~0~
1~

E~ ( CH2 ) -2 Ie phenyl wherein A7 E and Y are as de~ined in ~tep 2J and z i8 any radical taken from the dafinition o~ Z under Formula X, subject tc) the sam~ provisos given thereunder, and with 0 ~odium and ammonia to ~ive a compound of the formula ~ (cr~ 9Z

(Y~ 2 `~~
wherein AJ E and Y are a~ defined in step 2, n i9 1 to ~
and z is a~ defined under Foxmula I with limitations given thereunder.
Step 10) Optionally react~ng the free ~ase of any 20 compound prepar~d in steps 5 ~o 9 wi~h a pharmaceutically acceptable acid or guaternary forming halide or sulfate ~o form a p~armaceutically acoep~able salt ther-of.
The compounds of Formula I wherein n i9 2 are pre~erred for their antihi~taminic activity.~ The pro~e3s which include~ step3 1 to 3, 5, 6 and 10 wherein compounds prepared have a methyl or ethyl side chain (n - 1 or 2) represent~ a preferred proce~s corresponding to a succession o~ step~ designated A to F as sxplained hereinbelow.
The compounds of Formula~ Ia~ Ib, IC-1 to IC_7, IC-la~
Id, Ie~ If are all encompasYed by Formula I and the compound~ of Fonmula IIa, II~, IIC, IId and IIe are all ~:
encom~assed by Formula II. ~;~
Steps 1 to 4 also reprs~ent a novel proce~s for prepar~ng compounds of Formula IIa, IIb, II~, 811 ~nco~pag5ed by Formula II
It is therefore an object of th~ pre ent ~nvention to provide certain novel ~romatic 2:,3-dihydro-1,4 oxazepin- :

' ~

~2~ )9

5(4~)-ones ~and sulfur analog~ thereof) sub~tituted in the 2-position with ~hort chain aminoalkyl radicals which have antihi3taminic activity~
, Another object is to provide certain novel aromatic 2,3-dihydro-1,4-oxazepin-5(4H)-one~ (and sulfur analogs thereof) substituted in ths 2-po~ition with alXyl halo or alkyl cyano radicals which ar~ chemical intermediates.
Still another object i8 ~0 provide a novel route and process for preparation o~ aromatic 2,~-dihydro-1,4-ox~zepine-5(4H)-ones (and sulfur analog~ thereof) substi-tuted in the 2-po~ition with ~hort chain alkylhalo or alXyl-cy~no or alkylamino radicals.
Addi~ional object~ and advantages of the pre~ent invention will be apparent to one ~killed in the art and others will become apparent from the following description of the b~st mode of carrying out the present invention and from the appended claims.
DEI~ILED DESCRIPTIO~ OF THE INVENTIO~
The pr~sent invention eneompasse~ the novel oxazepine and thiazepine derivative3 ~et forth in Formula~ I and II
and certain novel compounds of Fonmulas III, IVa and rvb a~
composition of matter and a proces~ for the preparation of compounds of Formula~ I, II and III.
Chart~ I and II illustrate the preparation of all intermediate3. R i8 never hydrogen.
Chart III illustrates reaction sea,uence for preparing ~nd-products wherein R is other ~han hydrogen and n is 1 or 2.
chart IV illustrate~ preparation of compounds having 2-Po8itioned ethyl and propyl radicals-omega substituted by primary ami~e (-~H~). R is ~ver hydrogen.
Chart V illustrates method~ of converting the omega-NH4-su~stituted ethyl and propyl compounds to secondary and tertiary amines. ~hi8 i8 an alternate method for preparing the othyl secondary and tertiary amine R i~
never hydrogen.

419A~CIP

34~09 - chart VI illu~trates preparation of compounds wherein R i3 hydrogen.
Preparation3 1-2~ illuqtrate ~yntheses of compounds o Formulas rva, IVb ox provide certain starting matexials therefor. Intermediates 1-~6 (3ee also Tabl~ 1) illu~trate preparation of compounds encompassed by Formula II, which are aromatic-2,3-dihydro-1,4-oxazepin-5(4H)-one3 (and ~ulfur analog~ thereof) ~ubsti~uted in the 2-position with alkylhalo or alkylcyano radicals. The compounds of Formula III are formed in the reaction mixture~ u~ually without isslation . Example~ 1-71 t see also Table 2) illu~trate preparation of co~pound~ encompa.qsed by Formula I.
The ~oope of the invention i3 not limited by the preparationsJ
intermediates and examples, however.

~ ~ 419A-CIP

CH~RT I
Preparat on of Intermediate~ (a) (b) n ~ J~ )n ~Va 0 ~ yds~lys~
~E ~ . (CH~ )n ~ "lC ~
(Y)0-2 o~ ~OR!~ R IVb 8~log~n-t~
~e -~ r--~C~
. ,~ ~
X ~ b~lo~
-2 ~II
\ H-at ~nd/or utrali2~ wh2n r~quir~d E ~ (CH4)n hopltO~ n~ ~ (C~n-halo ~ Sulfurl~ing ; A
(Y ~ ~ ~ llb ~ (~
OP~$on~1 to rootnotos: l-ngth~n ch~tn 3 R $~ n vor hydrog-n. XCN
x ~ Halogon tCl, ~r~
W Aryl ~ulfonat-, o~kyl ulfonnto or X. ` ,.--~ ~E _ (CE~)n-CN
Ac$~ ncutr~l$~1ng ton, A `r . .g.~olkrl$-3 tol~
Q 1~ H~, -C~ OR~
wh~r- R9 io ~, ~ or O ~ ~Ic stor~fyfn9 ~tC~l.
3 ~ydsolys~ whon QQl- oth-r ~hhn -~-0~ o~ OM.
4~Dl-qr~m tllu~tr~t$ng th-~ugg--t-d for~ation ~n~
clo~vag- of b~dJ to ff-ct ~r~ngo~-nt.

3~

O ~

:

, .
~3~09 Alternate Method of Preparing Pyr~do Ring -~alogenated Intermediate~a~
~(C~) -X ,~(CE~)1 2-X

R IId + S02C12 Cl ~, I IIe dimethylformamide R

Footnote~:
X = Cl, Br, CN
E and R are aq defined in Formula I
a) n = 1 or 2 ~H~R~ III
Preparation of End P~oducts (n = 1 or 2; R ~ other than H) '~(CE4)n-halo " ,~ 2)n-halo (Y) `-~" I ( ) j~~~"~ I IIa Iz~ ¦ZH
~ 1 ".~ E ~ (C~4)D-Z ,_.~ E ~ ~CH~)n~Z
(Y) ~ ~-~ ~ N Sulfurizing ( ) ~ . ,( 0-2 5 ~ R Agent o-2 ' R
Ib Ia Footno'ce:
Z is a~ defined ~or n = 1 or 2 :
under Formula ~.
' ~

. 419A-CIP
, . . .

15 ~ 23~

~H~RT IV
Preparation o~ Primary Ethyl and Propyl amino Compounds wherein R i~ other thaYl Hydrogen from Cyarlo ~ntermediata -" ~ E ~ (CH4)1-2~C~ " ,~ (CH2~2_3-NH2 (Y)0_2 IIc (Y)0_2 R Ia CH~RT VI
Preparation o~ Compounds Having Unsubstituted Azepine Nitrogen ~R=H) _ ~

" ~ ~ (CE2)l_3 Z" ~ E ~ tcH2)l 3~Z*

( ~0-2 0 C~k (Y)0_2 ~ H
I~H5 I~ I~
R = ~enzyl :R ~ H

Footnote:
*Z cannot be a pr~mary or ~econdary amine.
~0 ~ :

:~:

:

. 419A-CIP

16 ~234~

CH~RT V
Additional Preparation~ of Secondary and Tertiary Amino-alkyl Compounds wherein R is other than H

..~ E~(C~) -~
: A ~ 3 ,.~ CElQ)nl~(C~)12 ~ ~ I C (Y)0~
4 ~ ~c-2 O ~ E ( ~ ~ ) n~N ~t 10 "~c-tc~2) -c~ el Ar~
Z NaEI~ ' (y)~
CE190EE ~pH 6-8) } 0~ r I ~c-3 ~I
1 molo ald~hy~ or ke~ton,~ "' ~E~(C~2)n-N-R~
1 molc Na~H3CN ;~ ~,~
~OH ~ pH o -~ ) ( y~ ~ ~ _ " ~
I¢--1 in ~xc-~ 0-2 ~ R Ic-4 1 molo ~ama or diff~r-nt aldsbydo or 1c-tonu;
1 mols ~11 CN r ~OH(pH 6-8 2 1- ~ldchyd~ or k~ton~
CN ~ ~A I
~0}1 (pEI 6-8) (Y)o :t ~ R I~_5 ct ~n ~oqu-nce 1-4 "~ ~ tCE2)n-N-R~
l Tr$fluoroac-tyl 2hlor$des '~
2' 2 Alkyl or phonyl~lkyl-h~l$do~ ~ ~ (YJ0-2 ~ R ~c-6 Mot~l hydroxidc, cuitn~l~
~olvont R~ ~ ~lkyl or p-~lkyl-IC-1 opt$on~1 to pso~u~o ~ ~ ~ (CE~)n-z to thlono~ ~
~0 Sulfurizi~g g-~t (y)~ ' ~ R ~c-7 PoOtnOt~d 2 ~n 1-3 ~nthod d ~crib~d ~y ~. F ~orch, ~t nl , J. A~-r Ch~m 80c 52J 2897(1971) ~cont.) .

~23~i~0~
Footnote Chart V continued under *.
Illustration of reaction of a compound of Formula Ic 1 wherein Z is NH2 with aldehydes and ketones follows:

Reactant Z-Radical Produced 1) 1 mole acetaldehyde -NHC2H5 1 mole NaBH3CN
excess primary amine (Z=NH2) 2) 1 mole acetone -NHCH(CH3)2 1 mole NaBH3CN
3) 1 mole benzaldehyde -NHCH2C6H5 1 mole NaBH3CN
excess prlmary amlne ( Z=NH2 ) 4) 1 mole cyclohexanone -NHC6H
1 mole NaBH3CN
5) 2 mole acetaldehyde N(C2H5)2 2 mole NaBH3CN

6) 1 mole acetaldehyde ) 1 mole NaBH3CN
excess primary amine) (Z=H) followed by 1 mole formaldehyde ) N(CH3)C2H5 1 mole NaBH3CN

**J.E. Norlander et al., Tetrahedron Letters 1~78(50) pp 4987-4990.

18 ~23~309 In reference to the proce~e3 and the proces3 ~tep~
of the invention summarized above as they apply to the preparation of compounds o~ Formulas I3 II and III, the following further de~cription i8 applicable.
In 3tep 1J ~tarting compoundQ of Formula IVb (See Chart I) bearing a carboxylic acid or an acid neutralizing ion 3uch a~ an alkali-metal salt thereo~ on the A ring ortho to the ether linkage as a substantially pure entity or pre~erably deriv~d in a reaction mLxture re~ultin~ from hydrolysi3 of precursor bearing in the _am~ ortho positionJ carbamoyl, cyano or carboxylic acid ester ~unctions without sub~tantial isolation of the carboxylic acid ~or salt) compound ~rom the rea~tion mixture, are treated with any suitable halogenating ~gent such a~ are described above, preferably thionyl chloride or triphenyl phosphine and carbon tetrachloride. The halogenation i8 conducted in any ~uitable organic ~olvent, pre~erably a refluxing organic ~olvent or a refluxing halogenating agent such as the preferred thionyl chloride. Temperatures for the chlorination over a wide range may be empLoyed, for exampleJ frQm room temperature to 100C. or aboveJ
however, temperatures of 50-80C. a~e preferred, which temperatureQ encompass that of refluxing chloroform or thionyl ~hloride. When ~xce~ halogenating agent ~uch a~
thionyl chloride has been used as carrier, it iq advanta-geously evaporated. When solvent ~uch as chloroform is used, it may, but not nece~sarily, be avaporated away. In any event a solution comprising a solvent and compound~ of Formula III or a residue compxi3ed o~ Fo~mula III compounds, all of which are con~irmed by inra-red analysis is available for U8~ in the next step.
In step 2, ~he halo~enated compounds o Formula III, prepared n step 1, if not alr~aay in a solvent, are solubilized with organic ~olvent, pr~rably chloroform and usually neutr~lized or basified preferably with a tertiary amihe such a~ trie hyl amine, ana then ~eated at a temperature and or a time sufficient to e~fect a fusion lg 1234~9 of the carbonyl with the ba~ic nitrogen and cleavage of the cyclic amine and formation of the 2-(2-alXylchloxo or bromo) oxazepine or thiazepine compound~ of Form~la IIa, ~or example, in refluxing triethylamine. If the tendency to fuss i3 qufficiently great, the neturalization o~ ba~ificat~on may be eliminated. The ~ormula IIa compounds may be i301ated by conventional mean~, for example, by partitioning ~etween a 3uitable organic ~olvent or mixture of solvents and aaueou~
acid or base followed by drying and evaporating the organic layer and recrystallizing the re~idue from a suitable 801 vent.
In step 3~ the compound~ of Formula IIa may optionally be converted to the oxazepinethione or thiazepinethione (IIb) by heating together with a sulfurizing agent in a suitable organic 301Yent ~uch as toluene. The thione (IIb) may be i~olated by conventional mean3, preferably by paxtitioning between an organic ~olvent and dilute alkali-metal base and crystallizing from a ~uitable solvent ~uch a~ ethanol.
In step 4, an oxazepinone or thiazepinone (IIa) is reacted with potas~ium cyanide in a hot protic solvent using a phase transfer catalyqt such as tetrabutyl ammonium bromide.
The reQulting cyano compound i~ then extracted into a 5Uit-able solvent such as ethyl aoetate, and the ~olution dried and evaporated. The re~idue i3 then recrystallized from quitable solvent uch as a mixture of ethyl acetate and isopropyl ether or ethyl acetate alon~. A~ will be realizedt the compounds produced ha~e methyl and ethyl cyano ~ide chain~ (n = 1 or 2) which lead to side chain lengthening to amino propyl n _ 3 or as an alternat~ starting material for longthenin~ of a methyl chain to amino ethyl.
In ~tep 5, the oxazepinone and thiazepinone (IIa) obtained in step 2 or the oxazepinethione and hiazepine-thione (IIb) obtained in ~tep ~ are reacted with pyrazole, ~5 imidazole or with an amine of the formula ~HRlR2 wherein , .. ~
~L23~ 9 and R2 have the value given und~r Formula I above t~ give compounds of Formula~ Ia and Ib, re3pectively. The latt~r reaction i~ preferably conducted in excess amine as in the in~tance of volatile methylamine~. ~he free bases of 5 products o~ Formula Ia and Ib are i~olated by conventional means by removing volatiles and partitioning between dilute aqueous alXali metal ba~e and a ~olvent such ~9 chloro~orm or ~ethylene chloride followed by evaporation. The free baRe may be converted to a pharmaceutically acceptable salt with an appropria~e acid and ~n the case of a ~uaternary salt with a loweralkyl halide or sulfate and recry~tallized by conventional m~ans. The ~ree bases may be recovered from the acid addition salts, usually in a purer form, by again partitioning the ~alt between a~ueou~ base and a ~uitable ~olvent followed by evaporation. As will be realized and a~ shown in Chart I, the ~ide chain o~ the intermediate produced is 1~mited to aminometh~l and amino-ethyl tn = 2).
In step 6, when it i~ de~irable, a compound prepared in ætep 5 wherein B i9 oxygen, i3 3ul~urized, pre~exably by refluxing in dry pyridine with phoqphoru~ penta~ulfide for 3everal hours. The resulting thione i3 isolated by cooling the ~olution and partitioning between a suitable solvent ~uch as chloroform and an agNeou~ base and evapo-rating the organic phase and i~olating by conventionalmeans.
In step 7, a cyano compound (IIc) prepared in step 4 which is an oxazepinone and thiazepinone i~ reduced, prefer-ably with hydrogen u~ing Raney nickel catalyst at about ~o 60c. me primary aminoethyl or aminopropyl compound (n = 2 or 3) produced i~ i~olated by conventional means, -pre~erably a~ an acid addi~ion salt which ~y be ~onver~ed back to the free ba~e by partitioning betw~en a ~uitable solvent and aqueous base and thereafter drying and evaporating ~he organic layer.
In 3tep 8 (se~ Chart V), a primary amine i8 converted to a secondary or tertiary amine by a choice o~ rea~tan~.

~L234 The method provides a route to ~econdary and tertiary amino compound~ of Formula I having n = 3 not af~orded by ~tep 5 and, in addition, provide~ ~n alternate route to ~econdary and tertiary amino compounds of ~ormula I wherein n = 1 or 2. Th~ preparation of dimethylamino derivative3 by re~ction of primary Emine with formaldehyde and formic acid i8 a conventional method for preparing tertiary dimethyl amines as i_ reaction o~ a dihalide to give a heterocyclic amine 3uch a3 l-pyrrolidino, ~iperidiAo or 4-morpholino. The alternat-ives employing sodium cyanoborohydride follow the procedure~ described by R. F. Borch et al, J. Amer. Chem.
Soc. ~ 2897 (1971). The procedure which employ~ conversion to a trifluoroacetamiae i~ described by J. E. Norlander et al, Tetrahedron Letters, 1978 (50) pp 4987-4990.
In 3tep 9, a 4-benzyloxazepinone or thiazepinone derivative (R = Benzyl) under Formula I ~xcluding primary or s~condary amine~ i~ converted to the corresponding 4-unsubstituted (R = H) oxazepinone or thiazepinone by reaction with sodium and ammonia and may be isolated as illus~rated in Example 68.
Step 10 is optional depending on whether th~ compound o~ Formula I is already in th~ ~orm of a pharmaceutically acceptable _alt or whether it i-Q de3irable to convert to another salt or whether the free ba~e i8 deQired. To obtain the ~r~e ba~ from any addition salt o~ Formula I, the salt i9 partitioned b~tween a suitable organic solvent such as chloroform and a dilute aqueous base. The organic layer i~ dried and condensed to give th~ free ba~e which i3 then, if desired, reacted with an acid describad above to ~o give the de~ired nalt.
As mentioned above, the preferred 3teps ~or reaching ~he pre~rred compounds having an ethyl side chain in the 2-po~ition include staps 1 to ~, 5, 6 and 10 of the gen~ral proce3~ ~or preparing all the compounds of Formula I.
~nasmuch ~8 the compounds having a methyl ~ide ~hain can be mada by the 3am2 proce3~ compound~ wherein n - 1 are included in the pre~erred pro~_s. The3e ~tep~ of a 22 1~:3~

preferred proces~ are designated A to F corre4ponding to the numbered steps of the ~eneral proce~ with the limita-tion that n = l or 2 and R i9 other than hydrogen ac follow~:
Corresponding General Step Number ~ith Preferred Process~escription Pertaininy Ste~ De~i~nation to n = l or 2 A

C

F lO

2~ 9 Preparation 1 2~ Benz~1-7-pyrrolidinvloxy)benzamide.
To æ ~u~pen~ion o~ 4.~ g (0.11 mole) o~ sodium amide in 60 ml sf dry toluene was added 19.~ g (0.11 mole) of l-benzyl-3-py.rolidinol at a r~te to maintain a temperature of 35C. Stirrin~ wa~ continued at room temp~rature ~or hour~. ~o the mix~ure was adde~ ~t rapid drop 19 g (0.1 mole) of o-toluene~ulfonyl chloride with ice ba~h cooling t~ maintain a temper~Pre of 20 30C. Stirring wa~ continued at room temperature ~or 2.5 hour~ and th~
mixture ~llowed t~ ~t~nd ov~rnight. The toluene wa~
wa~hed twic~ wit~ water~ dried with sodium ~ulfate and concentrat~d.
To ~ Ru~penR io~ of 5.4 g t0.1 mol~) of ~odium methoxide in 50 ml OE dim~thylformamide in another vessel Wa8 added 1~.6 g (0.1 le) o~ ~licylamide in 75 ~1 o~
dimethyl~ormamids at a rate to maintain a temperature of 50 C. After stirring 15 minutes, the ~bove prepared sulfonate in 25 ml of dimethylforma~ide was ~dded drop-wise and tha ~olution refluxed 5 ~ours. The material `20 was partitioned between 500 ml o~ ethyl acetate and 500 ml o~.water. ~he ~thyl acetate was extr~cted with dilu~e hydrochloric acid~ ~h~ acid basifi~d with dilute ~odium hydroxide ~nd extracted with ~thyl acetate. The organic layer was dried, concentrated, and the residue crystal-lized twice from i30propyl ether-ethyl ~cetate. Yield o~
product was 12.5 g (42%), m.p. 120.5-122 C.
Analy~is: Calculated for Cl~oN202: C,72.95: H,6.80;
N,9.46 Found : C,7 5.23: ~I,6.78.
~1,9 .56 Preparation 2 2 - ( 1 -Methyl -3-pyrrol idinylox~ benzamide .
To 85.6 9 (2.2 moles) o~ sodium amide in 1.5 liter of dry tolu~n~ w~s ~dded 202 g (2 ~aole~) of l-methyl 3- -pysrolidi~aol 80 a~8 not ~o ~xcee:d a t~mpera~aro of 50C.
35 The mixture wag~ ~he~n h~ated to 70C. ~or ~5 hour~. ~he mixture wa~ cool~d ana 381 g ~2 mol~a~ of o-toluene!-sul~o~ylchlorid~ waa added ~t a r~pid drop while ~naint ining ? 419A- CI~?

24 ~L239L~0~

a t~mperature of 20-30 C. with an ice bath. The mixture was stirred at room temper~ture ~or 2.5 hours and wa~hed with water. The ~slu~na solution w~ dried with sodium sulfate and conc~n~rated. The residue, dis~olved in 500 ml of dimethylformamide, was added to a re~ction mixture yrepared by adding 119 ~ (2.2 mole~) o~ ~odium ~ethoxide ~nd 274 g (2.0 moles) o~ sslicylami~e to onz lit~r o~
dimethylformamide and th~ mixtur~ was worked up ~3 in preparation 1. Yield of product w~8 170 g ~38%~, m.p.
116-118~.
Analysis: Caleulated for Cl2~1~N~02: C,65.43; H,7.~2;
N,12.72 Found : C,65.28; H,7.28 ~,12.77 Preparation 3 2-L~-(l-Benzyl)pyrrolidinyloxy ~ zoic acid.
To a solution of 20.~ g (0.52 mole) of sodium hydroxide in 600 ml o~ ~th~nol and 400 ml of water wa3 added 150 g (0.51 mole) of 2-~3~ benzyl~pyrrolidinyloxyJ
benz~mide and the mixture was ~tirred at reflux for 48 hour~. The mixture was concentrated on the rotary evaporator to o~e-half volume and th~ rssidue wa~ extracted with ethyl acetate to remo~ unreacted amid~. ~he water layer was filter~d and tha pH o~ the filtrate adjusted to 6.5 with hydrochloric ~cid. The ~iltr~te wa~ concentrated on the rotary ~vaporator. ~he residue wa~ dis~olved in isopropyl ~lcohol. The resulting mi~ture wa~ ered and ~he filtrate concentrated. The residue 85.7 g wa~ comprised substantia~ly of tho title compound.
Prel2aration 4 3-rtl-Methyl-3-pyrrolidinyl)oxyl-2-naphthalen~-~arbox~mide.
To ~ ~ool~d ~olution o 68 g (0.67 mole) of l-methyl-3-pysrolidinol ~nd 74 g (0.73 mol~ triethylamine in 700 ml of dry bsnzons wa~ add~d aropwi~e 74 g (0.6~ ~ole) of ~5 methanesulfonyl chloride. After ~irrlng a~ room ~emp~r~ura ~or 45 min, ~h~ ~ix~urg wa~ ored and ~he iltr~e co~c~ntrated und~r roauced pres~ur~ ~d di~solved in 100 ml .
1~34~0~

of dime~hyl~orm~miae.
To a c0012d ~uspen~ion o~ 10.8 g (0.45 mole) o~
~odi~m hydrids in 75 ml o~ dimethylformamîde in another ve~sel, 84 g (0.45 mole) of 3-hydroxy-2-naphthalene-carboxamide di~solved in 400 ml of dimethylformamide wasadded dropwisa. The abov~ prepared ~ulfonate ~olution wa~ added dr9pwi8e and the reactlon mixture stirred and heated at re~lux for 16 hr. Ths cooled solu~ion was diluted with 1000 ml o~ water ~nd extr~cted twice with 1~ 500 ml portionQ o~ chloroform. The chloroform wa~ w~shed with water and extracted twice with 500 ml portions of 3~ hydrochloric acid. ~he a~ueou~ extracts were made alkalin~ with 50% sodium hydroxide and extracted thrice with 500 ml portion~ Of chloroform. After drying over magne~ium ~ulfate, the chloroform w~ evaporatea under reduced pressura ~fording 27.4 g (22%) of a pale yellow solid. Rec~ystallized from ethyl ac~tate, m.p. =
128-130C.
Analysiq: Calculated for C~H~2O2: C,71.09: H~6.71;
NJ 10 .35 Found . : C,70.8~; H/6.68;
~,10.37 Preparation~5 3-r ( 1-Methyl-3-pyrrolidinyl ) oxy~-?-naphthalene-carboxylic acid oxalate r2 i]-To a ~olution o~ 21.6 g (0.54 m~le) o ~odium hydroxide in 500 ml of water wa~ added 74 g to.27 mole1 o~
3-~1-methyl-3-pyrrolinyl)oxy]-2-naphthalenecarboxamide.
The ~olution was heatod at re$1ux ~or 16 hr~ and on cooling, the p~ wa~ ad~usted to 6.8 with concentrated hydrochloric acid. Tha resultant ~olid was ~eparated by filtration and the p~ of the ~iltrate was ad~usted ~o 6.02. The fil~ra~e was ~onc~ntsate~ unde~ r~duc~d prossura ~nd ~he re~adue boil~d in 200 ml of i~opro~yl alcohol ~nd iltered. ~he ~iltrate was ag~in conc~ntr~t~a under reduced pre~sure to give 69 g (94~ of an rphou~ ~olidO An ~ uot wa~
di~svlv~d in i~opropanol and ~reatad with oxalic acid.
The oxal~t~ ~lt Wa8 recry~talliz~d ~rQm ~tha~ol ~ater~

- 419P,CIP

2~ ~ ~ 3 m.p. 209-212C.
Analysi~: Calculated ~or Cl7Hl8YOs: C,64.55; ~,5.74:
N,4.43 Found : C,63.86; ~,5.68;
N,4.37 reparation 6 Sodium 2-~(1 methvl-~ ~yrrolidinYl ~xv~ Pyridin~-car~ox~late.
To a ~tirred suspenRion of 6.4 g (0.13 mole) o~ 50 ~odium hydri~æ (~i~ral oil~ an 50 ml of dimethyl-sulfoxide WZ8 ~ddad dropwi~e 6.4 g (0.063 mole) of l-methyl-3-pyrrolidinol. During ~ddition, ~he t2mperature ro~e from 2~ & . to 31C. After 10 minute3, a solution of 10 g (o.o63 mole) of 2-chloronicotinic acid in 50 ml of d~methylsulfoxide wa~ added dropwi-~e causing the temperature to riso. When the tomperature reached 55 C., it wa~ maint~ined there by the intermittent use of an ice bath until addition wa3 completa. The mixture was then heate~ to 55-60C. ~or 1.5 hr., ~ooled and ~iltered. The filter cake was su~penaed in 100 ml of ethyl acetate and filtered. 5~ solid was recrystallized from ethyl acPtate-methanol. Yield of product was 5 g., dec. 240C. The NMR analy~is showed tha~ th~ compound contained 1/3 mole of sodium acetat2 a~ ~mpuri~y.
Analysis: ~alculated ~or C1lRl3~2O3Na-l~C2~902~a:
CJ 51 . 62; El~ 5 .20 ; N, 10 . 32 Found: C,51.81; }I,5.15: ~,10039 Preparation 7 4-Chloro-2- ~l-methyl-3-pyrrolidinyl)oxy]benzamide.
To a ~olution of 55.5 g (0.55 mol~) of triethylamine in 500 ml of dry b~nz~ne was added dropwi3e jO.5 g (0.50 -mol~) of l-methyl-~-pyr~olidinol ~t such ~ rate as to ~in~ain ~ temper~tu:re of 25-35C. To the mixture, m~intained at 20-50C.~ adde~d ~ropwi~eJ 57 g (~050 mole~) of mothane~ulfonyl chloride. After stirring for 1 hr Zlt roon~ t~mp~rature, ~he mixtur~ was fil~ered ~nd ~5 the p~cipit~te w~he~l with 250 ml of ho~ benzeneO Th~
filtrat0 an~ wa~h war~ cor~in~d and c:oncenerat-d under ~ . ~

2~ 123~

reduc~d pressure ~nd th~ re3id~le ai~solved in 200 ml dimethylfonnamide .
~o a cooled l3u~pension of 19.6 g (0.41 le) of Rodium hydride in 100 ~1 of dimethylfonnam~de in another vessel wa~ add~d dropwi3e a solution of 70 g (0.41 mols) of 4-chlorosalicylamide in 209 ml dimothylformamide at a rate ~uch as to maintain a temper~ture of 20 & . To the ro ulting reaction mixtura was added dropwise the ~bove-prepared sulfonate salt ~nd the sn~turo w~ heated at reflux for 19 hr~. Th~ r~action mixture wa~ cooled and dilut~d with one liter of wat~r. q~he diluted mixture wa~
extracted thr~e . i~es with 300 ml portions of chloroform.
The ~hloro~orm ¢xtr~ct~ wore combined and extracted with ~wo 500 ml portionQ of 3N hydrochloric acid. The combined aqueou~ oxtract was made alkaline with 50% sodium hydroxide and extractod thre~e times wi~h 500 ml por~ion~ of ethyl acetate. The ~:ombined ethyl ace~ate extract wa~ dried sver magne~ium aulfate and conc~ntrat~d under reduced pressure to give 46.5 g (45%) beige ~olid. ~he solid was r~crystall~zed ~rom ethyl acetate, m.p. 122-12~5~.
Analy~is: Calculated for C12~IlS~C102: C,56.58; }1,5.94;
~, 10 .99 Found : C,56.48; ~,5.96;
~910 .~4 Preo~ration 8 ~-Bromo 2-r(l-methyl-3-pyrrolidinyl)oxylbenz~mide.
To a cQoled solution of 101 g (1.0 mole) 1-methyl~3 pyrrolidinol, 111 g (1.1 mol~) tr~thylamin~ in 1000 ml of dry benzene was added dropwi~e 114 g (1.0 mol~) of methan~ulfonyl shlorid~. The reaction mixtur~ was ~tirr~d at room tomper~ure for 1 hour ~nd filtered. ~hQ filtr~te Wa3 concentr~t~d under reducod pr~s~ur~ and dissolved in 100 ml dimethylformamida.
To a cooled ~u~pension of 30 g (O.63 mole) odium hydride in 100 ml d~ethyl~or~amide in anot~ex ves~el wa~
35 added aropwi~o 5-bromo~licyl~mide (137 g, 0.6~ mol~) di3Jolvea ~n 750 ml of d~methylfo~mia~. Th~ a~ove prepar~d sulfonate W~8 added dropwi~8 an~ th~ r~ ion 28 ~ 34~

~ixture heated at reflux ~r 18 hr~. The cooled ~olution wa~ ailutod with 1000 ml of water and extractea thxice with 500 ml portion~ of chloroform. The chloro~orm ~xtract~ were wa3hed with water and ~xt~acted ~our time~
with 500 ml port~on~ o$ ~ hyd~ochloric acid. ~he aqueous layer wa3 made alkaline with 50% ~odium hydroxide and extracted with chloroform. ~h~ chlorofsrm ~xtract~ were w~shed with w~ter, dried ov~r mngnesium ~ulfat~ and .. 2vapor~tsd under reduced pres~u~o to give 52 g (28%) o~
yellow solid. Th~ solid wa~ recry3tallized ~rom ethyl ac~tate/chloroform, m.p. 160-162 C.
Analysi: Calculated for C~2~ls~BrO2s C,48.18; ~,5.05;
N,9-36 Found : C,48.02; H,5.01:
N,9.22 PreParation 9 5-Chloro-2 -r ( 1-methyl-3-pyrrolidinyl)oxyl~enzamide hemihYdrate .
To a cooled suspension of 2.4 g tO~41 mole) sodium hydride in 50 ml of dimethyl~ormamide wa~ added dropwise 17 g ~0.1 mole) of 5-chlorosalicylamide dissolved in 50 ml of dimethylformamide at a rate ~ueh that the temperature did not 2xceed 20C. A~ter addition o the salicyl~mide was compl~te, 16.7 g (0.1 mole) o~ 3-bromo-1-methyl-pyrrolidine dissolved in 50 ml of dimethylformamide was add~d dsopwi~e. ~h~ reaction mixture was ~tirred and heated ~t reflux for 19 hr. The cQolad ~olu~ion wa~
diluted with 250 ml of water ~nd extracted twice with 250 ml portion~ o~ chloroform. The chloroform wa~
extracted thrice with 500 ml portion~ of 3~ hydrochloric acid. ~he aqueous extracts were made a~kaline with 50%
sodium hydroxide a~d oxtracted with ethyl ~cet~te. Drying over mag~e~ium sulfate and avaporation of the ethyl ~cetate under reduced pxessu~e gàve 6 g (2~%) o~ produc~ ~8 a beige solid. ~he ~olid wa3 ~ecry~alliz2d ~rom e~hyl 3~ acetat~, m.pO 126-12~C.
Analysi~: C~lculate~ ~or C2~9~Cl205. C,54.65: ~,6.11:
~,10.6 Found ~ 4.87: ~,6.12;
~,10.69 29 ~.2;3 ~0~
Pre~aration 10 _- r ( l-Methyl-~-pyrrolid~nyl)oxylnaphthalene-carboxamidc.
A ~olution o~ 118 g (o.6~ mole) o~ 1-hydroxy-2-naphthalenecarbox~m~de in 250 ~1 of dimethyl~ul~oxide w~s added dropwi~e to ~ su~pension o~ 27.6 g (o.69 mole) o~ 50% sodium hyd~ide (mineral oil) in 250 ~1 oi dimethyl-~ulfoxid~. T~2 react~on wa~ Qxothermic and the temperature ro~ to 60C.
. In ~nother vessel, 79 g (o.69 ~ole) of methane-~ulfonylchloride was added dropwise to a solu~ion of 69.7 g (o.69 mole) o~ 1-methyl-3-pyrrolidinol and 77 g (0076 ~ole) of triethylamine in 500 ml of dry ben2ene .
while coaling wi~h an ico bathO The mLxture was stirred 15 ~inutes and filter~d~ The ~ilter cak~ wa~ wa3hed with 5 ml o benzene And the benzene ~iltra~es were combined and concentratad OIl the rot~ry evaporator to abou~ 200 ml.
~rhe re~idue was added dropwi~e to the above prepared dimethyl~ulfoxids solution containing the sodium 3alt of l-hydroxy-2-naphthalenecarboxamide while 3tirri~g at 75C.
The temperature was maintained a~ 75C. for 18 hr with ext2rnal heat. Th~ resul~ing solution was cooled and a~
equal volume of wat~r was added. The mix~ure wa~ ~xtracted with three portion~ o~ ~hloroform. The washe~ were combined and concentra~d. The residue wa~ partition~d betw0en e~hyl acet~te ~nd dilute hydrochloric acid. Tha acid layer WA~
made basic with sodi~m hydroxid~ ~nd extracted twice with ethyl acetate. q!he ethyl ~cetate wash~s were combined, dried over ~odium sulfato ~nd conc~ntrated. The residue was ~rystallized ~rom ethyl aceta~e-~sooctane. Yield o~
eolid wa~ 55 g (32%). A port~on w~ s~cryatallized twice from ethyl ~ce at~-isooct~ne, m.p. 122-129C.
Analysis: Calculat~d ~or Cl~a~N20~: .C,71.11: ~,6.71:
~ ,10.36 Found : ~,70.96: ~,6.71:
~,10.31 30 ~L23~

reparation_ll ~ethoxv-2 -r (1 -methvl-3-PYrrolidinvl~oxY~benzamide.
To a solution o~ 151 g (1.5 ~ole) 1-methyl-3-pyrrolidinol and 166 g (1.6 mole) triethylamine in 1500 ml of ~ry b~nz~ne W~8 added dropwise 171 g (1.5 mole) o~
methan~ulfonyl chlori-de with cooling. The rQaction mixture wns ~tir~ed ~t room tomper~tur~ ~sr one hour and filtered. ~he filtrat~ was concentrated und~r r~duced pres~ure to give ~n or~nge-colored oil~
I~ another vo93el, to a su~pen~ion of 50~ sodiu~ ~ydride/
mineral oil (72 g: 1.5 mole~ in 1~0 ml dimethyl~orm~mide th~ 3ulfonat~ pr~pare~ ~bov~ and 139 g (0.9~ mole) of 5-methoxy ~alicyl2mide di~ olvsd in 600 ml dimethylform~mide were added dropwi~e with cooling. The ~eaction mixture was he~ted ~t reflux for 14 hr. After coo}ing, the reaction was diluted with 1000 ml of w~tor ~nd extracted three tImes with 700 ml portions o chloroform. Th~ combined chloroform ~xtracts were washed thrice with wat~r and e~tracted thrica with 500 ml portions of 3~ hydrochloric acid. The aqu~ous layer was made alkaline and extracted with chloroform. The chloroform ~xtracts were wa~hed thrice with water7 dried over magne3ium sulfate and avaporated undar r~duced pre~ure to give a vi8cou~ brown oil. Vacuum di~tillation o~ thi3 material yielded a vi~cou~ orange oil which was di~solvea in chloroform, extracted in acid; ~ade alkalina ana ex~ractQd into chloro-~orm again. Evaporation o~ the solvent gave a dark ~rown oil which ~olidified under reduced pr~sure. Three recrystalliza~ions from ~t~yl ~cetate gav~ 10 g of white crystals ~4%), m.p. 85-87C.
Analysis: Calculated for Cl~H-~N209: C,62.38; H,7.25:
~ ,11.19 Found ~ C,62.47, H,7.~6;
~, 11 .~0 . ') 419A--CIP

~1 ~ Z3~09 Prep~rat ion 12 3-Lt l-P~ethyl-3-pyrrolidinyl)oxyl-4-pyridine-carbonitrile ~umarate ~1~2~.
A solution of 55 g (O.55 nole) of l-methyl-3-pyrrolidinol in 55 ml of dry dime~hylformRmide was added dropwi~e to a ~uEIpension oi~ 2? g ~0.58 mole) of 60~
~odium hydride/40% minoral oil in ~00 ml of dim~thy~-formamide. The mixtur~ w~ stirred at room temperature 40r orle ~lour and 73 g (0.5~S ~Qale) o~ chloro-4-cyano-pyridine in 200 ml o~ dim~thylformamide was ~d~ed dropwi~e 10 with Mild cooling to maintain a temperatur~ o:E ~o~ 40c.
Th~ solution was stirred ~ hours ~nd an eQu~l volume of water ~dded. The solution wa~ mAde ~cidic with dilute hydrochloric acid and extracted with aaopropyl ether.
The ataueouQ layer waY m~ds b~s~: with ~o~lium hydroxide 15 and ~txtracted 5 tim~3 with chloroform. The extrac~s were combined~ dried over aodium 6ulfate and conc~ntrated.
The residu~ wa3 tre~t~d with 5û g of fum~ric acid in 400 ml of ~sopropyl alcohol and 40 ml of w~ter. The resultin~ c:rystal~ (51 g; 21%) were collect~d. A 2 g 20 sample was recry~tallizea from. methyl i~obutyl ketone.
Yield of produc~ was 1.5 g, m.p. 172-174C.
Analy~ calculated fo~ CleHalNgO~ : C,52.42; H,4.86:
Found : C,52.40; H,~ 90:
N~9.68 ~ J~C4~
~ Methyl-~-pyrrolidinyl)oxyl~2-naphthalene-carbonitrile oxalzlte.
A solutio~ o~ 29 g (0.11 mole) o~ methyl-pyrrolidinyl)oxy-2-naphth~len2c~box2mide:and ~8 g (0~2 mole) o~ thionyl chloride in 150 ml o chloxo~orm wa3 heat~d to ~flux for 6 hr. ~he solution w 8 poured in~o :
ico and made ba~ic with ~odium hyaroxide. m e chloro~orm layor wa~ sep~rat~d, dri~d o~er ~odium ~ulfate an~
concentrat~d~ ~he re~iduo Wa8 di~olved ~n hot i800Ctane.
The ~olution was tr~at~d with c~arcoal, ~ilt~r~a and concentrated. Th~ residu~ wa~ solv~d in i80pr~pyl , 419A-CIP

3~ 9 ~lcohol ~nd ox~lic acid was ~dded. Tho precipltat~ was recryst~llized ~om isopropyl alcohol-water mixture.
Yi~ld of product was 11.5 g (31~, m.p. 176-184 C0 Analyais: calculated for Cl8Hl~2O5: C,6~.15; ~ 8;
Found : C,63.00; H,~ 2g;

PreParation 14 3.~-Diiodo-methYlsalycilate.
To one litex o~ ab~olut~ methanol was added 150 g (0.~9 ~ol~) of ~,5-diiodosalicylic acid. Hydrogen chlo~ide waq ~ubbled through the r~a~tion mixture under ~gitation ~nd reflux~d for 3 hrg. The re~ction mixture turn~d cloudy and suddenly ~ large v~lume o~ whit~ cry3tal~
precipitated. The mixtur~ was filtered to give, after drying, 136 g (83%) of proauctJ m.p. 198-202~.

2-E~vdroxY-3, 'j-diiodobenzamide .
A ~tai~less ~teel bomb, cooled with dry ice acetone, wa~ charged with ~xcess liquid ammoni~ 3,5-diiodomethyl-salicylate and a c~t~lytic ~mQunt of ~odium hydride. The bomb Wa8 sealed ~nd shaken at room t~mperature ~or 16 hr~.
on cooling aganJ th~ content~ of the bomb were poured out and ex~:ess ~mmonia allow~d to evnporate at room temperatur~ he product ~elted 190-195&. with decompo3ition. Ma8~ spec analysi~ confi~3ned molecular weight o~ ~he title compound.
Pre~aration 16 3,5-Diiodo-2-r(1-methyl-3-pyrrolidinyl~oxylbenzami~e.
Following the procedur~ of prep~xation 2, aubstituting-2-hydroxy-3,5-diiodobenz~mide ~or sacicylamide~ the title-compound i8 prep~red~.

~~ L r , ~

~3 ~23~09 Preparation 17 5Odium-2-~(1-methyl-3-azetidinyl)oxy~-3-pyridine-arboxylate.
~ he titl~ ~ompound i8 prepared by following the procedur~ of preparation 6 but ~ubs~ituting l-methyl-3-5 . azetidinol fQr l-methyl-3-pyrrolidinol.
PrePa rat ion 18 acid ~odium Elalt.
4~hls~ropyridin~ i8 xe~cted with diisQp~opyl lithium 10 amide ~nd c~r~on dioxiae to give the lithium ~alt c>f 3-carboxy-4~chloropyridino which iE ~llen reacted wi~h l-methyl-3-pyrrolidinol a in PrQp~ration 6.
Pr~Daration 12 3-r(1-Meth~-3-pYrrolidinYl)oxvl-2-pvridinecarb~nitrile ~umarat~, Cl 2-C~rboxamido-~-hydroxypyridine i8 reacted with 0-P=o to give 2-cyano-3-chloropyridine which i3 th~n ~1 .
reac~ed with l-methyl-3-pyrrolidinol as in preparation 12 to give the title compound.
` PreParation 20 l-Methvl~ vrrolidinethiol acetate ( e~ter~_ethan~-dioate.
To a solution of 191 g (1 mole) of 1-methyl-3-pyrrolidinol and 110 g (1.1 mole) of triethylamine in 700 ml of dry benz0no Wa8 add~d dropwi~ 115 g (1 mole) o~
methan~sulfonyl chloride while stirring and cooling with an ic~ bath. ~he re~ulting mLxture wa~ stirred for 0.5 hr.
and filtered. The filtrat~ wa~ concen~r~te~ on the r~t~ry evaporator ~o about 200 ml b~in~ c~re~ul not ~o overhea~.-~0 The re~idu2 was di~solved in about 150 ml of ethanol. - -In a ~eparate ve!~8~1~: 25.3 g (1.1 mole) o~ Esodiumwas di~solved in 800 ~1 of 200 proof ethanol u~er nitrogen ga~ sweep. A~tçr ~i8801u~ion wa~ c~mpleto, 83.6 g (1.~ mole) of t~iolac~ti~ acid W~3 added lowly ~nd ~5 the r~sulting ~olu~ion W~8 ~irred ~n ~d~i~ion~} 10 mi~.

' ~ ~ 4l9A-cIp 3~ 0 9 The above prepared othanolic 301uti~n ~f methane~ul~onate was added and the r~sulting ~olution wa~ heated to 60 C.
for 20 hrs. The mixture was cooled to 25C. and filtered and the filtrate wa~ concentrated on a rotasy evaporator.
The re3idue was di~solved in $~opropyl ether and the mixtu~e ~ilter~d to remov~ a 8m~11 amount o~ ~olid. The filtrate wa~ concentrated and tha residue di~tilled to yield 70 g of the free h2se titl~ ester, b.p. 95-105/15 mm.
A 7 g portion o t~e ~re~ base WR~ treated with 4 g Of oxalio ~cia i~ i30propyl ~lcohol and the salt obtained was recrystallized $rom i80propyl alcohol to gi~e 8.4 g o title produet, m.p. 108-111C.
Pre~aration 21 l-Me~hvl-3-pyrrolidinethiol oxalate.
A ~olution of 62 g (0.39 mole) o 1-methyl-3-pyrrolidinethiol acetat~ (e~ter) in 200 ml of absolute.
methanol wa~ treated with a 2 mm sphers o~ ~odium and the resulting solution was distilled at 1 atm. pres~ure to ~ pot t2mperature of 100C. Vacuum was apptied and the pressure was 810wly decrea~ed to 100 mm. The residue wa3 distilled to a pot temperature o~ 130~., yielding 25 g (56%) of di~tillate with a boiling point of 95-100C./
100 mm which waR the free base o~ the title compound. A
4 g sample wa~ treated with oxaliG and in isopropyl alcohol to give 5~5 S o oxalate salt, m.p.. 80-~2c.
Prepa~ation 22 2 -r (1-Methyl-3-p~rrolidinyl)thio~ pyr dine-carboxYlic acid.
To a stirred suspension of 8Q g (2 mole) of 60% sodium hydride (in mineral oil) in 800 ml of dry dimethylformamide9 all heated to 60C. and using nit~ogon gas ~low w~Y a~ded: -dropwi~e, a ~olu~cion of 157.0 g ( 1 mol~) o 2-e~hloro-nicotinic! ~cid and }17 g ( 1 mole) of 1-melthyl-3-pyrrolidinethiol in ~00 TDl of dimothylformamiae at a ~t~
which ~intained a tempera~ur0 of 60-67C. q~e m~ur0 w~s~ heated to 65C. or 6 hr ~ 1QWed to ~t~n~ overnigh~
at room temper~ture and thon ~ilt~3r~d. ~he c!ollected ~ 234~

solid wa~ suspended in onc lit~r o~ isopropyl alcohol and hydrogen chloride was bubbled into the suspension until a p~ of 6.2 was reached. The mixture was brought to a boil and filterad. Th~ ~olid w~ di3solved in 2 liter~
of wa~er a~d extr~cted with ~sopropyl ether. The pH was ~djul3~ed to 6.o ~nd the ~olution was concentrated to a volume of 800 ml ana plnced in a refrigerator. ~he requlting aolid (85 g) co~l~ct~d by filtration, WA8 ~
mixture consisting of a~out 85~ o the title compound and 15~ ~odium chloride. A sampl~ portion of ~hls wa~
crystallized onc~ from ethanol and twice from isopropyl alcDhol-water. The r~cry~tallized product decomposed at about 225C.
Pr~paration 2~
Sodium 2 -L( l-Cyclohexyl-3-azetidinyl)oxy]-3-pyridine carboxvlate.
A ~olution o~ 105 g (o.68 mole) of l-cyclohexyl-~-azetidinol and 106 g (o.68 mole) of 2-chloronicotinic acid in 400 ml of dry dimethyl~ormamide wa~ added at a rapid drop to 52 g (1.35 mole) of 60% sodium hydride/mineral oil ~uspended in 400 ml of dry dimethylformamide at 60C.
Mild exothermic reaction was noted. After stirring ~or 2 hr at 60C.,the mixture was filtered. ~he filter cake was wa~hed with ethylacetate and dried at 80C./2 mm to give 174 g (86%) of crude title compound.
.

123~ 6 ntermediate 1 2 ~( ? -ChloroethYl ~ -? ~ dihydro-4 -methvl -1, 4 -benzox-azePin-Fj ( 4~) -one .
To 54 9 (1.35 mole) o~ sodium hydroxide in 800 ml of water wa~ ~dded 148 g to.67 mole) of 2~ m2thyl-~-pyrrolidinyl)oxy~benzamide and th2 mixture brough~ tore~iux for 18 hr. The pH wa~ adjusted to r with hydro-chloric acid ~nd the Elolution i~iltared ~nd concerltrat0d.
The re~idue was ~oiled with 4pO ml o~ isopropanol and filtered. The ~iltrate wa~ l:oncentrated and the residue (whi~h ~rystallized) wa~ re~luxed with 300 ml of thionyl chloride for 0.5 hr. and ~oncentrated in va~uo. The resiaue w~ di~olved in 300 ml of chloroform and the qolvent boiled off ~n vacuo. The re~idue was redi~solved in chloro~onm, 150 ~1 o~ triethyl amine addad and the mixtura re~luxed 1 hr. The solution wa3 concentrated ln acuo and the r~sidue partitioned betw~en 400 ml o~ ethyl acetate, 400 ml of isopropyl ether and 500 ml o~ dilute hydrochloric acid. The organic layer was washed twice with water and once with dilute sodium hydroxide, dried 20 with sodium sul~ate and concentrated. The re~idue wa~
cry~tallize~ from i~opropanol-water. Yield of product wa9 75 g (47%), m.p. 97-107C.
Analysis: Calculated ~or ~2E~ 02Cl: C,60.13: H,5 89;
Found : C,60~35: EI95.91;
N,5-65 `
Intenn_ediate 2 4-Benzvl-2-(2 -c~hloroethyl~-2.3-dih~dro-1.4-benzox-aze~in-~ 4}~) -one .
To 85.7 g (0.29 mole)o~ 2-~(1-benzyl-3-pyrrolidinyl) oxy~-benzoic ~cid was ~dded 150 ml of thionly-~hloride.
The solution ~tood for 15 min ~nd was:~hen refluxe~ 30 min.
~nd concentr~ted ~n vacuo. The r~ ue wa~ twi~e ~reated with 250 ml of ~hloro~orm and concen~rated ~n vacuo. The residue Wa8 dis~olved in 500 ml o~ ohloro~o~m ~nd lOi g tl ~olo) of triethyl~mine ~dd~d ~lowly with stirri~g. The ~olution was refluxed 1 hr. ~nd concentrated in v~cuo.

~7 ~L2~4~3()9 The re~dua wa~ p~rtitioned between 50% ethyl aceta~-50% i~opropyl ether and dilute hydrochloric acid. ~he organic layer wa~ washed with dilut~ ~odium hydroxide ~nd ~oncontrated. The residue wa8 cry~tallized 5 times from i~opxopyl ether-athyl acetate. Yield o~ pr~duct was 23.8 g t260 , m.p. 145.0-147C.
Analysi~: Calculated f~r C~HlB~02Cl: C,68.46t ~,5.74;
. N,4.44 Found : C,68.47; R~5~8g7 . N,4.~2 ntermediate 3 L~l~
To a solution of 21.6 g (0.54 mole) sodium hydroxide in 500 ml of water was sdded 74 g (0.27 mole) of 3-Cl-me~hyl-3-pyrrolidinyl)oxy]-2-naphthalenecarboxamide ~nd th~ ~ixture heated at re~lux ~or 16 hrr The pH was adjusted to 6.8 with concontr~ted hydrochlori~: acid, the solution was filtered and ~oncentra~ed. The residue wa~
boiled wi~h 200 ml o~ isopropyl alcohol ~nd filteredO The filtra~e was concentra~ed under reduced pre~ure and the residuQ di~solved in chloro~orn. Thiorlyl c:hloride ~59 g"
0.50 mole) wa8 add~d a~d th~ r~action mixtuxe heated at r~flux for~4 hr. After cooling (67 g~ 0.67 mole3 tri-ethylamine wa8 added droFwise. The mixture wa~
washed s~guentially: twic~ with 3~ hydrochloric ~cid, twic~ with water, ~wice with 10% ~odium hydroxide, twice wi~h water and ariad over magn~sium sulfate. ~vaporation of the chloroform under reducod pre8~ure gava 44 ~ (580.
o~ a vi~cous dark ~rown o~l. The m~t~ri~l was puriied by high pres~ure liquid chroma~ography (50/50 ethy~ ac~t~t0/
hexane) and recrystallized ~rom isopropyl ai~ohol to-yi01d-brown crystnl~ m.p. - 101-102~
An~lysis: C~lculated for C~ ClOk: C,66.~2; E,5.~7;
~,~.8~ .
Found : C,66.19: ~,5.63;: :
~,4.77 , . 41~JA-Cl~

~23~a~309 Ifflermediate 11 2-(2-Chloroethyl) -2 ,3-dillydro-4-methylpyridoC3,2-~
-- . ~
~1, 4 ~-oxazepin-5 ~ 4H) -one hydrochloride .
~ ydrogen chloride gas was bubbled into a suspension of 150 g (0.61 mole) of ~odium 2-~(1-methyl-~-pyrrolidinyl) oxy]-~-pyridinecarboxylate in 1 liter o~ chloro~orm until pR o~ 6 was reachsd. To ~he 3tirred mlxtuxe W~3 added ~50 g (1.34 mole) of triphenylpho~phine and ~50 g (2.3 mol~) o~ ~arbon tetrachloride,and th~ re~ulting cloudy 801ution w~s ~tix~ed at re~lux ~or 1.5 hr. About 100 ml of ethanol wa~ add~d ~nd the heat r~moYed. The ~olutlon wa~ ~tirred for 1 hour while cooli~g and 200 ml o~
~sooctane wa3 added. The solution wa~ ~xtracted 4 time~
with a total of ~00 ml of dilute hydro~hloric acid. The acid extracts were combined, made ba~ic with sodium hydroxide and extracted with chloroform~ ~he chloroform layer was separated and dried over sodium sulfat~ and concentrated. The re~idu~ was dissolv~d in a mixture of 500 ml each of isopropyl alcohol and isopropyl ether and acidi~ied with ether~al hydroyen chloride. The resulting cry~tals weighed 82 g (490 . A portion was recrystallized from i30propyl alcohol, m.p. 14g-153C.
Analysis: Calculated for C~ Z02C1~: CJ47.67; H~5.09;
~10.11 Found : C,47.57: H,5.18:
~J 10 .00 Intermediate ~
8-chloro-2-(2~chloroeth~1)-2 ~- ih~dro-4-methyl-1.4-benzoxazepin-~(4H~-one.
To a solution of lQ.4 g (0.26 mol~) o~ sodium hydroxi~e in 150 ml of watar was ~dded ~2 g (0.13 ~ole) of 4-chloro-2-t(l-methyl-3-pyrrolidinyl)oxy]b~nzamide and the mix~ure was heated at ~eflux for 24 hr. ~he reaction mixture-was adju~ted to pH 6 w~h con~entra~ed hydroohloric ~oid and filtere~ and tha iltrnte concen~rated. Thæ r~idue wa~
boiled with 100 ml of ~sopropyl alcohol an~ th~ ~Lxture filtered. Th~ f~l~rst~ Wn~ con~en~rated a~d heate~ at reflux with 98 g (0.83 mol~) o~ thionyl ~hloride ~or 1 hr.

419~-CIP

~59 ~2~

The exces~ thionyl chloride w~ evaporated under reduced pres~ure. The re~idue W~3 dissolved in 70 ml oi~ chloro-form and ~he aolvent ~vaporated undRr reduced pr~ure.
The residue was redissolved in 75 sl~l of chloxoform and 40 ml of triethylamine Wa8 added gradually. The mLxture was hQated at reflux fo:r 1 hr. ~he ~olvent was evaporated under reduced pre~ure to give ~ darX-brown ~olid. The solid was di~solv~d in ethyl acstate! and tho re~ulting 801UtiOrl washed ~wice with 2O0~M1 of water and twice with 250 ml of 20% ~odium hydroxid~0 The organic layer wa~
dried o-ver magnenium sulfate and concentrated under reduced preEIsure to give 21 g (59%) o~ dark-brc~wn 801ia. The ~olid was recrystallized from i~opropyl alcohol to give the title compound, m.p. 85-87C.
Analysi~: Calcul~ted for Cl2~I sNC1202: C~52.57: ~,4.78:
~,5.11 Found : C,52.57: ~,4.77;
Nls~04 Intermediate 6 benzoxazePine-$~4~?-one.
To a ~olution of 9.6 g (0.24 mole) of sodium hydroxide in 200 ml of water was added 37 g (0.12 mole) of 5-bromo 2-~ t 1-methyl-3- pyrrolidinyl)oxy~-benz~mide and the mixture was heated at roflux for 18 hr. The p~ of the mixture 25 W~8 adjustsd to 6.7 with concentrated hydrochloric ~cid solution. The ~olution wa~ concentrated under reduced pres3ure and the residue W~8 boiled in 250 ml of isopropyl alcohol for 1 hr. Th~ m$x~ure was filtered and the filtrate wa concentrated. ~ha residue was dis~olved in .
~iO chlorofosm ~nd to the Jolution was added 28.~ g (0.24 mole) o~ thionyl chlor$de. Th2 mixturs W'~8 heated a~ reflux for 0.5 hr ~nd cooled to 15C. with ~n ice bath. ~o ~he mixture w~ added dropwi~e 26.6 g (0.26 mole) of triethyl-amine nt uch a ~e tha~ the~ 3ra ur~ did slot ~xceed 25C. Th~ r~action ~nix~u2~0 Wa8 ~tirred ~t ~oom t~mperature for 1 hr, thes~ wi~shed c~ cutiv~ly with ~ hydEochloric acid, 15,4 a~ueou~ ~odium hydroxid~ arld wat~r~ Th~

~ 419A-CIP

12~4~9 ~hloroform l~yer was d~ied over ~agne~ium ~ulf~te and concentrated under reduced pressure to give 23 y (60%) of ~rown solid. A portion o~ the solid Wa8 recry~tallized from ethyl acetate-i~opropyl ether, m.p. 92-94C.
~naly~is: Calculated for C~ 9NBrCl02: C,45.24: ~,4.11 ~,4~40 Found : C,45.61; ~,4.17;
N,4.4Z
ntermediat~ 7 ~
Xydrogen ~hloside wa~ bubbled through 8 ~olukion of 113 g (0.44 mole) 5-chloro-2~ methyl-~-pyrrolidinyl)oxy]
benzamide dis~olved in 500 ml of glacial acetic aci~ for 15 min while the reaction was ~ooled with an ice bath.
Butylnitrit.e ~142 g, 1.38 mole) wa~ then added in one portion; the reaction WaB ~tirred at room temperature for 16 hr ~nd heated at re~lux for ~n additional 6 hr. The acetic acid was evaporated under reduced p~e3sureJ tetra-chloroethane wa~ Added twice to tha r~sidue and evaporated.
The residue wa~ di~solved in chloroform, treated with 163 g (1.~8 mole) of thionyl chloride and heated at reflux for 22 hr. The reaction mixture was cooled with an ice bath and 152 g ~1.5 mole) of triethylamine w~ added drop-wise at such a rate that th~ ~emperature was kept at 25-~0C. Th~ r~action mLKture was diluted with 200 ml of chlorofonm and w~shed consecutiv21y with 3~ hydrochloric acid, wa~er, 10% 60dium hydroxide and wa~er. The chloro-form wa~ evaporated under reduced pre3suxe to give 40 g of a blac7c, t~r-liXe rosidue (33%).
An ~liquot of this residue was purified on ~ ~ilica gel column using ethyl acetate a~ th~. ~luting solvent.
Recry~talliz~tion fxom i~opropyl ~7cohQl gave beige cry~talY, m.p. 101-10~5C.
Analysis: Cal~ulat~d for C~l~2Hl9NCl802: C,52.57: ~I,4.78:
Found : ~,52.63: ~9~ 83.-1~. 5 ~5 41 ~L23~:~0 Intermediate 8 2-~ (2-Chloroethyl) -2 ,3-dihydro-4-methylnaphth~2 ,1-~r 1, 41oxazspin-5 ( 4H) -one .
~ ydrogen chlorid~ ga w~ bubbled into a ~olution o~
8 g (0.03 mole) o~ 1-r(l-methyl-3-pyrrolidinyl)oxy~-2-naphth~len~c~r~oxamid~ in 40 ml o acetic ~cid ~or about2 min. The ~olution wa~ cooled with an ice bath ~nd 6.1 g (o.o6 mol2) of n-butyl nitrite w~s ~dded ~lowly b~neath the ~ur~a~ of the liquid ~t 1~-15C. (about 10 minute~
reouired). The eolution W~8 ~tirred ~t 25C. for 18 hr and h~at~d on th~ steam b~th for ~ hr. The solution wa~
concentrated on th~ rotary ~vaporator. Tha residue was di3solved in 60 ml of 11,1,2,2-tetrachloroethane which wa3 removed on the rotary ~v~porator at 0.5 mm/~t~am tempera-ture.
~he residue wa~ d~solved in 75 ml of chloroforsn and treated with 7 g (0.06 mol~) of thionyl chloride and brought to reflux for 12 hr. The solution wa~ extracted with water (te~tod acidi~) ~ollowed by dilute Yodium hydroxide, dri~d over ~odium ~ulfate and concon~rated.
Th~ r~idue wa~ cryst~llized twice ~rom isopropyl e~her-ethyl ~cetat~. Yield o~ product was 3.2 ~ ~7 0 ~ m.p.
109-111t~ .
Analy~ Calculated for Cl~lBN02Cl: C,66.32: ~,5.~7;
N,4.84 ~ound : C,66~15; H,5.56;
~,4.76 ntenne~iate 9 2-(2-ChloroethYl)-2 3-dihvdro-7-methoxy-4-meth;yl-1,4-n~ lD~-o~
To a ~olution of 19.2 g (o.48 mole) of ~odium hydroxide i~l 500 ml of wat~r~ dd~d 60 g (0.24 mol~) o~ ~-me~hoxy-2-r(l-methyl-3-pyrroliainyl)oxy~-benzamide and th~ ~nixture wa~ he~ted at re~lux ~or 24 hr. The r@~ction ~ixture W21~ -~:ool~d ~nd th~ p~ adjusted ~:R 6.8 with csnc~ntr~t~dl hydro-c~hlori~ aci~. Th~ m~cture W~8 conce~tr~ted under r~duc:~d pressure ~nd ~h~ re~idue! w~ bo$1ed ln i~opropyl al60hol for 1 hour. q!he mixtur~ filt:~ar~l and ~he fil~rat~ wa~

42 ~34~

concentrated. ThQ residue w~s dis301v~d in 500 ml of chlorof4rm and to this holution W~3 added 114 g (o.96 mole) o~ thionyl chloride. The mixture was hsated at re~lux for 48 hr, then coolRd with an i~e/acetone bath. To th~
mixture W~8 added dropwi~e 97 g (0.96 ~ole) of triethyl-nmin~ at 8~ch a rate that the te~per~ture did not excRed 25C. The r~action ~olution was wa~hed in se~uence with water, ~N hydroc~loric acid ~ol~tion, water, 15~ a~ueous ~odiu~ hyaroxid~ ~nd wnter ~nd ~inally dried over magne~ium ulfat~. ~h~ ~olvent wa~ ~vaporated under reduced pr~ssure to give a bl~ck solid. ~h~ ~olid was purified on a silica gel column u~ing othyl acstate as the eluting 801v~nt to give on isolation 15 g (23~ o~ beige colored product, m.p. 98-100C.
Analy~ Calculated for C19~1B~C109: C, 57.89; H,5~98;
N,5 .19 Pound ~,57.53; ~,~.0O, N,5.16 Int~rm~diate 10 2 (?-Chloroet- hyl)~ d h~dro-4-methyl-1,4-benzox-azepine-~ 4H)-thione.
A mixture of 18.5 g (o.o8~4 mole) of phosphorus pentasulfide and 18.5 g pota8sium ~ulfide wa~ ground tog~ther and added to a Yolution of 100 g ~0.417 mole) of 2-~2-chloroethyl)-2,3-dihydro~4-methyl-1,4-benzoxazepin-5(4~)-on~ in dry toluen2, th~ mixtur~ refluxed 24 hr. and filtered. The ~iltr~te wa~ conc~nt~ated ana partitioned b~tween chloro~orm ~nd dilute sodium hydroxide. ~he-chloro~onm lay~r w~ concentr~ted and the re~idue was cry3tallized ~everal t~mes ~rom ~thanol. ~ield of produ~t wa~ 55 g (52%), m.p. 105-108C.
Analusi~: Calculated ~or~ C12~14~SCl ~,56-35; H~5-52;
~,5.48; S,1~.54-Found s C,56.~5; ~,5.47;~
~,5.49; S~12.55 3a~30 Intermediate 11 - 2 - ( 2 -Chloroethyl ) -?, 3-d ihydro-4 -methylpyr idor 3, 2 - f Ll, 4 1 -oxazepine 5 ( 4H) -thione .
To a solution of 59 g (0.25 mole) of 2-(2~chloroethyl)-2,3-dihydro-4-methylpyridot~,2-fJEl,4~oxazepin-5(4H)one hydrochloride in 1500 ml of chloroform wa~ added 41.5 g (0.19 mole~ of phosphoru~ pentasul~ide and the mi~cture wa~
heated to re~lux ~or 18 hr. The mixture was ~iltered and the filtrat~ extr~ted wit~ dilute ~odium hydroxiae.
The ~hloroform l~yer w 8 ~oncentrat~d and the r~.qidue was 10 ~i~301ved in 250 ml of boiling isopropyl alcohol. On cooling, 28 g (44%) of yellow solid precipitated.
portion was recry~talli~ed from isopropyl alcohol, m.p.
134-136C.
Analy~i3: Calculated for C~lH~gN2ClOS: C,51.46t H,5.10:
~,10 .ôl 1~ Found : C,51.~5; H,5.21;
~,10.7 Intermediate 12 2-(2-Chloroethyl)-2?~-dihydro-4-methylnaphthr2,3-f~
~1,4~oxazepine-5~ 4H)-thione.
To a solution of 16.6 g (0.06 mole) of 2-(2-chloro-ethyl)-2 J 3-dihydro-4-methylnaphth~2,3-f~1,4~oxazepin-5(4H)-one in 150 ml of dry toluene was added a m~ture of 8.6 g to-o45 mole) of phosphorus penta~ulfide and 806 g of potaq~ium sulfide which had been grou~d ~ogether. The reaction m~xture was ~tirred and heated at reflux for ?4 hr. Ihe mixture wa~ filtered hot ~nd the filtrate concentrated under reduced pressure. Yellow solid, 6.5 g (35%) was obtained which was recryst~llized from ethanol, m.p. 166-168C.
Analygis: Calculated for C~o~lo~C10S: C962.84: H,5 27;
Found : C,62.29; H,~.~8;
~4.47 i~, ! 419A-CIP

44 ~L23~0~

,, . In'cermediate 1~
8-chloro-2~L?-chloroethyl)-2,~-dihydro-4-meth~1-1,4-benzoxazepine-~(4H~-thione.
To a solution o~ 43 g t0.16 le) of 8-ch}oro-2-(2-chloroethyl)-2,~-dihydro-4-methyl-1~4-benzoxazepin-5(4H)-one in 400 ml of dry toluene wa~ ad~ed a mixture o~ 2~ g(0.12 mole) of pho~phorus pentasul~ide and 23 g o~ pota~sium ~ul~ide which had b~ ground togother. 5he ~eaction mixture wa3 st;rred and heated at reflux for 24 hr. The mixture was filtered hot and the filtrate conc~ntrated under reduced pres~ure to give 25.5 g (55%) of orange oil which ~olidiied on standing at roo~ temperature. The solid wa~ recrystallized ~rom ethanol, m.p. 105-lQ6C.
Analy~Calculated for Cl2Hl9NCl20S: ~J49.66; H,4.52:
N,4.83 Found : C,49.63t H,4.53:
N,4.75 Intermediate 14 ?-Bromo-2-(2-chloroethyl ? -? ~-dihYdro-4-meth~l-1,4-benzoxaze~ine- ~ -thione.
To a solution of 11.0 g (0.0~5 mole) o~ 7-bromo-2-(2-~hloroethyl)-2,3-dihydro-4-methyl-1~4-benzoxazepin-5(4H)-one in 150 ml sf dry toluene Wa8 added a mixture o 13.4 g (0.07 mole) of phosphorus penta~ulfide and 13.4 g of potassium ~ulfide which had been ground together. The reac~ion mLx~ur~ was heated ~ reflux ~or 5 hr under a ni~rogen ~mo~phere. ~he m~xtura wa~ filtered hot and the filtrate concentrated under reduced pressure. Th~ re~i~ue was dissolved in chloro~orm. Th~ c~loroform solution wa~
washed twi~e wi~h dilut~ aoueous ~odium hydrDxide, dried over magno~ium sulfate and concentrated under rsduc~d pre~sure to give 8.5 g (72 ~ of yellow ~olid. The solid wa~
recrystallized ~rom eth~nol, m.p. 118-120 C.
~n~ly~is: ealeulated for C~ ~BrClOS: C,43.07: ~,3.92:
~,4.18 Found : c,4~.o8; ~,~.88:
~,4.12 ' ! ~ '; 41yA~

45 ~L23~1~0~

Intermediate 1 ?-(2-chloroet~ 2 .3-dihYdro-4-methylna~hthr2 .
r 1 . 4 ~oxazepine-~ ( 4H~ -thione .
A mixture of 9 . 55 g of phosphoru~ pentasul~ide and 9.5 g of potassium suli~id~ were ground together Ind add~d to a ~olutiorl o~ 20.2 g (0.07 mole) of 2-(2-chloroethyl)-2,~-dihydro-4-methylnaph~h~2,1-f~1,4~oxazepin-5(4H)-one in 200 ml of dry toluene. Th9 mixture was ~tirred ~nd heated at reflux for 7 hr. T~e hot reaction mixtur~ w~
fil~e~ed and the product cry~tallized from th~ cooled ~iltr~. Recry~tallization ~rom chloroform gave 18 (84%) of yollow Grystals, m.p. 167-170C.
Analysi-~: calculatea for Cl~Hl~NClOS: C,62.84; ~,5.27:
N,4.58 ~ound : C,62.85: H,5.20s ~4.55 ntermediste 16 2-(2-Chloroethyl)-2,~ hydro-4-methylpyrido ~,7-f r 1,41-oxazepin-5~4H)-one hydrochlorid~.
A 49 g (0.11 mole) ~ample o~ 3-~tl-methyl-3-pyrrolidinyl)oxy]-4-pyridinecarbonitril~ fumara~e ~ ]
was partition~d between chloroform and a ~aturated ~olution of pota~sium ~arbonate. The aqueou~ layer was extracted twice with chloroform. All chloroform extraot~ were combined, dri~d and concentrat~d. The residue wa~
di~solv~d in 125 ml of t-butanol ~nd added to 34 g (0.6 mole) o~ potas ium hydroxide pellet~. The mixture wa3 stirr~d at room temperatur~ for 88 hr. and then diluted with 150 ml of toluene. This mixture Wa8 filt3red and the ~iltrate con~entrated. ~h~ se~idue Wa9 dis~olved in chloroorm, with coollng, and the pH adjusted to 6.o with ~0 hydrogen ~hlo~ide ga~. ~h~ r0sulting mixture wa~ conceR- -~trated ~nd 400 ml of dry toluen~ was added to the r~ idue.
Th~ tolu~ne W2~ romov~d o~ the rot~ry ~vaporator (steam heat/reduc~d pres~ure~ to re~ova hny w~ter. Th~ rosidu~
W~8 di~olved in 400 ml of 6hlorofoxm and 6~ g of ~ripheny~-phosphine W~3 3dded ~sllow~ by 70 g of ~arbon tetra-ohloride. Th* solution w~ irr~d at re~lux for 2 hr ~nd .. 419A--C IP

46 ~.2~09 ~nother ~0 g o~ t~iphenylphosphine added. Af~er an - additional hour re~lux, 70 g more carbon tetrachloride and 63 g ~ore of triphenylp~osphine were added and re1ux wa~ continued ~or 4 hr. Th~ ~olution wa~ extracted with dilute 40dium hydroxide, then concentrated. ~he residue wa~ partitioned between toluene ~nd dilute hydsochlo~lc acid. Th~ toluene lay2r was Qxtracted ~ivc t~m~ with dilute hydroc~lori~ acid. ~he acid extract~ were combined, basified with sodium hydr~xid~ and extracted with chloro-~orm. ~he chloro~orm layer wa~ dried over sodium ~ulfa~eand concentra$e~. The residue was chromatographed on a

7 x 25 ~m column of silica gel with acetone liquid pha~s.
Free base of the title compound isolated after evaporation 2mounted to 5.8 g (20%). ~o a portion of th~ ree ba~e dissolved in isopropyl alcohol wa~ added ethereal hydro~en chloride and i~opropyl ~th~r. The re~ul~ing cry~tal~
were collected and dried, m.p. 188-190C.
Analysis: calcul~ted 40r C~lHl~202Clæ: C,4~.67; H,5.09;
N,10.11 Found : C,48.~3: H,5.22:
~,9-7 Intermedia~e 17 2-(2-Chloroethyl)-2J3-dihydro-4-methylpyrido~4-f ~1,41oxazepin-5( 4H? -one hy~ro~hlor~de.
~n th~ proc~dure of ~ntermediate 4~ equal molar amount~ o~ sodium 4-~(1-methyl-3-pyrrolidinyl)oxyJ-3-pyridinecarboxylataw~s substituted ~or 2-~(1-methyl-3-pyrrolidinyl)oxy~-~-pyridinecar~oxylic acid and the title compound W~8 obt~ined.
Intermediate 18 ~0 ~ L~]
~1,4~oxa~epin-5(4H)-one hydrochloride.
the proc~d~re o~ Intermedi2te 16, 3~ methyl-3-pyrroli~inyl)oxy~-2 pyri~in~c~r~onitrile fum~r~te i~
~ub~tituted for ~-~(1 methyl-3-pyrrolidinyl)oxy3-4-~5 pyri~ine~arbonitril~ fum~rat~, th~ ti~ o~pound i~
obtaine~.

( ~ - ; 419A-CIP

Intermediate 14 7-Chloro-?-(?-chloroethyl)~ -dih~dro-4-methy~ ~4-benzoxazeeine-5~4H)-thione.
~o a oolution of 20 g (0.07 mole) of 7-chloro-2-(2-chloroethyl)-2,~-dihydro-4-methyl-1,4-b~nzoxazepin-5(4H~-one in 200 ~1 o~ toluene was added ~ mixture o~ 9.55 g (0.05 mole) of phosphorus penta~ulfi~0 and 9.5 g o~
potassium ~ulfido which had beon grcund togother~ The reactlon mixtur~ was filt@re~'~nd the filtrate concentrated und~ reduced pr~suro to give ~ yellow ~olid. ~cry~tal-lization ~rom absolute ethanol gave 12.5 g (680 o~ the product, ~.p. 102-104 C0 Analy0i3: Caleulated for C~2~13~C12OS: CJ49.66: H 4 52;
Found s C,49.62; HJ4 55;

2-(?-ChloroethYl)-7.9-diiodo-?.3-dihydro-4-meth 1.4-benzoxazepin- ~ H)-one.
When in tho procedure o~ Intermediate 1, 3,5-diido~
2-~(1-methyl-3-pyrrOliainyl)oxy~-~Qnza~llide i8 sub~tituted ~or 2-~(1-me~hyl-3-pyrrolidinyl)oxy~benzæmide, the title co~pound i9 prepared~
Intermediate 21 2-Chloromethyl-2~3-dihydro-4-methylpyrido~3,2- ~1,4 oxazepin-5(4H)-hydrochloriae.
.. . .
Wh~n in th~ procedur~ o Intermediate 4, an equal mol~r amount of sodium 2-Ctl-methyl-3-axetidinyl)oxy~-3-pyridine-carboxylate ~odlum acetate i~ ~ubstitute~.~or ~odium 2-t(l-methyl-3-pyrrolidinyl)oxy~-3-pyridinec~rboxylate, the title compound ~ prepnr~d.
In~rmediat, . ??
2-t2-Chloroethyl)-2,~-d~hydro-4-methylpyrido~4 9 3- f rl,4 pxazepine-5(4~-thio~.
A ~olution o~ 5 g (0.021 mol~) of 2-(2-~hloroe~hyl)-2,3 dihydso-4-m~thylpyridot4,3-f~tl,4~-oxazepin-5(4~)-on~
and 5.1 g (0~0126 le) of 2~ 40biR( 4-~e~hoxyphenyP)-1,3,2 J4~
ithiodip~osph~t~no-2J4-~isul~ide in 100.~1 of dry ~' ` 3 419A-CIP

48 ~ 2 3 4 ~0 ~

toluene wa~ Etirred at reflux for 2.5 hr. ~he 801ution was cooled and extracted three times with sodium bicarbonat~ ~olution. The toluene layer was dried over sodium ~ul~ate and conc~ntr~ted. The residue was chromato-graphed (high pressure liquid chromatograph) using asilica column ~nd ~thyl aceta~e liquid p~a~e. The fraction containing ~he produc~ wa~ concentsate~ ~y ovaporation and the r~sidue was crystallized ~rom ~thyl alcohol to give o.6 g (11%) o the titls ~ompound.
Intermediate 23 2 -( ? -Chloroethyl)-2,3-di~ydro-7-methoxy-4-methyl-1,4 benzoxazepine-5(4~2-thione.
To a solution of lO.~ g (0.04 mole) of 2-(2-chloro_ ethyl ) -2 " 3-dihydro-7-methoxy-4-methyl-1, 4 -benzoxazepin-5(4~)-one in 200 ml of c~loroform was ~dded ~ mixture of 5.7 g (0~0~ mol~) o~ phosphorus pentasul ide and 5.7 g of potas~ium ~ulfide whi~h hnd been ground together. The reaction mixture was ~tirred ~nd heated a~ reflux under nitrog~n atmospherQ for 5 hr. The mixtur~ was filtered hot and the ~iltrate concentrated under reduced pre~suxe.
The residue, ~n orange ~olid, wa~ recry~allized from ethanol to give 7.4 g (65%) of product, m.p. 98-lO0 C.
Analysi~: ~alculated ~or C~gHle~Cl02S: C,54.64: H)~.65:
N,4.90 Found : C,~4.57; H,~ 67;

Intermediate 24 When in the procedure o~ ~ntermediate 2, equal molar amounts of the following are ~ub~ti~uted ~or 2~ benzyl-3-pyrrolidinyloxy)benzoic acid:
2-C(l-cyclohexyl-3-pyrrolidinyl)oxy]b~zoic ~id, 2-~(1-qthyl-~-pyrrolidinyl)oxy~benzoic acid, 2 ~(l-i~opropyl-3-pyrrolidinyl)oxy~benzoic acid, 2-~ 1-(4-~hlorobcnzyl)-3-pyrrolidinyl~oxy~be~zoic acidg 2~ (4-methyl~onzyl)-3-pyrrolidinyl~oxy~be~zoic acid, 2 ~tl-(3,5-~imcthox~benzyl) ~-pyrrolidinyl~oxy]be~zoic acia, 2-~tl-(trifluorom~thylbenzyl)-3-pyrrol~dinyl~oxy~
~ zoic aci~9 ~rld , ' 419~ IP

49 ~2341~

2~ (4-nitr.obenzyl)-~-pyrrolidinyl~oxy~benzoic acidJ and ther~ aro obtained:
~) 2~ chloroethyl)-4-cyclohexyl-2,3-dihydro-1,4-bonzoxa~cpin-5(4~)-one, b) 2-(2-chloroethyl)-2,3-dihydro-4-ethyl-1,4~enzox-az~pin-5(4~)-one, ~) 2-(2-~hloroethyl)-2,3~dihydro-4-isopropyl~1,4-benzoxazepin-5(4H~-ons, d) 2-(2-chloroethyl)-4-t4-chlorobçnzyl)-2~3-dihydro-1,4-benzoxazepin-5(4~)-one, e ) 2 - (2 -chloroethyl ) -2, ~5-dihydro-4-( 4 -methylbenzyl ~ -1,4-~enzoxazepin-5(4~)-one, ~) 2 (2-~hloroethyl)-2,3-dihydro-4-(3,5 d~meth~xy~enzyl)-1,4-b2nzoxazepin-~(4~)-one, g) 2-~2-Ghloroethyl)-2,3-dihydro-4-(~-tri~luoromethyl-benzyl)-1,4-benzoxazepin-5(4~)-on~, h) 2-(2-chloroethyl)-2,3-dihydro-4-(4-nit~obenzyl)-1,4-benzoxazepin-5(4H)-one.

ntermediate 2~
~hen in th~ proced~re of Intermediat~ 4, ~qual molar amounts of th~ ~oll~wing axn substituted for sodium 2-~(l-methyl 3-pyrrolidinyl)oxy~-3-pyridine ~arboxylate:
2-~ cyclohexyl-3-pyrrolidinyl)oxy~-3-pyridine c~rboxylate~
2-~tl-ethyl-3-pyrrolidinyl)oxy~-3-pyridine carboxy-late9 2-~1-isopropyl-3-pyrrolidinyl)oxy~-~-pyridine ~arboxyl~te, 2-~tl-(4-~hlo~obenzyl~ pyrxolidinylloxy~-3 pyridine~
car~oxylh~e, :
2 ~ (4-m~thyl~onzyl)-3-pyrrolidinyl~xy~ pyri~in-carb3xylate, -j 419A-CIP

5~ 1~3~3Q~31 ?~ (4-methoxyb~nzyl)-3-pyrrolidinyl~oxy~-3-pyriaine carboxylate, 2-~tl~ rifluor~m~thylbenzyl)-~-pyxrolidinyl]oxy]-3-pyridine carboxylate, and 52 -r ~ 1-( 4-nitrobenzyl)-3-pyrrolidinyl]oxy3-~-pyridine -- carboxylate, there ~r~ obtained:

10a3 2-(2-chloroothyl)-4-cyclohexyl-2,3-dihydro-pyrido 3~2-i]~l,4]oxazepin~5(4~)-one hydrochlorid~, b) 2-~2-chloroe~hyl)-2,3-dihydro-4-e~hylpyrido~3,2-f]
~1,4]-oxazepin-5(4~)one hydrochlsride, c) 2-(2-chloroethyl)-2 ,~-dihydro-4-isopropylpyrido~3,2-f3 15rl,43-oxazepin-5(4H)-one hydro~hloride3 d) 2-(2-~hloroe~hyl)-4-(4-chlorobenzyl?-2~3-dihydro-pyridor3,2-~els4~-oxazepin-5(4H)-one hydrochloride, e) 2-(2-chloroethyl)-2,3-dihydro-4-(4~methylbenzyl) pyrido~3,2-f~rl,4~-oxaz~pin-5(4H)-on~ hydrochloride, 2 0f ) 2 -(2-chlo~oethyl)-2,~-dihydro-4-(4-m~thoxybenzyl) pyrido~3,2~ 1,4~-ox~zepin-5(4E~):-one hydrochloride, g) 2-(2-chloroethyl)-2,3-~ihydro-4-(3-trîfluoromethyl-benzyl)pyrido~3,2-f~rl,4~-5(4H)-one hydrochloride,and h) 2-(2-ehloro~thyl)-2,3-dihydro-4-(4-nitrobenzyl)-25pyrido)r3,2-f~tl,4~-oxazepin-5(4H)-on~ hydro-chloride.

Intermediate 26 302-(2-Chloroethyl)~2,3-dihydro-4-methylpyri r 1, 4~-thiaz~pin-5(4H,l-one .
A ~ixture of 80.75 g (0.34 ~ol~) of 2-~ ma~yl-~-pyrrolidinyl)~hio~-3-pyridin~rboxylic ~cid, 500 ml o~
~hloroform, 200 g o~ ~asbon tetr~chlorid~ ~nd 178 g ~o.68 mol~) of triph~nylpho~phine was stirrea at r~lux ~or 2.5-~ .
~he resulting ~olutio~ was ~xtract~d with on~ 500 ml and three 1?5 ml ~ortions of 1~ hyd~oehlorie a~id. ~he acid ~L~34~30~3 extract_ were combined and extracted with i~opropyl ether.
- The aqueou~ layer was ba~ified with ~odium hydroxide and extracted three times with chloro~orm. The combined chloro-form extract wa~ dried over sodium sulfate and concentrated.
5 A portion of the residue wa~ chromatographed on the high pressure liquid chromatograph using a silica column and ethyl acetate. The compound obtained was cry~tallized ~rom iRopropyl ether-isopropyl alcohol, m.p. 97-100C.
Analysis: calculated for C1lHl3~2OSCl: C,51.46; H,5.10;
N,10.91 Found : C,51.63; ~I,5.12:
N, 10 . 85 Intermediate 27 ?-~2-Chloroethyl)-2J3-dihydro-4-methylpyri~o~3,2-f ~1, 4 ]-~hiazepine-5 ( 4H? -thione .
A mixture of 4.3 g (0.017 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~,2-f~1,4]thiazepin-5(4H)-one, 100 ml of toluene and 4.8 g (0.012 mole) of 2~4-bis(4-methoxyphenyl)-1,~,2,4-dithiadiphosphetane-2,4-disulfide was refluxed ~or 3 hr and then extracted twice with dilute -Qodium hydroxida. The organic layer was concentrated and the re~idue chromatograp~ed on the high pre~3ure liquid chromatograph u~ing a silica column and 50~ ethyl acetate-50% hexane. The yield of title compound wa~ 2 g, m.p.
160-162C.
25 Analysis: Calculated for C~ 3N2S2Cl: C,48.4~; ~J4.80;
N910.27 Found: C,48.46; HJ4.81;
~,10.51 Intermedia _ 28 2-(2-Chloroethyl) -? ~-dihydro-4-methylpyrido~3,4-f3 ~
~0 ~l~4~oxazepin-5(4H)-one.
A 301ution of 78 g (0.5 mole) o~ 4-chlor~nicotinic acid and 52 g ~0.52 mole) of l-methylpyrrolidinol in 150 ml of dimethylformamide wa~ added to a su~pension of 44 g (1.1 mole) of 60% ~odium hydride/mineral oil in 800 ml of ~5 dimethylformamide at a rate ~o a~ to maintain a temperature -of 55-70 C. (preheated to 55C.~. ~he re~ulting mixture wa~
heated to 60C. ~or 4 hr and ~iltered while hot. The filtrate Wa8 concentrated on the ~otary evaporator (5 mm/steam o~

bath). The residue was dissolved in 600 ml of water and extracted with isopropyl ether. The pH of the aqueous layer was adjusted to 6 with hydrochloride acid and the solution was concentrated on the rotary evaporator (5 mm/steam bath). The residue was suspended in 800 ml of chloroform and 188 g (1.1 mole) of triphenylphosphine added followed by 250 ml of carbon tetrachloride. The mixture was gently heaked to 60C. whereupon the reaction became exothermic and an ice bath was used to maintain a temperature of 60-65C. for about 20 minutes. The ice bath was removed and the mixture was ~eated to reflux for 3.5 hr and cooled. The solution was extracted with 600 ml of water followed by two 200 ml portions of lN hydrochloric acid.
The acid layer was made basic with sodium hydroxide and extracted three times with chloroform. The chloroform was concentrated and the residue was chromatographed by high pressure liquid chromatography using silica gel and eluting with ethyl acetate.
Yield of product was 30 g (25%). The mass spectra and NMR are in agreement with the structure of the title compound.
Intermediate 29 2-(2-Chloroethyl)~2,3-dihydro-4-methylpyrido[3,4-fJ[1,4]
oxazepine-5(4H)-thione monohydrochloride.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f]
[1,4]oxazepin-5(4H)-one, 15 g (0.06 mole), was dissolved in 200 ml of dry toluene and 15 g (0.037 mole) of 2,4-bis(4-methoxy-phenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide was added. The mixture was refluxed for 2.5 hr and the toluene solution decanted. The residue was par~itioned between dilute sodium hydroxide and chloroform. The chloroform was dried and concen-trated. The residue~was chromatographed on a high pressure liquid chromatograph (Waters 500) using a silica column and eluting with ethyl acetate. The fraction containing material of molecular weight 257 was concentrated. The resldue in iso-52a ~L234~09 propyl alcohol was treated with hydrogen chloride and the re-sulting crystals were collected. Yield of hydrochloride salt was 0.1 g (0.6%), m.p. 168~171C.

!~ .

53 ~:3~09 Analy~Calculated for C.~Hl~N20SCl2: C,45.06; H,4.81;
~,9-55 Found : C,45.15; H,4.98;
~,9.26 Intermediate 30 2,3,4,5-~etrahydro-4-methyl-5-oxopyridoL3,2-~C1,4 oxazepine-2-propanenitrile.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyridoC3,2-~
~1,4~oxazepin-5(4H)-one hydrochloride, 100 g (0.415 mole) Wa3 partitioned ~etween dilute aqueous ~odium hydroxide (200 ml) and chloroform (200 ml). ~he organic layer was ~aved and the aqueou~ layer extracted with chloroform (~ X 50 ml). The organic layer wRre combined, dried over ~odium ~ulfate and concentrated ~y rotary evaporation (70 C., water a-~pirator). The re3idue, the free base of the 3tarting hydrochloride~ 89 g (0.37 mole) was dissolved in 150 ml o~ toluene and to the solution was added tetra-butyl ammonium bromide, 9 g (0.027 mole). Saturated a~ueous potasQium cyanide (100 ml) was then added and the mixture stirred mechanically at reflux~ After 2 hr, additional tetrabutyl ammonium bromide, 3 g (0.009 mole) and ~aturated aqueou3 potas~ium cyanide (20 ml) were added and the mixture stirred ~or 0075 hr at reflux. The content3 of tha reaction vesqel were extracted with ethyl acetate (3 X 50 m). (Note:
chloFoform ~hould be uQed instead). The organic layar dried over 30dium sulfate and concentrated by rotary evaporation (70C., water a~pirator) to 1~3 tne original volume. Upon cooling, crystallization ensued. ~he crystals were filtered and washed with several portions of ethyl acetate and isopropyl ether. Thirty g (350 of off-white crystal were collectedJ m.p. 104-105C. A sample wa~
recrystallized from ethyl a~etate, m.p. 104-105 C.
Analys i3: calculated for C ~2~13~g2 C~ 62-3~ 5-67:
~,18.17 Found : CJ62 .06 j H,5 .6 ~,17.97 : L234~09 Intexmediata 31 .

2-(2-Chloroetl~y 1 ) 11 e~hyl~,~ ydropyridof~
rl,4~oxa2epin-5(4H)-one hydrochloride.
To a stirred suspen~ion of soaium hydride mineral oil (81.45 g of 60% dispersion 2.036 mole~ in dimethyl-sulfoxide (500 ml) heated to 50C. wa~ added dropwise a solution o~ 2-chloronicotinic acid (142 g, 0.905 mole) and N-ethyl-2-pyrrolidinol (99 g, o.86 mole) in dimethyl-sul~oxide (500 ml) at a rate to maintain 55 -60C.
(occasional cooling wa~ neceqsary~. After the addition was complete) the mixture wa~ stirred at 50~-60 C. for 1.5 hr and allowed to cool. The solid which precipitated was filtered, wa~hed with ethyl acetate and dried.
The dry ~odium salt (172.5~ g, 0.62 mole) wa~
~uspended in chloroform (1 liter). Hydrogen chloride gas wa~
bubbled through the suspen~ion until the ~H meter read 5.76. Triphenylpho~phine (365.5 g, 1.395 mol2) and CCl~
(365.5 g) were added and the mixture 3tirred a~ r~flu~.
After 45 minutesJ IR 3howed 95% reaction. Additional triphenylphosphine (100 g, 0.38 mole) and CC14 ( 100 g) were added and the solution stirred at reflux an additional 45 min. IR showed >99% reaction. ~fter cooling, the solution was extractea Reve~al t~mes with dilute hydro-chloric acid t-1.5 liter total) ~he aqueous layer was then made basic with concentrated sodium hydroxid~ solution and extracted into chlorofonm (3 x 250 ml). The o~ganic layer waq dried over sodium sulate and concentrated by rotaxy evaporation (70C, watar aQpirator). The re~iduel oil was di~olved in isopropyl alcohol (500 ml) and acidi~ied with hydxogen chloride sas. ~pon cooling, an oil;
wa~ noted and the voluma roduced to 1/3 the original volum~. -Upon coo}ingJ 70 g (.241 mole, 28O of pale brown crystal~
were collected, m.p. 15~-155C.
Analysis: Calculated ~or C.2Hl9N2O2Cl2: C,49.50: H,5.53;
~,9.62 Found . C,49~64; ~,5.62;
~,9.32 ~L23~09 Intermediate 32 2-(2-chloroethy.1)-4-ethyl-2,3-dihydropyrido~,2-f]
~1,4~oxaz~pln-5(4H)-thione hydrochloride.
2-(2-Chloroethyl) 4-ethyl-2,3-dihydropyridoC~,2-f~
~1,4~oxazepin-5(4H)-one hydrochloride, approxima'cely 5 50 g, Wa9 partitioned between dilute aqueou~ ~odium hydroxide ( 50 ml) and chloroform t:50 ml). The organic layer wa8 aved and the aqueous layer extracted with additional methylene chloride (2 x 5Q ml). The organic layers were combined, dried over sodium ~ulfate, filtered 1~ and con~entrated by rotary evaporation (70C, wa~er aspirator) yielding 39 g (0.153 mole) of the free ba~e.
The free ba30 thuR obtained wa~ dissolved in chloroform (1.2 1), and phosphorus penta~ul~ide t3~.9 g, 0.153 mole) wa~ added while 3tirring. The resultin~ mixture was heated to reflux for 16 hr. After ~ooling, the reaction mixture was ~iltered, washed with dilute a~ueous sodium hydroxide (3 x 300 ml)J dried over sodium ~ul~ate and concentrated by rotary evaporation (70C, water a~pirator) to a yellow vi~cous oil. m e oil wa~ taken up in isopropyl alcohol ~200 ml) and made acidic with hydrogen chloride ga~. Upon cooling, 20 g (43 O of crystals were collected, m.p. 133-135C.
Analy~ aloulated ~or Cl2~l~N20SCl2: C,46.91; H,5.25;
~,9.12 Found : C,47.33t H,5.38, N,9.10 Inter~ediate 3 r3.2-f]rl~4~oxazepin-~(4H)-one .
A sample of 2-(2-chloroethyl)-2,3-dihydro-4-methyl- - -pyrido~3,2 -f ~E 1, 4 ]-oxazepin-5-( 4H) -one hydrochloride ( 10 ~, ~0 1~6 mole) was dis301ved in dImethylformamide (150 ml) and .
heated to reflux. Suluryl chloride (20 g, 0.148 mole) wa~
then added dropwise over a psriod of 40-~0 minu~e~. The rea~tion wa~ allow~d to ~tir ~t reflux for ~0 minute following the addition of S0zCL2:. After cooling/ the :

~2341~0i9 co~tents of the fla~k were partitioned between water (150 ml) and benzene tl50 ml). The benzene layer wa~
~aved and the water layer extracted with an additional amount of benzene (2 x 50 ml). The benzene extract~ were 5 combined and wa~hed with dilute a~ueou~ potassium hydroxide (2 X 50 ml) followed by dilute aqueous hydrochloric aci~
(2 X 50 ml). The benzene layer waq ~ried ovor sodium sulfate and concentrated by rotary evaporation (~70C., water a~pirator) yieldi~g 2.61 g of crude material. The crude material wa~ recrystallized from i~opropyl ether giving 1.25 g (12.60 o off-white crystal m.p. 78-79C.
Analysi~: Calculated for CllHl2N202Cl2: c,48.o2; H,4.40;
~,lQ.18 Found : C,48.07: H,4.53;
N,10.10 Intermediate ~4 7-chloro-2 -(2 -chloroethyl ) -2,3-dihydro-4-methylpyrido ~;,2-flrl,4~oxazepine-5(4H)thlone.
7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido r3,2-f~el,4~oxazepine-5~4H)-one, 6.o g (0.022 mole) was suspended in 200 ml of toluene. ~o thi~ suspension wa~
added 2,4-bis(4-methoxyphenyl)~ -dithia-2,4-diphosphetane-2,4-dil~ulfide. The m~xture Wa3 heated to reflux with vigorou~ ~tirring for 2 hours. Becau~ the reac~ion was not complete, an additional amount (3.0 g) of 2,4-bi~(4~methoxy-phenyl)-1,3-dithia-2,4-diphosphetane-2/4-disulfide wa~ added and the mixture qtirred at reflux for 2 hr and left ~tan~ing for 56 hr at room temperature. The toluene layer was decanted and wa~hed with 50 ml of dilute aqueous sodium -hydroxide and 50 ml of dilute hydrochloric a~id. Toluene was removed by rotary evaporation (~80~., wa er aspirator).
~he ~rude oil waq recrystalliz~d from isopropyl alcohol giving 3.5 g ~54%) of pale yellow cry3tal~3 m~p. 125-127C.
Analy~is: calculated for CllHl2~20SClæ: C,45.37; H,4.15;- -~,9.62 Found - : C,45.407 H,4.20, ~99-71 `

57 :~234~

ntermeaiate ~;S
2- f chloromethyl)-4-cYclohexyl-2,3-dihvdroPYrido r 7,2-~
Cl.4 ]oxazePin-s (4H) -one .
A 15 g (0.05 mole) s~mple of sodium 2-~(1-cyclohexyl-3-azetidinyl)oxy]-3-pyridine carboxylate obtained in Preparation 23 wa~ ~uspended in 100 ml of chloroform and hydrogen chloxide passed in until.a pH o~ 508 remained steaay. To the ~tirred mixture was added 18 g of thionyl chloride. ~he resulting ~olut'ion was stirred at room temperature for 3 hr. An I.R. spectrum ~howed a peak ~o at 1770 cml which iq characteris~ic ~f acid chloride.
Forty m~lliliters o triethylamine was added dropwi~e while cooling to about 25C. with an ice bath. The chloro-fonm solution wa3 ~tirred an additional 0.5 hr and was extracted with water, dried over sodium sulfate and concentrated. The re3idue wa~ chromatographed on a 7 x 20 cm 3ili~a column u~ing ethanol as the eluent. The de~ired material was the ~irst to be removed from tho column.
The ethanolic solution wa~ concentrated and the reqidue cry~tallized once from ethyl acetate-i opropyl ether and once from isopropyl alcohol. Yield of title compound was 1 g (70 , m.p. 120-122C.
Analy-~is: Calculated for Cl5Hl9N202Cl: C,61.12; H,6.50;
Found s C 9 61 .11; H, ~
~1., 9 . 32 25Intermediate ~6 2-(2-Chloroethyl)-2,~-dihydro-4-(phenYlmethyl)pyrido ~3,2-f~tl,41oxazspin-5( 4H)one .
The title compound was prepared in crude form in the fir~t part o~ Example 67.

58 ~L2;~30~
~xamPle 1 benzoxazeDin-~f4H~-one hvdroc~lorid~.
A ~olut$on of 9 g (0.2 mole) of ~imethylamine in 2~0 ml o~ ethanol was added to 24 g (0.1 ~ole) of 2-~2 chloro-~thyl)-2~-dihydro-4-m~thy~ 4-b~nzoxazepin-5~4H~one in ~ ~t~ omb. Tho mixturo wa~ he~ted at 100e. ~or 18 hrs.
Th~ ~olution wn3 concontrat~d ~n vacuo and the ~o~$~ue partition~d ~w~n ~thyl ac~t~te and dilut~ ~odium hydroxide. Th~ ~thyl ~ot~to laye~ wa~ ~on~entrated and the residue c~m~risod ~ubstanti~lly o~ the free b~se of the ~itle comp~und wa~ di~301ved i~ ~ethyl isobutyl ketone-~opropanol ~ixt~re. The ~olution w~ a~idified with hydrogen chl~ride gas to sive ~he title ~Gmpound, m.p.
188-197C~
Ex~mPle 2 2-~2~ methylamino)~thyll-2J3-dihydro-4-methyl-1,4-benzoxazepine-S(4H)-one.
~ 11 of the hydroc~hlorido salt obt~ined in Example 1 was partitioned be'cwl~en ~hloroform ~na diluts sodium hydroxide ~nd th~ chloroform l~yer c~ncentrat~d. The r~qidu~ wa~ ~rystalliz¢d ~v~ral ~im~ from isopropyl ether to give 6 g t21~ o~ the free b~, m.p. ~6-76C.
AQaly~is: c~lculated for C1~20N22; C,67.72: ~J8.12:
~,11.28 ~ound : ~,67.35: ~,8.16:

EX~mPl~ ~
2, 3-Dihydro-4-methyl-212-t 4-morpholino) ethyl~-l, 4-benzox~z~p~n-5 ( 4~) -one fumarate r ~
To 50 ~al of morpholino wa~ added 20 g to.o84 mole) of 2-(2-chloro~thyl) 2j3-dihydro-4-m~thyl-1,4-benzox~zepin~
5(4~)-on~. The ~olut on was ~efluxed or 5 hr~ ~na then ~oncantr~t~d in aeuo. Th~ r~ u~ wan ai~olved in ~hloro~o~, ~na th- ~olution w~ w~8hei~1 wi~h ~lilu~e ~odium hydroxid~ d ov~r sodium ~ul~at~ ~n~ conc~ntr~t~ i 35 va~uo. q~h~ residu~ ompri~ed su~tanti~lly o~ t~ ree ; 419A-CIP

ba~e o~ th~ title compound was reacted with 10.5 ~
(0.09 mole) o~ fumaric ~cid in i~oprop~nol-w~ter. The resulting solid was rocrystallized ~rom i~opropanol-watex to give 21.5 g (64%), m.p. 199-201C.
Analy~calculated for C~o~N207: C,59.10: ~,6.45, ~,6.89 Found ~ : C,58.95; ~,6.52:
. N,6.~8 Example 4 4-Benzyl-2,3-dihyd~o-2- ~ -(4-morpholino)e ~ yll-1,4 ~enzoxazepin-~(4H)-one.
To 200 ml of morpholine WZl~ ~dded 30 g (0.095 mole) of 4-benzyl-2-(2-chloroethyl)~ dihydro-1,4-benzox~zepin-5_~4~)-one. The ~olution was refluxea ~or 3 hrs and then concentrated in vacuo. ~h~ residue was partitioned between dilute sodium hydroxiae and ~hloroform. The chloroform layer wa~ dried ov~r sodium ~ulfate and concentrated ~n vacuo. The solid obtainod was recrystallized from isopropyl ether-ethyl acet~te three times to give 15.2 g of solid ( 43%), m.p. 97-ggc . 0 Analy8i8: Calculated ~o~ C~2H~N209: C,72.10; ~J7~15 N,7.64 Found : C,72.25; ~,7.22:
~,7.64 4-Banzyl-2,3-dihydro-2-r?25 ~
A solution of 5.95 g (0.19 mole) of monomethylamine in 200 ml of ethanol was added to 30 g to-og5 mola) of 4-benzyl-2-(2-chloroethyl)-2,3-~ihydro-1,4-benzoxazepin~
5(4H)-ono in a ateel bo~b. Tho m~xture W~8 heated at ~0 100C. for 16 hr. Th9` ~olution waa concentrated ln vacuo and the resiauo p~rtit~on~d betwe~n ~hloro~or~ ~nd dilut~
sodium hydroxid~. ~he chloro~orm lay~r was ~oncentra~ed~
nnd ~h~ re~idue ~ompris~d ~ub~tantially o the ~rae bas~
of tho titlo compound wa~ ai~olvad in isoprop~ol ~nd reacted with ~u~ric acid to give the umara~o, ~h~ ~alt wa aried under v~uum at loo&. until entr~pped ~opropyl 419A,CIP

60 1~3~09 alcohol was removed, m.p. 178-81C.
Analy3is: calculatcd ~or Ce9H2~20~: C,64.77~ ~,6.15;
~,6.57 Found : C~64.87t H,6.20;
N,6.62 Exam~10 6 ? -~2-(DimethYlamino)~thyll-2,3-dihydro-~-meth benzoxazsPine-s(~H~thione hydrochloride rl ll.
To ~ solution o~. 7.2 g (0.16 mole) of dimethylamine ;n 350 ml o~ absolut~ e~h~nol wa8 add~d 20.4 g (o.o8 mole) of 2-(2-~hloroet~yl)-2,3-dihy~ro-4-methyl-1,4-~enzoxazepine-5(4H)thione. The ~olution wa~ heated in a steel bomb for 18 hr at 100C. a~d then con~ntrated. ~he residue was pa~ti~ione~ between chlo~oform nnd dilute ~odium hydroxid~.
Th~ chloroform layer was dsi~d over sodium sul~te and ~on~e~tr~ted. The solid compri~ed ~ubstant~lly o~ the gre~ base of the title compound was reac~ed with hydrogen chloride gas in ethanol to give th~ hydrochloride ~alt.
m e ~alt was recrystallized ~rom ethanol and dimethyl-~ormamide ~ollowed by three re~rystallization~ from ethanol to give 7.5 g (28~ , m.p. 2~3-236C`.
Analy~Calculated for Cl4~21~2S~Cl: C,55.90; ~,7.04;
~,9 3~
Found : C,~5.?2; H,7.26;
~,8.94 Exam~le 7 4-Benzyl -2-r2 ~ dime ~ lamino~ethyll-2~-dih ~ o-1~4-benzoxa~pin-5(4H)-one monohydrate.
Follow$ng the procedure o~ Example 1, 4 benzyl 2-(2-chloroethyl)-2,3-dihydro-1,4-b~nzoxazepin-5(4H) on~
and d$methylaminQ wer~ reacted and ~h~ ~ree base o~ th~
title compound Wa8. obt~ined.in ~he concentr~tsd residue.
Recry~talliz~tion f~om ethanol-water gave the produ~, m.p.
7~-77C.
Analys$~: Calculated ~or Cæo~4~Nzo9: C,70013; H,7.65; ~,8.21 Found : C,70002, ~,7.5~ ,8~25 .. j ~ '11yA-CI~

61 ~234~30 ~XamP1e 8 2,~-DIhydr~ methyl-2-r2-(4-morpholino~thyll-1,4-~enzoxazepin~(4H)-thaone hydrochloride ~
A ~olution o~ 20.4 g (0.08 mole) o~ 2,~-dihydro-4-methyl-2-(2-chloroethyl)-1,4-benzoxazepin-5(4~)-thione in 60 ml of morpholine was refluxed $or 5 hr. then conc~ntrated. Th~ re~iduo W~3 partitioned b~tween dilut~
eodium hydrox~de and chloro~orJn. !rh6~ chloroform layer was dried ov~r ~odium ~ulfate ~nd c~ncentrat~d to give a re3idue com~rised ~ub~tanti~l~y of the 4ree base o~ the title compou~d. The hydxochlorid~ salt wa~ prepared in me~hyl isobutyl ~aton2-d~methyl~ormamide solution with hydrogen ~hloride gas. The ~al~ wa~ r~crystallized from ~thanol-dimethyl~ormamid~ to give 14 g solid ~51%), ~.p. 253-256C~
Analy~calculat~d for C1BH~9~2S02C1: C,56.04: ~,6.76:
~,8.17 Found : C,55.7~: H,6.63:
~,7-97 Example 9 `
2 -r 2 - ( Dimethylamino )ethyl ~ -2, ~5-dihydro-4-methylna~th r2,3-~1rl,4~oxazepin-5(4H)-one oxalate ~1.1~.
A ~te~l bomb wa3 ~harged with 5.0 g (0.017 mole~ of 2-(2-chloroathyl)-2,~-dihydro-4-methylnaphth~2J~ 1,4~
oxazepin-5(4~)-one, 50. ml of ab~olut~ ~thanol and S.78 g (0.034 ~ole) o~ d~nethylamin~ as 40% aoueous ~olutionO The bomb wa.~ heated st 100~. for 16 hr. Vola~ile~ were remove~
under reduced pres~ur~ ~nd the resiaue partitioned betwe~n chloroform ~nd 15~ aqueouA sodium hydroxid~. ~he ehloroform layer wa~ washed twico with water, dried over ~gnesium . ~ulfat~ and concentrat~d under reducQd pressur~ to give 2.7 g (540 Of vi~cou~ yallow oil comprised ~u~st~nti~lly o~
thQ free b~8~ of the title compound. Th~ oil was di~olv~d -in isopropyl ~lcohol and reacted with oxalic acid. The~
oxalate ~alt was recry~tall~zed ~rom eth~nol-w~ter~ ~.p.
1~2-194~C.
Analy~is: calculat~d ~or C~c~44~a~: C,61.84, ~,6.23; ~,7.21 Founa : C,61.41; ~,6.27: N,7.09 ' ~ CIP

~2 ~34~0~9 2-r2-(Dimethylamino~ethyl~-2,3-di~ydro-4-methylpyrido ~3,2-f~1,4~-oxazepin-5(4H)-one ~umarate t2:3~.
~ in a ~teel bomb was added 25 g (0.09 mole) of 2-~2-chloroethyl)-2,~-5 dihydro-4-methylpyrido~ ~,2-f~1,4~-oxazepin-5(4H)-one hydrochloride. The mixture wa~ heated to 100C. for 15 hr und~r mild agitation. The mixtura was partition~d u~ing dilute ~odiu~ hydroxide and two chloro~orm ~xtractions.
Tho chloroform lay~rs were combined and concentrated. The ~esidue compxi~ed sub5tantially o~ the ~re~ ba~e of ~he title compound wa~ dis olved in 200 ml of i opropyl alcohol ~nd 9 g of oxalic acid ~dded. The oxala~e ~alt wa~
recrystallized rom 95% ethanol to give 18 g. The oxalate ~alt was than ~onverted ~o the free base by partitioning betwesn chloro~orm and dilu~e sodium hydroxide hnd evaporating the c:hloroform layer. The residue9 the ~ree base of the title compound, wa~ disYolv~a in isopropyl alcohol and reacted with ~umaric a~id to give 13 g of white ~olid (~4%), m.p. 146-148C.
2~ Analy~i3: calculatad for Cl~H~5~0a: C,5~.90; ~,5.90t Found : C,53.76; H,~ 02;
N~9.96 Exam~le 11 2-r2-(D~methylamino)ethyll-2,3-dihydro-4-methylpyrido r3,2-f~Ll,41-oxazepine-5(4~)-thione fumarate rl 1], ethanol ~2 llr To ~ ~olution o 32.8 g (0.29 mole) o~ 40% a~ueous dimethylamine and 100 ml of ~thanol in stael bomb wa~ added 15 g (o.058 mole) of 2-(2-chloroethyl)-2,3-dihydr~-4-methylpyrido~,2-~]~1,4~-ox~zepin~-5(4~)-thione. The mixture wa~ heated to 100C. for 18 hr under mild agitation.
The solution w~ cool~d and partitioned between ~hlo~orm ~nd dilut~ ~odium hydroxide. The chloro~orm layos was dried ovor ~odium ~ulfat0 and ~oncentrated. gh~ idue comprined aub-~tantially o~ th~ e b~e o~ th~ title ~omp~und was ~issolved i~ isopropyl alcohol ana react~d ~tly~

~3 ~ 9 with 7 g of fum~ric ncid. The fumzlrate ~alt wa8 rzcrystal-liz~d from isopropyl nlc~hc~l to giv~ 19 g ( 86~¢), m.p .
105-129C. A 14 g ~ample o~ tha salt wa~ re~rystallized ~rom ethanol to give 10.5 g yellow ~olid, m.p~ 10~-118C.
5 ~rhe ~MR spectra indicate~ the cry~tals contain 1/2 mole ethanol .
Analysi~: Calculated for C3~H52Ne,0llS2: C,5~5.45; ~I,6.48:
~, 10 . 39 Founa : C, 53 . 07: EI, 6 . 53;
M, 10 .23 ~a~
~ 2 - ~ Dime~hylamino ) ethyl l -2, 3 -d ihydro-4 -methylpyr :Ldo r3,2 f~l,4~-oxaze~pine 5(4~? ~hione fumarate To ~ ~olution o 113 m} (1.0 mole) of 40~ ~ueou~
dimethylamine ~nd 326 ml o~ ethanol in a ~teel bomb was 15 added 48.4 g (0.189 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido3,2-~tl,4~-ox~zepirle-5~ 4}I)-thione.
Ths mixturo was heatea at 100C. for 14 hr. The ethanol wa~ removed in ~ rotary evaporator leaving some water in the re~idue. Ths residue was dis~olved in 200 ml of 20 methylene chloride and waQhsd with ~hree 100 ml portion~
o* 20% acIueou~ a~3ium carbona~e solution. The combined aqueou~ layers were ~xtracted with three 150 ml portion~ D:~
methylene ~hloride . Methyl~n~ chloride 801ut ion~ wera combinsd and treated with charcoal7 Charcoal was filtered 25 off and the filtrate was ~vaporated to giv~ an oil. The oil was ~i~solved in 215 ml isopropyl alcohol and the solu~ion wa~ heat~d to 8 ~low boil. A solution of 21.9 g (0.19 mole) of fumaric acid in 150 ml of boiling methanol wa~ add~d to the i~opropyl alcohol ~olution. Crystalline solid was obtained weighing 63.4 9 (88%). ~he 801ia was recrystallized from hot 200 proof ~thyl alc:ohol. q~he cryqtsls were f iltered o~ and tritu~a~ed in i80propyl ~t~er at room temperature an~ aqain ~eparated by fil~eringN
A~ter drying in a vacuu~ oven overnight at 85UC.9 cry~tals 35 in the amount of 72 .45 g ~79%), m.p. 130-133C , jwere obtained .
Analys i~: ca~ a~ced fox C ~ 7~ s~os s: ~ , 53 - 5~ 6 . ~ . 02 Found : C.~5~5O23, ~6~ ;1,10.64 - L~lY*--Cl~

64 ~;~3~09 4-Benzyl-2,~-dihydro-2- ~ -(4-morpholino~ethyl benzoxaze~ine-~4H)_thione.
To a ~uspension of a ~inely gro~nd mixture of 2.9 g 7 (0.013 mole) o~ phosphorus pentasulfide and 2.9 9 3f pot~38ium ~ulfide in 75 ml of dry toluene was added 12 g (0.0~3 mole) o~ 4-benzyl-2,3-dihydro-2-~2-(~-morpholino) ethyl~-1,4-benzox~zepine-5(4~)-one. The mixtur~ wa~
1 stirred at re~lux for 10 h~ d ~iltered. The filtrat~
wa~ concentr~ted 3nd the re3idue cry~tallized from i80propyl ether-toluene tD give 2.~ ~ (20~ , m.p. 236-238C.
Analysi~: Calculat~d for C~2E45~2O2S: c,6g.o8; ~,6.~, Found : C,69,60; ~,6 96:
N,7-15 ~
?,~-Dihydro-4-~ethyl-2 ~ -(methylamino~ethyl]-1,4-benzoxazepin-~( 4~? -one f~mar~ce r~
Following the procedure of Exæmple 5, 50 ~ (0.21 mole) of 2-(2-~hloroethyl)-2 J ~-dihydro-4-~ethyl-1,4-benzoxazepin-5(4H)-one and 1~.0 g (0.42 mole) o~ monomethylamine (in 400 ml e~hanol) were re~cted to giv~ the ~r~e ~ase of the title eompound which was reacted with ~umaric acid to giv~, after iso1ation and recrystallization ~rom ethyl alcohol, 17 g (23%) o:~ the title compound, m.p ~ 154; 156 C O
25 Analysis: Calculated for C~7~22N20~,: C,58.27; ~,6.3~:
~, 8.oo Found : C,58.~54; ~1,6.52;
~1,7 .82 Example lS
2, ~-Dihydro-4-methyl-2 -r2 - (me~hylamino ~ ethyl ~1, 4 -30 benzox~zepin-5 ( 4EI) -one .
2, ~;-Dihydro-4-m2thyl~ 2~ thylamino~ethyl~-134-benzoxazopin-5(4H)-one fu~ar~-t~ WZI~ conv~rted back ~o the .
~reo Sa~ç~ by partitioning i~ ~ilute sodium hydrox~de an~ -c~hloro~orm. Ev~poration of the chlorofo~ lay~r and 3~ distili~ng, b.p. ~L82~0.2 mm, gaYe 403 g o:C ~h~ produc~.
Analy3is: Caleulated ~or C~ C,6~5.6~: ~,7.74: ~711.96 Found : C,66048; ~,7.69; ~11.88 ~5 34~0

8~
2,~-Dihydro-2-~2-(4-hydroxy-4-phenyl)-pip~ridinyl-ethyll-4-methyl-1,4-benzoxazepine-5(4H)-thione (and hydro~hloride salt ~
A suspen~ion of 10.7 g (0.078 mOlQ) of potas~ium carbonat~ .7 g (0.078 mole) o~ 4-hydroxy-4-phenyl-pip@rid~ne ~nd lg.B g (o.078 mole) o~ 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-b~nzoxazepine-5(4~)-thione in 200 ml of n-butanol was refluxea overnight. The mixture wa~ ~ilt~red and the filtrate concentrated in vacuo.
The r~sidue W~8 ~s~olv~d in ethanol-ligroin and r~cted with hydrogen chloride gas to give the hydrochloride E~alt which wa~ recrystallized from ethanol-dirnethyl-formamide. The hydlrochloride salt wa.~ convarted ba~k to the free base by partitioning in chloroform and dilute sodiu~ ~iydroxide and evapor~t$ng the chloroform. Recry~tal-lization twice ~rom isopropyl al~ohol gave 9.27 g (30,~) product free ~ase, m.p. 142-148C~.
Analysis: Calcula~ed ~or C~23~2~N202S C,69.66; R>7.12:
~.7 07 Found s C, 69 . 78: }I, 7 .18:
~j7 0 ExamPle 17 ?,3-Dihydro-4-methyl-2-~1-(4-phenyl-1,2J3,6-tetrahydrQ)pyridanyl~ethyl~,4-benzoxazepine-5(4H)th~one.
A ~usp~nsion of 24.3 g ~0.176 mola) o~ pota~ium carbonate, 11.5 g (0.059 molQ) of 4-phenyl-3,4-tetrahydro-pyridine and 15 g (0.059 mol~) o~ 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazopino-5(4H)-thione and enough n-butanol to $orm a ~lurry were refluxed for 72 hr. The reaction mixtur~ Wa8 filtere~ hot ~nd th~ filtrate coole~
to room temperatur~ and r~filtered. Tha la.~t ~ rate ~a~
concentrat~d and the residuQ dissolved in ~thyl acetate. - -The cryst~l~ obtained on cooling were ~ecry~talli2ed ~rom ~thyl aceta~e to give 7 g o~ produ~t (310 ~ ~.p. 153-15~ C.
Analysis: C~lcul~ted for ~2~9~20S~ C,72a98: ~g6~Q; ~7~40 Found C,73.36: ~,7.01: ~,7.47 '' ' ~ 419A -CIP

66 ~ ~3~8~)~3 Example 18 8-chloro _-C2-~dimethyl~mlno~ethvl~-2,3-dihydro-4-methy~-~4-benzoxazePine-5 ~ drochloride r A solution of 9.8 g (0.04 mole) of 8-chloro-2-(2-chlor~ethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5 5 ( 4H) -thione in 50 ml of ab~olute e~hanol ~nd 10 ml of a 40% ~aueou~ solution of dimethyl~mine were mix~d and heated in a st~el bomb at 100~. for 16 hr. The ~thanol was evapo~ated under reduced pr~sure and ~he re~iaue dis~olvad in chloroform and partitioned wich 10% sodium hydroxide 10 E~olution. The c~loroform layer wP.~ evapor~t~d under reduced pr~s.ure to ~ive ~n amorphous ~olid. Th~ solid wa~ dissolved in 6~ hydrochlori~ acid ~nd the solution washed with ethyl acetate. ~he agueou~ layer was ba~ified with 50% ~odium hydroxide and extracted with ethyl acetate.
The ~hyl acet~t~ 12yer was ~vaporated under reduced pres~ure to give a vi3cous oil compriaed subRtantially of the free ba~e of the titl~ compound which was di3solved in absolute ethanol and reacted with etheraal hydrogen chloride. ~he hydrochloride ~alt wa~ re~ry3tallized from ethanol ~o giv~ 30 g (25 O product, m.p. 196-199 C.
~nalyYis: Calculated for Cl4~20N2Cl~OS: C,50.15: ~,6.01;
N, 8.35 Found . C, 50 .15; ~I, 6 .18;
~1, 8.~)7 Example 19 8-Chloro-2-~2-(dimethylamino)ethyll-2~3-dihy~ro-4~
methyl-1,4-benzoxazepin-5(4H)-one o~alate ~
A solution o~ 10 g (0.037 mole) o~ 8-chloro-2~(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxa~epin-5~4H~-on~ in 50 ml o~ absoluta e~hanol and lQ ml of 40~ aqueou~
~0 solution of dimethylamine wero mixed ~nd heated in a ~teel bomb at 100C. for 16 hr. The soIution wa~ cDnc~trated under r~duced pr~ure ~nd th~ residue ais~olved i~ chloro-~or~ and partition~d with 15% sodium hyaroxide (2 washe~).
The chloro~orm lay~r was dri~d ov~r mag~eQium ~ulfate and 35 evaporatod under reduced pr~uro to give an oil, comprised ~ub~t~ntially of th~ ~re~ bA~e of the title ~ompound.

! ~

67 ~ )9 ~he oil was di~o~ved in ~b~olute e~hanol and reacted with oxalic: scid. The oxalate 3alt was recrystallized from ethanol in the amount of 4 g (38q~o) ) m.p. 198-201C.
Analy~i3. Calcul~ted ~or ~2C10~,: C,51.55, ~,5.68, ~,7 .51 Found : C~51.07: ~,5.69;
.~,7-43 ExamPl~ ?

To a sc~lution of 3-0 Si (0.01 mQle)of 7 bro-2-( 2 -chloroethyl ) ~, 3-dihydro-4-me~hyl-l, 4-benzoxaæepisl-5(4~)-on~ in 50 ml of~ olutQ ~ as~c~1 w~ ~d~lad 2;2 ml of a 1~o% a~ueou~ ~olution of dim~thylamine. T~a reaction mixtur~ wa~ heated in a Atainless ~teel bomb at 100C.
1~ for 16 hr ~nd concentratod urlder reduc~d pre~qure. The re3idue wa~ partitionea be~woen c~lorofonn and 15,~ sodium hydroxide ~olution. Th~ chloro~orm layer wa~ ~eparated and extracted with SN ~gueoua hydrochloric acid. ~rhe acid layer was ~aqified wit~ 50% aqueous ~odium hydroxid~ ~nd extract~d with ~hloro~orm. The chlorofonm wa~ evaporated under reauced pr~ssure to give 2.4 g (73~) Yi8~0UY brown oil, the free ba~e of the t~tle compound. The oil Wa8 di~801Yed in i~opropyl alcohol and reacted with oxali~ acid. The oxalate ~alt was recrystallized from isopropyl alcohol/
w~t~r to give the tit~o ~alt, m.p. 192-194~C.
Analy~ C~loulated for Cl~E4l0~Br~2: c,46.o6: H~5007;
~I~.71 Found : c,46.oo: ~,5.10;
~,6.68 ExamPle 21 2-~2-(Dimethylamin ~ 11-2~3-dihydro-4-methylnaph~h ~_ .
A ~olution of 8 g (0.028 mol~) of 2-(2 c~loro~thyl)-2, ~5-dihydro-4-methylnaphth~2, l-f ~ l, 4 ~oxazepin-5 ( 4E~ one and 6.2 g o~ 40% dim~hylamine (0.05~ molo) ~n lO0 ml o ethanol wa~ heat~d in a ~t~el bomb o 100C~ or 18 hr.
The ro~ulting ~olution wa~ rtitioned botw~n ~ethylone cihlori~ ana dilute g~odium hydroxlde ~olution. Th~
methyleno ~lorido l~y~r w~s d~i0d ovx~ so~um s~ at0 ~nd y~ r 68 ~L~3~

~oncentrate~. ~he residu~ compri~ed su~t~ntially of the free base of ~he title compound wa~ dis~olved in isopropyl al~ohol and reacted with 2.6 g oxalic ~cid. The oxalate ~alt obtained wa~ recrystallized ~rom i~opropyl alcDhol in watgr, m.p. 206-209C.
Analy3i~: c~lcula~ed for C20E4~N200: C,61.85: ~,6.2~
N,7 ~1 Found : C,61.61; ~6 26;
~,7-13 Example ?2 When in the pro~edu~ of Ex~mple 10 eoual mol~r ~mount~
of the following ar2 ~ubstituted ~or 2-(2-chloroethyl)-2,~-dihyd~o-4-methylpyridot7,2 f]~l,4J-oxazepin -5t4~)-one hydrochloride:
2-(2-~hloroethyl)-2~-dihydro-4-methylpyridot4~3-~]
~1,4J-oxazepin-~(4R)-on~ hydrochloride, 2-~2-~hloroethyl)-2,3-dihydro-4-methylpyridoC3,4-~
tl,4~-oxazepin-5(4H)-~n2 hydrochloride9 and 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~2 9 3-f~
tl,4~-oxazepin-5(4H)-one hydrochloride, there are obtained:
2-t2-(di~ethylamino)ethyl~-2,3-dihy~ro-4-methylpyrido ~4,3~ 1,4~-oxazepin-5~4H3-one ~umarate, 2-~2-(dimethylamino)ethylJ-2,3-dihydso-4-methylpyrido ~,4-f~1,4~-oxazepin-5(4H)-one fumarateJ and 2-C2;(dimethylamino)ethyl~-2,3-d~hydro-4~methylpyriao t2g3-f~tl,~l-oxazepin-5(4~)-on~ fumarate.
~xam~l 23 2- ~ amino)ethy~ -2,3-dihydro~4-methylpyrldo .
~o a solution of 0.5 g ~0.002 mol~) of 2-(2-chloro- .
ethyl)-2,3-dihydro-4-methylpyridor4,3-f~1,4~oxazepinQ
5(4~)-thion~ in 20 ml of ethyl ~lcohol wa~ added 2 ml of 40% aQuaous dimethylami~e. The ~ixture wa~ h~ated in a ~t~el bomb to 100C. ~or 14 hr~ The resultin~ ~olu~io~ -was ~ilt~r~d ~d concont~ated. ~ho residue w~ di~olv~
in i~op~opyl ~lcohol ~nd a few drops of o~h~roal ~ydrog~n c~loride were ~aded. Th2 hy~ro~hlori~e 3alt ~rystal~ w~ro . ; 419~CIP

~L23~
recry~tallized by di~olving in Qthyl alcohol and boiling while replncing the ethyl ~lcohol with isopropyl alcohol.
The yield of product wa~ 0.3 g (47%), m.p.: de~empO Above 200C.
Analysi~: calculated for C2~H4~0zS2Cl9: C,48.78; H,6.46:
M,13 13 Found : C,49.34t H,6.47:
~,13.03 Example 24.
2-t2-(~iethyl~mino)~thyl~-2,3~dihydro-4-methylpyrido ~3,2~ tl,4Joxazepine-5(4H)-thionQ.
2-(2aChloro~thyl)-2,3-dihydro-4-methylpyrido~3,2-f~
C1,4~-oxazepine-5(4~)-thione ~nd diethylhmina in ethanol are heat~d togeth~r to obtain the title compound.
Example 2~
2-~2-fDimethvlamino)ethvll-2L~-dih~dro-4-me~hylnaphth 2,3-~tl,4~-oxazepine-5(4~)thione oxalate ~ hemihydrate.
To a ~olution of 15 g (0.05 mole) of 2-(2-chloroethyl)-2,~-dihydro-4-methylnaphth~2,3-f~1,4~-oxazepine-~(4H)-thion~ in 50 ml o~ absolute ethanol waR added 10 ml of a 45% aqueous solution of dLm~thylamin~. The solution wa~
h~ated in a steel bomb ~or 16 hr. The e~hanol was ~vaporated under reduced pressure and the r~sidue par-titioned b~tween chloroform and 15~ aqueous ~odium hydroxid2.
The ~hloroform layer wa3 ~eparated and extra~ted with 3 aqueou~ hydrochloric ~cid. The acid layer wa~ ba~i~ied with 50% aqueou~ ~odium hydroxide and ~xtract~d with ~hloroform. The chloroform solution wa~ concentrated under reduced pr~sur~ ~nd the residue wa~ diqsolved in i~opropyl ~lcohol and reac~ad with oxalic acid. The Ralt waq recry3tallized fr~m i80propyl alcohol and wat~r to give -the title compound9 m.p. 115-118C.
Analysis: Calcula~ed fox e~OE~O~o. lS2: CJ58~09 ~,6.og;
~,6.77 Found ~ 5~ o 42 ~ 85 ~,~.70 :

. .
70 ~3~0 ExamPle 26 2-r2-(Dimethylamino~ethyll-2,5-dihydro-7,9-diiodo-4-methyl~ benzoxazepin-5(4H~-one.
.
Ut~lizing the procedure~ o ~xample 1 and 2 ~nd ~ubstitutlng 2-(2-~hloroethyl) -7, 9-diiodo-4-methyl-2, 3-5 dihydro-1l-mothyl-l,4-~enzoxazepin-5(4H)-one ~c~r 2-(chloro-~thyl)-4-m~thyl-2,3-dihydro-1,4-benzoxazepin 5(4H)~one, the title compound i~ obtain0d~
Exampl~ 27 10 =~LI--L
To a ~olution of 9.0 g (0.035 mole) of 7-chloro-2-(2 -chloroethyl) -2,3-dihydro-4-methyl-1, 4-ben~oxazepin-5 ( 4EI~-one in 50 ml ~b~oluto athanol wa~ added 7 g (o.o66 mole) of a 45% aoueouR ~olution o~ dimethylamin~. The ~olution w~ h~ated in ~ s~cainl~s~ ~to~l bomb at 100C. or 14 hr.
The reactiorl mixtur~ wa~ concentrntQd under r~duced pr~3ur~ ~nd th~ residue wa~ partitioned between chloro-form and 15% ~aueous sodium hydroxide. ~he c~loroorm layer was ~eparated and evapora~ed und~r reduced pre~uxe 20 to give a viscous brown oil. Th~ oil wa~ di~olved in isopropyl alcohol and oxalic acid a~ded. Recry~tallization from isopropyl alc~holh~ator gave 7.0 g (57~ ox~late salt, m.p. 199~00CO
Analy~ calculated ox C~oEk~N20~Cl: C,51.55; ,5.68;
~7.51 Found~ C,51.52: ~,5.72s . ~.7.4~
~a~
2-(r)imethyl~mino)m~thyl-2 J3-d~ydro-4-methylp~
~2-f~rl~4l-oxaz~pin-5(4~ n~.
When in the pro~edur~ o~ Exampl~ 1OJ 2-~hloromethyl-2,~-dihydro-4-m~thylpyrido~3,2-~El,43-oxaz~pin-5(4H)-one i8 ~ub~tituted for 2-(2-chloroethyl~2,3 d~hydro-4-m~thyl~
pyrido~3,2-~1,4~-oxaa:epi~-5(4E3)-ono, t~e ~itl~ compourld i8 prep~red and i~ i801a1:od i~ d~Jsirod 1~8 a pha~ac~uti-35 s:ally accept~bl~ sal~.

~ . 419A--CIP

~2~
Exam~le 2~
? -r2 -( DImethylamino)ethyll-2,3-dihydro-4-methylpyriao r 3 9 2-~ r ~ oxazepine-5(4~)-thione methiodide.
2 r2 (Dimethylamino~thyl]-2,3-dihydro-4-methylpyrido t3~2-f]~lJ4~-oxazepine-5(4H)-~hion2 fumarate ~
ethanol r2:1~9 3.8 g (0.01 ~ole) was partitioned b0tween chloro~orm and dilute sodium hydroxide. Th~ chloroform extr~t wa8 dri~d over ~odium ~ul~at~ and concentr~ted.
The r~oidue was dis~olved ~n 15 ~1 o~ methyl i80butyl ketone nnd add0d to ~ ~olutio~ ~ 1.4 g ~0~01 mole) of methyl ~o~ide in 15 ml o isobutyl ~tone. Recr~otal-lization from 50~ othanol - 50% me~hyl i~obutyl ketone gave 275 g ~78%~ o~ the ~rodurt, m.p. 221-225C.
Analy~i~s Cal~ul~ted for Cl4~2~90SI: ~,41~28: H,5.44;
~,10.31 Found s C,41.29; ~9 5.51;
N,10.30 ~a~.
7-Chloro-2-t2-(dimethylamino)ethyl~-2,3-dihydro-4-methyl-1,4-b~nzoxazepine-5(4H)-thione oxalate hemihydrate.
.
To a solution o~ 8.o g (0.027 mole) o$ 7-chloro-2-(2-~hloro~thyl~2,3-dihydro-4-methyl-19 4-~en2Oxazepine-5(4H)-thione in 50 ml of ~bsolute ethanol was ad~ed 6 ml ~0.054 mole) o~ 40% a~ueou~ ~olution o~ dimethylami~e. Th~
~olution was heat~d in a oteel bomb at 90C. ~or 14 hr.
25 Th~ ethanol was removed under reduced pr~ssure and the re~idu2 w~ partitioned be~ween ~hloroform and aqueou~
sodium hydroxide. The chloroform layer was concentrated to-give a v~acous yellow oil. The oil wa~ dissolved in isopropyl ~lcohol and reacted wi~h oxalic acid. The oxalate salt im~ediately precipitated. The mixture wa~ heated and a small ~mount of water wa~ added to ~ olve the salt. A
whit~ c~ys~alline powd~r w~ obt~in*d9 m.p. 150-151~C.
Analysi~: c~lculatsd for C~2 ~4~4C12 11 S2: C,48-3~ 5 9 57;
~.7.04 Found : C,48.74; ~,5.~4;
~,6.~5 4 l9A~CIP
. i 1 7~
~3~0~9 Exam~e 31 ?-~2-(D~ethylamino)ethyll -2,3-dihydro-4-methylnaphth r2,1-fl~1,4~-oxazepine-5(4H)-thione hydrochlor~l~
To a solution o~ 15.0 g ~0.05 molz) of 2-(2-chloro-~thyl ) -2, ~;-dihydro-4-methylnaphth~2, l-f ] ~ -ox~zepine-5 ( 4EI) -thione in 50 ml of absolute ethanol w~18 added 10 g o~ a l~o,~ ~queoua ~olut~on o~ dimethyl~min~. The resultirlg ~ol~tior~ was h~at~d in ~ ~tesl bomb at 100C. ~or 40 hr and conc~ntra~ed urlder reduced pr~ssure. T~e residue wa~
partitioned between 15% a~ueous sodium hydroxide and chloroform. The chloroform layer wa~ evapora'ced and the re~i~ue partitioned between 3~1 hydrochloric: acid and chloro~orm. Th~ ~queous lay~r was made alkaline with 50,~
sodium hydroxide and extract2d with chloroform. The chloroform ~xtract was concentrate~ and ~he residue dissolvel~l in i~opropyl alcohol. Ether~al hydrogen chlc)ride was ~dd~d. ~ecrystallizatlon o~ ~he preoipitate from ~opropyl alcohol ~ ter gave ~.0 g (200 of the product~
m.p. 238-240C.
Analysi : Calculated for Cle~ 2ClOS: c~61o61; H~6~61;
~,7.98 Found : C,61.80, ~16.61;
~,7.91 Example 32 Whe~ in the proce~ure of Exampl~ qual mol~r amount~ of the following are ~ubstitut~d for 2-t2-~hloro~
ethyl)-2,3-dihydro-4-methylpyridor 5~2-f~ 4]-oxazepine 5~4H~-thion~:
2-(2-chloroethyl) -2 ,3-dihydro-4-methylpyrido~3, 4-f ~1,4~-oxaz~pine-5~4~3-thions, and 2-(2-chlorG~thyl-2,3-dihydro-4-me~hylpyridoE2,~
~1,4~-oxazepine-5(4H~-~hion~, there ~re obt~ined:
~) 2-~2-(d~me~hylh~ino)ethyl~-2,~-dihydro-4-m~thylpyrido ~3~4-f~ 4J-oxazapine-5(4H)-~hioa~ fum~r~te, and b) 2-r2-(dimethylamino)~thyl~-2,3-~ihydro-4-~ethylpyrido ~293-f3~1,4J-ox~z@pi~-5(4~)-thione fumara~s.

419A_CIP

~3~
ExamplQ ~
? -~2-(~imethylamino)ethyl~-~,3-dihydro 7-methoxy-4-methyl-1,4-ben~oxazepin-5(4H)-one oxalat~ r hemihydr~te .
.
To ~ ~olution of ~.0 g (0.011 mole) o~ 2-(2-chloro-ethyl)-2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5(4H)-one in 50 ml o~ ab~olutu othanol was added ~.0 g of a 40~ aqueous ~olution of dimethylamine. The reaction mix~ure W~8 heated i~ a stainl~s ~teel bomb ~t 100C. for 16 hr, cooled and ovaporated under reduced pressur2. Th8 re idue wa3 p rtitio~ed betw~en chloroform and 15~ Rodium hydroxide ~olution. The chl~roform layer wa~ concentrated and the residue~ th~ free ba~e, wa~ dis~olved in i~opropyl alcohol and reacted with oxalic acid. ~he re~ulting oxalate ~alt was recry~tallized from isopropyl alcohol/H20 to give 1.9 g ~45%) of th~ title ~alt, m.p. 176-178 C.
Analy3i~: calculated for Cg~H~o~o~s: C,54.10: ~,6.67;
~,7.42 Found : C,54.29; H,6.59:
N,7~53 ~E~
7-Bromo-2-r2-(dimethylamino)ethyll-2,3-dihydxo 4-methyl-1,4-be~zoxazepine-5(4H)-thione oxalate r~

To a ~olution o~ 1~ g (0.04 mola) of 7-bromo-2-(2-chloroethyl) 2,3-dihydro 4-methyl-1,4-benzoxazepine-5(4H)-thione in 50 ml of absolute ethanol wa3 added 8 ml of 45~ aou~ou3 solution o~ dimethylamine. The solutio~ wa~
heated ~t 100C. in a steel bomb for 16 hr. Th~ ethanol was evapor~ted under reduc~d pres~ure and ~he re id~e partitioned between ethyl ace~ate and ~N a~ueous hydro-chloric acid. Tho aaueou~ extract wa~ baRi~ied with 50%
~gueous ~o~ium hydroxid~ and e~tracted with chloroform.
Th8 ~hloroform wa~ concentr~t~d un~er reduced pre~ure.--The residue, ~h~ free baQe o~ the ti~le c~mpoun~, w.~
di~solved ~n i~opropyl alcDhol and rea~ted with oxalic ~id. Th~ ox~l te salt wa~ recryst~lliz~d ~rom 35% e~hanol to give ~he titl~ ~alt, m.p. 155-157C, ~; i ! 419A-CIP

74 ~ 2 ~

Ana~ y8 i8 : calculat~d for C92~4~N~Br20l2S2: C,42.~8; H,5.14;
~,6.12 Found ~ C,42.93; ~,4~79 ~,6.19 When in the procedure of Example 27, equal molar amount~ of the followiny ~ro sub~tituted ~o~ 7-chloro-2-(2-chloroethyl)~2,~-dihydro-4 methyl-1,4~banzoxaz~pin-5(4~)-one, 2-(2-~hlor~thyl)-4-eyclohexyl~2,3-dihydro 1,4 benzoxazepin;5(4~)-one, 2-(2-chloro~thyl)-2,3-dihydro-4-ethyl-1,4-be~z-oxazapin-5(4~)-one9 2-~ -~hloroethyl)-2,3-dihydro-4-i~opropyl-1,4-benz-oxazepin-5~4H)-one, 2-(2-chloro~thyl3-4-(4-chlorobenzyl)-2,3-dihydro-1,4-benzoxazepin-~(4~)-on~, 2-(2-chloroethyl) -:2 ,3-dihydro-4-( 4-methylb2nzyl)-1~4-benzoxazepin-5(4H)-one, 2-(~-chloroethyl) -2 ,3-dihydro-4-( ~ 5-dimethoxybenzyl) -1, 4-benzox~zepin-5 ( 4H) -one, 2-(2-chloroothyl) -2 ,3 ~dihydro-4-(3-trifluoromethyl-benzyl)-1,4-~enzoxaz~pin-~4H)-one~ an~
2-(2-c~loroethyl)-2,3-dihydro-4-(4-nitrobenzyl) 1,4-benzoxazepin-$(4H)-one, there are obta~ned:
a) 4-cyclohexyl-2-~2-(dimethylamino)ethyl~-~,3-dihydro-1,4-benzoxazepin-5(4~)-one oxalat~, b~ 2-~2-~dimethylamino)ethyl~-2,3-~ihydroo4-athyl-1,4 benzox~zepin-5(4H)-one oxal~te, c) 2-~2-(dimethylamino)~thyl~-2~-dihydro-4~isopropyl-1,~ b~nzox~z~pin-~(4~)-one ox~late, d) 4-(4-~hlorobenzyl)-2-~-(dL~ethyl~mino)ethyl~-2~3- .
dihydro-lJ4-b~nzoxazepi~-5(~ one ox~l~te~
~) 2-Z2 (d~e~hylamiNo)~thyl~-2~-dihyd~o-4-~4-methyl-b~nzyl)-1,4-~nzox~zspin-5~4~) on~ ox~late, ) 419~-CIP
~23~30~

f) 2-~2-(dimethylEmino)e~hyl~-2,~-a~hydro-4-~3~5-- dim~thoxy~enzyl)-1,4_benzoxazepin-5~4~)-one oxal~te, g) 2-~2-(di~ethylamino)~thyl~-2,3-dihydro-4-~(3-ttri~luoro~ethyl)ba~zyl~-1,4-benzoxazepin-5(4~)-one oxalate, ~nd h) 2-t2-(~imethylamino)ethyl]-2,3-dihydro-4-~4-nitro-bes~yl ) -1, 4-benzoxazepin-5 ~ 4EI) -one oxalate .

~1~
When in the p~o~edure o~ Example 10, equ~l molar amounts of the following ar~ substitut~d for 2-(2-chloro-eth~ 2J~-dihyaro-4-methylpyrido~3,2-f]~1,4]-oxazepin-5(4~)-on~ hydrochloriae, 2-(2-chloroethyl)-4-cyc~ohexyl-2,3-dihydropyrido ~3~2-f]~l~4~-oxazepin-5(4~)-one hydroc~loride, 2 - ( 2 -chloroethyl ) -2, 3-dihydro-4-ethylpyrido ~2-~ 4] -oxazepin-5( 4H) -one hydro~hloride, 2-(2-chloroethyl)-2 J ~-dihydro-4 - i~opropylpyrido t~ tl,4J-oxazepin-5(4H)-one hydrochloride, 2-(2-chloroethyl) 4-( 4-chlorobenzoyl) -2, ~-dihydro-pyrido~3,2-f~1,4~-oxazepin-5(4H)-one hydrochloride, 2-(2-chloroethyl)-2,3-dihydso-4-(4-methylb~nzyl~
pyrido~3,2-f~1,4]-oxaz~pi~-5(4H)-one hydrochloride, 2-(2-chloroethyl)-213-dihydro-4-(4 methoxyben~yl~-pyrido~2-f]~lJ4~-oxEzepin-~(4~)-one hydrochloride~
2-(2-chloroethyl)-2,3-dihydro-4-(3-trifluoromethyl-banzyl)pyrido~3,2-~ltl,4]-ox~zepin-5(4H) one hydrochloride, and 2-(2-~hloroethyl)-2,~-dihydro-4-(4-nitroben2yl)-pyrido t3,2-fJtl,4~-oxa~pin-5(4H~-one hydxochloride, there ar~ obtaineds ~) 4-cycloh ~ yl-2 -t? - ( dim~thyl~ino)ethyl~-2~-dihydro pyrido~392-~tl,4~ox~zspin-5(4~)-on~ ~um~rat~, '~ 1 y~

3~

b) 2-t2-tdim~thylamino)Q~hyl]-2,3~aihydro-~-ethyl-pyrids~,2-f}~1,4~-oxaz~pin-5(4H)-one ~umarate, ~) 2-~2-~dimethyl~mino)ethyl~ 2,3-dihydro-4-~sopropyl-pyrido~392-f~1,4J-oxazepin-5(4~)-one fumarate, d) 4-(4-~hlorobenzyl)2-~2-(dimethylamino)~thyl~-2,3-dihydro-pyrido~3,2-~1,4~-o~zepin-5(4H)-on~ ~umarato, e) 2-t2-(dimsthylnmino)ethyl~-2,3-dihydro-4-~4-methyl benzyl)-pyrido~3,2-~rlJ4~-oxazepin-5~4H)-o~e fumarate, f) 2-t2-(dimethylamino)~thyl~-2,~-dihydro-4~(4-methoxybenzyl)-pyrido~;,2-f~1,4~-oxaz2pin-5 (4H)-one ~umarat~, g) 2-~2-(dLmethylamino~ethyl~-2,~-dihydro-4-(3-txi~
fluoromethylbenzyl)-pyrido~3,2-~]~1~4~-oxazspin-5(4H)-one fumarat~, ~n~
h) 2-~2-(dimethylamino)ethyl~-2,3-dihydxo-4-(4-nitro-benzyl)-pyrido~,2-f~rl,4~-oxazepin-5(4H)-one fumarat~.

~xampl~ ~7a to d .. ~hen in the procedure o~ Example 3~ equal molar 5 amounts of the follswing are ~ubstituted ~or morpholine:
pyrr~lidine~ 4 piper~dine, pipe~azine, and 4 -m~thyl-piperaz ine, there are obtained:
a ) 2, 3-dihydro-4-methyl-2 -~2 -t l-pyr~ol idino ) e~hyl~ -1, 4-b~nzoxaz~pin-5 ( 4EI) -one ~umarate, b) 2J~5-dihydro-4-~nethyl-2-~2~ piperidino~ethyl~-19 4-~nzoxazepir~ 5t4~-on~ fumara~e, ~5 ~) 2,3-dihydro-4-m~thyl-2~2~ piper~z~no)ethyl~-1,4-b~nzoxazepin 4(4~-on~ ~uma~t~
d) 2,~-dihydro-4-~ethyl-2-t2-(4-me~hylpip~r~in-l~yl3 ~thyl]-l~4-b~zox~z~pin r~(4~)-on~ ~um~r~te.

( 419A,CIP

7~ 9 ExamPle ~8 2 -r?-(Dimethylamino)ethyl1-2 ~ dihydro-4-methylpyrido ~3 ~? -f ~ ~1, 4 ~ -thiazepin-5 ( 4H) -one dihydrochloride .
~ solution of 1.5 g (0.0058 mole) of 2 (2-chloroet~yl) 2,~-dihydro~4-methylpyri~o~,2-~]~1,4~-thiazepin-5(4~)-one in 20 ml o~ dimethylamine wa3 ~tirred ~t 25C. i~ ~ ~ealed contal~er or 72 hr. The oxce~ dimethylamine w~ allowed ~o 0vaporate ~nd the r~idua wa3 part~tioned between ~hloro~orm and dilute sodium hydroxide. The ohlorsform layer wa~ con~entrated and ~he residu~, ~h~ free b~e of the title compouna, wa~ di~solved in i opropyl al~ohol and reacted with hydrogon chlorid~. The resulting hydro-chloride ~alt weighed 1.5 g (770 9 m.p. > 250 C.
Analysi~: calclllated for Cl9H~ 90SCl2: C,46.16; H,6.27 N, 12 .42 Found : c/45.68: H76.18;
N . 12 . 35 ExamE~e ~9 2-C2-(Dimethylamino)ethyll-2,3-dihydro-4-methylpyrido ~3,2-f~1,41-thiazepine-5t~H)-thione oxal~te.
A ~olution of 1.5 g (0.0~5 mole) ~f 2-(2-chloroe~hyl)-2,~5-aihydro-4-methylpyridot3~2-~C1~4~-thiazepine-5(4H)-thione in 40 ~1 o~ dim~thyl~min~ wa~ stirred at 25C. in a sealed ~ontaine~ for 96 hr. The d~methylamine was allowed to evaporate and the r~sidu~ wa~ partitioned between methylene ~hloride and dilute 3cdium hydroxide. The chloro-form layer was concentrated and the ~esidu~ the ree ba~
o~ the title compound, wa~ reacted with 0.4 g oxalic acid in a solution of 30 ~1 of 90-100 isopropyl alcohol water.
The resulting cry3t~18 w~r~ rocrystall~zed rom the same - -~olvent to gi.ve 1 g.o~ the product, m.p. 191-193C.
Analy3is: Calculated ~or Cl5~ 3S204: C,48.50: ~,5.70;
~,11.33-~ound : C,48.49; ~5.84;:
~,lO.g9~

4 lgA--CIP

78 ~ 09 2 - r2 ~ imeth~lamino ) e thyl ~ -2, ~i-dihydro -4 -me thylpyr i do ~3~4-flrl,4~xaze A solution of 5 g (0.02 mole) of 2-(2 chloroethyl)-2 7 3-dihydro-4-methy~pyridoC3,4-f]~1,4]oxazepin-5(4H)-one, in 25 ml of dimethylamine wa~ placed in a sealea vess~l and stirred ~or 72 hr. The ve~sel was opened and the exce~s dimethylamine allowed to evaporat~.: The residue wa~
dis301ved in chlorofonn and t~he solvent wa~ stripped off in vacuo to ren~v~ exce~3 dimethylamine. q~he re~idue wa0 partitioned between dilute ~odium hydroxide and ethyl acetate. The ethyl acetate solution was concentrated and the residue wa~ treated with 3 g ~0.033 mole) o~ oxalic acid in 50 ml of isopropyl alcohol and enough water to dis~olve the salt while boiling. The re~ulting crystal~ were recrystallized from the same ~olvent. Yield of product wa~
5.3 g (60 0 , m.p. 179-181C.
Analysis: calculated for C94H4~Ng02l: C,46.48; H,5.52;
N,9.58 Found : C,46.58; H,5.70 ~9 9 .61 Exampl~ 41 2-~?-(Dimethy~amino)ethvl~ 2,~ ih~dro-4-meth~ yrido t~,4-fl~1,4~oxazepine-5(4H)-thione oxalate (1:2).
A 4 g (0.009 mol~) sample of 2-~2-(dimethylamino)ethy}]-2,3-dihydro-4-methylpyrido~3,4~ 1,4~oxazepin-5(4H)-one oxalate (1:2) hemihydrate wa~ partitioned between dilute ~odium hydroxide and chloroform. The aqueous layer wa~
extracted three times and the combined ~hloroorm extracts were dried over ~odium ~ulfate and conc~ntrated. ~he residue was dissolved in 200 ml of dry toluene and again-concentrat~d in vacuo to effect drying. The re~idue-wa~ dissolved in dry - -pyridine (.10 ml) and treated with 2.8 g (0.01 mole).o~ :
phosporu~ pentasul~ide. The mixture wa3 stirred at reflux for 20 hr. The cooled mixture wa~ partitioned between dilute sodium hydroxide and ~hloroform. Tho aqueous layer was extracted three time with chloroform. The com~ined chloro-form extr~ct~ wexe dried over sodiam ~ul~ate and concentrated.

4 l9A-CIP

79 ~3~0~

One gram of the residue was treated with 0.6 g of oxalic acid in i~opropyl alcohol/10% water. The re~ulting crystal3 were collected by filtration. Yield of oxalate ~alt wa3 0.37 g., m.p. 111-114C.
Analysis: Cal~ulated for Cl7H23N9SO~: C,45.84: H,5.20;
Found : C,45.46; H,5.~8 . N,9.28 Example 42:
2~
rl,41-oxazepin-5(4~)-one oxalate ~ 11.
2,~-D~hydro-4-methyl-5(4H)-oxopyrido~,2-f]~1,4~
oxazepine-2-propanenitrile, 5 g tO.22 moley in 150 ml of ethanol wac trea~ed with about 1.5 g of wet Raney nickel.
The mixture wa3 hydrogenated in a Parr apparatus at 60 C.
and 40 psi. The mixture was cooled and ~iltered and the filtrate concentrated. The residue Wa3 ~reated with ~.9 g of oxalic acid in 1~0 ml of boiling isopropyl alcohol containing 2 ml of water. The hot solution was filtered and allowed to cool. The re~ulting solid wa~ reerystal-lized from ethanol. Yield of oxalate hemihydrate wa~7 g (4~0 , m.p. 126-134C.
Analysis: Calculated ~or C2BH~0~07: ,50.~0; H,6.o3 ~,12.57 Found : C,50.46, ~,5.71;
~,12.21 ExamPle 43 2,~-Dihydro-4-methyl-2-r2-(4-morpholinyl)ethyl~-pyrido~3,2-fl~l,4~oxazepin-5(4H)-one maleate ~. lL
2-t2~Chloroethyl)-2,3-dihydro-4-methylpyridoC3,2-f]
~1,4]oxaæepin-5(4H)-one hydrochloride, 16 g (o58 mo~e) was 30 di~olved in morpholine (30 ml) and ~tirred overnight at room temperatuxe. To the solution wa~ added dilute Qodium hydroxide solution ( 50 ml) and the resulting mixture extracted with chloroforI~i (3 X 30 ml). The chloroform wa~
removed on the rotary evaporator with a3piration. The ~5 re~idual morphol~ne was removed in vacuo at 50C. (rotary evaporator) . To the residual free base ( 15 .5 g, .053 mole) 80 ~ 309 was added isopropyl alcohol (1 liter) and maleic acid (9.24 g g, .o80 mole). ~he mixture wa~ heated t~ boiling and the clear solution cooled at 20C. for several hours.
The xesultiny crystal~, 16 g (68.1%), were recrystallized from isopropyl alcohol, m.p. 163-165C.
Analysis: calculated for C~ 5N307: C,56.01: H,6.187 N,10.~1 Found : C,55.71: H,6.21;
: ~,10.18 Example 44 2, 3-D ihydro-4 -me thyl? -~_( 1 -p~rrol idinyl ~ e thyl lp~r i do ~3,2-fl~l 41-oxazepin-5(4H)-one fumarat~
A sample o~ 2-(2-chloroethyl) -2 ,3-dihydro-4-methyl-pyrido~3,2-f]~1,4~-oxazepine-5(4H)-one hydrochloride, 16 g (0.058 mole), waR di~solved in 65 ml of pyrrolidine. The ~tirred ~olution was heated to 80C. for 3 hr. The solution wa~ cooled to room temperature and dilute sodium hydroxide solution (50 ml) was added. The resulting solution was extracted with chloro~orm (3 X 30 ml) and concentrated in vacuo. The residue wa~ taken up in boiling isopropyl alcohol (500 ml/' and fumaric acid (9.2 g, .079 mola) was added. The solution wa~ filtered hot and the filtrate cooled to 20C. for several hour3. The re~ulting crystal~, 14 g (47-ôO were collected and recrystallized from i30propyl alcohol, m.p. 147-149C.
Analy~is: cal~ulated Xor C29OloN3H~: C,54.43: H,5.76, N,8.20 Found : C,54.38; H,5.83;
NJ 8 .27 Example 45 2~ Dibutylamino~ethyll-2, 3-dihydro-4-methyl-pyr~do ~,2-fl r 1, 4~oxazepin-5(4H)-one maleate r 2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-~~lJ4]oxazepine-5(4H)-one hydrochloride, 16 g (o.058 mole):
wa3 dis301ved in dimethy}formamid~ (30 ml) and di-n-butyl-amine (30 ml). The solution was stirrea at ~0C. for 3 hr at 100C. for 2.5 hr. The ~olution wa3 cooled and to it was added 50 ml o~ dilute qodiu~ hydroxide olution. The resulting mixture was extra~ted wit~ ~hloroform (3 X 50 ml).

81 ~23~0~3 The chloro~orm wa3 rem~ved on ~he rotary evaporator with water aspiration at 50C. Residual dimethylfoxmamide and di-n-butylamine were removed at low vacuum and 50C. (rotary evaporator). To the re~idual free base, 1~.8 g (0.041 mole) was added i~opropyl alcohol (900 ml) and oxalic acid) 5.6 g (0.062 mole) and the solution heated to boiling. The clear solution was cooled overnight at 20C. a~d filter~d to give 13.6 g (56.5 O of crystals w~ich were recry~tallized from isopropyl alcohol, m.p. 195-196C.
Analysi~: Calculated for C2lH93N3O~: C,59.59: H,7.85:
N,9.72 Found : Cj59.~7: H,7.91:
~,9.~6 ExamPle 46 2-r2-(Diethylamino~ethyll-2,~-dihydro-4-methylPyrido ~.2=~ 4~oxazaPin-~(4H)-one oxalate ~l:I~.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyridor3,2-f~
~1,4~oxazepin-5(4H)-one hydrochloride, 16 g (0.058 mole) was suqpended in diethylamine (30 ml). The 3u~pension was stirred ~or 72 hr at room temperature. ~he mass ~pectrum indicated that the reaction had progre3~ed ~3% at this point. The mix~ure wa~ then heated to reflux for 6 hr.
Diethylamine wa~ remov~d by rotary evaporation (70C. water a~pirator). ~he residue WZ3 taken up in chloroform (laO ml) and wa~hed with dilute aqueous ~odium hydroxide (2 X ~0 ml).
The organic layer was concentrated by rotary avaporation (70C, water aspirator). The re-qidue was di~solved in boi}ing isopropyl alcohol an~ treated with oxalic acid.
Upon cooling, 18.6 g (87.7%) of light brown cry3tal~ were collected (m.p. 150-155C.). A sample wa~ recrystallized.
~0 three more times rom isopropyl alcohol,.m.p. 156-157 C.
Analysi~: Calculated for C~7H~5~30~: C,55.57: H,6.86;
~/11.4 Found : C,55.28; ~6.85:
~,11.27 82 ~23~Bo9 Exam~e 47 2,~-Dihydro-4-methyl-2 ~ (l-piperidinyl~ethyllpyrido ~2-f~ 4]oxazepin-5(4H)-on~ oxalate 2-(2~Chloroethyl)-2,~5-dihydro-4-methylpyriao~3,2-f~
t.l,4~oxazepin- 5(4H)-one hydrochloride, 4 g (0.015 mole~
wa~ dissolved in piperidine (30 ml) and heated to 80 C.
with stirring for 20 minuteQ. The piperidine was removed by rotary evaporation (85C, vacuum pump) and the re~idue taken up in chloroform (50 ml). The organac layer wa~
washed with dilute agueou3 30~ium hydroxide (2 x ~0 ml) and concentrat~d by rotary evaporation (80 C, water a~pirator). The resulting oil wa~ t3ken up in hot isopropyl alcohol and treated with oxalic acid. Upon cooling, crystals o~ the oxalate ~alt were collected and recrystallized from isopropyl al~ohol, to give ~.4 g (62%) f pale brown cry-Rtal3 m.p. 133-136C.
Analysis: Calculated for C~aH4S~3oe: C,56.98; H,6.64:
~,11.07 Found : CJ56~95; ~,6.87;
~,10.79 Example 48 2,3-Dihydro-4-methyl-2-~2-~methyl(phenylmethyl)amino ethyl~pyridor3,2-f~ 4~oxazepin-5(4~)-one malaate 2-(2-chloroethyl)-2,~-dihydro-4-methylpyridoi3,2-~1,4~oxazepin-5(4~)-one hydrochloride~ 4 g (0.015 mole) wa~ dissolved in methyl benzyl amine t~o ml) and heat~d to 80 C. with stirring. After three hour~, the exces~ amine wa~ ramoved by rotary evaporation t90C, vacuum pump~. The residual oi~ was taken up in chloroform (40 ml) and washed with dilute aquQous ~odium hydroxide ~30 ml). The chloro-~orm layer was concentrated by-rotary evaporation (9~C~
3o water aspirator). ~ re~idual oil wa~ di3solved in hot isopropyl alcohol and treated with maleic acid. Upon cooling, 4.23 g (66 0 o~ pale brown cry~tals were collected9 m.p. 167-169C.
Analysi3: Calculated for C23~7~30~: C,62,57; ~,6.~6;
Found : C,62.28, ~,~ 16:
~,9.2~

419A-cIP

~ ;~3~ 09 8~

Example ~9 2,3-Dihydro-4-methyl-2-~2-(methylphenylamino)ethyl~
pyrido ~ 2-f~1,4~oxazepin-5(4~)-one.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~,2-~~lJ4]oxazepin-5 (4H)-one hydrochloride~ 4.00 g (0.015 mole) was dissolved in N-methylaniline (30 ml~ and heated to 95 C. with stirring for 2 day~. Exce~ ~-methylaniline wa~
removed by rotary evaporation (95C3 vacuum pump). The residue wa~ taken up in chloro~orm (80 ml)and washed with dilute agueous sodium hydroxide (~0 ml) The chloroform layer wa~ decolorized with activated carbon and dried over ~odium sulfata, filtered and concentrated ~y rotaxy evaporation. The remaining residue wa~ ~issolved in ethyl acetate (50 ml) and puri~ied by high pressure li~uid chromatography using a silica gel column and ethyl acetate as the eluent. After purification, crystals ~ormed from ethyl acetate. The~e cry~tals were recry~tallized from ethyl acetate, giving 1.40 g (31%) o~ pale brown crystals.
Analysis: Calculated for C18H~lN902: C,69.43: H,6.79;
~,13.49 Pound : CJ69.31; H,6.77;
~ .54 Example ~
2-~?-(2,5-Dimethyl-l-pyrrolidinyl)ethyll 2,3-dih~
4-methylpyrido r3,2-flrl~41oxazepin-5(4H)-one fumarate r ~
2-(2-Chloroethyl)-2~3-dihydro-4-methylpyridor3,2-~
~l~4]oxazepin-5 (4H)-one, 5.0 g ~0.021 mole), was di~solved in 25 ml of ab~oiute ethanol and ~ g (0003 mole3 of 2,5- ~ :
dimethylpyrrolidine was added. -The ~olution was heated to 75C. for 48 hrs ~ith-sti~ring. Recause the reaction w~s - --incomplete at thi3 time, an additional amount of 2,5-~0 dimethylpyrrolidine (1.00 g, 0.01 mole) wa3 added and the reaction continued. Aftar 5 day~3, the reaction wa~ ~till incomplete and more 235-dimethylpyrrolidine (1.00 g, 0.01 mole) wa~ added. The reaction appeared complete 2 days later. Solvent wa~ remc~ved by rotary ev~poration (80Co~
35 water aspirator). I3xce3s 2,5-dimethylpyrrolidine was 419~ -C IP

~L~3 removed by rotary evaporation (80C, vacuum pump). The residue was taken up in chloroform (200 ml) and washed with dilute aoueous sodium hydroxide (2 x 75 ml). The organic layer wa~ dried over ~odium sulfate, filtered, and concentrated by rota~y evaporation (70C, water aspirator).
The resulting oil wa~ dis~olved in hot isopropyl ~lcohol and treated with fumaric acid. Upon cooling, 2.38 g (27~4%) of pale brown crystal~ was collected, m.p. 161-162C.
Analy i8' Calculated for C2lH~g~90~: C,60.13; H,6.96;
~,10.0 FouIld : C, 59 . 79; EI, 6 . 9:~;
N,9.76 Example ~1 2,3-Dihydro-4-methyl-2-~2-(2-methyl-1-pyrrolidinyl) ethyl~pyrido~3,2~ 1,4~oxazepin-5(4H)-on~.
To a solution of ~.5 g (0.0145 m~le) o 2-~2-chl~ro-ethyl)-2l3-dihydro 4-methylpyrido ~J2-f]~l~4}oxazepine-5(4H)-one in ethanol (15 ml) was added 2-methyl pyrrolidine (5.0 g, 0.063 mole). ~he solution was heated to reflux for 3 hour~ with stirring. The ethanol was removed by rotary evaporation (water aspiratorl 80 C.). The residual oil was partitioned between dilute aaueous sodium hydroxide ~50 ml) and chloroform (50 ml). The organic layer wa3 saved and the aqueous layer ~xtracted with chloroform ~2 x 30 ml). All the chloroform layerR were combined, dried over anhydrous sodium 5ul fate and concentrated by rotary evaporation (water aspirator, 70C.). The residual oil was then distilled at 20QC. and low vacuum (vacuum pump) giving 1.5 g (35.7%) o~ a clear oil.
Analysis: Calculated for Cl3Hk3N~0z: C,66.41; H,8.017 N,14.52 Found : C,65.83; ~,8.o6;-. ~91~.39 . 419~-CIP

1234~

Exam~le 52 2?3-Dihydro-4-methyl-2-12-(lH pyrazol-l-y}~ethyl]
pyrido r~92-flrl~4loxazepin-5(4H)-one.
. .._ , ~o a su~pension of sodium hydride (1~2 g active, 0.05 mole) in dimethylform~mide (15 ml) w~s added drQpwise a ~olution o~ pyrazole (3.10 g, 0.045 mole) i~ dimethyl-formamide (15 ml). The resulting ~olution was then ad~ed to a ~olution of 2-(2-chLoroethyl) -2 ,3-dihydro-4-methyl-pyrido~2-f]~lJ4~ oxazepine-5~4H)-one (9.12 g, 0.038 mole) - in ~0 ml of dLmethyl~ormamid.e. The fla X was sealed and stirred overnight. Becau~e the reaction had not yet gone to completion at this point, pyrazole (3.12 g, 0.045 mole) was added to th2 reaction ~olution and ~tirred overnight.
The reaction was still not complete and another ~u-~pen~ion of ~odium hydride . (0.5 g active, 0.021 mole) ana pyxazole (} 5 9~ 0.022 mole) in dimethylformamide tlO ml) wa~ added and the reaction stirred overnight. The reaction appeared to be complete. D~m~thylformamide wa~ xemoved by rotary evaporation (80C, vacuum pump), and the residue taken up ln chloroform (100 ml) which was washed with dilute aqueous ~odium hydroxide (1 x 50 ml)~ dried ov2r anhydrous ~odium sulfate and concentrated by rotary evaporation (70C, water a~pirator). The material was purified by high pres~ure liquid chromatography, 95:5 by volume ethanol: .
methanol on a silica gel ~olumn. The fractions containing the desired product were concentrated by rotary evaporation (70 C, watar aspirator). Crystallization Qnsued upon cooling. The cry~tal~ were collected and recry~tallized ~rom ethanol. The yield was 1.5 (14.5 0 , m.p. 132-134C.
Analy~ calculated for C~H~N402: C,61.75; H,5.92, ~,20.58 Found : C,61.35: H,5.89; --~,20.67 86 ~3 Example 5~
2 3-Dihydxo-2 -r2~ -Lmidazol-l-yl)ethyll-4-methyl-pyrido~,2-f~1,41oxazepin-5(4H)-one.
To a solution of 2-(2- hloroethyl)-2,3-dihydro 4-methylpyrido ~2-~]~lJ4~-oxazepine-5(4H)-one~ 9.12 g (0.038 mola) in d~methyl~ormamide (30 ml) was added imidazole, 5.66 g (0.083 mole). The 301ution wa~ heated to 130C. for 18 hr. DLmethylPrmamide wa~ removed by rotary evaporation (80C, vacuum pump) and the resid~e take~ up in chloroform (100 ml). The chloroorm was washed wi~. dilute aqueous sodium hydrsxide (~50 ml), dried over 30dium ~ulfate a~d concentrated by rotary evaporation (70~, water aspirator) to an oil. Cry~tallization was induced with ethanol. White cry3tals, 1.5 g (14.5%) were collected, m.p. 150-152C.
Analy~calculated for C14~1~N40z: C,61.75; H~5.92;
~,20.58 Found : C,61.~6: H,5.92;
N,20.60 ExamPle 54 2-~? -(Dimethylamino)ethyll-4-ethyl-2,3-dihydropyrido 20 ~,2 -f ~1, 4~oxaæepin ~ .
To 30 ml of dimethylamin~ collected at 0C. was added 6 g tO.021 le~ 2-~2-chloroethyl)-4-ethyl-2,3-dihydropyrido ~3,2-~1,4~oxazepin-5(4H)-one, h~drochloride. The fla k was sealed tightly and ~tirred 70 hr at room temperature.
25 The solution wa~ then cooled to 0C. and the stopper c the flask removed. Dimethylamine was allowed to evaporate. The.
residue was taken up in chloroform (1 x 150 ml) and washed with dilute aqueous sodium hydroxide (1 x 50 ml). The organic layer was dried over sodium sulfate, filtered and concen~rated by ro~ary evaporation (70C, water aspirator).
The residue was di~olved in hot isopropyl alcohol and treated with oxalic acid. Upon cooling, 4.5 (61.5%) waq collected, m.p. 208 C.
~nalysi3: calculated for Cl~H4~s~ ~,54~ 5~;
~,11.8g ~5~ound : C,54.26; ~,6~61;
~,ll.Bl 87 ~ 2 Example 5~
2,3-Dihydro-4-ethyl-2-r2-(1-pyrrolidinyl)ethyllpyrido ~3,2-fl~1,41oxazepin-5(4H)-one oxalate tl~
2-(2-Chloroethyl)-4-ethyl-2,3-dihydropyrido~3,2-f]
rl,4]oxazepin-5(4H)-one hydrochloriae, 3 g (0.01 mole) wa3 di3solved in pyrrolidine (30 ml) and heated to 70 C. Por ~0 minutes with stl2~ g. A~tes cooling, the content~ o~
the reaction fla~X were diluted with diiute aqueou3 ~odium hydroxide (40 ml) and extracted with chloroform (2 x ~0 ml).
The chloroform layer was dried over sodium sulfateJ iltered and concentrated to a viscous brown oil ~y rotary evaporation (70 C9 water a~pirator). The oil wa~ taken up in hot isopropyl alcohol and treated with oxalic acid. Upon cooling, the re~ulting solid wa~ recrystallized ~rom isopropyl alcohol, giving pale br~wn ~rystal~, 1.80 g (45 40 , m.p.
185-188C.
Analy~Calculated for Cl~H~5~90~: C,56.98; H,6.64;
~,ll.Q7 Found : C,56.90, H,6.67;
~,10.90 Example 56 2 3-Dihydro-4-methyl-2-r2-(4-morpholinyl)ethyllpyrido ~3~2-fl~l ~ n-5(4H)-thione.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-f]
~1,4~oxazepine-5(4H)-thione, 4.5 g (0.018 mole) was dicsolved in morpholine (30 ml). The ~olution was heat~d with stirring to 50-60~. ~or 6 hr. The morpholine was then removed by rotary evaporation (~0C, vacuum pump).
The residue was taken up in chloroform (100 ml) and washed wi~h dilute aqueous sodium hydroxide (2 x 30 ml~. The organic layar wa~ con~entrated by rotary evaporation ~60 C, water aspirator). ~he residue was re~rvstallized ~rom ethanol giving 3.26 g (60~) of light yellow cry~tals, m.p. 152-153C.
Analy~is: Calculated ~or Cl5H4l~30zS: c,58.61; ~,6.89 ~ .66 Found : C,58.48; H,6.92, ~,13.62 419~-CIP

88 ~L~ 3~;~0 Example ~7 2-L2-(Dibutylamino)ethyl~-2, 5-dihydro-4-methylpyrido ~3,2-f]~l,~azepine-5(4H)-thione oxalate ? - ( 2 -Chloroethyl ) -2, 3-dihydro-4 -methylpyrido ~ 3, 2 -~
~1,4]-oxazepina-5(4H)-thione, 4 g (O.016 mol~) was 5 suspended in di-n-butylamir~o (30 ml). Dimethyl:Eonnamide (ca. 10 ml) was added to the ~tirred m~xture until dissolution occurred. The 901ution was heated to 140C.
for ~.5 hr with stirring. Di-n-butylamine and dimethyl-formamide were removed by rotary ~vaporation t80c. vacuum pump). The residue was then diluted with dilute aqueous sodium hydroxide (50 ml) and extracted with chloroform (3 x 40 ml). Chloro~onm wa~ removed by rotary evaporation ( 7OCJ water aspirator). The residue was dissolved in boiling i~opropyl alcohol and treated with oxalic acid.
Upon cooling, the resulting oxalate salt wa~ filtered and recrystallized from isopropyl alcohol to give ~.2 g (470 of yellow crystalq, m.p. 208C.
Analy~is: Calculated for C21~93N305S: C,57.~8; H~7.57;
~.9.56 Found : C,57.04; H,7.63;
N,9.~1 ExamPle ~8 2-r?-(Diethy,lamino)ethvl]? ,3-dihYdro-4-methYlpyrido ~3.2-f~rl.4~oxazepine-$(4H~thione oxalate ll:l].
2-(2-Chloroethyl)-2,3-dihydro-4-methyl~3,2-f~1,4~
oxazepine-5(4H)-thioneJ 4 g (0.016 mole) was suspended in diethylamine (~0 ml). Dimethylformamide was added to the stirred ~uspen~ion until dis olution-oc~urred ~10 ml). T~e stirred solution was h~ated to 65C. for 8 hr. ~iethylamine was removed by rotary evaporation (70C, water aspi~ator);:
the remainin~ dimethylformamide was removed at low pressure-(vacuum pump) and 90~. The residue Wa9 take~ up in chloroform (100 ml) and washed wi~h dilute aqueous ~odium hydroxide (2 x ~50 ml). The organic layer wa~ concentrate~l by rotary ~vaporation (70C, water a~pira~or). Th~2 residu~
35 was di3solvad in boiling isopropyl alcohol and tre~ted with oxali~ ac~id. Upon coolin~, ths oxalate salt, 1.7 g (28.5~$) wa3 obtained, m.p. 142-144~C.

89 ~34~

Analysis: calculated for Cl7~45N305S: C,53.25; H~6.57;
N,10.95 Found : C,53.14; H,6.607 N,10.72 ExamPle 2,~-Dihydro-4-methyl-2-r2-(1-pyrrolidinyl)ethyl pyrido~,2-f~rl,41oxazepine-5t4H)-thione oxalate 2-(2-Chloroethyl)-2,3-dihydro-4-methylpyridor3,2-f~
~1,4~oxazepine-5(4~)-thione, 5 g (0.02 mole) was di~solved in 30 ml of pyrrolidine. The solution wa~ heat~d to 60 80C. for 35 minutes with stirring. After cooling to room temperature, the reaction mixture wa~ dilut~d with dilute agueou~ sodium hydroxide (50 ml) and extraoted with chloroform (2 x 50 ml). The organic layer wa~ concentrated by rotary evaporation t70C, water a~pirator). Residual pyrrolidine was removed at 90C. and vacuum pump. The re~idue wa~ di~solved i~ hot ethanol and treated with oxalic acid. Upon cooling, the o~alate salt was collected and recrystallized twi~e ~rom ~thanol to give 3-35 gJ (45 0 o~ product, m.p. 141 C.
Analysis: calculated for Cl7H~N205S: ~,53.53; ~, 6 . o8:
NJ11~O2 Found : C,53.39; H,6.11;
N,10.91 Example 60 ?, 3-Dihydro-2-r2-(lH-imidazol-l-yl)ethyll-4-methyl-pyrido-C3. ~ 1,4~oxazepine-5(4H)-thione oxalate ~2 To a ~olution of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-f]~1,4~oxazepine-5(4H)-~hione, 4.5 g (Q.018 mole) in dimethylformamide (35 ml) wa3 ~dded imidazole (2.20 g, 0.038 mole). The resulting ~olution was heated to 130C. for 15 hr~. Dimethylformamide wa~
r~moved by rotary avaporation (80C, vacuum pump), and the re idue diluted with dilute aoueou~ ~odium hydroxide (50 ml). ~he aqu~ous soIution wa~ extracted with chloro-~orm (1 x 5Q ml~, dried over anhydrou~ ~odium 8U~ ~ate. and ~5 concentrated by rotary evaporation (water a~pirator, 70C~.
~he resulting oil wa3 tr~ated with oxali~ ~id in ethanol.
~our gram~ (54 0 of pal2 yellow ~ry~tal~ were collect~d and go ~:3~

- recry~tallized again with ethanol, m.p. 16~-167 C.
Analysi~o calculated ~or Cl7H1aO7~S: C,48.22; H,4.52:
Found : c,48.o4; H,4.62, ~ .18 5Exampls 61 ~,2-fl~1,4~oxazepin-5(4~)-thion~.
2-~2-Chloroethyl)-4-ethyl-2,~-dihydropyrido~3,2-~]
~1,4~ oxazepin-5(4~)-thione hydrochloride, 5.00 g (0,016 mole) wa~ added to 20 ml of anhydrou~ dimethylamine. The reactiQn fla~k Wa9 ~ealed tightly and ~tirred at room temperature for 6 days. The flask was opened after cooling to 0C. and dimethylamine allowed to evaporate at room temperature. The re~idue wa~ taken up in ~hloroform (100 ml) and wa~hed with dilute aqueous ~odium hydroxide (1 x 30 ml). The chloroform lay~r was dried over sodium ~ulfate, ~iltered and concentrated by rotary evaporation.
~he residual oil was di~colved in hot cyclohexane. Upon cooling, 1.7Q g (39.4%) of light YQ11OW cry~tal~ were collected, m.p. 73C.
AnalyQi-~: Calculated for Cl4H4lN90S: C,60.18; H,7.5~;
N,1$.03 Found : C,60.32; ~,7.70;
~J 15-13 Exam~le 62 252,3- 1hydro-4-methyl-2-C2-~me~hyl(phenylmethyl)amino]
ethyl~pyxido~3,2-~1,41oxaæepine-5(4H)-thione oxalate TQ a ~olution of 4 g (0.0155 mole) o~ 2-t2-chloro~
ethyl,~-293-dihydro-4-methylpyrido~3,2~ rl,4~oxazepine~ -:
305t4H)-thione in 70 ml of chloroform was:added 10.0 g (o.o86:
mole) oi~ benzylmethylamin~. The soluti3n was ~tirre~d at reflux ~or 24 hr. The reas~tion 301ution was wa~hed with . water (2 x 50 ml) and concentrated by rotary ~vaporatiorl (~70C, water aspirator). The xesidue wa~ distilled on a 35molecular ~till a 165C./0.1 ~un. Th~ ro3idue wa~ xeated wi~h oxalic: ~:id ir~ ho~ isopropyl ~ ohsl. Uporl ~ooling, ~1 ~23~V~

t~o crops o~ cry~als were coll~cted. The purity of each crop was checked. The two crop~ were combined and recry~tallized together in hot isopropyl alcohol. Upon cooling, 3.69 g (55%) of pale yellow ~rystal~, m.p.
163-166C were collected.
Analysi~: Calculat~d for C2 lH~5~305S: C,58.45; H,5.84;
N,9.74 Found : C,58.24; ~,5.92;
N,9.~1 ExamPle 6~
2,~-Dihydro-2-~?-(methylamino)ethyl)-4-methylpyrido ~3?? fl~l,41oxazepine-5(4H)-thione oxalate ~1:1.5~.
2-~2-chloroethyl~-2J~i-dihydro-4-methylpyridc>C3,2-f~
~1,4~oxa~epine-5(4H)-thiOneJ 4.0 g (0-016 mole) was su~pended in a 30% solution of methylamine in 70 ml of ethanol and allowed to stir ~or 56 hr at room tamperature.
Becau~e of incomplete rea~tion~ the reaction solution was heated ~lowly over a 2 hr period to 55C. and stirred at tha~ temperature for 24 hr. Methylamine wa~ re~oved by water aspiration for 1.5 hr. The rasulting ~olu~ion wa~
concentrated by xotary evaporation (70C~ water a~pirator).
The residual oil was taken up in chloroform (150 ml) and washed with 2 M aqueou~ potas3ium hydroxide (2 x 50 ml).
The chloroform layer wa~ dried over sodium ~ulfate and concentrated by rotary ~vaporation (70Cg water aspirator).
The re~idue wa~ dissolved in hot ethanol and treated with oxalic acid. Upon coolingJ 2.0 g (37.5 O of yellow crystal~ were collected, m.p. 137-1~8C.`
Analysis: calculated for C.5H40~307S: C,46.6~: H,5.22:
~,10.67 Found : C,46.47; H,5.35;
N,10.85 3o Example 64 ~ L~y~) ethyllpyrido ~ -f ~1,4 ~xazepin-5(4H)-one fumarate_ 7-Chloro-2 - (2 -chloroethyl ) -2, 3-dihydro-4-methylpyrido ~3,2-~]~1~4]oxazepi~-5(4~)-one ~205 g, 0.009 mole) wa~
~5 dis~olved in 50 ml pyrrolidine and the olution wa~ heated to 80C. for 1 hr. ~he pyrrolidine waq removed by rotary 4 l9A-CIP

92 ~L23~ 9 evaporation (80C., water aspirator) and the residue dissolved in 100 ml of chloroform. The orsanic lay~r was washed with water (2 X 50 ml), dried over sodium sul~ate and concentrated by rotary evaporation (~80C., water aspirator). The residue was treated with fumaxic acid and allowed to stand overnight. The re ulting cry~tals were ~ollected, 1.25 g t23.2%), m.p. 164-166C.
Analysis: Calculated for C2SH3oN3ol2cl: C~50.05; H,5.04;
~J7.00 Found : C,50.22; H,5.14;
~,7.02 Example 65 7-Chloro-2~2-tdimethylamino)ethyll-2,3-dihy~ro-4-methylpyrido~3J2-f ~1,41oxazepin-5(4H)-one oxalate ~
A 2.8 g (0.01 mole) ~ample of 7-chloro-2-(2-chloro-ethyl)-2,3-dihydro-4-methylpyridor3,2 f~l,4~oxazepin-5(4H)-15 one wa~ added to 25 ml of dimethylamine and stirred for96 hr in a sealed flasX. The excess amine wa~ allowed to evaporate and the re3idue wa~ partitioned between chloro~orm and dilute sodium hydroxide. The chloroform was dried over sodium ~ulfate and concentrated. The residue was treated with 0.7 g of oxalic acid in i~opropyl alcohol. The re~ulting crystals were recrystallized from the ~ame solvent.
yield was 1.5 g of oxalate salt (40 0 , m.p. 150-156Co Analy~is: Calculated for Cl5H~0~30~Cl: C,48.20; H,5.397 ~,11.~4 Found : c~48,og; H,5.47 N,11.12 ExamPle 66 4-C~clohexyl-2 -r ( dimethylamino)methyll-2,~-dihydro-pyrido~3,2-fl~1,41oxazepin-5(4H)-one oxalate.
Utilizing the procedure.o~ Example 10l.2-(chloro-methyl)-4-cyclohexyl-2~-dihydropy~ido~3~2-f]~l~4~oxazepin 5(4H) one (Intermediate-35)-i~ rea~ted with 40% a~ueous dimethylamine and reacted with oxalic acid in isopropyl alcohol.

9~

Bxample 67 2-~2-(Dimethylamino)ethyl]-2 ,3-dihydro-4-ph enylmethyl-pyr~doL3,2-f~1,4~oxazepin-5(4H)-one oxalate ~1:1.5 hem ihydrat e .
A ~olution containing 94.2 g (0.6 mole) of 2 chloro-nicotinic acid and 100 g (0.54 mole) of 1-benzyl-3-pyrrolidinol in 800 ml of dry tetrahydrofuran was added at a rapid drop to a ~tirred ~u~pen~ion of 52 g (1.3 mole) of 60~ sodium hydride/mineral oil in 500 ml of dry tetrahydro-furan at reflux temperature (addition time wa~ about 1 hr).
The mixture wa3 heated to reflux for an additional 1.5 hr and then cooled to room temperature. Approximately 1 liter of ethyl acetate wa~ added and filtration attempted un~uccessfully. The mixture was allowed to stand overnight at room temperature ~nd ~hen wa~ concentrated on the rotary evaporator at 100C. and 50 mm pre~sure. The residue was dis~olved in 1 liter of chlorofoxm and the pH of the solution waR adju~ted to 6.15 with hydrogen chloride ga~.
To the solution was added, with stirring, 383 g (1.0 mole) of triphenylphosphine and 383 g (2.48 mole) o~ carbon tetrachloride. The mixture was refluxed for 1 hr and 50 ml of ethanol was added. The solution wa~ cooled to room temperature and extracted thrae times with 400 ml portion~
of dilute hydrochloric acid. The ~hloroform layer wa~
extracted with dilute sodium hydroxide, dried over sodium sulfate and concentrated. ~he masq spectr~ indioated the pre~ence of 2-(2-chloroethyl)-2,~-dihydro-4-(phenylmethyl) pyrido~3~2-f]~l~4~oxazepin-5(4H)-one (ma~s ~16), triphenyl- -phosphine (ma~s 262) and triphanylphosphine oxide (ma~ 278).
one-third of the residue wa.q chromatographed on a high ~50 pressure li~uid chromatopraph in an un-~uccess~ul attempt to purify the ~ompound. The other 2/3 of the residu~ wa~
dissolved in 30 ml of chloroform and added ~o a ~olution of ~0 g of dimethyl amine in ethanol. The ~olution was heated to r~3flux for 4 hr and eoncentrated on the rotary evaporator. The residue was partitioned between chloroform and 1 ~ hydrochloric a~id. Th2 acid layer was made basic ~23 9~

with sodium hydroxide and extracted with chloroform. The chloroform layer was dried over ~odium ~ulfate and concen-trated. The residue (10 g) was treated with an e~uivalent amount of oxalic acid in a mixture of isopropyl alcohol-ethanol-isopropyl ether. The resulting crystal~ in the amount of 9 g (5 0 were recry tallized from the same solvent mixtureJ m.p. 95-98C.
Analysis: calculated for C44H4 ~B017 S C~ 56-28; H,5-79:
~,8.95 Found : C,56.61; H,5.76, ~,8.77 Example 68 2-r2-(Dimethylamino)ethyl~-2,3-dihydropyrido~,2-f ~1,4loxazepin-5(4H)-one.
A ~olution of ~.0 g (0.006 mole) of 2-~2-(dimethyl-amino ethyl]-2,~-dihydro-4-phenylmethylpyrido~3J2-~]~1,4]
oxazepin-5(4H)-ons oxalate ~1:1.5]-hemihydrate in about 50 ml of water was made b~sic with dilute aqueous sodium hydroxide solution and then extracted with three 50 ml portion~ of benzene. The combined benæene extract was dried over anhydrous ~odium sulfate and concentrated on the rotary evaporator (steam bath/50 mm). The residue was dried further by azeotroping 2 time~ with about 50 ml of dry benzene, evaporating to dryness each time. The final residue Wa5 dis301ved in 40 ml o~ liquid ammonia and small spheres of 30dium were added with ~tirring to the solution until a bluè color persi~ted ~or 20 minute-q.
(Addition time was about 1 hr). Three gram3 of ammonium chloride wa~ added 910wly and the ammonia was allowed to evaporate. The residue Wa5 su~pen~d in chlorofoxm and the mixture wa3 filtered. The filtrate waC c~ncentrated and the residue chromatographed on preparative high pres~ure liquid chromatograph using a silica gel column and eluting with 75% ethyl acetate/~5~ dimethylformamide. The yield of produc~ was 0.1 g (7~ he chemical ioni~ation mas3 spectrophotometer gave a peak at 2~6 correspo~ding to a molecular weight o 235. The ~ ~MR spectrum o the 41yA--CIP

~ ~34~30~3 o~ the ~ubj~ct compound wa~ obtained in CDC13 containing 1~ tetxamethylsilane (TMS) and is consistent with the propo~ed 3tructure nd dimethylformamide (DMF) and mineral oil as minor impurities. The chemical shift~, multi-plicities, and assignment~ are given below:
2 ~ a 7 ~ CH4CH4~(CHg)2 Chemical Shifts (multiplicitie~) Assiqnment~
8 . 45 multiplet) ~(8) and H(6) 8.oo singlet) C H (DMF) 7-85 broad ~inglet) N-H
7.20 doublet of doublet~) H 7 4.65 pentet) H 2 4 .05 broad ~inglet) u~ Ik own lmpurity 3.50 triplet E4(~) 2.95 3 inglet CH3(DMF
2.90 singlet CH3(DMF
2.60 (triplet H2-xto mino nitrogen 2.25 (~inglet N~CH3)2 2.05 (multiplet) ~ to amino nitrogen 0.7-1.7 ~multiplet) mineral oil Example 6~
2-r3-(Dimethylamino)propyll-2, 3-dihydro-4-methylpyrido r3,2-flrl,410x ~
v, . ,~
To 5.0 g (O.021 mole) of 2-(3-aminopropyl)-2,3-dihydro-4-methylpyrido~3,2-f~1,41-oxazepin-5(4H)-one Wa5 added, while cooling in a water bath, an 88~ a~ueous ~olutio~ of ormic acid, 20 g (o.~8 mole). To the resulting solution was added a 301ution of 37% a~ueous formaldehyde (inhibited with 13% methanol), 10.7 g (0.13 mole). The resulting solution was heated on a steam bath for 5.5 hr. The mixture~
wa~ cooled and 100 ml Q~ dilute aqueous hydrochloric acid wa~ added. ~h~ golution was evaporated to dryne~s and th~
residue wa~ dissolved in 50 ml o~ water. The-solution was - :
neutralized with dilut~ aqueou~ potassium hydroxide and ~xtracted with four 50 ml portions of chloro~orm~ T~e combined chloroform extract~ wa~ dried over sodium sulfate and concentrated by rotary evaporation. ~he re~idue wa~

~ 9 reacted with fumaric acid in hot iRopropyl alc~hol. The csllected produ~t; ~.0 ~ (31.8~ was recrystallized twice from isopropyl alcohol, m.p. 108-110C.
Analy~is: Calculated for C~oHs~N~0l7: CJ53.81; H~6.32 ~,9.41 Found : C,5~.69: H,6.3~:
N,9.41 Example 70 r ~ 2~f~l,41oxaze~ine-Cjt4H)-thione oxalate ~L:?~
To a ~olution of 11.0 g (0.042 mole) of 2~ (dimethyl-amino)propyl~-2~3-dihydro-4-mel:hylpyrido~3~2-f]rlJ4~-oxazepin-5(4H~-one in 125 ml of pyridine was added 9.25 g (0.042 mola) of pho~phorus penta3ulfide. The mixture was heated to reflux ~or 3.5 hr whil~ stirring. After cooling to room t~mperature, the reaction ~olution was added to an equal volume of 2 molar pota sium hydroxide. ~he mixture wa~
axtracted with 800 ml o~ methylene chlorid~ in several portions. The organic phase wa9 wa~hed with three 100 ml portion9 of dilute potas~ium hydroxide, dried ovsr sodium sulfate, ~iltered and concentrated by rotary evaporator (water-aspirator, 70C.). The residual oil was subjected to reducad pres~ure o~ the vacuum pump for 2 hr ~t 90C.
and then cooled and reacted with oxalic acid in isopropyl alcohol. Two crops, 4.5 and ~.1 g were collected, combined and recrystallized from isopropyl 1 ohol to give 6.5 g (34%) of y~ w crystals~ m-p- 136-1~8C.
Analy~is: calculated ~or C-aH~S~90~S: C,47.05: H,5.42 N,9~16 Found : C,46.76; H,5.75:
~.9.04 ExamPle 71 7 Chloro-2-r2-(dimethylamino)e~hyll-2,3-dihydro~
methylpyrido_2 _oxazepine-5(4~1)thione ~umarate r 1 11 hemihyarate, ~emii30propyl E~lco~olate .
To 55 ml of a ~ethanolic 801ut~0n contaiQing 57,q~ by volume dimethylamine wa3 added 2.50 g ~0.009 mole) of 7-chloro-2 -( 2 -chloroethyl ) -2, 3-dihydro-4 -me thylpyrido ~3,2-f~1,4]_oxazepine-5(4H)-thione. The reaction vesRel was sealed and allowed to stand for 16 hr. Tl~in-layer chromatography indicated the reaction was about 60~
complete. ~he ~olution wa~ heated gradually to 45C.
(heating time about 5 hr). Methanol and unr~aeted dlmethyl-amine were removed by rotary ~svaporator (water ~pixator, 60C. ) . The residue wa~ taken up in 100 ml o~ chloroform and the Qolution wa~ wa~hed with two 40 ml portionQ of water. The organi~ layer wa~ dried over sodium su1fate, filtered and concentrated by rotary evaporator. The resi~ue wa~ reacted with fumaric acid in i~opropyl alcohol.
The re~ulting cryQtal3, 1.43 y (36.5O were recrystallized from i30propyl alcohol and dried thoroughly in a drying pi~tol, m.p. 98-104C. 5 Analy~ i5: calculated for C9 7H5 4~1~ C12 S2: C,48.84s H,5.98;
~9.23 Found : C,48.82; H,5.80;
~,9-~7 ~19A-CIP
98 ~23~

Table 1 ", ~ E~ t ~H 2 ) n~X
A I ) ~ B R
Inte~-mediate No A(Y~0-2 B ~ E X n Salt 1 benz O -C~g O Cl 2 2 benz o -CE2-C~Hs Q Cl 2 3 naphth~2,3-f~ 0 -C~3 0 Cl 2 4 ~yrido~3,2-f] 0 -C~ O Cl 2 ~C1 ~Cl-benz o -CH~ O Cl 2 6 7-Br-benz O -CH9 0 Cl 2 7 7-Cl-benz O -CH9 0 Cl 2 8 ~aphthC2,1-~ 0 -C~ O Cl 2 9 7-0CH9-benz 0 -CR9 0 Cl 2 benz S -C~9 0 Cl 2 11 pyrido~3,2-f~ S -CH3 0 Cl 2 12 naphth~2,3-~] S -CH3 0 Cl 2 13 8-Cl-b~nz S -C~9 0 cl 2 14 7-Br-benz S -ca~ O Cl 2 naphthc2~l-f] S -CH9 0 Cl 2 16 pyrido~4,3-f~ 0 -C~3 0 cl 2 ~1 17 pyrido~3,4-f~ 0 -CH3 0 Cl 2 HCl 18 pyridor2,3~f] 0 -C~3 0 Cl 2 HCl 19 7-Cl-benz S -CH3 0 Cl 2 7,9-diiodo-benz 0 -CH3 0 Cl 2 21 pyrido~3~2-f~ S -CH3 0 Cl 1 HCl 22 pyrido~4,3-f] 5 -CH~ O Cl 2 23 7-OCHs-benz S -C~3 0 Cl 2 24a benz o -C~H.~l O Cl 2 b benz O -~2Hs 0 Cl 2 c~ benz O -CH(CH3)2 0 Cl 2 dl b~nz 0 4-Cl-C~H~-CH~- O Cl 2 e~ benz 0 4 CH9 C~H4-CH~- O- Cl 2 -f) benz 0 3,5-(OCH3)2- 0 Cl 2 Ce,~I -CH~2 - ' g benz 0 3-CF~-C~H4-C~4- O- ~1 2 : -h ban2 0 4-No2-C~H~-C~4- O Cl 25a~ pyrido~3,2-f~ - O -C~Hl~ Q Cl 2 H~l :
b? pyrido~3,2-f] O -4 H~ O Cl 2 ~CI :
c pyrido~3,2-f~ 0 -CH(C~s)2 0 Cl 2 ~Cl d pyrido~3,2-~ 0 4-Cl-C8~-C~ Cl 2 ~Cl -e? pyrido~3~2-f] 0 4-CH -C~X4-CE4- 0 Cl 2 ~Cl f) pyridoE3,2-fJ O 3,5-~OCH3)~- O Cl 2 HC1 C~H -CH~-g pyrido~3,2-f~ 0 3-C~3-C~ C~2- 0 Cl 2 H~l h pyrido~3,2-f~ 0 4-No2-C~H4-CH~- O Cl 2 ~Cl 26 pyrido~3,2-f] 0 ~CHg S Cl 2 - :
27 pyriao~3,2-~] s ~9 S C~ 2 ~L~3~30 Table 1 cont.
Inter-mediate No.__ ~(Y)0-2 B R E X n Sal~
28 pyrido~3, 4-f ~ -CH3 0 C1 2 29 pyrido~ ~,4-f] S -CH3 0 Cl 2 HCl ~50 pyrido~ 3,2 -f ] O -CH9 0 -CN 2 ~1 pyridor3~2-f~ -C2Hs o::1 2 HCl ~52 pyrido~3,2-~ S -c2p~ 0C1 2 E~Cl ~3 7-Cl-pyrldo 0 -~3 0cl 2 -f ~
34 7-cl-pyrlao s -C~3 0Cl 2 ~3,2-f ~
pyrido~,2-f~ 0 -C~Hll 0Cl ~6 pyrido~3,2-f] 0 -CH~2C~E~ 0C1 2 '. ! ! 41~A-CIP

~nb1Q 2 , ",,,~ F~tC~n~Z
(15)2~`~ ~
~ a ~ a R~lt 2 b~ o ~ - Nt~Y)8 a 3 l~s O ~ - O -~ t~
~ o ~ o ~3 2 ~ 0 ~0 0 ~8~9 2 ~r~
g O --tl CE~ ~ D 2 7 ~ æ O ~ O ~1 ~9 a a 40 8 bo~ It ~ O _~3 2 9 ~b'~h 2,3-~ ~1~ 0 -'a C~ ~ 2 o~ta~
~yr1do ~3,2-~ ~ O -1~ ca~ ~ u~r~le~
11 py~l~o 3,2-~ 8 ~4 O -El ca~
12 pyY~dot~,2-~ r ~ ~~ )a 2 g 5 r~t~
13 b-na~ 8 -ca~ p' O -~ 2 1~ b3n~ 0 ~a O -~C~ a ~t~
b~n~ O ffb O ~ 9 2 16 b~n~ 8 ~ Q _~d 2 17 b~ ~ ~ O _~31t 2 1~ 8-1:1-bom~ o ~ c~ ~ ~ EIC1 19 8-Cl-b~ns O ~ O -1~ c~ ~ 2 ox~lat~
7~ o ~ O ^E~ C~ ~ 2 oxal~t~
21 naph~2"1-~ 0 ~5 0 -11 C~ 3 2 ~:al~t~
2a p~lao~,7 ~ o ~ o -~r ~9 2 2~
P~ Ot 3. ~-~ O ~, Q -2~ C~3 P ~2r~1t~
c ~ do~293-P O ~ O -~ C~ ~ ~ua~rato 2~ o~,3_~ 5 ~ e~ - 2 1.5 ~1 -2~1 ~phe~ E2 3-1! ~ ~ oO ll C Elt )R a ox~1at~, -26 r,s ~110~obqn~ o ~ O ~ C~ 2 1/2 ~o 2~ 7-C~ -CR~ O -11 CEID ~ 2 ox~lu~o - -cO~3~a~ o ~ o -11 ~4 ~
29 pyr1do~3,2-~ 11 ~9 ~ OEla 2 ~ot~ ido ~1~ s a ~ o -~l ~ ~ xa1~t~ O-.
~l ~phtbr2 ,1-~3 3 ~4 5~ _~ C~9 ~ 2 11~C1 32 . py~~ 3,~ ~:A9 ~ 2 ~s~atf~ -b ~yrl~o~2,3-f~ O ~ CE19 ft 2 ~:s~r~t~D
3~ 7~ ~ o ~ o ~ ~a ~
O
~4 7-~~ 8 ~9 ~ -~ C~9 s~ 2 o~ t~ 20 35 b~ns 0 ~ O -~ CB~ 3~ ~ ol~a1-to ~i ~a~ O ~ g O ~~ Q", ~ xa1 1~ ~S O ¢~ 9 ~21 --~ ~o 2 4X~lRt~
119 ~ - O -111 C~l~ 8 a ~ ~on~ . ~

4 l~C IP

101 ~IL23~ 9 O ~ O ~ (C~ 2 2 ~x~-lato O ~, 5~ O ~ 2 ox~ 0 9 2~ 0 ~S~9--C~ O --111 OE~9 R 2 oxr~l ~ t~
h ~ O ~ -1~ C~D 1~ 2 o~ t ~6 a 5~rs~do 3,2-~ O ~æO~ O ~ ~ ~ a ~r~
D ~pyr1ao ~,2-~ O -C~ 0 -91 C~ a a fmll~r~to c pysl~o 3,2-~ ~CBg~l~ O -21 Ct~ ~ 2 ih~r~tl~
d Elysl~ ~,2- t~ el-C~ . O -1~ CBg 3? ~at~3 ~yrl~go ~S,2- ~ ~a-Coll~cl4_ o O~ C~9 1~ 2 ~r~-tu ~ ~y~l~o 3,2- J~4-t~ O -11 C2~1~ ~ 2 ~u~r-to g ~yrid ~,2- O ~CE~- O - ~9 ~ 2 ~rat~
b l~y ~a ~3,2- ~ O~C~_ O ~t CE4 ~ 2 ~ t~
37 a) ~ o d4 o l-pyrroll~!llnyl 2 ~sr~t~
b) b~ O ~ O l-5~ ldinyl a ~r~tl~
o) b~nr O ~1~ 0 l-plp~ nyl 2 ~u~rat-tl) ~ C~ -~9 0 ~ -p~pl~l- 2 ~u~r~to ~8 ~y~4t~2-~ 0 ~ 011(C~ 2 2-~Cl 39 ~l~t~,2-~ ~ ~8 8 ~(~ ox~l-t-pyr~or3,4-f~ 0 ~E~ O -~ 2 l/2 E~2O
2 ox~l~t~
41 pyriBor3,4-fl g -C~19 0 -N(c}~!l)2 2 2 ox2llate 1~2 pyridot3,2-f~ o -C119 0 -1~ 3 l/2 ~o r~ ox~late 43 pyrido~3,2-f~ 0 -CR~ 0 -N\J 2 m~ te pyr~dor~,2-~ CRy 0 l-pyr~lidinyl 2 2 fumarat~
pyrido~3,2-~ O ~ O -~tn-butyl)~ 2 m~ te 46 pyriao 3,2-f O -CR~ 0 -~(C~ 2 oxalate 47 pyr~ ~o 3,2-f O -C~ 0 l-EIiperi~inyl 2 oxal~t~
48 pyrido 3,2-~ 0 -CH 0 -N CH~ (bonzyl) 2 ~s~at~
49 pyr~do '3,2-fl 0 -CH~ 0 -N CR3 --C~ 2 pyrldo 3,2-~ 0 -C~ 0 C~ 2 funulrat~
_ ~J
51 pyridot3,2--f~ 0 ~ 0 CH~ 2 ._ ~
52 pyr~o~3,2-f~ 0 -CR~ 0 ~ 2 53 pyri~o~3~2-o] O .-C~ O ~ 2 54 pyridor3,2-f~ 0 --CZ2E3S o -~(CRj-)a ` 2 oxal~e 55 pyridot3,2-~ -C2~ - O l-pyrroli~lny 1 2 oxal~
56 pyrldo~3,2-fJ S ~ O r--~ 2 - :
pyrido 3,2-f~ 8 -CE~ o -~(n-~u~yl)~ 2 ox~lAé~, 5;~; pyri~oE3~2-~1 8 ~ 0 -N(C~B~ )2 2 oxs~l~t~ - -59 3~yr~ 392-f~ 8 -C}~ O l-pyrroli~inyl 2 o~al~t~
60 pyrl~S,2-f~ S ~C~a ~ 2 1.5 ox~lat~

( ~ 0~ ) 419A-C3:P

102 ~L23 Table ? ( cont . ) 61pyridot3,2-f] s -c~ o -~(CR9) 2 62pyrido 3,2-~ B -C~9 0 -N~CH9)~enzyl) 2 ox~l~t~
63pyrido 3,~-~] S -CW9 -~HC~9 2 1 5 ox~l~t~
64~3,2 ~rido -CH~ O -l-pyrrolidinyl 2 2 5 ~um~r~ta 657-Cl-pyr do O -CH~ ~~tCH~)a 2 oxDl~t~
66 pyridor3,2-~ o -C~H~ o -~(CHa~2 1 oxal~to 67 pyridDt3,2-~ 0 -CH~CoHB O -N(cHs)a 2 1.5 oxAl~ta, 68 pyri~or3,2- ~ O ~ ~~(C~3a 2 1/~ E~O
69 pyridot3,2-f~ -C~3 -~(Cfi~ ~ 3 1.5 fumar~tn, pyridDr3,2-~ s ~CH~ O -~(CE~ 3 2 ox91~t~
71 7-cl~pyriao 6-C~9 )~ -~(C~ 2 1/2 ~40, ~3,2-~ 1/2 (cH:!l)2 ~IOH

. l~l9A-CIP

103 ~ 2 3 Rharmaceutical Com~o~l ons The invention furth~r providQs pharmaceutical compo8ition8 for ~dministration to a living animal body compri~ing, ~8 ~ctive ingredients, at l~a~t one o~ the cDmpound~ of Formul~ I according tu the invention in a~ ociation with a pharmaceutical carrier or ~xcipie~t.
The compound~ are thu~ present~d in ~ therapeutic compo~ition suitabl~ fGr o~ ectal, par~nteral, ~ubcutaneou~, intra~u~cul~r, intraperitoneal, intravenous, or intrana~l admi~istration. Thus, fox ~xample~

10 compo8ition8 ~or tsrnl adminiAtration can take the ~orm of ~lixir8~ ca~8ule~, ta~let8 or coated tablets containing ca~riers conveniently used in the pharmaceutical art.
Suitable tabl~ting excipien~s include lacto~e, potato and maize s~arches, talc, g~latin and stearic and silicic acid~, magnesium st2arate and polyvinyl pyrxolidone.
For ~arenteral administration, the carrier or ~xcipient c~n be cQmprised of a sterile parenterally acceptabl~ liquid: ~.g. J water or arachis oil con~ained in ampoules.
In compo~itions for rectal administration, the carrier can be compri3ed o~ a ~uppository base, ~.g., cocoa butter or a glyceride.
Application to the nose, ~hroat or bronchial region can be in th~ ~orm of gargl~ or ~n aero~ol spray containing small particles of the agent of Formula I in ~ spr~y or dry powder fosm.
Advantageously, ~he compo~itions nr~-~ormulate~ ~
dosage uni~s, ~ach unit being adapted ~o Rupply a fixed dose of active ingrediont~. ~abl~ts, ~oated table~, capsules, ~mpoule~ and 8UppO~ itories are exa~ple~ of:
preferrea dos ge ~Orm8 according ~o the iRvention~ It i~ :-only n~ce~ry t~at the activ2 ingredient con~titute an eff~ctive amount~ such that ~ ~uitable ~f~ctive dosage will ~ con~istent with tho do~age for~ ~mployed.
Th~ exact lndividu~l dosages~ as wel~ a d~ily do~age , 419~-CIP
30~

will of course be determined according to ~tandard medical principle~ under the direction o~ a physician or veteri-n~rian. G~nerally, the pharmacology te~ts on guinea pigs in compar~son to certain other sntihistaminic drug3 suggests an effective do~e for an adult will be in the range of 2 to 8 ~g ~or t~e mor~ active compounds.
Based un the ~nimal data, unit dosage~ containing an amount of compound equivalent to ~bouk 0.03 to 0,10 mg of Active drug per kilogram of ~ody weight are contemplated.
Daily do~ages of ~bout 0.2 to o.6 mg/~g of ~ody weight are ~ontemplated for humanq and obviou~ly several small unit dosage forms may be admini3ter~d at one t~me. ~owever, the scope o~ the ~nvention i~ not to be limited by the~2 contemplations due to uncer~ainty in transposing from animal data to human~.
Ex~mples o$ unit dosage composition3 are a~ $0110w8:
Capsul~:
In~r di~nt~ ~o~_s~
1. Active ingredient 4 mg.
2. Lactose 150 mg.
~. Magne~ium stearate 4 my.
Tablets:
Inqredients 1. Activ~ ingredient 4 mg.
2. Corn starch 20 mg.
~. K~lacid 20 mg.
4. Xeltose 20 mg, 5. Ma~nesium ~tearate 1.3 mg.
Proced~ure for tablets:
1. Blend 1, 2, 3, 4 in larger amounts.
~o 2. Add su~ici~nt water portionwise to blend ~o ~-the blend ~rom step 1 with car~ul stirring after each ~ddition. Such additionR of water and-~tirring conti~ue - -until the mass iQ 0~ a con3tituency to permit its conversion to wet g~anulo~.
~5 ~0 ~hs we~ 8 i~ COnV~r~Bd ~0 granule~ by pa~ing -it through ths oscill~ting granul~tox u~ing 8 me~h ~creen.
4. Th~ wet g~anules ar~ thon dried in an ov~n at 40F .

415~-cIP

5. The dry granul~s are lubric~ted with the magnesium ~tearate.
6. The lubricated granule~ ~re compre~sed on a ~uitable tnblet pr~ss.
~ntramuscul ~
Per ml.
1. ~ctive ingredient~ . 10.0 mg.
2. Isotonic buf~er ~olution;4.0 q.a to 1.0 ml.
~rocedure~ ' .
1~ Dis~olve the active ingredient i~ the buffer solution~
2. A~eptically fil~er the solution from ~tep 1.
~. The 8terile solution i~ now aseptic~lly filled into ~tarile ampul~.
4. The ampuls are ~ealed under a~e~tic conditi~n.
Suppositories:
Inqredients Per upp.
1. Active ingredient 10.0 mg.
2. Polyethylene Glycol 10001350.0 mg.
~. P~lye~hylene ~1YCQ1 4000450.0 mg.
- 20 Procedure~
1. Melt 2 and 3 together and stir until uniform.
2~ Di8~01ve ~o. 1 in the mol~en ma3~ from step 1 and stir un~il uni~orm.
3. ~our the ~olten mass ~rom step 2 in~o suppo~itory mol~ and chill.
4. Remove th~ suppositories from ~old~ ~nd wrap, ~ herapeutic compo3itions ~or combatting hi~amin~ in -~
unit ~osage form, compri~ing a pharmaceutical carrier and an e~ctive ~mount of a compound o~ Formula I or a pharmac~utically acceptable acid addition salt ther~of ar~ therofor~ an ~mbodim~nt of this invention.

i ! 419~cIP
lOo ~23~L~09 Variou~ ~odificat~on~ ~nd eguivalents will be npparent to one ~kilied in the art and may be made in the compounds, methods, procs3se~ and ph~rmaceutical composition~ o~ the present invention without departing from the ~pirit and scope thereof, and it i8 therefore to be undex~tood that the invention i8 to b~ l~mited only by th~ ~CoF~ of the appended claim~.

~23~

SUPPLEMENTARY DISC~OSURE
Further investigation has revealed that the novel oxazepine derivative of Formula I may also be produced by the ollowing processes:
Alterna-tive process A
A compound of the formula;

~O ~ (CEI2)n~Z
~ C NHR (V) 0-2, oR3 wherein A, Y, R, Z and n are as defined before, and R3 is H, a cation or an esterifying radical, is cycliæed into a compound of the formula:

(CH2)n~Z

~ ~ ~ N\
(Y)0~2 R

wherein the symbols are as de~ined before.
It is convenient to employ an alkali metal hydride, e.g., sodium hydride or potassium hydride to facilitate the cyclization.
The starting material (V) may be prepared by reac-ting a compound of the formula:

I A

/~ , C--oR3 (Y)0-2 wherein X i5 halogen and the other symbols are as defined -108- ~3~
be~ore,with a compound o the fo.rmula:

HO
~r (CH2)n~Z

R~IN ~
using a strong base, such as, potassium hydride.
The total scheme of a preferred method of alternative process A is depicted in CHART VII.
Al~rr~ti.e ~rocess B
A compound of the formula:

, ~ X OH

~ ~ ~ C - N (CH2)n~z (VI) (Y)0-2 O R

wherein A, Y, R, Z and n are as defined before, and X is halogen, is cyclized into a compound of the formula:

(CH2)n-Z
A I
~ ~ N
( )0-2 R

wherein the symbols are as deined before.
The cyclization is normally carried out employing a strong base, such as sodium hydride, potassium hydride, sodium amide and potassium tert-butoxide.

The starting material (VI) may be prepared by amidating a compound of the formula:

, _ ~ X

~ COR
(Y) 0~2 - . ~ . .i- ~ ~
., ~

wherein A, Y and X are as defined above, and R3 is hydrogen or an alkali metal, with an amine of the formula:

HO \
~ (CH2)n Z

RHM /
wherein the symbols are as defined above. The amidation may be facilitated by, for example, dicyclohexylcarbodiimide (DCC) or a comblnation of methane sulfonyl chloride and a tertiary amine.
The total scheme of a preferred method of alternative process B is depicted in CH~RT VIII.

, ,.
. ., -110- ~ 4~
CHART VI
Alternative Method A of Preparing Oxazepines ~ Cl (Y) O ~ '(coR3 KH O / ~ ~ (CH2)n-Z
HO J (CH2)n-Z ~ KO ~ (CH2)n ~ " ~ ~HR (V) RHN RHN (Y)o 2 ~ ` 3 NaH or KH

~¢ ~ (CH2 ) n-Z

( )0-2 O R
CHART VIII
Alternative Method B of Preparing Oxazepines , _ HO

~ CooR3* HN MeSO2Cl/Et3N
(Y)o 2 (Y)o 2 strong base \ ~

~ l CH 2 ) n - 2 ~ _ ~ ~ N~
(~)0~2 R

,~,7' ~2;~

The following description includes further examples.
These examples include the working examples covered by the claims of this application as well as those of Serial No.
478,539, filed April 9, 1985.
Preparation 24 _ N V th 1, N-(3-(1=eth~lpyrrolidinyl)~-benzoic acid lithium salt.
A mixture of 1068 g (6 mole) of 3-bromo-1-ethyl-pyrrolidine, 828 g (6 mole) of potassium carbonate and 1700 ml of N-methylaniline was stirred at reflux for 2 hr, cooled and filtered. The filtrate was extracted with dilute aqueous sodium hydroxide, dried over anhydrous sodium sulfate and distilled. Yield of l-ethyl-3-(N-methyl, N-phenylamino)-pyrrolidine was 452 g (37.5%), b.p~ 100-105/0.1 mm.
The above prepared compound, 20.5 g (0.1 mole) and 46~5 g of 15.1% butyllithium and 20 ml of diethyl ether were heated at reflux for 2 hr. The reaction mixture was / ` ~ 1 ....: '~ i 12;~30~

then poured onto a slurry of dry ice in diethyl ether. The excess carbon dioxide was allowed to evaporate over a period of time and the residue was s~irred in diethyl ether and filtered. The filter cake was dried ln vacuo to give 15 g o~ the title product.
Preparation 2~
?-Chloro-3-quinolinecarboxylic acid.
To a solution of 21.3 ml (0.15 mole) of diisopropyl amine in 300 ml of dry tetrahydrofuran under a continuous nitrogen blanket, at -70C., was added 61.6 ml o 2.7 M
n-butyllithium in hexane ~0.165 mole) while maintaini~g the temperature at -60 to -70C. Subse~uent to this addition, the temperature was maintained at -65C. for approximately 20 minutes. A solution of 20 g (0.12 mole) of 2-chloro~uinoline in 60 ml of tetrahydrofuran was added dropwise while maintaining the temperature at -60 to -70C.
After holding the temperature at -65C. for 20 minutes subsequent to this addition, the entire reaction mixture was poured onto a large excess of dry ice. Most of the solvent was evaporated in a stream of air; the residual solvent was removed by rotary evaporation. The residue was taken up in 300 ml water, made basic with dil aq. sodium hydroxide and washed with 3 x 50 ml of isopropyl ether. The aqueous layer was filtered and made acidic ( 4 to 5 pH) with dilute aqueous hydrochloric acid. The precipitate was collected, washed with waterJ isopropyl alcohol, and isopropyl ether, and dried, giving 15.4 g (62%) of white crystals, m.p.
190-210C. (decomp.). A sample was recrystallized from isopropyl alcohol giving an analytical sample, m.p. 190-210C. (decomp.).Analysis: calculated for CloH~N02: C,57.85; H,2.91, N,6.75 Found : C,57.80, H,2.95; N,6.6 ~-~ æ~ ~
.~ 5 ~234~

Pre~a rat ion 2 6 4-Chloro-7-(trifluoromethyl~ u inol ine ca rbox yl i c acid.
To a co~led solution of 15.~ ml (0.11 mol~) of diisopropyl amine in 250 ml of tetrahydroflran undsr a blanket of dry nitrogen at -70C. was add~d 44 ml of 2.7 M
n-butyllithium in hexane at -60 to -70C. The ~olution was stirred for 20 minutes at -70C. and a solution/suspension of 25 g (0.11 mole) of 3-chloro-7-trifluoromethyl ~uinoline in 125 ml of tetrahydrofuran was added dropwise while maintaining the temperature between -60 and -70C. The temperature was held at -70C. for 2~ minutes subsequent to the addition of the ~uinoline. The solution (deep rad~
was poured onto a large excess of dry ice and the solvent allowed to evaporate overnight at room temperature. The residual solvent was removed by rotary evaporation (60 C. J
30 mm) and the residue taken up in 800 ml of dil sodium hydroxide. An attempted wash with 75 ml of chlorororm caused the sodium salt of the product acid to preeipitate out. This precipitate was coll~cted and washed with 1 liter Qf chloroform and suspended in 500 ml of water. The suspension was stirred while acidifying with 6N hydro-chloric acid to pH 2. The solid was collected and washed with 500 ml of water. After drying, 16.2 g (53 0 of white solid was collected, m.p. 310C.
Analysis: Calculated for CllH5N02ClF9: C,47.94; H,1.83;
N,5.o8 Found : C,47.56; H,1.79 N,4.99 Preparatio~
3L~-Dichloro-4-~vridinecarboxyllc acid.
To a solution of 4.96 ml (0.036 mole) of diisopropyl-amine in 200 ml of tetrahydrofuran at -65 C. under a nitrogen blanket was added dropwiRe 14.9 ml of 2.5 M
n-butyllithium in hexane while maintaining the abo~e temperature. Twenty minutes subsequent to that addi~ion, a solution 5.0 g (0.034 mole) of 3,5-dichloropyridine in 30 ml tetrahydrofuran at -60 to -70 C. was added. The reaction mixture was ~tirred a~ -70 C. for 1~ hr, poured ~,,.

1234130~

onto a large excess of dry ice and allowed to evaporate overnight at room temperature. ~he residue was taken up in 100 ml of dilute aqueous sodium hydro~ide, washed with 3 x 30 ml o~ methylenechloride and filtered. The filtrata was acidified to ~ pH 2 with dilute hydrochloric acid to precipitate out the product. ~ter cooling, the precipitate was collected and recrystallized from ethyl acet~te~hexane giving 1.9 g (29O of white analytically pure crystals, m.p. 231-35c.(decomp.).
Analysis: Calculated for C6H3NO2Cl2: C~37.53; H,1.57;
N,7.~0 Found : C,37.33; .H,1.56:
N,7.21 Preparation 28 5-Hydr ~ olinecarboxamide.
5-Hydroxy-6-isoquinolinecarboxylic acid methyl ester as reported by Dyke, S. F. et al., in Tetrahedron 1973, 29(6), 857-62, is reacted with excess ammonia in a steel bomb for 12-18 hr. The excess ammonia is allowed to evaporate and the residue is crystallized from a suitable solvent mix such as ethyl acetate-toluene to give the title compound.
Preparation 2~2 5-~ Methyl-~-pyrrolidinyl)oxy~-5-isoquinoline-.
carboxamide.
Following the procedure of Preparation 10, but substituting 5-hydroxy-6-isoquinolinecarboxamide for l-hydroxy-2-naphthalenecarboxamide~ the title compound is pxepared.
Pre~aration ~0 7-Hydroxy-6-iso~uinolinecarboxamide.
7-Hydroxy-5-isopuinolinecarboXylic acid methyl ester as reported by Dyke ~see ref. given in Prep. 28) is reacted with excess ammonia in a steel bomb for 12-18 hr.
The excess ammonia is allowed to evaporate and the residue ~5 is crystallized from a suitable solvent mix ~uch as ethyl acetate-toluene to give the title compound.
:

-115- ~2~ 9 Preparation ~1 7-r ~l-Methyl-3-pvrrolidinyl) carboxamide.
Followin~ the procedure of Preparation 10, but substitut ing 5-hyd roxy-6 - i 5 oquinolinecarboxamide for 1-hydroxy-2-naphthale~ecarboxamide, the title compound is prepar~d.
- PreDaration 32 5-Methyl-8-r(l-methyl-~-P~rrolidinyl) Qxyl~l-quinoline carboxamide.
Following the procedure of Preparation 10, but substituting 8-hydroxy-5-methyl-7-quinolinecarboxamide ras reported by V-~apoor et al, Indian J. Chem. 4(10), 438-51 (1966); (C.A. 66, 75802p)] for 1 hydroxy-2-naphthalenecarboxamide, the title compound is prepared.
Pre~aration 3~
8-HYdroxy-2-methyl-7-auinolinecarboxvlic acid methyl ester.
8-Hydroxy-2-methyl-7-quinolinecarboxylic acid (a 5 reported by Meek, W. H. et al., in J. Chem. Eng. Data 1969, 14(3), 388-91) is reacted with methanolic boron tri1uoride solution for several hours. The resulting mixture is added to an aqueous solution of sodium bicarbonate to give finally a basic solution. The solution is extracted with chloroform. The chloroform extract is dried over anhydrous sodium sul~ate and concentrated and the residue is crystal-lized from a suitable solvent such as isooctane to give the title compound.
Preparation 34 8-Hydroxy-2-methyl-7-auinolinecarboxamide.
8-Hydroxy-2-methyl-7-qUinolinecarboxylic acid methyl ester i~ reacted with excess ammonia in a ~teel bomb for 12-18 hr. The excess ammonia is allowed to evaporate and the residue is crystallized from a suitable ~olvent to give the title compound.

~, .
,, . .~

~L23~ )9 PreDaration ?-Methyl-8~ -methvl~3-Pyrrolidinyl)oxv~-7~auinoline carboxamide.
Following the procedure of Preparation 10, but substituting 8-hydroxy-2-methyl-7-quinolinecarboxamide for 1-hydroxy-2-naphthalenecarboxamide, the title compound i5 prepared.
Pre~aration 36 6-HYdroxv-5-quinolinecarboxvlic acid methyl ester.
6-Hydroxy-5-quinolinecarboxylic acid ~as reported by Da Re, P. et al. in Ann. Chem. (Rome) 1970, 60(3), 215-24 ~C.A. ~, 253~8m)~ is reacted with methanolic boron trifluoride solution for several hours. The resulting mixture is added to an aqueous solution of sodium bicarbon-ate to give finally a basic solution. The solution is extracted with chloroform. The chloroform extract is dried over anhydrous sodium sulfate and concentrated and the residue is crystallized from a suitable solvent.
PreParation 37 6-HydroxY-~-quinolinecarboxamide.
6-Hydroxy-5-quinolinecarboxylic acid methyl ester is reacted with excess ammonia in a steel bomb for 12-18 hr.
~he excess ammonia is allowed to evaporate and the residue is crystallized from a suitable solvent to give the title -compound.
PreParation 38 6-r(l-MethYl-3-PYrrolidinyl)oxy]-~-quinolinecarobxamide.
Following the procedure of Preparation 10, but substituting 6-hydroxy-5-quinolinecarboxamide for l-hydroxy-2-naphthalenecarboxamide, the title compound is prepared.
Preparation 79 8-HYdroxy-7~quinolinecarboxamide.
8-Hydroxy-7-quinolinecarboxylic acid methyl ester ~as reported by EcXstein, Z. et al. in Pol. J. Chem. 1979, 5~tll), 2~73-7 ~C.A. ~, 215243s)~ is reacted with excess ammonia in a steel bomb for 12-lB hr. The excess ammonia is allowed to evaporate and the residue is crystallized from a ~uita~le solvent to giv2 the title compound.

,. ~

-117- ~2~4~9 Preparation 40 8-r(l-Methyl-3-pvrrolidinyl~oxy]-7-quinolinecarboxamide~
Folling the procedure of Preparation 10, but substituting 8-hydroxy-7-quinolinecarboxamide for l-hydroxy-2-naphthalenecarboxamide, the title compound is prepared.
Preparation 41 (Re~er to chart VIII) 2-Chloro-N-r4-~dimethylamino)-2-hvdroxybutyl~
pvridinecarboxamide mo ohydrochloride.
To a susp~nsion of 11.9 g (o.076 mole) of 2-chloro-nicotinic in 200 ml of methylene chloride was added 10.2 g (0.076 mole) of l-hydroxybenzotriazole, 10 g (0.076 mole) of l-amino-4-(dimethylamino)-2-butanol, and 15.6 g (0.075 mole) o~ dicyclohexylcarbodiimide. The xesulting solution was stirred at room temperature for 6 hr and allowed to stand for 66 hr. The resulting mixture was filtered and the filtrate concentrated on the rotary evaporator. The residue was shaken with a mixture of dilute hudrochloric acid and isopropyl ether. The resultinq 3 phase system (1 solid, 2 liquid) was filtered and the solid discarded.
The aqueous layer was separated, made basic with sodium hydroxide and extracted 3 times with chloroform. The combined chloroform extracts were combined~ dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in isopropyl alcohol and acidified with ethereal hydrogen chloride. The resulting precipitate was dissolved by heating and adding methanol. The crystals obtained on cooling were recrystallized from ethanol to give 9.6 g (41%), m.p. 182-192C.
Analysis: calculated for Cl2HlsN~02Cl2: C,46.77; H,6.21, Found : C,46.67; H,6.42, N,13.91 . ~ ,~ . .

-118- ~23~0~

Intermediate 37 2,3-Dihydro-2-~1,3-dihydro~ -dioxo-2H-isoindol-2-yl) ethyl-4-methylpyrido~3,2-f~1,4~oxazepin-5(4~)-one.
To a solution of 4.92 g (0.02 mole) of 2-(2-chloroethyl)-2J3-dihydro-4-methylpyridoC3,2-f] -1,4-oxazepin-5 (4H)one in 35 ml of dirnethylformamide was added 7.55 g (0.041 mole) of potassium phthalimide. The mixture was stirred for 5 hr at 100C and left standing at room temperature overnight.
Dimethylformamide was removed by rotary evaporation (80 C.
vacuum pump). The residue was taken up in 100 ml of chloro-form and washed with water (2 x 30 ml) and 2M potassium hydroxide (2 x ~ ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (70 C., water aspirator). The 6.26 g of crude product was recrystallized from isopropyl alcohol to give 2.60 g (36 0 white cyrstalline powder, m.p. 146-47C.
Analysis: Calculated for ClgHl7N304: C,64.95; H,4.88; N,11.95 Found : C,65.18, H,4.91; N,12.09 Intermediate 38 2~I2-(2 3-DihYdro-4-methvl-5(4H)-thioxopyridor3,2-~
rl,4-oxazepin-2-ylj-ethyll-lH-isoindole-1,3(2H)-dione.
_ _ To a solution of 1.0 g (o.oo38 mole) of 2-(2-chloroethyl)-2J3-dihydro-4 methylpyrido~3,2-f]-1,4-oxazepine-5(4H)-thione in 20 ml dimethylformamide was added 1.43 g (0.0078 mole) of potassium phthalimide. The mixture was heated to 100 C.
for 6 hr with stirring.
The dimethylformamide was removed by rotary evaporation (70, vacuum pump) and the residue taken up in chloroform ~100 ml). The organic layer was washed with 2N potassium hydroxide (2 x 30 ml), aried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation ~70 C., water aspirator). The crude oil (1.2 g) was recrystallized from isopropyl alcohol giving 0.95 g (68%) of pale white crystals, m.p. 172-73C.
Analysis: Calculated for ClsHl7N3o3s: C,62.11; H,4.66;
~,11.44 Found : C~61.85; H,4.70;
N,11.5 .

~) -119- ~23~

Intermediate 3~
2,3,4,5-Tetrahydro-4-methyl-5-thioxopyrido~3,2-fl r 1,41-oxazeDine-2-~ropanenitrile.
To a solution of 11.0 g (0.04 mole) of 2J3,4,5-tetrahydro-4-methyl-5-oxopyrido~3,2-f]~1,4~-oxazepine-2 propanenitrile in 175 ml toluene was added 10.5 g (0.026 mole) of 2,4-bis (4-methoxyphenyl) -1J 3-dithia-2,4-diphosphetane-2,4-disulfide.
The reaction mixture was heated to reflux for 2 hr with vigorous mechanical stirring. Another 3.0 g (0.007 mole) of 2,4 bis (4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide was added and heating continued for 1 hr additional. The reaction mixture was allowed to cool and stand overnight at room temperature. Toluene was removed by rotary evaporation (90C.~ water aspirator) and the residue taken up in 200 ml chloroform. This was washed with 2 x 50 ml 2M aqueous potassium hydroxide and concentrated by rotary evaporator (90C., water aspirator). Crystallization ensued upon cooling. Recrystallization from isopropyl alcohol affordPd 1.60 g (13.8%) product, m.p. 155-56 C.
Analysis: calculated for ClzHl~N30S: C,58~28; H,5.30;
N,16.99 Found : C,58.00; H,5.26;
N,17.13 Intermediate 40 2-(2-chloro-l-methYlethYl)-2.3-dihydro-A-methvlpvrido r3.2-f~ oxazepin-5~4}I)-one hYdrochloride.
To a suspension of 59.6 g (60%) in oil, 1.49 mole) of sodium hydride in 400 ml of tetrahydrofuran heated to reflux was added a solUtion of 110 g (0.71 mole) o~ 2-chloro-nicotinic acid and 81.3 g (0.71 mole) o 1,4-dimethyl-3-pyrrolidinol in 400 ml of te$rahydrofuran at a rate such that good reflux was maintained (20-35 minutes). Heating at reflux was continued for 2 hr sUbsequent to the completion of the ad~ition. Be~ause mass spectra ~howed 30% ~tarting material at this point, 25.0 g (o.63 mole) addition~l sodium -hydride was added ~nd reflux continued for 4 hr. The ~5 reaction mixture was left standing overnight.

~, :

-120~ 4~9 The mixture was guenched with isopropyl alcohol and filtration attempted. However, when filtration failed, the solvent was stripped off by rotary evaporation.
This crude salt was suspended in 1 liter of chloroform and hydrogen chloride gas was bubbled in until a pH of 6 was reached. To this suspension was added 372 g (1.42 mole) or triphenylphosphine and 372 g carbon tetrachloride and the entire mixture heated at reflux for 1.5 hr. However, reaction was not complete as evidenced by I. R. An additional 100 g (0.38 mole) of triphenyl phosphine and 100 g of car~n tetrachloride was added and reflux continued overnight.
After cooling the reaction, 100 g of triethylamine was added.
The reaction mixture was extracted with 4 x 200 ml of dil aqueous hydrochloric acid. ThP hydrochloric acid extracts were made basic with conc. sodium hydroxide and extracted into a total of 1 liter of chloroform. The chloroform was removed by rotary evaporation (70 C; 3 mm) and the residue taken up in 300 ml toluene.
The toluene was extracted with 4 x 125 ml of dil aqueo~s hydrochloric acid. The hydrochloric acid extracts were combined and washed with 4 x 200 ml of meth~lene chloride. The hydrochloric acid layer was basified with conc. sodium hydroxide and extracted with methylene chl~ride.
The organic extracts were co~oined, dried over sodium sulfate, filtered and concentrated by rotary evaporation.
The residue was taken up in isopropyl alcohol and treated with hydrogen chloride gas. Approximately 34 g (16~) of white crystals were collected. Recrystallization in isopropyl alcohol gave an analytical sample, m.p. 178-81C.
Analysis: Calculated for Cl2Hl~N2O2Cl2: C, 49.50: H,5.54;
N,9.62 Found C~ 49.46; H,5.54;
N,9.50 ~ ;~
~`~?

1234~0~

Intermediate 41 2-~2-Chlor~ethy1)-2,3-dihydro-2~4-dimethylpyridol3,2-fl-~4-oxazepin-5(4H)-one hvdrochl~ride.
To a suspensi~n o 60 g ~60~ in oil, 1.5 m~le) of sodium hydride in 400 ml of tetrahydrofuran heated to reflux was added a solution of 110 g (0.70 mole) of 2-chloronicotinic acid and 80 g (0.70 mole) of 1,3-dimethyl-3-pyrrolidinol so as to maintain good reflux. Heating at reflux was continued overnight. The mass spectra showed very little prod~ct at this point; there~ore, 400 ml of dimethylformamide was added and heating at 77C. was continued overnight. Approximately 10% of the desired product was then observed by mass spectra.
The tetrahydrofuran was evaporated by passing nitrogen gas over the reaction mixture while at the same time being replaced with dimethylformamide. The temperature was concomitantly increased to 100C. The mixture was stirred overnisht at 100 C. After cooling, no salt precipitated out; therefore, dimethylformamide was removed by rotary evaporation (90C.; 5 mm). Approximately 250 g of crude salt was collected.
Into a suspension of 2~0 g (~o.88 mole) of this crude salt in 1 liter of chloroform was bubbled hydrogen chloride gas to pH 6. To this suspension was added 463 g (1.77 mole) of triphenyl phosphine and 46~ g of carbon tetrachloride.
The mixture was then heated to reflux. After 8 minutes a vigorous exotherm ensued which subsided in 30 minutes.
Reflux was continued for 2.5 hr. According to infrared analysis, the reaction was near completion. Approximately 40 ml of triethylamine was added to drive the reaction to completion. The mixture was left standing overnight at room temperature.
The reaction mixture was extracted with 700 ml dil. aq.
hydrochloric acid. The hydrochloric acid extracts were combined and washed with 4 x 100 ml of chloro~orm. ThP
combined aqueous hydrochloric acid extract~ were then made basic with conc. sodium hydroxide and extracted with 5 x 200 ml of methylene chloride. The organic extracts were combined, dried over anhydrous ~odium ~ulfate, filtered and concentrated by rotary evaporation (70C.; 30 mm). ~he ~122- ~23~

residue was taken up in 600 ml of toluene and treated w~th activated charcoal 4 times. The toluene was then removed by rotary evaporation and the residue treated with hydrogen chloride in isopropyl alcohol which afforded 53 g (21~).
Recrystallization from isopropyl alcohol afforded an analytically pure sample, m.p. 155-158C.).
Analysis: Calculated for Cl2Hl~N202Cl2: C,49-50; H~5-54;
N 9.62 Found : C,49.49; H,5.61 N,9-75 Intermediate 42 2-~2-Chloroethy~ 2~3--dihvdro-?t4-dimethvlpyridor3~2-f~
1,4-oxazePine-5(4H)-thione.
To a suspension of 4.6 g (0.04 mole) of phosphorus pentasulfide in 50 ml of acetonitrile was added, all at once, a solution of 20 g (0~079 mole) of 2-(2-chloroethyl)-2,3-dihydro-2,4-dimethylpyrido~3,2-f]-1,4-oxazepin-5(4H)-one in 50 ml of acetoni~rile. The mixture was heated to reflux for 4 hr with stirring, at which time the mass spectra showed no starting material. The reaction was left standing overnight at room temperature.
To the reaction mixture was added 100 ml of toluene followed by stirring for 15 minutes. Some tar-lik~ material collected on the sides of the reaction vessel. The solution was filtered with much difficulty. The filtrate was saved and washed cautiouslY with 3 x 50 ml of saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, treated with activated charcoal, filtered~ dried again over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation (80 C.; 30 mm~. The crude oil (9.2 g) was crystallized from isopropyl alcohol, giving 6.o g (28%) of yellow crystals, m.p. 119-121C
Analysis: Cal~ulated for Cl2~l5N20SCl: C,53.23: H,5.58;
N.10.35 Found : C,53.0~; H,5.60;
N,10.34 - ~:

..~' c~

~23~109 Tntermediate 4 2-(2-Chloropropyl~-2,3-dihydro-4-methylpyridO[3,2-f~
1,4-oxazepin-5(4H)-one hydrochloride.
To a suspension of 36.1 g of 60% sodium hydride in oil (0.90 mole) in 300 ml of tetrahydrofuran heatzd to reflux and under a nitrogen blanket was added a solution o~ 68.3 g (0.43 mole) of 2-chloronicotinic acid and 50 g (0.43 mole) of 1,2-dimethyl-4-pyrrolidlnol in 300 ml of tetr2hydrofura~
at a rate such that good reflux was maintained (20 min).
Subse~uent to this addition, heating at reflux was maintained for 2.5 hr at which time the reaction appeared tG be c~mplete (by mass spec.). The crude sodium salt was filtered and washed with ethyl acetate affording 135 g of the crude sodium salt.
To a suspension of 115 g (~0.44 mole) of the above sodium salt in 650 ml of chloroform was added hydrogen chloride to reach a pH of 6. To this mixture was added 2~1.8 g (o.88 mole) of triphenylphosphine and 231.8 g of carbon tetrachloride and the entire reaction mixture heated to reflux for 3 hr. After cooling, the reaction mixture was extracted with 4 x 250 ml of di hydrochloric acid.
The aqueous layer was washed with 4 x 125 ml o~ chloroform and made basic with concentrated sodium hydroxide. The aqueous layer was then extracted with ~ x 25~ ml of chloroform. The organic extracts were combined, dried over anhydrous sodium sul~ate, filtered and concentrated by rotary evaporation. To the residue was added 800 ml of toluene and the resulting solution decolorized ~ times with activated charcoal. The solvent was removed by rotary evaporation (90 C., 30 mm). The residue was taken up in 300 ml of isopropyl alcohol and the solution was saturated with hydrogen chloride, seeded, and left standing overnight at room temperature. Approximately 30 g (~230 of salt was collected. An analytical sample was prepared by recrystal-lizating the salt ~ times from isopropyl alcohol, m.p.
143-49C.
Analysis: Calculated for Cl2HlBN2o2cl2: CJ49~50; H~5~54 N,9.62 Found : C, 49~85; H,5.62 N,9 o84 r~

:~LZ3~309 Intermediate 44 2-(2-Chloropropyl)-2,3-dihydro-3-methylpyrido~3,2-~-1,4-oxazepine-5(4H)-thione.
To a suspension of 4.90 g ~0.022 mo~e) of phosphorus pentasulfide in 30 ml of acetonitrile was add~d ~ solution of 10 g (0.0~9 mole) of 2-(2-chloropropyl)-2,3-dihydro-4-methylpyrido~3,2-f]-1,4-oxazepin-5(4H)-one in 25 ml of acetonitrile. The mixture was heated to reflux, with stirring, for 5.5 hours and left standing at room temperature overnight. T~ the reaction mixture was added 50 ml of toluene, followed by stirring for a few minutes. The mixture was filtered and the residue washed with 25 ml of toluene/
acetonitrile. The filtrate was washed cautiously with 3 x 75 ml of saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, treated with activated charcoal, filtered and concentrated by rotary evaporation (90 C.; 30 mm). The crude syrup (10.0 g) was crystallized from isopropyl ether/isopropyl alcohol, giving 5 g of yellow crystals, m.p. 95-97 C. A second crop was collected, bringing the total to 6 g (57 O .
Analysis: calculated for ClzHl5~2OSCl: C~5~.28; H,5.58;
N,10.35 Found : C,53.13; H,5~58;
N,10.35 Intermediate 4~ `
?-(2-Chloro-l-methylethyl)-2~3-dihydro-4-methylpyrido ~3,2-f ~1,4-oxazepine-5(4H)-thione hydrochloride.
To a suspension of 5.35 g (0.024 mole) of phosphorus pentasulfide in 25 ml of acetonitrile was added a solution of 10.9 g (0.043 mole) of 2-(2-chloro-1-methylethyl)-2,3-dihydro-4-methylpyrido~3,2-f]-1,4-oxa~epin-5(4H3-one in 25 ml of acetonitrile. The mixture was heated to reflux for 2.75 hr and left standing at room temperature overni~ht.
To the cooled reaction mixture was added 50 ml of toluene, followed by filtration. The residue was washed with 45 ml of 3/1, V~V toluenejacetonitrile. The filtrate was washed cautiouslY with ~ x 75 ml of saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, treated with activated charcoal, flltered,and concentxated by rotary . .

--125- ~234~9 evaporation. The residue was treated with hydrogen chloride in isopropyl alcohol/isopropyl ether which yielded one crop of 4.5 g o~ yellow crystals, m.p. 148~51C. ~(Note: a second crop of 1.5 g was collectedJ bringing the total yield to 6.o g (45.~0].
Analysis: Calculated for Cl2Hl6N20SC12: C,46.91; H,5.25;
~,9.12 Found : C~48.86; H,5.34;
~,9.05 Intermediate 46 ?-(2-Chloroethyl)-2,3-dihvdro-4-methyl-1,4-oxazepino r 6~7-b]-quinolin-5(4H)-one.
To 21.3 ml (0.15 mole) of diisopropylamine in 300 ml of tetrahydrofuran at -70C. was added dropwise, at a rate to keep the temperature between -70 and -60C., 61.1 ml of 15 2.7 M n-butyllithium (0.16 mole). The temperature was maintained at -70 C. + 3 C. for 20 minutes. A solution of 2-chloroquinoline in 60 ml of tetrahydrofuran was added dropwise at a rate such that temperature remained between -70 and -60C. After 20 minutes, the darkened reaction solution was poured onto a large excess of dry ice. The solvent was evaporated with a stream of air.
The residue was taken up in ~00 ml of water~ made basic with dilute aqueous sodium hydroxide and washed with ~ x 50 ml of isopropyl ether. The aqueous phase was filtered and treated with dilute hydrochloric acid to -pH 4-5, at which time a copious precipitate formed. The precipitate was collected and the filtrate reacidified yielding more precipitate. The precipitates were combined and washed with water, isopropyl alcohol, and isopropyl ether. Approximately 30 15.4 g (61.5%) of off-white crystals were collected.
To a suspension of 4.0 g of 60% sodium hydride in oil (0.10 mole) in 100 ml tetrahydrofuran heated to reflux was added a solution of 5.5 g (o.o48 mole) of N-methyl-~-pyrrolidinol and 10 g (o.o48 mole~ of the above prepared 2-chloro-3-auinolinecarboxylic and in 50 ml of tetrahydroruran at such rate as to maintain good reflux. ~eflux was maintained for 1.5 hr and the reaction mixture oooled. The solvent was removed by rotary evapor~tion yielding 26 g -126- ~2~4809 crude product.
The entire crude product from above was suspended in 150 ml chloroform and hydrogen chloride bubbled in until pi~
of 5.76 was reached (note: after hydr~ge~ chloride addition ceasedJ the pH continued to lower to 1.7). To this suspension was added 25.0 g (o.og6 m~le) of triphenylphosphine and 25 g of carbon tetrachloride. After 45 min, an additional 10 g (0.03~ mole) of triphenylphosphine and 10 g o~ carbon tetrachloride was added~ Aft~r ~0 minutes, the heat was removed and the reaction driven to completion by dropwise addition of 20 ml of triethylamine.
The reaction mixture was extracted with 3 x 50 ml of 3N hydrochloric acid. The aqueous extracts were combine~, washed with 2 x 50 ml chloroform, made basic with con~en-trated sodium hydroxide and extracted with 3 x 50 ml ofchloroform. The organic extracts were combined and conce~-trated by rotary evaporation. The syrupy residue was taken up in 100 ml of toluene and treated with activated charcoal.
The toluene was removed by rotary evapora~ion and the syrupy residue crystallized from isopr~pyl alcohol, giving 1.5 g tll%) of white crystals, m.p. 133-1~4C.
Analysis: Calculated for ClsHl5N202Cl: C,61.97: H,5.20, N,9.63 Found : C,61.7~; H,5.1 N,9.54 Intarmediate 47 2-(2-Chloroethyl)-2,3-dihYdro-4-meth~l-1.4-oxazepino L6,7-b~quinoline-~(4H)-thione.
To 3.0 g (0.0~ mole) of 2-(2-chloroethyl)-2~3-dihydro-4-methyl-1,4-oxazepinor6,7-b~-quinolin-5(4H)-one in ~0 ml of acetonitrile was added 1.3 g (o.oo6 mole) of phosphorus pentasulfide. The mixture was stirred vigorously at re~ x for 2 hr. After cooling, the reaction mixture was diluted with 60 ml of toluene and fil.ere~. Tn- residue on the filter paper was washed with 50 ml of additional toluene/
acetonitrile, ~/1, V/V. The filtrate was wa~hed with 3 x 50 ml saturated sodium carbonate (caution: gas evolved~, dried over anhydrous sodium sulfate, filtered, treated with activated charcoal, filtered again and concentrated by rotary evaporation ~90 C., 30 mm). The residual syrup was r~.

-1~7 ~234~30~

crystallized from isopropyl alcohol, yielding 1.6 g (52~) o~ yellow crystals, m.p. 114-116 C.
Analysis: calculated ~or Cl5Hl5N20ClS: C,58.72; H,4.93, N~9~l3 Found : c)~8.~8, H,4.92;
N~9-07 Intermediate 48 2-(2-Chloroethvl)-? L~i-dihvdro-4-methvl-9-(trifluoro-methyl)-1,4-oxazepino~6,7-c]quininolin-5(4H)-one hydro-chloride.
To a suspension of 3.16 g (60% in oil, o.o8 mole) o~
sodium hydride in 250 ml of tetrahydrofuran under dry nitrogen atmosphere heated to reflux was added a solution of 10.42 g (o.o38 mole) of 4-chloro-7-(trifluoromethyl)-3-guinolinecarboxylic acid and 3.81 g (o.o3fl molè) of N-methyl-3-pyrrolidinol in 50 ml of tetrahydrofuran at such a rate as to maintain good reflux. Heating at reflux was continued fox 3 hr. The solvent was removed by rotary evaporation (80C., 30 mm), and the crude sodium salt (12 g) was dried overnight.
The entire amount of crude sodium salt was suspended in 250 ml of methylene chloride. Hydrogen chloride was added to a pH of 2. To this suspension was added 19.4 g (0.074 mole) of triphenyl phosphine and 19.4 g of carbon tetrachloride. The extire mixture was heated to reflux for 3 hrs- IR indicated presence of acid chloride; therefore, the reaction was driven to completion by the addition of 15 ml of triethylamine. After cooling, the reaction mixture was extracted with 2 x 75 ml of 3N hydrochloric acid. The acid washings were combined and washed with 75 ml of methylene chloride. The water layer was made basic (after cooling with ice) and extracted with 3 x 75 ml methylene chloride. The methylene chloride was removed by rotary evaporation and the residue taken up in 100 ml of toluene.
The soluti~n was treated with activated charcoal, filtered, ~5 and concentrated by rotary evaporation (90 C., 30 mm~. The residue was dissolved in isopropyl alcohol and acidified with ethereal hydrogen chloride. Appraximately 1.1 g ~7.3~b) of white needles were collected, m.p. 172-174 C.

, -12~- ~234~0~

Analysis: Calculated for Cl8Hl5N202Cl2F3: C,48.63; H,3.83;
N,7.09 Found : C,48.78; H~3.84;
N,7.o4 Intermediate ~
2-~2-Chlorophenyl)-2,3-dihydro-4-methyl-9-~trifluoro-methyl-1 4-oxazepino ~ 7-cJquinoline-~(4H)-thione.
To a suspension of 0.85 g (.004 mole) of phosphorus pentasulfide in 25 ml of acetonitrile was added to a solution of 2.3 g (0.0064 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-9-(trifluoromethyl)-1,4-oxazepino~6,7-c]guinolin-5(4H)-one and the mixture heated t4 reflux. TLC in ethyl acetate showed only 50% conversion; therefore, 0.5 g (0.0022 mole) of phosphoruspentasulfide was added. After an additional 2 hr, no change was seen in starting material/
product. Heat was removed and the reaction mixture left standing overnight. The mixture was diluted with 75 ml of toluene and washed cautiously (gas evolved) with 3 x 50 ml of saturated sodium bicarbonate. The solvent was removed by rotary evaporation and the residue combined with a previous run of the same material. The combined products were purified by column chromatography over silica gel eluting with ethyl acetate. The solvent was rem~ved ~rom the fractions containing the product giving 0.9 g of yellow oil. The oil was recrystallized from isopropyl ether giving 0.55 g of yellow crystals, m.p. 135-37C.
Analysis: calculated for Cl8Hl4N20SF3Cl: C~51.27; H,3.77;
N,7.47 Found : C,51.41; H,3.83, N,7.42 Intermediate 50 ~ ;
2 chloromethyl-1.2 4-tetrahydro-1-eth~ 5H)1,4-benzodiazePin-~-one.
To a stirring solution of 266 ml (0.64 mole) of 2.4 m butyllithium solution in hexane, was slowly added 117.5 g :~
(o.58 mole) of N-methyl-N-phenyl-l~ methylethyl~
azetidineamine. The temperature of the mixture rose to 55C. which was than allowed to reflux for 5.5 hours.
When cooled) ~he 801ution was poured ~lowly with vigorous 123~1~09 stirring onto a slurry of dry ice in hexane and allowed to stand overnight. The residue wa~ dissolved in chloroform and 117.0 g (1.16 mole) of phosphorous oxychloride was add~d drop~ise while stirring. The solution was refluxed for two hours. Upon coolingJ the solution was washed, first with a dilute hydrochloric acid solution, then with a dilute sodium hydroxide solution. The hexane layer was dried over anhydrous sodium sulfate, filtered, and concentrated ln vacuo.
The residue was dissolved in hot isopropyl ether. The crystals obtained on cooling were recrystallized from the same solvent. The white solid weighed 45.0 g (29O . The solid was recrystallized twice more to give an analytical sample, m.p. 90-92C.
Analysis: Calculated for Cl~Hl~CllN20: C,6~.03; ~,7.18, N,10.50 Found : C,62.59; H,7.09;
~,10.40 Intermediate ~1 2-(2-Chloroethyl)-4-ethyl-1-methyl-1 2 ~ 4-tetrahydro-~H-1,4-benzodiazepin-5-one.
To 206 g (1 mole) of 1-ethyl-3-methylanilinopyrrolidine was added 660 ml (1.05 moles) of 14.98% butyllithium in hexane and the solution refluxed for 2 hours and poured on solid carbon dioxide. The carbon dioxide hexane mixture was allowed to evaporate overnight, leaving a dry yellow solid.
The solid W2S dissolved in chloroform. To this solution was added dropwise with stirring 1 mole of phosphorous tri-chloride. The temperature rose to reflux during addition and remained there throughout most of the addition. When the addition was complete, the mixture was stirred one hour and water was added cautiously. The resulting mixture was made basic with sodium hydroxide. The chloroform layer was separated, dried over anhydrous sodium sulfate and concen-trated. The residue was crystallized rom isopropyl ether to yield 112 g (42 O , m.p. 75-79 C. A 25 g sample was ~5 recrystallized from isopropyl ether to sive 18 g Gf product, m.p. 78-80C.
Analysis: Calculated for Cl4HleN2olcl: c,6~.o3, H,7.13, N,10.50 Found : C,63.27; H,7~22;
N,10.55 ~ ~J) ~130~ 9 Intermediate ~2 6-Chloro-2-(2-chloroethvl~-2.7-dihYdro-4-methvlPYrido ~4,~-f~-1,4-oxazepin-~(4H-one.
To a suspension of 2.1g (60% in oil, 0.052 mole) of sodium hydride in 125 ml of dimethylformamide heated to 60C.
under a nitrogen gas blanket was added a solution of 2.65 g (0.026 mole) of N-methyl-3-pyrrolidinol and 5.0 g ~0.026 mole) of 3,5-dichloropyridine-4-carboxylic acid in 40 ml of dimethyl ormamide dropwise at such a rate as to maintain 60C. Subsequent to this addition, the mixture was heated to 75C~ for 3 hr. The solvent was then removed by rotary evaporation (60C., 5 mm). The entixe solid residue was suspended in 150 ml methylene chloride and hydrogen chloride added until a pH of 3 was reached. To the resulting mixture was added 15 g (0.057 mole) of triphenylphosphine and 15 g carbon tetrachloride and the entire mixture heated to reflux.
After 1 hr, 7.5 g (0.029 mole) of triphenylphosphine and 7.5 g carbon tetrachloride were added, followed by the same increments 1 hr later. The reaction was driven to completion by adding 20 ml of trietlyla~ine. The reaction mixture was washed with 6 x 50 ml of 3N hydrochloric acid~ drie~ o~er sodi~m sulfate, filtered and concentrated by rotary evaporation. To the residue was added ethyl acetate, which caused much tarry material to fall out of solution~ leaving the desired product and triphenylPhosphine oxide in solution.
The mixture was chromatographed by column chromatography using silica gel as the stationary phase and ethyl acetate as eluent. Similar ~ractions were combined and ethyl acetate removed by rotary evaporation, yielding o.6 g (7~), of white crystals, m.p. 134-38C.
Analysis: Calculated for C.lHl2N202C12: C,48.02; H~4.40 ~,10.18 Found : C,47.89; H,4.38, ~,10.12 , ~ - . ~

-l3l= 12~

Intermediate ~3 2-~2-Chloroethyl)-2,3-dihydro-4-methyl-l,4-oxazepino r 7J6-f~isoquinol-n-5(4H)-one.
Following the procedure of Intermediate 8, 5-~ methyl-~-pyrrolidinyl)oxy]-6-isoquinolinecarboxamide is converted to the title compound.
Intermediate 54 2-(2-Chloroethyl) -? ,3-dihydro-4-methyl-l,4-oxazepino r7.6-f~isoquinoline-Cj(4H)-thione .
Following the procedure of Intermediate 471 2-(2-chloroethyl)-2,3-dihydro-4-methyl-l,4-oxazepino~7,6-f]
isoquinoline-5(4H)-one is sulfuri~ed to give the title compound.
Intermediate 5~
2-(2-Chloroethy~-2,3-dihydro-4-methyl-l.4-oxazepino 5 r 6,7-q~isoquinolin-5(4H)-one Following the procedure of Intermediate 8, 7-~
methyl-~-pyrrolidinyl)oxy]-6-isoauinolinecarboxamide is converted to the title compound.
Intenmediate 56 2-(2-ChloroethYl)-2,3-dihydro-4-methyl-l,4-oxazepino ~6.7-q3iso~uinoline-5(4H)-thione.
Following the procedure of Intermediate 47, 2-(2-chloro-ethyl)-2,~-dihydro-4-methyl-l,4-oxazepino~6,7-g]isoauinolin-5( 4H)-one is sulfurized to give the title compound.
Intermediate ~1 2-~2-chloroethYl)-2~3-dihYdro-4,7-dimethyl-l,4-oxazepino ~6,7-h~quinolln-~(4H)-one.
Following the procedure of Intermediate 8, 5-methyl-8-~(l-methyl-3-pyrrolidinyl)oxy]-7-quinolinecarboxamide is converted to the title compound.
Intermediate ~8 2-(2-ChloroethYl)-2,~-dihydro-4.7-dimethyl-l,4-oxazepino -r 6~7-hlquinoline-5(4H)-thione.
Following the procedure of Intermediate 47, 2-(2-chloro-ethyl)-2~-dihydro-4,7-dimethyl-l,4-oxazepino~6,7-h~auinoline-5(4H)-one is sulfurized to~give the title compound.

,~ ., -132- ~23~809 Intermediate 59 2-(2-Chloroethyl~-2~-dihydro-~ o-dimethy~ 4 oxazepinoL6,7-h~quinolin-~(4H)-one.
Following the ~rocedure of Intermediate 8, 2-methyl-8[(1-methyl-3- pyrrolidinyl)oxy~-7-quinolinecarboxamide is converted to the title compound.
Intermediate 60 2-(2-Chloroethyl)-2,3-dihydro-4,10-dimethyl-1,4-oxzaepino~6,7-h~quinoline(5-4H)-thione.
Following the procedure of Intermediate 47, 2-(2-chloro-ethyl)-2,3-dihydro-4,10-dimethyl-1,4-oxazepino~6,7-h]
quinoline-5(4H)-one is sulfurized to give the title compound.
Intermediate 61 2-(2-Chloroethyl)-3 4-dihydro-?-methyl 1 4~-oxa~ep no r6,7-flquinolin-1(2H)-one.
Following the procedure of Inter~ediate 8, 6-~(1-methyl-3-pyrrolidinyl)-oxy]-5-quinolinecarboxamide is converted to the title compound.
Intermediate 62 4-~2-Chloroethyl)-3,4-dihydro-2-meth~lrl,4-oxazepino ~6,7-f]quinoline-lt2H)-thione.
Following the procedure of Intermediate 47, 2-(2-chloroethyl)-3,4-dihydro-2-methyl~1,4]-oxazepino~6,7-f]
quinolin-1(2H)one is sulfurized to give the title compound.
Intermediate 63 2-(2-ChloroethYl)-2,~-dihYdro-4-methYl-1.4-oxazepino r 6 7-hlquinolin-S(4H)-one.
Following the procedure of Intermediate 8, 8-~(1-methyl-3-pyrrolidinyl)oxy]-7-quinolinecar~oxamide is converted to the title compound.
Intermediate 64 2-~2-Chloroeth~l)-2,~-dihydro-4-methyl-1 4-oxaze~i o ~6,7-h~quinoline-5(4H)-thione.
Following the procedure of Intermediate 477 2-(2-chloro-ethyl)-2~-dih-ydro-4-methyl-lJ4-oxazepino~6l7-h]quinolin 5(4H)-one is sulfurized to give the title compound.

..~

-133- 1 2 ~ ~ ~ 0 9 Table 1 R4 Rs E--~cH)n-x A I
( )0-2 ~ ~, I

Inter- Rs mediate No. A(Y)0 ? B R R E X ~(CH)n~ S~lt 1 benz O -CH9 H O Cl _ CH2~2- -2 benz O -CH2-CoH~ H O Cl _ CH2~2 -3 n~phtht2,3-f~ O -CH9 R O Cl _ CH2 )2-4 ~yrido[~,2-f] o -CH9 H O Cl _ CH2) ~ HC1 ~-Cl-benz O -CB~ H O Cl _ CH2?2-6 7-Br-benz O -CH9 .~ O Cl _ CH2 )2-7 7-Cl-benz O -CH9 ~ O Cl _ CH2 ~2- -8 naphtht2,1-f] O -CH9 H O Cl _ CH2~2-9 7-OCH~-benz O -CH9 H O Cl ~ CH2 2-benz S -CH3 ~ O Cl - c~2 2-

11 pyrido~3,2-f~ S -CH9 H O Cl _ C~)2-

12 naphth~2,3-f] S -CH3 H O Cl _ CH2~2-

13 8-Cl-benz S -CH3 ~ O Cl _ CH~ ~_ _

14 7-Br-benz S -CH3 ~ O Cl ~ CH2 2-n~phtht2Jl-f] S -CH9 ~ Cl _ CH2 )2 -16 pyrido[4,3-f] O -CB3 H O Cl _ CH2~2- HCl 17 pyrido~4-f] O -CH3 H O Cl _ CH2 2- HC1 18 pyridor2.3~f] O -CH3 H O Cl _ CH2 ~- HCl 19 7-Cl-benz S -CH3 H O Cl _ CH2~2-2D 7,9-diiodo-benz O -CH3 ~ O Cl _ CH2)2-21 pyridor~2~f] S -CH9 H O Cl - CHa- HCl 22 pyridot4.3~f] S -CH9 H O Cl _ CH2)2-23 7-OCH9-benz S -CH3 ~ O Cl _ CH2 2-24a b~n~ O -CoHl~ H O Cl ~ CH2 2- -b ben~ O -C2Hs H O Cl ~ CH2 2 - -c benz O -CH(CH9)2 ~ Cl ~ CH2 2-d ben2 O 4-Cl-CoH~~CH2~ ~ Cl ~ CH2 2-e benz O 4-CH3-CoH~-C~2- H O Cl ~ CH2 ~- ~
f benz O 3,5-(OCH3)2- ~ O Cl _ C~ 2-CO~ -CHz-g) ben O 3~CFg-CoH~~CHa~ H Cl -~CH2)2-h) benz O 4-No2-CoH~-C~2- B Cl -(CH2 )2-25a pyridot3,2-f~ O -CoH~- ~ Cl _ CH2)~- RC1 b pyrido~3,2-f~ O -C2H5 ~ O Cl CH2 2- HCL
c pyrido~3.2~f] O -CH(CH~2 ~ O Cl _ CH2 2- HC1 d pyrido[3,2-f] O 4-Cl-CoH~-C~b- ~ O Cl _ CH2)2- HCl e pyrido[3-2~f] O 4-CH~-CoR~-CHk- ~ Cl _ CH2~2- HC1 f) pyrido~,2-~ O ~.5-~OCH9)2- H O Cl _ CH2)2- HCl C~H -CH2-g~ pyrido~ 2-~] 0 3-CF9-C~H~-CH2- H O Cl -~CH~ C1 h~ pyrido~3,2-f] o 4-No2-coH~-cx2- ~ C1 -(CH2)2- HCl .- 26 pyridot3,2-~ 0 -CH~ ~ S Cl -~CE~)2- ~
27 pyridot3,2-~] 5 ¢H9 H S C1 ~ -(C~ )2- - :~
: ( cont . ) ~2~4~3~)9 Table 1 ( cont . ) Inter- R5 mediaee N~. A(Y)0-2 ~ R R4 ~ ~ -(CH)n- salt 2~ pyridor3,4~f] 0 -CH3 H O Cl _ CH2 )2 29 pyrido~3,4-f~ S -CH3 H O Cl _ CH2)2- HCl pyridor3,2-f~ 0 -CH3 H O -CN _ CHb )2-31 pyrido~3,2-f~ 0 -C2Hs H O Cl _ CH2)2- RCl 32 pyridor3,2-f] S -C~H5 H O Cl _ CH2)2- HCl 33 7-Cl-pyrido O -CH3 H O Cl _ CH2)~- ~
~3,2-f~
34 7-Cl-pyrido S -CH3 H O Cl -(CH2 )2-t3,2-f 1 pyridor3~2-f] 0 -C~H~ H O Cl -CH2-36 pyrido~,2-f~ 0 -CH2C9H~ H O Cl -(C~2 )2-~7 pyrido~3,2-f] 0 -CH3 H O l-phtha-limido - CH2)z-38 pyridor3,2-f~ s -CH3 H O ~' _ CH2~2-39 pyrido[3J2-f] S -CH3 H O CN ~ ~H3 pYrid~r3,2-f~ 0 -CH3 H O Cl -c-CH2- HCl 41 pyridot3.2~f~ 0 -CH3 -CH3 0 Cl -(CH2~2- HCl 42 pyridor3~2~f] 0 -CH3 -CH3 0 Cl -(CH2)2-C,H3 43 pyrido~3,2-f] 0 -CH3 H O Cl -CH2-C-Cl HCl 44 pyridor3J2-f~ S -CH3 H O Cl -CHz-C-Cl HCl f~3 H
pyridor3J2-f] S -CH3 H O Cl -C-CH2- HCl 46 ~ o -CH3 H O Cl -(CH2)2-47 ~ S -CH3 H O Cl -(CH2)2- ' ~

~8 CF ~ O -CH9 H O Cl -(C}12 )2- HCl E

CFa S -CH9 H O Cl -(CH2 )2 benz 0 -CH(CH3 )2 H fN~ Cl -CH2 -51 benz O -C2H~ Cl -(CH2 )2-52 6-Cl-pyrido O -CH3 H O Cl -tCH2)2-'[4'3-f]E

53 ~ O -CH3 H O Cl -(C}~

N ~ S -C~ H O Cl -(CH2 )2-( cont . ) . .. .

-135- 1239~309 Table 1 ( cont . ) Inter-mediate R~
No. A(Y~0-2 B R R4 E X ~(C~l~n- Salt N~ O -CH3 H O cl -(CH2 )2-56 N~E E S --CH3 H 0 Cl - ( CH2 )2 -57 ~ 0 -CH3 H 0 Cl -(CH2)2 58 ~ S -CH3 H O Cl -(C1~2 )2-CH~ 0 -CH3 H 0 cl -(cH2 )z- _ 60 CH~ S --CH3 H O Cl -(CH2 )2 61 ~E 0 -CH3 H 0 Cl -(CH2 )2 62 ~ S -CH3 ~ 2 Cl -(CH2 )2 63 (~ 0 -CH3 H 0 Cl -(CH2 )2 64 ~ 5 -C~ O C1 -(C82)8 L~l 1~39~

Example 68~b (Refer to Chart VIII) 2-[2-(Dimeth~lamino)ethyl _ 2,3-dihydropyrido[3,2-~]-1,4-oxazepin-5(4H)-one fumarate [l l]
An 8 g (0.026 mole) sample o~ 2-chloro-N-[4-(dimethyl-amino)-2-hydroxybutyl]-3-pyridinecarboxamide monohydrochloride was partitioned between chlorofrm and dilute sodium hydroxide.
The chloroform was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in 80 ml of dry benzene which was removed on the rotary evaporator (100C./30 min). The residue in 20 ml of dry tetrahydrofuran was added slowly to a stirred suspension of 8.3 g (0.052 mole) of pot-aSsium hydride/mineral oil in 80 ml of dry tetrahydrofuran.
The mixture was stirred at reflux for 4 hr, cooled and treated with lO ml of isopropyl alcohol. The solution was partitioned between isopropyl ether and dilute hydrochloric acid. The acid layer was made basic with sodium hydroxide and extracted 4 times with chloroform. The chloro~orm was concentrated and the residue was chromatographed on HPLC (silica; 90~ ethanol-10% triethylamine). The desired fractions-~were concentrated and the residue (1.3 g) treated with 0.7 g of fumaric acid in 25 ml of isopropyl alcohol. The resulting crystals weighed 1.2 g (13%) and melted at 160-164C.
~nalysis: Calculated ~or Cl6H21N3O6: C,54.69; H,6.02;
N~11.96 Found : C,54.29; H,6.02;
N,11.54 Example 72 2,3-Dihydro-4-m_thy1-2-[2-(methylamino)ethyl]pyrido-~3, 2-f] ~1, 4~-oxaze~ _-5(4H)-one oxalate ~
30To 90 ml of a solution of 30% monomethylamine in ethanol was added 11.0 g (0.04 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-meth~lpyrido[3,2-f]-1,4-oxazepin-5(4H)-one hydro-. ~
.

~L23~

chloride. The solution was heated gradually over a period o~
2 hr to 55C. and held at that temperature overnight.
~ onomethylamine and ethanol were removed by rotary e~aporation (water aspirator, 70C.) and the residue was taken up in 100 ml o~ chlorofrm. The organic layer was washed with dilute aqueous sodium hydroxide (2 x 30 ml), dried over anhydr-ous sodium sulfate, filtered, and concentrated by rotary evaporation (70C, water aspirator). The 9.0 g of crude oil was treated with oxalic acid in isoprcpyl alcohol. The result-ing crystals weighed 8.77 g (67.8%), m.p. 148-50C.
~nalysis: Calculated ~or C14HlgN3O6: C,51.69; H,5.89;
N,12.92 ~ound : C,51.88; H,5.97;
N,12.96 Example 73 2-(2-Aminoethyl) ~ 4-methylpyrido[3,2-f]-[1,4~ oxazepin-5(4H)-one, cumarate [1:1].

_ To a suspension of 17.0 g (0.048 mole) of 2,3-dihydro-2-[1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-4-methylpyrido[3,2-f]oxazepin-5(4H)-one in 100 ml of absolute ethanol was added 3.0 g (0.051 mole~ of 85% hydrazine hydrate in water and the mixture heated to reflux with stirring. In

15 minutes the reaction mixture became clear. After 40 min .~
.. ,~,.

-138- 123~

a copious precipiL~ate of presumably p~haly hydrazide had for~ed. Another 100 ml o~ ~bs~lu~ eth~nol .~as added to ensure good mixing. A~t~r 2 h~ ~t r~flu:c, the cooled mixture was ~iltered. The fil~rat~ was conce~trat2d on the rotary evaporator (water aspirator, ~0C.) .~l~d th~ r3sidue taken up in 75 ml of chloroform. The organic l~yer r.~as washed with dilute aqueous ~odium hydroxi~e (2 x 3 ml), dried over anhydrous -odium sulfate, filtered, and the riltrate concen-trated by rotary evaporation (wa.er aspirator, 75C.). The residua was treatea with fumaric acid in isopropyl alcohol and yielded 7.0 g (43%) of pale white crystals, m.p.
195-197C.
Analysis: calculated for Cl5Hl8N30~: C,53-41~ H~5.~8;
N,12.46 Fou~d : C,5~.63; H,5-7~
N,12.33 ~xam~le 74 2 - ( 2 -Am ino e thyl ) -2, ~ - dihydro-4-methylpyrido r 3,2-f~ 4 oxazepin-5(4H)-thione, fumarate ~2~
-To a suspension of 12.15 (0.033 mole) of 2-~2-(2,3-dihydro-5(4H)- thioxopyridoC3~2-f]~1,4~oxazepin-2-yl)ethyl]-lH-isoindole-1,3(2H)dione in 150 ml of absolute ethanol was added 2.o8 g (0.035 mole) of an 85~ solution of hydrazine hydrate in water. The mixture was heated to rèflux for 2 hrs.
After cooling, solid phthalylnydrazide w~s filtered off.
Ethanol was removed by rotary evaporation (85C.Jwater aspirator) and the residue partitioned between 180 ml chloroform and 50 ml dilute aqueous sodium hydroxide. The organic layer was washed further with dilute aqueous sodium hydroxide (3 x 30 ml), dried over anhydrous sodium sulfate, ~iltered and concen-trated by rotary evaporation (water aspirator, 70 C.). The crude oil was treated with fumaric acid in isopropyl alcohol which yielded 6.70 g (68.7 O o~ pale yellow crystals m.p. 208-ogc.
Analysis: Calculated for Cl9Hl7N3O3S: C,52.87; H,5.80;
~, 14 .23 Found : C,52.72; R,5.81;
~l14.16 ..~

-~2~ 309 Example 7~, 2,3-Dihydro-4-methyl-2~2-~(l-methylethyl)aminolethyl Pyridor3~2-f~ 4~oxazepin-5(4H)-one~ fumarate ~1:2~.
To a solution of 2.52 g ~0.011 mole) of 2-(2-amin~ethyl)-2~3-dihydro-4-methylpyridoc3~2-l']cl,4]oxazepin-5(l~H)-one in 5 50 ml dry methanol was added meth~nolic hydrogen chloride until pH 6 was reached. To t~lis sol~ltion was added 3.29 g ~0.057 mole) of acetone, 1.79 g (0.029 mole) of sodium cyanoborohydride and 5 g 3A molecular sieves. The pH was checked and readjusted to pH 7-8 with methanolic hydrogen 10 chloride and stirred 24 hr at room temperatuxe. The reaction mixture was ~iltered, and concentrated by rotary evaporation (70 C., water aspirator). The residue was taken up in 100 ml of chloroform, washed with dilute aqueous sodium hydroxide, dried over anhydrous sodium sulfate, filtered, 15 and concentrated by rotary evaporation (water aspirator, 70 C.). The residue was treated with fumaric acid in isopropyl alcohol which gave 1.58 g (29~) of white crystals~
m.p. 152-153 C.
Analysis: Calculated for C22H29N3Olo: C,53.33; H,5.89;
~,8.48 Found : C,53.43; H,5.94 N,8.54 Examl~le 76 2-~2-[Bis(phenylmethyl)amino~ethyll-2,3-dihydro~4-methylpyridor3,2-fl[1,41oxazepine-5(4H)-thione~ fumarate ~1:11.
To a solution of 3.16 g (0.013 mole) of 2-(2-aminoethyl)-2, 5-dihydro-4-methylpyrido~3,2-f~[1,4]oxazepine-5(4H)-thione in ~25 ml dry methanol was added methanolic hydrogen chloride to pH 5-6, followed by~ 2~3 g ~iA molecular sieves, 6.89 g (0.065 mole) benzaldehyde and 2.04 g (0.0325 g)sodium cyano-borohydride. The pH was again adjusted to pH 7 with methanolic hydrogen chloride. After 6 hr of stirring at room temperature, TLC (eluting with 6% triethylamine in methanol) ~howed what appeared to be exclusively monoalkylated product with very little starting material. To the reaction mixture was then ~dded 1.0 g (0.009 mole) o~ benzaldehyde and the mixture 6tirred overnight at room temperature. The reaction mixture was filtered and concentrated by rotary evaporatic~n (70 C., f ~1 -140- ~Z3~9 water aspirator). The residue was taken up in 100 ml of chloroform and washed with 2 x ~0 ml dilute aqueous sodium hydroxide. The chloroform ~as remDved ~y rotary evaporation (70 C., water aspirator). The residu~ was dissolved in 100 ml dilute hydrochloric acid which was subsequently washed with 2 x 30 ml ethyl acetate, made basic with dilute aqueous sodium hydroxide, extracted with 4 x 30 ml chloroform. The chloroform was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (70C, water aspirator. The residue showed both the mono- and di-alkylated product by TLC (6~ triethylamine/g4 methanol) and NMR.
To a solution of the 3.0 g crude material dissolved in 30 ml dry methanol was added methanolic hydrogen chloride to pH 4-5, 10.0 g (I0.094 mole) of benzaldehyde and 2~00 g (0.0319 mole) of sodium cy~noborohydride. The pH was neutral.
To the reaction mixture was added ~l g of ~A molecular sieves. The reaction mixture was stirred for 6 days at room temperature.
The methanol was removed by rotary evaporation ~70C, water aspirator) after filtration. The residu~ was dissolved in ~100 ml chloroform and washed with 2 x 50 ml dilute aqueous sodium hydroxide. The chloroform was removed by rotary evaporation (70, water aspirator) and the residue dissolved in 100 ml of dilute aqueous hydrochloric acid.
The aqueous layer was washed with 2 x 50 ml of ethyl acetate tthe ethyl acetate was extracted with 2 x ~0 ml of dilute hydrochloric acid and all acid layers combined; this was done because the product appeared to be somewhat soluble in ethyl acetate). The hydrochloric acid layer was made basic with concentrated sodium hydroxide solution and extracted with 2 x 50 ml of chloroform. The chloro~orm layer was dried over anhydrous 50dium sulfate, ~iltered ~nd concentrated by rotary evaporation (70 C, water aspirator. The 3.0 g of crude product obtained was dissolved in hot isopropyl alcohol)and treated with fumaric acid. The resulting crystals, 1.40 g (20.2%), melted at 123-12~ C. with slight shrinkage occurring at 118 C.
Analysis: Calculated for C2sR~lN3o~s: C,65.27; H,5.86: N,7.87 Found : ~,65.11; H,5.87; N,8.o5 ~l ~
r:~

-141_ ~34~

~xa~ple 77 2,3-Dihydro-4-meth~ 2-r2~ -methyl-l-piperazinyl)eth . _ ~ . . _ _ pyrido~3,2-~ ~ xazeDin-5(4H)-one fumarate ~1:2~mono-hydrate.
. .
To a solution of 10.45 g (0.043 mole) of 2-(2-chlGro ethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1~ll-oXazepine-5(4H)-one in 80 ml of absolute ethanol was added 10.84 g (0.1084 mole) of N-methyl piperazine and the resulting solution heated to reflux for 4 hr. ~t that time, because ~25% starting material was present by mass spec, an additional 5.0 g (0.05 mole) of N-methyl piperazine was added and heating to reflux was continued for 2 hr. Ethanol was removed by rotary evaporation (70, water aspirator) and the residue diluted with 150 ml of water. The water was extracted with 4 x 50 ml of chloro-form and the organic layer was washed with 2 x 50 ml of water, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (70CJ water aspirator). The residue was concentrated (vacuum pump/95-100C.) for ~.5 hr. Treat-ment of the residue with fumaric acid in isopropyl alcohol yielded 8.45 g (~5.4%) of pale white crystals, m.p. 162 157C.
Analysis: calculated for C24H34N~0ll: C,51.98; H,6.17;
N,10.10 Found : C,52.03; H/6.oo;
N,10.17 Example ~8 2~-DihYdro-4-met~y~l-2---r2-(4-methyl-l-p~e-erazinyl)eth ~ I_4:oxa ~ e-~L4H ~thion ~ 1-2 hemihvdrate.
To 8.o g t0.031 mole of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-f]-1,4-oxazepine-5-t4H)-thione in 80 ml of absolute ethanol was added 9.30 g (0.093 mole) of N-m~thyl piperazine. The mixture was heated to reflux for 2 hr and an additional 5.0 g (0.05 mole) N-methyl piperazine was added. Reflux was continued for an additional 5 hr.
Ethanol was removed by rotary evaporation ~90C, water aspirator). Residual N-methyl piperazine was r~moved at 90 C. with vacuum pump ~or 2 hr. The residue was taken up in 150 ml of chloroform and washed with 2 x 50 ml of water.
~he organic layer was ~ried over anhydrous sodium sul~ate, filtered and concentrated by rotary evaporation (90C, water ,~
.. ~. .. -. .
.:

-142- 123~9 aspirator). The residue was concentrated ~urther with a vacuum pump at goc. The 10.0 g or crude material was treated with fumaric acid in isopropyl alcohol which yielded 10.0 g (57.4~) or light yellow ~rystals, m.p. 184-185 C.
Analysis: Calculated ~or C24H33N4o9~5s:c~5l~32~ H,5.92;
~J,g.98 Found :C,51.56; H,5.89;
N,9.8 Exampl~ 7 2-r2-~4-rBis(4-fluorophenyl)methyll-1-pipPridinyl ethyl~-2,3-dihydro-4-methylpyridor~,2-f~ 4l-xaZepin-5(4H) one dihvdrochloride hemih~drate.
_ Ten grams (o.o36 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyridor3,2-f]-1,4-oxazepin-5-(4H)-one hydrochloride were partitioned between dilute sodium hydroxide and chloroform. The chloroform was dried over sodium sulfate and concentrated on the rotary evaporator. The residue was dissolved in 50 ml of ethanol and 10.3 g (o.o36 mole) of 4-~bis(4-fluorophenyl)-methyl~piperidine was added. The solution was heated to reflux for 18 hr and concentrated on the rotary evaporator. The residue was partitioned between dilute sodium hydroxide and chloroform. The chloroform was dried over anhydrous sodium sul~ate and concentrated. The residue was chromatographed on a ~aters 500 HPlC (silica/92~ ethyl acetate-8~ triethylamine). After concentration of the desired product, the residue was dissolved in isopropyl alcohol and treated with ethereal hydrogen chloride. The resulting crystals weighed 3 g (14~) and melted at 160-180C.
Analysis- Calculated for Cs~H6sN~o5clqF4: C,60.73; H,5.98 N,7.33 Found : C,60.60; H,6~o4 N,7.12 ExamPle 80 2-r2-(4,~-Dihxdro-lH-imidazol-2-yl)ethyl]-2 ,3-dih5~dro-4-methylp5Jridor3,2-flrl,4]oxazepin-~(4H~-one oxalate ~1.1~.
Into a cooled (water bath) ~olution of 10 g (0.043 mole) of 2,3,4,5-tetrahydro-4-methyl-5-oxopyrido[3,2-f~1,4]
oxazepine-2-propane-nitrile in 50 ml of ethylenediamine wa~
bubbled hydrogen ~ulfide gas for 10 min. The reaction flask r~ i~
>,~

-~:34~

was tightly stoppered and left standing at room temperature for 5 days. The reaction solution ~now parti~lly solidified) was dilut~d with 100 ml of dilute 30dium hydro~ide and extract~d with 5 x 30 ml of chloroform. The organic extracts were dried over anhydrous sodium sul~ate, filtered, and concentrated by xotary evapora'ion (70C. water aspirat~r).
The entire residue was dissolved in 50 ml or ethylenediamine and saturated with hydro~en sulfide ~or 10 minutes while cooling in a water bath. ~he ~lask was tightly stoppered and left standing at room temperature for 5 days. The contents of the rPaction flas~ were diluted with 200 ml of 2N
aqueous potassium hydroxide and extracted with ~ x 125 ml of chloroform. The organic extracts were washed ~ith ~ x 50 ml 2N aqueous potassium hydroxide and extracted into 3 x 50 ml of dilute aqueous hydrochloric acid. The acid extxacts were basified with concentrated sodium hydroxide and extracted into 3 x 40 ml of cnlofoform. The organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation. The syrupy residue was treated with oxalic acid in isopropyl alcohol to give 3.5 g (22 O of white crystals.
One recrystallization from isopropyl alcohol afforded an analyti~al sample, m.p. 198C. with decomposition.
Analysis: Calculated for Cl6H2lN~O6: C,52.74; H,5.53;
N,15.38 Found : C,52.76; H,5.58;
N,15-51 Exam~le 81 2,~-Dihydro-4-methyl-2-~2-(methylphenyl~mino)ethyl pyridor3,2-~ ~ pine-5(4H)-thione.
To a suspension of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]~1,4]oxazepine-5(4H)-thione in 100 ml of toluene was added 11.49 g to-ll mole) ~-methylaniline and the mixture heated to reflux with stirring for 2 days ~after approx. 6 hr, 23.0 9 (0.22 mole) additional N-methylaniline was added). Toluene was removed by rotary evaporation (90 C., water aspirator). The N-methylaniline was removed also by rotary evaporation (90 C., vacuum pumpj. The resid~e was taken up in 100 ml of chloroform and washed with ~ x 30 ml dilute aqueous sodium hydroxide. The organic layer was dried over anhydrous 80dium sulfate, ~iltered and concentrated -144- ~4~09 by rotary evaporation (80~C., water aspirator). More N-methylaniline was removed with th~ vacuum purnp at 90C.
ror several hours. To the residue ~as added 150 ml of ethyl acetate at which point some product crystallized out.
However, since much remainod in solution, preparative HPLC
on a silica gel col~mn eluting with 60$ hexane/40% eth~l acetate was effected. After concentrating the flasXs containing the product, crystallization ~as effected induced by seeding. The chromatographed product was recrystallized from ethyl acetate/isop~opyl alcohol and amounted to 1.1 g m.p. 164-5C. Approximately 2 g additional was collected by r~crystallization of crude product, m.p. 163-4 C. The combined yield was 3.1 g (26~).
Analysis: Calculated for Cl8~2lN30S: C,66.03, H,6.46;
N,12.83 Found C,65.72; H,6.51 N,1~.13 ExamDle 82 2-(~-AminoT~ro~Yl)-2 .3-dihvdro-4-methylpyridor~2-f~rl ,4 oxazepine-~(4H)-thione fumarate ~
A sample of 15.0 g (o.o64 mole) of 2-(3-aminopropyl)-2,3-dihydro-4-methylpyrido~3,2-f]rlJ43-oxazepin-5(4H)-one was dissolved in 50 ml methylene chioride and to it was added 15.24 g (0.07 mole) of di-tertbutyl dicarbonate. The sol~tion was stixred for 30 minutes at room temperature. The protected amin~ was purifled by HPLC on a silica gel column, eluting with ethyl acetate. ~pproximately 15 g (0.045 mole 70-30 of the protected amine was collected as an oil. To a solutio~ of 1~.5 g (0.04 mole) of this oil in dry toluene was added 8.15 g (0.02 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide. The reaction mixture was heated to 80C. for 2 hr. An additional amount (2.0 ~, 0.005 mole) of 2,4-bis(4-methoxyphenyl)-1,~-dithia-2,4-di~hosphetane-2~4-disulfide was added and heating continued for 1 hr. Another 4.0 g (0.01 mole) of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide was added and the heating continued for 5 hr. After cooling, the toluene was decanted off, washed with 5 x 30 ml dilute aqueous sodium hydroxide, dried over sodium ~ulfate, filtered and concentrated by rotary evaporation. Isopropyl alcohol ~ ,";......................................... .

~234~09 was added to the residue, resultir.g in precipi~ation of an im~urity (possibly spent LawessDn's Reagent). Isopr~pyl alcohol was removed by rotary ~vaporation and the residue purified by HPLC on a silica gel column, eluting with 1%
methanol/99~ chloroform. Approximately 6 g (0.017 mole, 42.6~) of ~aterial was collected and treated with 100 ml of a solution of trifluoro acetic acid,~anisole/methylen2 chloride, 40/10/50, v/v/v for ~0 minutes. The solvent blend was removed by rotary ~vaporation (70C, water aspirator) and the residue taken up in 150 ml ~f methylene chl~ride.
This layer was washed with ~ x 40 ml di'ute a~ueous s~dium hydroxide) dried over anhydrou3 sodium ~ulfate, filtered and concentrated by rotary evaporation. The residue was treated with fumaric acid in isopropyl alcohol, which yielded 4.0 g (0.011 mole, 64~) of the salt. Recrystallization fr~m isopropyl alcohol afforded an analytical sample, m.p.
154-166C.
Analysis: Calculated for Cl~H21N20s: C,52.30, H,5.76;
N311.43 Found : C,52.43; H,5.83:
N,11.51 Exam~le_8 2-r2-(Dimeth~amino~ethYl]-2 ,~-dih~dropvridor3,2-flrl,4 oxaze~ine-5~4~)-thione dihydrochloride monohydrate.
To 5 g ~0.021 mole of 2-~2-(dimethylamino)ethy~ -2,~-dihydropyridot3,2-f]-1,4-oxazepin-5(4H)-one in 50 ml of pyridine was added 5.1 g (o.o46 mole) Df phosphorus penta-sulfide. An exothermic reaction insued, When the temperature dropped, the mixture was heated to 70 C. for 3.5 hr and allowed to cool. The mixture was partitioned between dilute sodium hydroxide and chloroform while cooling by addition ~o of ice. The aqueous layer was extracted ~ more times with chloroform. The combined chlofoform extracts were dried over anhydrous sodium s~lfate and concentrated. The residue was dissolved in 40 ml of ethanol and made acidic with ethereal hydrogen chloride. The resulting crystals were recrystal-lized from 95~ ethanol. Yield was 1.4 g (190 , m.p. 172-175C.

l Y
,,, .~ .
, ,~

-146~ 0 Analysis: calculated ~or Cl2H2lN~S02C12: C,42.1~ H,6.1~
N, 1~ .2~3 ~ound : C,42.~6; H,5.74 N,12.3l1 Example 84 2-~2-~4-tBis(4-fluorophenyl)methy~ piperidinyl~eth 2J3-dihydro-4-methylpyridor3,2-flrlJ41oxazepine-5(4H)-thione oxalate hydrate ~1:1:1~.
A solutio~ of 4 y (0.016 mole) of 2-(2-chloroethyl)-2~3-dihydro-4-methylpyrido[~,2-f]~1,4]-oxazepine-5(4H)-thione and 4.5 g (0.016 mole) of 4-~bis(4-fluorophenyl)-methyl]piperidine in 100 ml of ethanol was refluxed for 48 hr.
One gram of K2C03 was added and this mixture stirred at reflux for 144 hr. The mixture was concentrated and the residue partitioned between chloroform and dilute sodium hydroxide. The chloroform was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a Waters~ 500 HPLC using a silica column and eluting with absolute ethanol. The material with mass 507 was collected and concentrated. The residue (6 g) was reacted with 1.2 g of oxalic acid in ethanol. Yield was S g, m.p. 125-138 C.
Analysis: Calculated for C3lH35N30~SF2: C,60.47, HJ5~72 - N,6.8~
Found : C,60.62 H,5.60:
N,6.58 Example 8~
2~3-Dihvdro--4-methyl-2-r2-(lH-pyra ol~ et~vl~p~ o t3 2-f~[l 4~oxazepine-~(4H)-thione.
To a suspension of 2.16 g to.o54 mole) of sodium hydride in 20 ml of dimethylformamide was added dropwise a solution o~ 2.92 g (0.043 mole~of pyrazole in 10 ml of dimethyl-~0 formamide. There was a slight exotherm at this point withsome evolution of hydrogen gas. The resulting solution was then added dropwise to a solution of 10.0 g (0.039 mole) of 2-~2-chloroethyl)-2,~-dihydro-4-methylpyridoE3,2-f~-1,4-oxazepine-5(4H)-thione in ~0 ml of dimethylformamide. The ~5 reaction ~ask was sealed and stirred overnight at room temperature.
The solvent dimethylformamide was removed by rotary evaporation ~90 C; 30 mm). The residue was taken up in 200 ml of chloroform which was subsequently washed with 2 x 50 ml -147- ~234~09 of water followed by 50 ml dil. aaueous sodium hydroxide.
The organic layer was then dried over sodium sulfate, filtered and concentrated by rotary evaporation (70 C.; 30 mm).
Isopropyl alcohol was added to the residue and crystallization ensued after cooling. The crude crystals (4.5 g) were recrystallized from isopropyl alcohol giving 3.45 g (31~) of yellow crystals, m.p. 119-121C.
Analysis: calculated for Cl4HlBN40S: C~58.3l; H,5.59;
N,19.4 Found : c,58.01; H,5.59;
N,19.37 Example 86 2-r?-(Dimethylamino~ l-methvlethyl]-2,3-dihydro-4-methvlpvrido~ 2-f~ 4]-oxazePin-5(4H)-one oxalate ~1:1~.
To 4.5 g (0.018 mole of 2-(2-chloro-1-methylethyl)-2,~-dihydro-4-methylpyrido~3,2-f]-1,4-oxazepin-5(4H)-one was added 20 ml of methanol and 40 ml of dimethylamine.
The reaction flask was tightly sealed and left standing at room temperature for 72 hr. The flask was opened after cooling and the methanol and dimethylamine evaporated.
Another 15 ml of methanol and 40 ml of dimethylamine were added, the flask sealed tightly and left standing at room temperature for 7 days. The methanol and dimethylamine were evaporated and the residue taken up in 100 ml of chloroform. The chloroform layer was washed with 2 x 50 ml dil sodium hydroxide and 50 ml of water, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The crude material which was collected was treated with oxalic acid in isopropyl alcohol which afforded 3.5 g (55 0 white crystals, m.p. 204-05C.
Analysis: calculated for Cl~H23N30~: C,54.38; H,6.56 N,11.89 Found : C,54.32; H,6.61, N,11.86 ,, -1~8~ 0 9 Example 87 2 ~-Dihydro-2-r2-(4 s-dihydro-lH-imidazol-2-yl)eth 4-methylpyridoL~l2-f~rl~4]-oxazepine-~(4H)-thione oxalate ~2~
Into a suspension of 2,~,4,5-tetrahydro-4-methyl-5-thioxopyrido[3,2-f~[1,4]-oxazepine-2-propanenitrile in 30 ml of ethylene diamine was bubbled hydrogen sulfide gas for 15 min while cooling in a water bath. The ~lask was then sealed and stirred at room temperature for ~ days. Mass spectra showed much starting material. An additional 15 ml lG of methylene diamine was added and the mixtur~ saturated again with hydrogen sulfide. The flask was resealed and left standing for 8 days. The reaction mixture was diluted with 100 ml dil aqueous sodium hydroxide and extracted into 3 x 60 ml of chloroform. The chl~roform extracts were combined and washed with 5Q ml o~ water. Some crystal-lization occurred in the separatory funnel but complete crystallization could not be effected. The organic layer was concentrated by rotary evaporation and the residue treated with oxalic acid in isopropyl alcohol. The crude crystals, 7.0 g, (55 0 were recrystallized from methanol/
ethanol yielding an analytical sampleJ m.p. 198-200C.
Analysis: Calculated fox Cl7H2lN407S: C,47.99: ~,4.97;
N,13.16 Found : C,47.63; H,5.09;
N,13.04 Example 88 2-r2-(Dimethylamino)ethyll-2,3-dihydro-2,4-dimethyl-. _ . _ . .
pyridot3,2-fl~l,4~oxazepin-5(4H)-one dihydrochloride.
_ To 4.5 g (0.015 mole) of 2-(2-chloroethyl)-2~-dihydr 2,4-dimethylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one hydro-~0 chloride in 15 ml of methanol was added 40 ml of dimethylamine. The flask was ~ealed tightly and left standing at room temperature for 8 days. The methanol and dimethylamine were removed by rotary evaporation (70C; ~0 mm). The residue was taken up in 150 ml of chloroform, washed with 2 x 50 ml dil aqueou~ sodium hydroxide, dried over anhydrous sodium sulfate~ filtered and concentrated by rotary evaporation (70 C; ~0 mm). The syrupy residue was ~.
. . .~

-1~9- ~234~9 txeated with hydrogen chloride in isopropyl alcohol, which afforded ~-5 g (~70 of white crystals, m.p. 188-93 C.
Analysis: Calculated ~or Cl4~29N30~cl~: C,50~01; H,6.89;
~J,12.50 Found : c,50.00; H~6.g8 ~q, 1~ . IJ9 Exam~le 82 2-r2-(Dimethylamino)ethyl~-2~3-dih~dro-?~l~-dimeth~
pyrido~3~2-flrl~4loxazepine-5(4H)-thione monohydrochloride.
To a suspension of 4.5 g (0.017 mola) of 2-(2-chloro-ethyl)-2,3-dihydro-2,4-dimethylpyrido~3,2-~-lJ4-oxazepine-5(4H)-thione in 20 ml of methanol, cooled in an ice bath, was added 40 ml of dimethylamine. The flask was sealed tightly and left standing at room temperature for 10 days.
The dimethylamine and methanol were removed by xotary evaporation (60C; 30 mm). The residue was taken up in 150 ml of chloroform, washed with 3 x 50 ml dil sodium hydroxide, dried over anhydrous sodium sul~ate, filtsred and concentrated by rotary evaporation ~70C; 30 mm). The crude oil was dissolved in isopropyl alcohol and treated with ethereal hydrogen chloride, which yielded 4.0 g (76%) of yellow crystals, m.p. 255~C. with decomposition.
Analysis: Calculated for C 1 4H2 ~ ~3OSC1 : C,5~,23; ~,7.02;
NJ 13 .30 Found : C,53.21; H,7.15;
N,13.19 Exam~le ~0 (Re~er to Chart VII) 2-r2-(Dimethylamino)ethyl~-2,3-dihydro-4-methyl~1,4~-. . _ oxazepinQ~6,7-c1quinolin-5t4H)-one oxalate ~1 ~ .
To a 6uspension of 19.4 g (35% in oil, 0.172 mole) of XH in 150 ml tetrahydrofuran was added at a rapid drop 12.4 g (o.o85 mole) of 1-dimethylamino-4-methylamino-2-butanol.
After 10 minutes, 20 g (o.o85 mole) o~ ~-carboxyethyl 4-chloroquinoline was added by a powder dropping funnel over a period of 30 min. The mixture was ~tirred at room temperature overnight.
Approximately 50 ml or water was added to quench the reaction and the mixture partitioned between isopropyl ether and water. The aqueous layer was extr~cted again with 2 x 70.ml of i~opr~pyl ether. The auueous layer was then~
' :

r ~

~l234~09 continuously extracted for 15 hr with chloroform. The chloro-form layer was collected, filtered and concentrated by rotary evaporation (80C, 30 mm). The crude material (18 g) was purified by HPLC using silica gel as the stationary phase and 3% triethylamine/ethanol as the eluent. Appro~imately 4 g (15.6%) of reasonably pure free base of the title compound was collected. A 1.5 g sample of the free base was reacted with 0.5 q oxalic acid in 10 ml of ethanol. The resulting cyrstals weighed 2 g and melted at 214-218 C.
Analysis: calculated for ClgH23N3O6: C,58.60; H,5.95; N,10.79 Found : C,58.46: H,6.10; N,10.75 Example 91 2-~2-(Dimethylamino)-l-methylethyll-2,3-dihydro-4-methylpyridor3,2-fl~1,4~-oxazepine-5(4H)-thione oxalate ~1:11.
To a suspension of 4.0 g (0.013 mole) of 2-(2-chloxo-1-methylethyl)-2,3-dihydro-4-methylpyrido~3,2-f]~1,4]oxaPepine-5(4H)-thione hydrochloride in 20 ml of methanol cooled in an ice bath was added 35 ml of dimethylamine previously collected at C. The reaction flask was sealed tightly and left standing at room temperature for 10 days. The solvent was removed by rotary evaporation (80C, water aspirator) and the residue taken up in 150 ml of chloroform. The organi-c layer was washed with 2 x 50 ml of dilute aoueous sodium hydroxide, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The crude residue was treated with oxalic acid in isopropyl alcohol and left standing overnight at room temperature, yielding 3-1 9 (65O
of yellow crystals, m.p. 211-213C.
Analysis: Calculated for C~e,~30sN3S: C,52.02: H,6.18; ~,11.37 Found : C,51.79: H,6.34: N,11.24 ExamPle 92 2-~2-tDimethYlamino)propyl~-2~3-dihvdro-4-meth~Eyrido r ~,2-f~1,41oxazepin-5(4H)-one dihydrochloride~
Into a ~tain}ess steel bomb was placed 1.0 g ~odium iodide, 5.0 g (0.017 mole) of 2-(2-chloropropyl)-2,3_ dihydro-4-methylpyridO~3,2-f~1,4]oxazePin-5(4H)-one and 40 ml of dimethylamine. The bomb was sealed tightly, placed -151- 1~34~9 in the oven at 60C. and rolled conti~uously for 7 days.
The bomb was allowed to stand at room t~mperature for several days. The residue was combined with that of a previous run of equal size ~nd separated via column chromatography using silica gel and eluting with ethanol and then with ~ tri-ethylamine/ethanol. The fractions containing the desired product were combined and concentrated by rotary evaporation ~80C, ~0 mm). The residue was taken up in 150 ml or chloroform and washed with 2 x 50 ml diluted sodium hydroxide.
The chloroform was removed by rotaxy evaporation (70 C., 30 mm) and the residue treated with ethereal hydrogen chloride and hydrogen chloride in isopropyl alcohol. The white crystals which were collected weighed 3 g (28%), m.p. 173-76C.
Analysis: Calculated for Cl4H23~202Cl2: C,50.01; H,6.89;
N,12.50 Found : C,50.40; ~,7.04 N,12.~6 Exam~le 9~
2,~-Dihydro-4-methvl-2-r?-(2-methyl-l-pyrrolidinyl) ethyl~pyridor3,2-f~1,4~oxazepine-~(4H~-thione fumarate com~ound with 2-Pro~anol r To a suspension of 5.0 g (0.019 mole) of 2-(2-chloroethyl) 2,3-dihydro-4-methylpyrido~,2-f~-1,4-oxazepine-5(4H)-thione in 25 ml of absolute ethanol was added 3.5 g (0.0 mole) of 2-methylpyrrolidine. The mixture was heated to reflux for 6.5 hr and left standing at room temperature overnight. Mass spec and TLC showed presence of starting materials. Approximately 5 g of potassium carbonate was added and heating at reflux was continued for 24 hr.
Ethanol was removed by rotary evaporation (70C, 30 mm). The residue was taken up in 100 ml of methylene chloride and washed with 2 x 50 ml dil- aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation (70C, ~5 ~0 mm). The residual syrup was dissolved in isoprspyl aocohol and treated with fumaric acid affording 4.5 g (0.01 mole, 49.2 O of crude crystals- ~o recrystallizations from isopropyl afforded 1-5 g (16.4%) of yellow crystals, , .. .

-152- 123~0~

m.p., 92-95C.
Analysis: Calculated for C23H35N30~S: C,57.36; H,7.33, N,8.72 Found : C,57.12i H,7.30;
N,8.70 Exam~le 94 2-r2-(Dimeth~71amino)ethyll-2,~-dihydro-4-methyl-9-(trifluormethyl)-~1,4~oxazepino~6,7-c~quinolin-5(4H)-one fumarate r ~
To 55 ml of dimethylamine collected over an ice/methanol bath was added 2.2 9 (0.005 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-9-(trifluoromethyl)-1,4-oxazepino~6,7-c]
quinolin-5(4H)-one hydrochloride. The flask was sealed tightly and left standing at room temperature for 6 days.
After cooling to 0C. J the flask was opened and the solvent allowed to evaporate at room temperature overnight~ The xesidue was taken up in 100 ml of chloroform, washed with 3 x 30 ml of dil sodium hydroxide, dried over anhydrous sodium sulfate and concentrated to rotary evaporation (70 C, 30 mm). The residual oil was treated with fumaric acid in isopropyl alcohol and dried, giving 2.2 g (81~) of white crystals, m.p. 204-05C.
Analysis: Calculated for C22H24N3O~F3: C,54.66; H,5.00;
N~8.69 Found : C,54.74, H,5.12:
N,8-55 Example 9~
2i2-(DimethYlamino)ethYl]-2,3-dihYdro-4-methY1~1,41-oxazepino~6.7-b~quinolin-~(4~)-one fumarate hYdrate ~1:1:0 To 40 ml o~ dimethylamine cooled to ~0 C. in an ice water bath was added 3.85 g (0.013 mole) of 2-(2-chloro ethyl)-2,3-dihydro-4-methyl-1,4-oxazepinor6,7-b]-quinoline-5(4H)-one in 25 ml of methanol. The reaction flask was sealed tightly and left standing at room temperature fcr 5 days. After cooling, the reaction flask was opened and the solvent allowed to evaporate in a stream of air. The residue was taken up in 100 ml of chloroform and wa~hed with 2 x 50 ml of dilute aqueous sodium hydroxide. The organic layer was dried over anhydrous ~odium sulfate~ filtered~ and concentrated by rotary evaporation (70 J 30 mm) . The -153- ~234~0~

residual oil was treated with fumaric ~cid in isopropyl alcohol whicn afforded 3.7 g (67%) o~ w~ite crys~alsJ
m.p. 125-130C.
Analysis: Calculated for C21H2~N~0~.5: C,59.4~; H, 17;
N,9.90 Found : c,sg.s9; H,6.35;
N,9.oO
Example 95 2-~2-(Dime~hylamino)ethyl~-2,3-di~ydr~-4-methylrl,4 oxazepin~E5,7-blquinoline-5(4H)-thione ~mar~te com~ou~d with isopropanol hydrate ~ 0.5:0.5~.
To 45 ml of dimethylamine was added 0.95 g (0.003 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino ~6~7-b]quinoline-5(4H)-thione~ The reaction flask was sealed tightly and left standing at room temperature for 6 days.
After cooling to 0C., the flask was opened and the solvent allowed to evaporate at room temperature. The residue was taken up in 50 ml of chloroform and washed with 3 x 30 ml of dilute aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate, filt~ored, and concen-trated by rotary evaporation, yielding 0.94 g of syrup (99~).
This was combined with 1.0 g of the same product rom a previous run* and trea.ed with fumaric acid in isopropyl alcohol affording 1.5 g of yellow crystalsJ m.p.l23-26 C.
*Tha previous run was made in the same manner as above except that hydrochloride salt was collected. However, the hydrochloride salt partially decomposed upon drying in a drying pistol at 82.5 C. Caution should be exercised not to heat the product above the boiling point of acetone (56-57C) while drying.
Analysis: Calculated for C22~5H3oN3o~s:c~57~43; H,6.43;
N,8.92 Found :C,57.60; H,6.21:
N,9.02 -154- 123~09 Exam2le 97 4-Ethvl-1~2~3~4-tetrahydro-2-t2 -(~J-hydroxY-4-phenvl-1-piperidinyl)-ethyl~-l-methv~ H-l 4-b~nzodiazepin-5-one fumarate compound with 2-~ropanol r ~
A mixture o~ 13.4 g (o.o5 mole) of 2-(2-chloroethyl)-5 4-ethyl-l-methyl-l,2~,4-tetrahydro-sH-l~4-benzodiazepin-5-one, 8.85 g (0.05 mole) of 4-hydroxy-4-phenylpiperidine) and 14 g (0.1 mole) of potassium carbonate in 100 ml of n-butanol was refluxed for 18 hr and fil~ered. The filtrate was concentrated and the residue partitioned between chloroform 10 and dilute sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a 4.5 x 45 cm Florisil~) column eluting with chloroform-methanol mixture with a gradation from 100~ to 84% chloroform. The fractions containing the 15 pure product (as seen on tlc using 95~ chloroform-5~ methanol on Florisilfi)) were combined and concentrated. The residue was molecularly distilled at 250C. and 0.02 ITun Hg. The fumarate salt was prepared in isopropyl alcohol and recrystallized from isopropyl alcohol-water. Yield 5.8 g.
(20~) m.p. 12&-139C.
Analysis: calculated for C32Hd5N307: C,65.85; H,7.77 N,7.20 Found: C,64.85; H,7 4 N,~.0 Examl~le 98 4-E a~b~holln~e~
hYdro-~H-1,4-benzodiazepin-~-one.
A solution of 30 g (0.112 mole) of 2-(2-chloroethyl)-4-ethyl-1-methyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one in 70 ml of morpholine was refluxed for 3 hrs, concen-trated on the rotary evaporator and the residue partitioned between chloroform and dilute sodium hydroxide. The chloro-form was dried over anhydrous sodium sulfate and ~oncentrated on the rotary evaporator. The residue was crystallized twice from isopropyl ether containing a small amount o~
ethanol, m.p. 128-148 C. Recrystallization from toluene gave 19.5 g (61%) of product, m.p. 128-148C.
Analysis: Calculated for Cl~H272~90z :C,68.11; ~1,8.~7; N~13.24 Found-:C,58.29; H 8.57; ~,13.26 . "

-155- 1 2 3 4 ~0 9 Example 99 l~2~4-Tet ~ ro-l-methyl-2-~(dimethylamino)methyl1-4-(1-methylethyl)-5H-1,4-benzodiazepin-5-one.
_ _ _ _ A mixture of 5.0 g (0.02 mole) of 2-chloromethyl-1,2,3,4-tetrahydro-1-methyl-4-(1-methylethyl)-5H-lJ4-benzodiazepin-5-one, and 15.0 g (0.45 mole) of dimethyl-amine, and 200 ml of methanol were placed in a ~teel bomb and heated and stirred at 100C. for 15 hr. After concen-trating in vacuo, the residue partitioned between dilute sodium hydroxide solution and chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue crystallized in isopropyl ether and was recrystallized twice from the same. It weighed 29.0 g (68%), m.p. 9~-95C.
Analysis: Calculated for Cl~H25N30: C,69.78; H,9.15; N,15.26 Found : C,69.81; H,9.01; N,15.33 ExamPle 100 2-(2-DimethYlaminoethvl)-4-ethyl-1-methyl-1,2,3,4-tetrahydro-~H-1,4~benzodiazepin-~-one.
A ~olution of 30 g (0.112 mole) of 2-(2-chloroethyl)-4-ethyl-l-methyl-l~2J3J4-tetrahydro-sH-l~4-benzodiazepin-5 one and 10 g (0.224 mole) of dimethylamine in 300 ml of ethanol was heated at 125C. for 8 hrs and concentrated.
The residue was partitioned between chloroform and dilute sodium hydroxide. The chloroform was dried over anhydrous sodium sulfate, concentrated and distilled~ Yield o~
product was 20.5 g (66.5O , b.p. 175-178/0.1 mm.
Analysis: calculated for Cl~HzsN3o: C,69.78; H,9.15; N,15.25 Found : C169.60; H,9.17; N,15.20 Exam~le 101 . . ~
2,3-Dihydro~4-methyl-2-~ ? - ( 1 -p iperidinyl)ethyl~pyrldo-r~?-f]tl!4]oxazepine~(4H)-thione fumarate, hydrate comPound with isoproPvl alcohol tl:l:0.~:0.~1.
~o a suspension of 5.0 ~ (0.019 mole) of 2-(2-chloro-ethyl)-2,3-dihydro-4-methylpyrido~3,2-f]-1,4~oxazepine-5(4~)-thione in 75 ml of absolute ethanol was addPd 10 ml of pyridine and the mixture heated to 50 C. for 4 days. Ethanol -156- i234~0~

was removed by rotary evaporation (70C, 30 mm Hg).
Piperidine was removed by rotary evaporation (80C, 5 mm Hg) followed by azeotroping with 2 ;c 100 ml of toluene. The synlpy residue was taken up in 200 ml of isopropyl alcohol 5 and heated with fumaric acid which afforded 5.2 g (57~) yellow crystals J m.p. 133-40C.
Analysis: calculated for C2 1.5H32N30~S: C,56.07; H,7.00 N,9.12 Found : C,55.90; H,6.85;
2~,9.17 E~cample 102 6-Ch or -2~dihydro-4-methyl-2-r2-(dimethylam_no)ethvl~-4-me~hyl~yridor4,3-fl~1 41-oxazePin-'i(4H)-one fumarate.
rl o.~].
To 40 ml of freshly collected dimethylamine at -10C
was added 4.0 9 (0.015 mole) of 6-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~4,3-f]-1,4-oxazepin-5(4H)-one.
The reaction flask was sealed tightly and left standin~ at room temperature for 5 days. After cooling to -lO~C., the flask was opened and the dimethylamine allowed to evaporate 20 overnight. The residue was taken up in 100 ml of chloroform, washed with 2 x 30 ml of dilute sodium hydroxide, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (70C, 30 mm Hg). The residue was treated with fumaric acid in isopropyl alcohol which upon crystallization afforded 3.8 g (76.7O of yeliow crystals.
Analysis: calculated for C15H2oN30~Cl: C,52,70; H,5.90;
N,12.29 Found : CJ52.67; H,5.96:
N,12 .01 Example 103 2,3-Dihydro-4-methyl-6-dimethylamino-212-(dimethyl-amino)ethyll-4-methylpyridO~ 4,3-f~l,4]-oxazepin-5(4H)-one fumarate ~1:1.5~.
To 100 ml of freshly collected dimethylamine in a stainless steel bomb was added 4.5 ~ (0.016 mcle) o~ 6-chloro-35 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~4,3-f~_1,4-oxazepin-5(4H~-one. The bomb was 8ealed tightly and placed irl an oven at 100C. for 18 hr. A~ter cooling, the bomb was ~234~39 opened and the dimethylamine allowed to evaporate at room temperature. The residue was taken up in 150 ml of chloroform, washed with 2 x 40 ml of dilute aqueous sodium hydr~xide, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (70C, 30 mm Hg~.
The residue was treated with fumaric acid in i~opropyl alcohol. The resulting crystals were collected, dried overnight at room temperature, 0.5 mm Hg. The white crystals were collected and afforded 4.2 g (55.30 of the title compound, m.p. 172-75C.
Analysis: Calculated for C2lH30N~oa: C,54.07; H,6.48; N,12.01 Found : C,54.01; H,6.58; N,12.00 Example 104 2,~~Dihydro-2- r 2-(2J5-dihydro-lH-pyrrol-l-yl)ethyl~-4 methYlpyridor7,2-f~-1,4-oxa2eDin-5~4H)-one fumarate rlo21.
To a solution of 10.0 g (0.041 mole) o~ 2-(2-chloro-ethyl)-2,3-dihydro-4-methylpyrido~,2-f]-1,4-oxazepin-5(4H)-one in 50 ml of dimethylformamide was added 9.0 g (0.14 mole) o~ a mixture of 3-pyrroline:pyrrolidine*~ 3:1, v/v. The solution was heated to 65C. under an N2 blanket overnight. The solvent was removed by rotary evaporation (70 C., 0.5 mm Hg). The syrupy residue was taken up in 100 ml of chloroform, washed with 2 x 30 ml of dil. a~ueous sodium hydroxide, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (60C, 30 mm~.
The residue was azetroped with 3 x 100 ml o~ toluene. The residue was purified by HPLC to separate out the pyrrolidine derivative,eluting with 2% triethylamine in methylene chloride (v/v). Fr~ctions with similar TLC's were combined and concentrated by rotary evaporation. To the residue was added~100 ml of toluene and the mixture heated to 70C.
and filtered hot. A~proximately 0.2-0.3 g of hygroscopic crystals were collected. The toluene was removed by rotary evaporati~n (70 C, ~0 mm Hg). The residual syrup was treated with fumaric acid in isopropyl alcohol. Two crops of crystals were collected, combined and recrystallized together giving 4.6 g (22.1~) of white crystals, m.p. 158-159C.

~5`';~

~23~309 Analysis: C~lculated for C23H27N3olo: C,54,55, H~5-38;
N,8.~1 ~ound : C,54.58: H,5.49;
N,8.30 *Pyrroline contains pyrrolidine as impurity.
Exam~ 1 e 10C~
2,3-Dihydro-2-(2,5-dihydro-lH-pyrrol-l-yl)ethyll-4-methylpyridor~2-f~ 4-oxazepine-5~4H)-thione fumarate C1 To a solution of 9 0 g (0.035 mole) of 2-(2-chloro-ethyl)-2~3-dihydro-4-methylpyrido~3~2-f~ 4-oxazepine-5(4H~
thione in 50 ml of dry dimethylformamide was added 10.0 g (0.141 mole) of pyrroline/pyrrolidine*, 3:1, v/v, and the mixture heated to 60C. for 18 hr. The solvent was removed by rotary evaporation (70C, 0.5 mm ~g) and the syrupy residue purified ~y HP~C separating out the pyrrolidine derivative eluting with 2~ triethylamine in methylene chloride (v/v) over silica gel. Fractions having similar TLC's were combined and concentrated by rotary evaporation.
The syrupy residue was treated with fumaric acid in isopropyl alcohol which afforded 4.0 g (28.1%) of crystals.
One recrystallization from isopropyl alcohol afforded an analytical sample, m.p. 143-45C.
Analysis: Calculated for ClgH2~N9O5S: c,56.28; H,5.72;
N~ 10.~6 Found : c,56.o~; H,5.23;
*Pyrroline contains pyrrolidine as impurity.
Exam~le 105 2-r2-(l-Azetidinvl)ethyll-2~-dihydro-4-methylpyrido r3,2-frrlJ41oxazepin-5(4H)~one oxalate hydrate ~1:1.0 5~
To a solution of 4.1 g (0.017 mole) of 2-(2-chloro-ethyl)-2,3-dihydro-4-methylpyridoC:5,2-f]-1,4-oxazepin-5~4~)-one in 50 ml of dimethylformamide under nitrogen was added a solution/suspension o~ 0.7 g (60% in oil, 0.017 mole) of sodium hydride in .10 ml of dimethylformamide to which 1.0 g t0.017 mole) of azetidine in 20 ml of dimethylformamide had been added and allowed to stir under nitrogen atmosphere until hydrogen evolution ceased ( 15 min). The reaction m~xture was stirred for 18 hr under nitrogen at room temperature. The solvent was removed by rotary evaporation (70 C, 0.5 mm Hg) and the r~sidue taken up in 100 ml of chloroform, washed with 3 x ~0 ml dil. aqueous ~odium .
$

-159- ~34~0~

hydroxide, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The residue was treated with oxalic acid in isopropyl alcohol which afforded 1.3 g (21.2%) of white crystal~, m.p. 172-174~C. with slight decomposition.
Analysis: Calculated for c16H22M3O6.5: C,53-~; H~6.15;
N,11.65 Found : C,53.7~; H,6.11;
N,11.67 ExamPle lOZ (Refer to chart VIII) 2-r~Dimethylamino ~ethyl]-2,3-dihydro-4-methylpyrido r3,2-f~rl,4~oxazepin~5(4H)-one fumarate tl:ll.
Dime~hylamine 22.6 g, 40~ solution (0.2 mole) was added dropwise to a solution of 16 ml of epichlorohydrin (0.2 mole) in 100 ml of methanol at 5C. stirring in an ice bath. After two hours at 5C. a chilled solution of 85 ml methylamine of 40% solution (1 mole) was poured into the reaction mixture. Stirring was continued in ice bath for one hour and then room temperature overnight. The solvents were evaporated and the clear oil was pumped under vacuum at 75 C. for 1.5 hr to give 28.23 g (~84% yield) of l-dimethylamino-3~methylamino-2-propanol hydrochloride ~I) as the main product.
Compound I, 21.4 g (0.143 mole) and 22.6 q o~ 2-chloro~
nicotinic acid (0.14~ mole) were stirred in 150 ml acetoni-trile and 60 ml water as a two-layer system. Dicyclohexyl-carbodiimide, 3~ g (0.16 mole) dissolved in 90 ml of acetonitrile was added in four portions. After the addition of the second portion, an ice bath was necessary for controlling the temperature at around 2j C. Two and a half ~0 hours later, 10 g of 2-chloronicotinic acid was added to the reaction mixture and 15 g of dicyclohexylcarbodiimide in 200 ml of acetonitrile was added in another hour. The reaction was stirred at room temperature overnight. Concen- -trated hydrochloric acid was added to the reaction mixture to p~ 2 in order to convert the excess carbodiimide to urea.
The white solid was removed by filtration and rinsed with aqueous acetonitrile. The filtrate and washings were evaporated to a paste which was partitioned between methylene ~' , ~..

1~4~30~

chloride and potassium carbonate solution. The a~ueous layer was extracted two more times with methylene chloride.
The methylene chloride solutions were back washed with sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give 56 g of oil. This oil was chromatographed on 250 g of silica gel elutin~ with methanol to give 26.97 g of light brown ~il containing mainly the 2-chloronicotinamide of compound I.
The 26.97 g of compound obtained from chromatography was dissolved in 200 ml of toluene and heated to distill out about 40 ml solvent and then refluxed under a Dean-Stark trap for one half hour. Sodium hydride, 15 g (50% suspension in mineral oil, 0.3 mole) was added portionwise to the toluene solution at room temperature. The mixture was then heated to reflux for 20 min. The cooled mixture was treated with isopropanol and celite and then filtered. The filtrate was acidified with hydrogen chloride solution in isopropanol. The white solid thus formed was collected by filtration, rinsed with isopropyl alcohol-isopropyl ether and dried under nitrogen. This material weighed 11 g and absorbed moisture from air readily. Some second and third crop materials were obtained from the mother liquor and washings. All three crops were combined and dissolved in water, the solution was made basic with excess amount of potassium carbonate and then extracted three times with methylene chloride; the methylene chloride solutions were back washed with saturated sodium chloride solution, dried over magnesium sulfate and treated with activated charcoal, filtered and evaporated to give 8.8 g of brown oil, the free base of the title compound.
A 1.9 g sample of the brown oil was dissolved in methanol and kept warm on steam bath. Fumaric acid was added and the solution was concentrated to a small volume.
Excess amount of acetone was added to crystallize out the fumarate salt. The salt was recrystallized once to 1.4 g of white solid, m.p. 150-151C.
Analysis: calculated for Cl~EI2lN30~: C,54.70; H,6.o2; N,11.96 Found : C,54.69, H,6.o7; N,11.88 -161~ ~34~0~

Example 108 2- ~ methylamillo)methyll-2~-dihydro-4-methylpyrido ~3 J 2 -f l~lJ4]oxazepine-s(4H?-thione fumarate ~2:1J.
2-l~Dimethylamino)methyl]-2/~-dihydro-4-methylpyrido t3~2-f~[l~4~oxazepine-5(4H)-one~ 4.8 g, was dried azotropi-cally in about 50 ml of toluene. To the warm solution wasadded ~awesson reagent (Aldrich ~22, 743-9, 4.9 g) and the reduction mixture was kept at reflux for two hour~. On contact with concentrat~d potassium carbonate solution, the reaction mixture became a three-layer system; both the aqueous layer and the toluene layer contained product but not the third gummy layer. The layers were ~eparated and the aqueous layer was extracted three times with methylene chloride which was back washed with saturated sodium chloride solution, combined with the toluene layer, dried over sodium sulfate and evaporated to 5.25 g oil. This oil was dissolved in methanol and 2.45 g fumaric acid was added.
With heating and stirring, isopropanol was added to the point of cloudiness and then left stirring overnight. The mixture first deposited out a layer of brown gummy material and then crystallized to a yellow powder. The yellow powder, 2.85 g, was collected and recrystallized from methanol, m.p. 178-179C.
Analysis: Calculated for Cl~Hl9N3O3S: C,54.~5; H,6.19:
N,1~.58 Found : C,54.21; H,6.20;
25N~ 53 Example 109 (Rèfer to Chart VIII) 2 -~? -(Dimethylamino)ethvl]-2~3-dihydro-4-methvlPYrido ~3~?-~f~ Loxazepin-5(4H)-one.
To a cold (ice bath) solution of 3.2 g (0.02 mole) of 2-chloronicotinic acid and ~ g (0.02 mole) of l-dimethylamino-4-methylamino-2-butanol in 25 ml of methylene chloride was added 4.55 g ~0.022 mole) of dicyclohexyl carbodiimide~
Methanesulfonic acid, 1.8 ml, was added to bring the pH ~o 6. White solid appeared in the reaction mixture. The ice bath was removed after l hr and the mixture was allowed to stand at room temperature overnight. The whitP solid was removed by filtration and the filter cake rinsed with ~2~ g methylene chloride. The combined filtrate and wash was extracted twice with o.6 N hydrochloric acid (15 ml and lO ml). To the combined acidic aqueous extracts was added 6 g of potassium bicarbonate and methylene chloride with stirring. The layers were separated and the aaueous basic layer was extracted with methyl~ne chloride. The methylene chloride layers were combined, dried over anhydrous sodium sulfate and evaporated to give 4.5 g brown oil which was predominantly 2-chIoro-N-t4-(dimethylamino)-2-hydroxybutyl~-10 N-methyl-3-pyridinecarboxamide-The 4.26 g (0.0149 mole) of the foregoing prepared 3-pyridinecarboxamide was mi~ed with 50 ml of toluene and the mixture was heated to distill o~f about 20 ml of solvent and then kept at reflux using a Dean-StarX trap to collect moisture. The temperature of the solution was lowered somewhat and 0.864 g (0.018 mole) of sodium hydride in mineral oil was added to produce gentle reflux. After a total of 45 min, the mixture was cooled and to it was added 0.5 ml of isopropyl alcohol and 0.5 ml of water. Carbon dioxide was bubbled in to convert the sodium hydroxide produced to sodium bicarbonate. The mixture was then azeotroped to dryness using a ~ean-Stark trap. Some acetonitrile was added to the hot mixture. After cooling~ the mixture was filtered through celite rinsing with acetonitrile. The filtrate was evaporated to give a mixture of the title product and a trace of mineral oil. The amount of title product obtained was 3.45 g (93~ yield). The NMR and Mass Spec agreed with that of the free base of the compound prepared in Example 10.

t~

-163- ~Z3~9 Example 110 ?-~2-(~Dimethylamino)ethyl~-2~3-dihvdro-4-methvl-lt4 oxaze-pinor7~6-f~-isoquinolin-~(4H)-one oxalate.
Following the procedure of Example 21, 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[7,6-f]isoquinolin-5(4~
one is reacted with dimethylamine to give the title compound.
Exam~le 111 2-~2-(Dimethylamino)ethyll-2,3-dihydro-4-methyl-1,4-oxazepinor7,6-f~isoouinoline-5(4H)-thione hydrochloride.
_ .~ . ~ .
Following the procedure of Example 31, 2-(2-chloroethyl)-10 2l3-dihydro-4-methy~ 4-oxazepinoc7~6-f~isoquinoline-5(4H) thione is reacted with dimethylamine to give the title compound.
Exam~le 112 2 -r2 - (Dimethylamino)ethyl~-2~-dihydro-4-methY~ 4--=
oxaze~inor6,7-q~isouuinolin-~(4H)-one oxalate.
Following the procedure of Example 21J 2-(2-chloroethyl)-2,~-dihydro-4-methyl-1,4-oxazepino~6,7-g]isoquinolin-5(4H)-one is reacted with dimethylamine to give the title compound.
Example 113 2-~2-~Dimethylamino)ethyl]-2~3-dihydro-4-methy~ 4 oxazepiner6,7-qlisoauinoline-5(4H)-thione hvdrochloride ~ollowing the procedure of Example 31, 2-(2-chloroethyl)-2 J 3-dihydro-4-methyl-1,4-oxazepino~6,7-g]i90quinoline-5(4H)-thione is reacted with dimethylamine to give the title compound.
Example 114 2-r2-(DimethylaminoLethyl~-2 ,3-dihvdro~4 ,I-dimethyl-1,4-oxazepinor6,7-blquinolin-5~4H)-one oxalate.
Following the procedure of Example 21J 2-(2-chloroethyl)-50 2J3-dihydro-4~7-dimethyl-l~4-oxazepinoc6~7-h]auinolin-5t4H)~
one is reacted with dimethylamine to give the title compound.

.~r.--164- ~ 2 3 4 ~ 0 9 ExamDle 11~
?-~2-(Dimethylamino)ethyl~-2,~-dihydro-4,7-dimethyl-~4-oxazepino[6~7-h]quinoline-s(4H)-thione hydrochloride.
Following the procedure of Example 31, 2-(2-chloroethyl) 2,3-dihydro-4,7-dimethyl-1,4-oxazepino~6,7-h]~uinoline-5(4H)-thione is reacted with dimethylamine to give the title compound.
Exam~le 116 2-[2-(Dimethylamino)ethyll-2~3-dihydro-4~lo-dimeth l~4-oxazepino[6,7-hlqiinolin-5(4H)-one oxalate.
Following the procedure of Example 21, 2-(2-chloro-ethyl)-2,3-dihydro-4,10-dimethyl-1,4-oxazepinot6,7-h~-quinolin-5~4H)-one is reacted with dimethylamine to give the title compound.
ExamPle 117 2-r2-(Dimethylamino)ethyl~-2,3-dihydro-4,10-dimethyl~
1,4-oxazepino~ ,7-hlauinoline-5(4H)-thione hydrochloride.
Following the procedure of Example 31, 2-(2-chloro-ethyl)-2,3-dihydro-4,10-dimethyl-1,4-oxazepino~6,7-h) quinoline-5(4H)-thione is reacted with dimethylamine to give the title compound.
Example 118 4-r2-(Dimethylamino~ethyll--3~4-dihydro-2-methyl-tl~4 oxazepino[6,7-f~quinolin-1(2H)-one oxalate.
Following the procedure of Example 21, 2-(2-chloro-ethyl)-3,4-dihydro-2-methyltl,4]-oxazepino~6,7-f~quinolin-1(2H)-one is reacted with dimethylamine to give the title compound.
Example 119 4-r2~Dimethylamino ) ethyl~ 4-dihydro-2 -methylr l J 4 oxazepinor6~7-flquinoline-l(2H)-thione hydrochloride.
~ , _ . . _ , .
Following the Drocedure of Example 31, 4-(2-chloro-ethyl)-~,4-dihydro-2-methyl-[1,4]-oxazepino~6,7-f~quinoline-1(2H)-thione is reacted with dimethylamine to give the title compound.

~,, :
;.-.,~

-165- ~2~0~

Example 120 2-~2-(Dimethylamino~ethyll-2~3-dihydro-4-methyl-lJ4 oxazepino[6,7-h]quinolin-5(4H)-one oxalate.
_ Following the procedure o~ Example 21, 2-(2-chloro-ethyl)-2J3-dihydro-4~methyl-l~4-oxazepinoc6~7-h~quinolin-5(4H)-one is reacted with dimethylamine to give the title compound.
Example 121 2-r2-(Dimethylamino~ethyl~-2 3-dihydro-4-methvl-1~4-oxazepinor6~7-hlquinoline-s(4H)-thione hydrochloride.
Following the procedure of Example 31, 2-(2-chloro-ethyl)-2,3-dihydro-4-methyl-1,4-oxazepino~6,7-h~quinoline-5(4H)-thione is reacted with dimethylamine to give the title compound.
Example 122 2-[2-(1-Azetidinyl)ethyll-2,3-dihydro-4-methylpyrido r3,2-f~rl,41oxazepin-5(4H)-one oxalate hydrate rl:l:0.51.
~ _ . = . . _ _ To a solution of 5.0 g (0.021 mole) of 2-(2-chloro-ethyl)-2,3-dihydro-4-methylpyrido~3,2-f~-1,4-oxazepin-5(4H)-one dissolved in 40 ml of dimethylsulfoxide was added 8.7 g ( o.o63 mole) of potassium carbonate ~ollowed by 1.40 g (0.0~5 mole) of azetidine. The mixture was stirred for 4 days at room temperature*. Another 0.5 g (0.009 m~le) of azetidine was added and stirring ccntinued for 2~ hr.
Another 0.7 g (0.012 mole) of azetidine was added and the mixture was stirred for 24 hr. The potassium carbonate was filtered off and the dimethyl sulfoxide was removed from the filtrate by rotary evaporation at 90 C., 0.~ mm Hg.
The residue was taken up in 100 ml o~ methylene chloride and the solution was washed with two 30 ml portions of water followed by 30 ml of dilute a~ueous sodium hydroxide.
The organic layer was dried over magnesium sulfate~ filtered and concentrated by rotary evaporation. The residual syrup was reacted with oxalic acid in isopropyl alcohol giving 3.3 g (44%) of white crystals, m.p. 170-172C. lHNMR analysis was essentially the same as for the same compound obtained in Example 106.
*Stirrer had malfunctioned causing need for a longer 1~, ~, .

~2~4~0~3 stirring period than an estimated 1-2 days that should be re~uired.
Exam~le 123 2-r2~ Azetidinyl)ethyll-2,3-dihydro-4-methylpyrido r3~2-f~rl~4loxazepine-s(4~)-thione fumarate.
To 5.0 g (0.0914 mole) of 2-(2-chloroethyl)-2,5-dihydro-4-methylpyrido~,2-f]-1,4-oxazepine-5(4H)-thione dissolved in 50 ml of dimethylsulfoxide was added 8.o4 g (0.058 mole) of potassium carbonate and 1.21 g (0.021 mole) of azetidine. The reaction mixture was stirred at room temperature for 8 hr after which was added 0.5 g (0.009 mole) of azetidine and the mixture was stirred overnight at room temperature. An additional 0.3 g (0.005 mole of azetidine was added and stirring was continued for 24 hr.
The mixture was filtered and solvent removed by rotary evaporator at 80C., 0.5 mm Hg. The residue was taken up in 100 ml of chloroform and the solution was washed with two 30 ml portions of dilute a~ueous sodium hydroxide.
The organic layer was dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The residue was reacted with fumaric acid in isopropyl alcohol to give 2.5 g (310 of pale yellow crystals, m.p. 122-126 C.

~.

~23~g ~abl e R'~ ~p ,, /~ ( CH ) n-Z

0~_,'~
5~. ;R~
~tD. htY~n-2 n n ~ C~n~ ~:, ~on~ o ~ H o ~ C~
2 bonr O -Ca9 H 1) -3(Ca~)o ~:3n 0 ~ a -~ l f~r~tb 4 b~nr O ~a9' H 0 ~13 hon2 0 ~ d H O ~CR9 ~ ~rnto bDnz S ~ H O --E~ ca9 ~ It ~ICl 7 I~r~ O ~ o -;~ c~3, ~ ~ 3a0 8 bon3 ~ -Yf--~o 1, nc 9 Tupl~th~2,3-~ 0 -CB~ ~; O -~C~ Dl3t~
pyriClo 3,2-f~ 0 -CEI~ ~ O_~ C~ 1l 1l 1.5 ~u~rato 11 5~ysi~o 3,2--i~ S ~ H 0il C~9 ~ Dtll:, ~2 ~?Yrl~D~3.2-f~ C ~c~a H -~ ~ 0.5 ~th~nol 13 bons S -C9b~ ~ O - ~ 0 14 bonr 0 -C~b H o -~aca, " ~u~rseo b-n- o -C~b H O - ~C~

16 ~ o ~3cd "

17 b~ns 8 -C89 H 0 _~3d n

18 ~-Cl-~ns ~ -C~ H O -~C39 ~ ~I 3C1

19 a-cl-bon~ 0 -C~ H O - ~ Ca3 a ~ DX31~tO
7-Br-bOnS O ~ H O -~ C89 ~ oxal~to 21 ~ phr2,1-S~ O ~9 ~ O -~ C~ 1~ QtO
22 4 pyridor4,~-i' O -ca, H O -~ ~ n Y":;~r~tQ
b PY~i~lO~ ~,4_~ O ~3~ H O --a~C~ t2~
O PYri~tO 2,~ O ~1~ R O -~ CH~ 3 gh~r~to 23 PYr1aO '4,3~f S ~9 ~ O -~ CEI~ r ~ ~ 1.5 RCl 24 pyri~ 3,2-r~ ~ -e~ a ~~ CR~ )~
r~phth~2,~ 8 -C~b H o _~ C39)~ ~ ox-l9tr, æ6 7,~ o~o~ nz O -C~ H O -~ Cn~ ~ 11 _ 27 7-Cl-bon- -C~b a O -~ CHb ~ ~ o~ to 28 pyri~or3,2-~ O -ca~ H ~~ C~b -c~ -29 pyriao~3,2-~ C~ H o _~ CB~-(c~ )~ thlo~l~o ~ 7~ L 8 -C8n B O -~a CEI~ ~ oJtal~t'~ ,2 ~1 r~phtht2,1-~1 ~ -C~b ~ O _~ CH, ~ 8Cl ~2 a~ ~yrl~o~3,~-f~ 6 ~Cs~ ~ o _~ C~ ~ n ku~rnto b) pyr~o~2,3-S~ ~ -CH~ H o _~ CH~ ~ u~ur~to ~3 7-OC9~-bonr O -CB~ B O _~ C9~ ~ ll oxal~ee-~4 7-~r-b-n~ ~ -CEb n O _~ cs~ ~ n Q~alDeQ~2 O
~5 ~ b~nr O -CO0~ ~ o ~ c~, ~ n ~x-l~t~
b ~n2 ~ -C2H~ 8 ~ -~ ca~ ~ t-o bænr O ~(C8~)~ B --0 C~!l~ r 1l o~t~l6te:
tl ~n2 0 4-Cl- n O -~ C~ ~ n e~al~lt~-C~
~cont . ~ ~

.~,,~ ~

168- 123~09 ~;bl~ ~ (c~c~n~ . ) Ex. R!~ , No- ~y!o ~ Z~~C~ D~lt ~ ns C~ c$~t-c0~4c~- tt 1~ ~(C9J1't _(CH2~ to :~a tt 3,5~ -- Hj~ --iil(C~g)~ n ~DlDt~
c0a9c~
9 ~ O ~9--C~ O _~ C~ D ~lDt~
b ~nr o ~-D~-C~-C~ c~, n n~Dl~t~l ~!LD ~ py~dDr3,2-b~ 0 --CoSI~ De) ~ ~ ~ Ur~r~t--b ~yr~ao~3~2-~ o --C~E~ Et O -U Cli, 0~ ~~r~t~
.. ~yri~lor3,2-r~ 0 ~I(C~ El O -W C~3~ ~ h~rl~to Cl ~yri~o~3,2-~ O ~--Cl--C~Q~-Et O --~3 C~l, ~, 11 g~r~t~
~ pyri~3 ~2-S ~ -C~ - 110 -I-d CE3~ a n ~III~r-ee ~pyri~D 3,2-~ o ~-OCH~--cOa-c~,- H t~ CH~ 5~ ~I Sh ~ r~e~
9 pyrido 3,2-~ D 3-c~9-ce9~c~- El O -~ C~ ~ 1l ~u~r~te ~ ~yrLdo 3,2- ~-~02-CoE~C~ o -~ C~3 2 1l ~u~ r~ee 37 a) ~n~ ~C9a B O l-pyrrolldlnyl~l ~u~rate b) ~onz ~ -C~9 ~ O l-plp4rldinyl ~ ~u~rate c) bon~ ~ -C3~ a o ~-p~p~raxlnyl ~1 ~us~rat~
~) bJn~ O -C8~ 9 O ~CR9-plp~rl- ~~um~rnte 3B ~yrldo~3,2-~ 0 - CB9 ~lnyl ~t 2-~Cl 99 Py~4r3~2-~ CC~ R 8 -~(CB~)~ 11o~slatc pyrido~3,4-f~ o -C9~ R O ~~(C~a)~ 2 2 oxalnte 41 pyridor3,4-fl 5 -C~a R o ~~(C9a)2 112 oxalnte 42 pyrido~3,2-f~ 0 -C~ H O -NH2 axalnte 43 pyridot3,2-f~ 0 -C~ ~ O -N -~c~s~leate 44 pyrid~3~2~f~ -CH~ . 9 o l-oyrrolldinylll 2 fumDrate 4~ pyrido~3,2-f~ 0 -CH~ 9 o -Nt~-butyl) ~lcatc 4~ pyrido~3,2-f~ o ~CHa H o -N(Ca~s)~ ~Dx~late 47 pyrido,3,2-f~ 0 -CH~ R o l-pipsridinyl 1l oxalate 4B pyrido~3,2-f~ 0 -CHa 9 O -N5CR~(bc~2yl~r~sat~~
49 pyridot3,2-fl 0 -CH~ 9 o -N~CH31-C~
pyrido~3,2-f; o -CHa ~ O c~ fu~arate 51 pyrido~3,2-f~ 0 -C~ a o ~ ~1 _ -~1 52 pyrido~3,2-f~ O _cR~ ~ O _ 53 pyrleol3,2-f~ 0 -CH~ 9 O N
-54 pyridor3,2-f~ 0 -C~E5 E o -a(CH~)~ 1lox~l~te pyridD~3,2-f~ -C~5 9 l-pyrrolidinyl 1l ~x~l~t~

56 pyrldDt3,2-f~ 8 -CH~ ~ o 5~ pyrldor3,2-f~ ~ -CH~ ~ O -~ n-butyl)~ 1~ o~al~t~
58 pyrido~3,2-f~ ~ -CH~ ~ O -N C~Hs~ oxal~te ~9 ~yridot~,2-f] ~ ~C~a 8 o l-pyrrolidinyl ~ o~ e~
pyrldot3,2-f~ 5 -CE~ ~ o -~ ~ ~1 1.5 oxalat~
~cont.

~ .
.... "~

-169_ ~L23~ 9 ~nble ~ (eont.~
~5 ~o ~(~)C-' ~ R ~ 2 ~(r'~)r~ Salt ... ... _ _ ~ ,, ~
61 pyr~d~[3 2-f~ 6 ~CrHs ~ C11~ e - (C~
62 ~yridn~3 2-f~ 6 -CH~ ~ 0 -N CH~ ~en7yl) n oxal~te63 pyrido~3,2-f~ ~ - CH~ ~ O -~HCU~ " 1.5 ox~l~te 64 7-Cl-pyrido r3 2-) 0 -CH~ B O -l-pyrrDli~inyl R ~.5 fum~rate 65 7-Ci-pyrido 0 -C~ ~ O -~(CH~ x~l~t~
~3,2-~
65 pyridor3,2-f~ ~ -co~ O -~(CH~2 --C~-ox~lDt~
67 - pyrid~[3,2-~ 0 -C~C~5 B O -N(C~)2 ~(C~2)a~ 1.5 oxalate, 1/~ 20 68 n pyrido[3,2-f~ O B B 0 _~ C~)z 6B ~ pyrid3[3,2-fl ~ B 0 -N CRn)2 -(C~z)2- ~um~rnte 69 ~yridot3,2-~ 0 ~CH~ ~ O -N CL~ C~2)~- 1.5 ~umarate, 0.5 E40 pyridor3,2-f~ ~ -CH~ ~ O -N(CH~ 2 oxnlate 71 7-CI-pyrido ~ - CH~ B O -~(CH~ (C~2)a- 1~2 E20, t3,2-f1 ~ (C~ B
~2 pyridor3 2-f O -CB~ ~ O -~C~ n ~x~late 73 2yrido~3 2-f O -CH~ ~ O -NH2 ~ fu~ara~e 74 ~yrid~[3~2-f S - CH~ B O - ~t2 u o.5 ~u~rate 75 pyrido~3,2-f~ 0 - C~s B O _~-C~(C~ja 2.0 ~umnrnte 76 ~yrido~3,2-f~ ~ -C~ ~ O -N(C4 C0~5)~ R ~u~nrnt~
77 pyrido~2-~) 0 -CH~ ~ 0 4-methyl- ~ æ.o um~ratc, pipernzin-l-yl ~ydrnte 78 pyridD~3,2-f~ S -C~ B 0 4-~ethyl- ~ 2.0 fumnrnt~, pip~rn in-l-yl 1~2 E20 79 pyrido~3,2-f~ D -C~ ~ O t~ 2.0 ~umarate, 80 pYrid~t3.~-f~ o --c~, B O ~ u ~x~late .
Bl pyridot3-2~~ B 0 -N(C~S)~C~a~) u ~2 pyrido~3,2-fl 5 -C~ ~ O -~H~ _(CE2 ~ ~umnr~ee 83 py~ido~3,2-~ S ~ ~ 0 -N(CB~ C~k R - 2 BCl, E20 84 pyrid~3,2-~ ~ -C~ B (~) n. oxnlnse, ~a ., .. , ~ u 85 pyridot3,2-f~ S -C~9 ~ O ~N~ C~ ~
85 pyridot3,2-f~ 0 -C~ ~ 0 --~(CB~ --C~-C~4_ ~X~lat~
87 pYrid~t3 2~f] ~ -C~ ~ O ~/ 1 -~C~)2- i.5 ~x~lnte .. . . , ~B .
B8 pyridoL3,2-f~ 0 -C~ 0~~(C~3a)2 ~ 2 ~:1 89 pyrido~3,2-f~ ~ -C~ -CB~ 0 _~(C~)2 ~ ~Cl 90 ~ O -C~ B D -~(C~ xalnte 91 ~yrido~3,2-f~ ~ -C~ B O _~(cn~ c~2- o~nlate 9Q pyridD~3,2-~ 0 --Q ~ ~ D --~tc~9)~ -C~-C 8Cl C~ u~arnte, 93 pyridD~3,2-f~ S -CB~ ~ O ~J ~ nlco~ol 94 ~ o -c~, a o -~(c~ -(C~4)~- 2u~ te C ~ .

~ ~ ~' O . 5 ~

.~
, . . "~

-17O- ~ ~34~3~9 T~ble 2 ~ cc~nt . ~
2x. ~5 N~ ~(Y~ 3 R 3~ .Z -(CH~- Salt ~6 ~ 6 -C~ ~ o ~9(c~9)2 -(c~)~ = r~tei :~1 CDhO 1, B2 97 ~enz 0 ~CaE~ C2~ ~ ~um r tc ulcohol 98 b~nz -C2E~ 3 ~c~2 )2 99 benz O -C8(C~ (C~)2 _~E~_ -100 ~enz O -C~s 3 ~ -~(C~ tCE4)~- -~01 pyri~Dr3,2-f~ ~ -CB~ ~ D _ ~ -(CE~ Um~rat~
S l~oP~oPYl 102 6-Cl-pyrido O -C~ ~ Q -~(C8D)~ -tC~2 )n~ alcohol ~yridD~4,~ ~ O ~~tC~s)2 -(C~ - 1.5 ~u~arLte 104 ~yrido~3,2-~ O -C~ ~ O ~~ ~ -tCE~ 2.0 ~u~rnte 105 pyridD~,2-~ C8~ ~ O ~ C~ Yu3~rate 106 pyridD~3,2-~ 0 -C~ ~ ~ ~(C~)n-- ox~lDt~
107 ~yr~dD~r2-~ 0 --~D Q -~C~9)2 ~- Y~nrDte 108 pyri~D~3,2-f~ ~ ~caa ~ O -~tca~)~ -Cl~- O.5 O~umarnte 09 ~?yriAD~3~2--~ 0 --C~ ~ o _~ e (C~ )R ~-al0 ~ ~ O -C89 ~ O -~(CEb)~ -(C~ - ox~l~te 111 j~ S ~ 9 ~El O ~(C~

112 ~ ~ -C~ ~ O -~(C~b)~ a~)n- ~ql~te ,~S
113 ~ ~ i0(Ca~)2 -S~$~)2 al4 ~ o ~C3s ~ O -~C~b)~ 9k)~ te J

L~i .

~23~ 9 Table ? ( cont . ~_ r'x. R5 ~o. A(Y)0-2 ~ R R4 ~ z ~(C~)n~ Salt ,;,E
115 ~ S -CH3H O -N(CHg)2 -(C~2 )2- RCl 116 ~ O -CH9H 0 -N(CH3)2 -(CR2 )2- oxalate C~3s N ~
117 ~ S --CH3 ~ o --N(CH3)2 --(CH2)2-- 8Cl 118 [~ O -CHgH O -N(CH3)2 -(CH2)2- c~xalate 119 ~ S -CH9B O -~(CH9)2 -(CH2 )2- BCl 120 ~ -CH9H 0 -N(CH3)z -(CH2)2- oxalate 121 [~ S -CHg ~1 0 -N ( CH3 ) 2 - - ( CH2 ) 2 - RCl 122 pyrido~3~2-f] 0 -CH9 H 0 -N~> _(C~)2_ oxalate, 0.5 ~2 123 pyridot3,2-f~ S -CH9 H O -N~ -(C~'12 )2- fumarate Footnote:
( ) _N3CH-(4F-C,,H~,);, -172- 1~3~809 Additional Pharmacoloqy Experiments were conducted to determine whether sedation was present as a result of administration of the compounds of the invention as antihistaminics and the results on compounds tested suggests they are non-sedative anti-histaminics. The comparative antihistaminic agent used wasdiphenhydramine which does cause sedation. See Douglas) W. C.
~19oO), "Histamine and 5-hydroxytryptamine (serotonin) and their antagonists" in The Pharmacoloqical Basis of Thera-peutics (ed: A. G. Gilman, L. S. Goodman, A. Gilman, 6th edition, Macmillan, New YorX, pp 609-641. In the present tests, sedation is defined as a change in the electro-encephalograms (EEGs) from the normal pattern of low voltageJ
fast (~) cerebral cortical waves (1?-25 Hz, <50 mV
amplitude) to synchronized high voltage, 51cw (~, D) cerebral cortical waves (1-3, 4-7 Hz, > 50 m V amplitude) with frequent periods of sleep spindles predominating.
Experimental Method for Sedative Activitv .. .. _ Ten cats of both sexes were anesthetized with halothane and cannulae placed in the trachea, the left cephalic vein~
and the right femoral artery for artificial ventilation, drug ad~inistration, and blood pressure recording, respectively.
The head was fixed in a Kopf stereotaxic unit and the calvarium was widely exposed. Stainless steei screw electrodes (1/4") were placed through the calvarium so that the tips rested on the dura over the frontal, parietal, and occ~ipital areas, bilaterally. An electrode of the same type was placed in the right frontal sinus and served as the reference electrode ~or monopolar EEG recordings. After completion of the surgery, the animal was given gallamine triethiodide t20 mg, IV; supplemented as necessary) and the halothane withdrawn. Artificial respiration was instituted (10 ml ro~m air/kg/3 sec).
EEGs were made on a Grass, Model 5, electroencephalograph along with tlead II) EKG. Typically~ EEGs were recorded for 2-3 min every 10 min. Arterial blood pressure was continuously monitored on a Grass, Model 79, poly~raph.

-173- ~ 0 9 In most experiments, histamine (0.5 ~g/kg, IV) was given to produce a transient (c ~0 sec) hypotensive effect.
It was normally given 10, 20 and 30 min prior to the first dose of the test drug and then 5, 10 and 20 min after each dose o~ the test drug. In this way an indication of the antihistaminic activity of test drug could be quantified.
Concomitant with the antihistaminic ~uantification was the effect of test drug on EEG. Test drug was usually given in increasing doses of 0.1, 0.3, 0.5, 1J 3, 5, 10 and

20 mg~kg, IV.
Experimental Results on Sedative Potential Illustratively of the compounds tested ~Exanples 12, 65 and 71) the compound of Exampl- 12 produced a 50% reduction f the histamine-ind~lced depressor effect on blood p~essure at 0.3 mg/kg, IV and a 100% suppressio~ at 1-3 mg/kg, IV.
There were no signs of sedation in these animals at any dose up to 20 mg~g, IV.
On the other ha~d, the coinparative drug, diphen-hydra~line, known to produce sedation (tested here in 6 cats)prod~ced a 50~ supp~ession of the histamine-indllce~ depre~so-effect on blood pressure at 0.5 mg~kg, IV a~d a 100 suppression at 3-~ mg~kg, IV. Signs of sedation with diphenhydramine occ~rred in the EEG tracings as law as 5 mg ~g, IV with marked slowing, synchronized waves, and sleep spindles at 1-3 mg~kg, IV. In summary, di.phenhydra~ine produced an antihistaminic effect in doses which also produced a sedative efect. This is similar to what is seen i~ man with diphenhydramine.
In contrast to the effects of diphenhydramine, compounds such as that of Exa;nple 12 do not produce sedation at any dose up LO 20 ~ng/kg, even though the antihista.minic effects occurre~ at much lower doses. These data, therefore, s~1ggest the nonsedative nature of co~pounds ~f the invention.

~' .
", ~ ..

Claims (139)

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

1. A process for the preparation of an aromatic or heterocyclic oxazepine or thiazepine of the formula (I) wherein A represents an aromatic ring having two of its carbon atoms held mutually with the oxazepine or thiazepine moiety selected from the group consisting of benzene, naphthalene or a pyridine in any of its four posi-tions, any of the rings optionally substituted by one or two Y radicals selected from the group consisting of halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
B & E are selected from oxygen or sulfur and may be the same or different;
R is selected from the group consisting of hydrogen, loweralkyl, cyclo-alkyl, or phenyl-loweralkyl of which phenyl may be optionally substituted by one or two radicals selected from halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
n is 1, 2 or 3;
Z is selected from the group consisting of -NR1R2, 1H-pyrazol-l-yl or lH-imadazol-1-yl, R1 and R2 are selected from the group consisting of hydrogen, loweralkyl, cycloalkyl and phenyl-loweralkyl of which phenyl is unsubstituted or substituted by 1 or 2 radicals selected from halo, lower-alkyl, loweralkoxy, nitro, trifluoromethyl or cyano or R1 and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consisting of l-pyrrolidinyl, 2,5-dimethylpyrrolidin-l-yl, 2-methylpyrrolidin-1-yl, l-piperidinyl, 4-substituted piperidine-I-yl, 4-morpholinyl, l-piperazinyl, 4-substituted piperazin-l-yl and 1,2,3,6-tetrahydropyridin-l-yl and the pharmaceutically acceptable salts thereof with the proviso that when R is hydrogen, Z is never a primary or secondary amine and a further proviso that when n=3, Z is not lH-pyrazal-l-yl, 2,5-dimethylpyrrolidin-1-yl, 2-methylpyrrolidin-l-yl or 1,2,3,6-tetra-hydropyridin-l-yl, which comprises the steps of:
Step 1) halogenating a compound o the formula wherein A represents an aromatic ring selected from benzene, naphthalene or a pyridine in any of its four positions any of the rings optionally substituted by one or two Y-radicals selected from halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
E is oxygen or sulfur R is selected from the group consisting of loweralkyl, cycloalkyl or phenyl-loweralkyl of which phenyl may be optionally substituted by one or two radicals selected from halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl, R3 is hydrogen or an acid neutralizing ion and n is one or two, to give a compound of the formula or its free base wherein X is chlorine or bromine and A, E, R, Y and n are the same as the starting values, Step 2) fusing a compound prepared in step A to give a compound of the formula:

wherein A, E, R, n, X and Y are as defined in step A and A now has two of its carbon atoms held mutually with the oxazepine or thiazepine moiety, Step 3) optionally reacting a compound prepared in step 2 with a sulfurizing agent to obtain an azepinethione of the formula wherein A, E, R, n, X and Y are as defined in step 2, Step 4) when required, reacting a compound prepared in step 2 with an alkali-metal cyanide to obtain a compound of the formula wherein A) E, Y and R are as defined in step 2, Step 5) reacting a halogen compound prepared in steps 2 or 3 with a compound of the formula ZH
wherein Z is selected from -NRlR2, lH-pyrazol-l-yl, or lH-imidazol-l-yl and wherein R1 and R2 are selected from hydrogen, loweralkyl, cycloalkyl and phenyl-loweralkyl of which phenyl may be optionally substituted with 1 or 2 radicals selected from halo, loweralkyl, loweralkoxy, nitro, tri-fluoromethyl or cyano or R1 and R2 taken together with the adjacent nitro-gen atom may form a hetercyclic residue selected from the group consisting of l-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, l-piperidinyl, 4-substituted piperidin-l-yl, 4-morpholinyl, l-piperazinyl, 4-substituted piperazin-l-yl and 1,2,3,6-tetrahydropyridin-1-yl to give a compound of the formula wherein A, E, R, n and Y are as defined above in step 2, Z is the same as in the ZH compound and B is an oxygen or sulfur atom, Step 6) optionally reacting a compound prepared in step 5) wherein B is an oxygen with a sulfurizing agent to obtain a compound of the formula wherein A, E, R, n, Y and Z are as defined in step 5, Step 7) reducing a cyano compound prepared in step 4 to a primary amine of the formula wherein A, E, Y and R are the same as in steps 2 and 4, Step 8) when required reacting a primary amine prepared in step 5 or 7 of the formula wherein A, E, Y and R are as defined in step 2 with one of the following reactants or sets of reactants, a) formaldehyde and formic acid to give a tertiary dimethylamine, b) a dihalide to give a heterocyclic amine, c) a dialdehyde and sodium cyanoborohydride to give a heterocyclic amine, d) equal molar amounts of an aldehyde or ketane and sodium cyano-borohydride with large excess of above primary amine to give a secondary amine, e) equal molar amounts o the primary amine and sodium cyanoboro-hydride with at least two equivalents of aldehyde or ketane to give a tertiary amine, f) in sequence: trifluoroacetyl chloride, alkyl or phenylalkyl halide, potassium hydride and potassium hydroxide to give a secondary amine, to obtain a product of the formula wherein A, E, Y and R are as defined in step 2 and Z is -NR1R2 wherein R1 and R2 are loweralkyl, cycloalkyl and phenyl-loweralkyl, the phenyl of which may be optionally substituted by halo, loweralkyl, loweralkoxy, nitro, trifluoromethyl or cyano or R1 and R2 taken together with the adjacent nitrogen may form a heterocyclic residue selected from l-pyrrolidinyl, l-piperidinyl, 4-substituted piperidin-l-yl, 4-morpholinyl, l-piperazin-l-yl or 1,2,3,6-tetrahydropyridin-1-yl and sulfurizing the azepinone or thiazepinone to give a corresponding thione, Step 9) when required, reacting a benzyl or substituted benzyl compound where Z is a tertiary amine obtained in steps 5, 6 or 8 of the formula wherein A, E and Y are as defined in step 2 and Z is any radical under the definition of Z in Formula I subject to the same provisos given thereunder, Z never being a primary or secondary amine, with sodium and ammonia to give a compound of the formula wherein A, E and Y are as defined above in step 2J (n = 1 to 3) and Z
is the same as the starting compound in this step, Step 10) optionally reacting the free base of any compound prepared in steps 5 to 9 with a pharmaceutically acceptable acid or quaternary forming halide or sulfate to form a pharmaceutically acceptable salt thereof.

2. A process for the preparation of an aromatic or heterocyclic oxazepine or thiazepine of the formula:

( I ) wherein;
A represents an aromatic ring having two of its carbon atoms held mutually with the oxazepine or thiazepine moiety selected from the group consisting of benzene, naphthalene or a pyridine in any of its 4-positions,.
optionally substituted by one or two Y radicals selected from the group consisting of halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
B and E are selected from oxygen or sulfur and may be the same or different;

R is selected from the group consisting of loweralkyl, cycloalkyl or phenyl-loweralkyl wherein phenyl is optionally substituted by one or two radicals selected from halo, loweralkyl, loweralkoxy, nitro or trifluoro-methyl;
n is 1 or 2;
Z represents -N-R1R2, lH-pyrazol-l-yl or lH-imidazol-l-yl;
R1 and R2 are selected from the group consisting of hydrogen, lower-alkyl, cycloalkyl and phenyl-loweralkyl optionally substituted on phenyl by 1 or 2 radicals selected from halo, loweralkyl, loweralkoxy, nitro, trifluoromethyl or cyano, or R1 and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consisting of l-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2-methyl-pyrrolidin-l-yl, l-piperidinyl, 4-substituted piperadine-l-yl, 4-morpholinyl, l-piperazinyl, 4-substituted piperazin-l-yl and 1,2,3,6-tetrahydropyridin-l-yl and the pharmaceutically acceptable salts thereo, which comprise the steps of Step A) halogenating a compound of the formula IVb wherein A represents an aromatic ring selected from benzene, naphthalene, or a pyridine in any of its 4 positions, any of the rings optionally sub-stituted by one or two Y radicals selected from halo, loweralkyl, lower-alkoxy, nitro or trifluoromethyl, and E, R, and n are as defined above and R3 is hydrogen or an acid salt neutralizing ion to give an acid halide of the formula III

or its free base, wherein X is chlorine or bromine and A, E, R, n and Y
are the same as the starting values, Step B) fusing a compound prepared in Step A to give a compound of the formula wherein A, E, R, n, X and Y are as defined above in Step A and A now has two of its carbon atoms held mutually with the oxazepine or thiazepine moiety, Step C) optionally reacting a compound prepared in Step B with a sulfurizing agent to obtain an azepinethione of the formula wherein A, E, R, n, X and Y are as defined in step 2, Step D) reacting a halogen compound prepared in Steps B or C with a compound of the formula ZH
wherein Z is selected from -NR1R2, lH-pyrazol-l-yl or lH-imidazol-l-yl wherein R1 and R2 are selected from hydrogen, loweralkyl, cycloalkyl and phenyl-loweralkyl optionally substituted on phenyl with 1 or 2 radicals selected from halo, loweralkyl, loweralkoxy, nitro, trifluoromethyl or cyano, and R1 and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consisting of l-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, l-pyperidinyl, 4-substituted piperidine-l-yl, 4-morpholinyl, l-piperazinyl, 4-substituted piperazin-l-yl and 1,2,3,6-tetrahydropyridin-l-yl, to give a compound of the formula Ia wherein A, E, B, R, n and Y are as defined in step B and Z is the same as in the ZH compound, Step E) optionally reacting a compound prepared in Step D, wherein B is an oxygen atom with a sulfurizing agent to obtain a compound of the formula Ib wherein A, E, R, Z, n and Y are as defined above, and Step F) optionally reacting a free base of any compound prepared in Steps D or E with a) a pharmaceutically acceptable acid, b) a loweralkyl-halide, or c) a loweralkyl sulfate to form a pharmaceutically acceptable salt thereof.

3. The compound 2-[2-(dimethylamino)ethyl]-2,3 dihydro-4-methyl-1,4-benzoxazepine-5(4H)-one or a pharmaceutically accept-able sait thereof,

4. The compound 2,3-dillydro-4-metllyl-2-[2-(4-morpllolino)ethyl]-1,4-bcnzoxazepin-5(4H)-one or a pharmaceutically accept-able salt thcreof.

5. The compound 4-benzyl-2,3-dihydro-2-[2-(4-morpholino)ethyl3-1,4-benzoxazepln-5(4H)-one or a pharmaceutically acceptable salt thereof.

6. The compound 4-benzyl-2,3-dihydro-2-[2-(methylamino)etllyl]-1,4-benzoxazepin-5t4H)-one or a pharmaceutically accept-able salt thereof.

7. The compound 2- [2-(dimethylamino)ethyl]-2,3-dihydro-4-metllyl-1,4-benzoxazepine-5(4H)thione or a pharmaceutically accept-able salt thereof.

8. The compound 4-benzyl-2-[2-(dimethylamino)-ethyl]-2,3-dihydro-1,4-benzoxazepin-5(4H)-one or a pharmaceutically acceptale salt thereof.

9. The compound 2,3-dihydro-4-methyl-2-[2-(4-morpholino)ethyl]-1,4-benzoxazepine-5(4H)-thiono or a pharmaceutically acceptable salt thereof,

10. The compound 2-[2-(dimethylamillo)etllyl]-2,3-dihydro-4-methylnaphth[2,3-f][1,4]oxazepine-5(4H)-one or a pharmaceutically acceptable salt thereof.

11. The compound 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one or a pharmaceut-ically acceptable salt thereof.

12. The compound 2-[2- (dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5-(4H)-thione or a pharma-ceutically acceptable salt thereof.

13. The compound 4-benzyl-2,3-dihydro-2-[2-(4-morpholino)ethyl]-1,4-benzoxazepine-5(4H)thione or a pharmaceutically ac-ceptable salt thereof.

14. The compound 2,3-dihydro-4-methyl-2-[2-(methyl-amino)ethyl]-1,4-benzoxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof.

15. The compound 2,3-dihydro-2-[2-(4-hydroxy-4-phenyl)-piperidinylethyl]-4-methyl-1,4-benzoxazepine-5(4H)-thione or a pharma-ceutically acceptable salt thereof.

16. The compound 2,3-dihydro-4-methyl-2-[2-(4-phenyl-1,2,3,6-tetrahydropyridinyl)etilyl]-1,4-benzoxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof.

17. The compound 8-chloro-2-[2-(dimethylamino) ethyl]-2,3-dihydro-4-methyl-1,4-benzoxazepinc-5(4H)-thione or a pharma-ceutically acceptable salt thereof.

18. The compound 8-chloro-2-[2-(dimethylamino) ethyl]-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-one or a pharma-ceutically acceptable salt thereof.

19. The compound 7-bromo-2-[2-(dimethylamino) ethyl]-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof.

20. The compound 2-[2-(dimethylanino)ethyl[-2,3-dihydro-4-methylnaphth[2,1-f][1,4]oxazepine-5(4H)-one or a pharmaceutically acceptable salt thereof.

21. The compound 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[4,3-f][1,4]oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof.

22. The compound 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylnaphth[2,3-f][1,4]oxazepine-5(4H)-thione or a pharmaceutic-ally acceptable salt thereof,

23. The compound 7-chloro-2-[2-(dimethylamino) ethyl]-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-one or a pharmaceutically acceptable salt thereof.

24. The compound 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione methiodide

25. The compound 7-chloro-2-[2-(dimethylamino) cthyl]-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione or a pharma-ceutically acceptable salt thereof.

26. The compound 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylnaphth[2,1-f][1,4]oxazepine-5(4H)-tlliolle or a pharmaceut-ically acceptable salt thereof.

27. The compound 2-[2-(dimethylamillo)etllyl]-2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5(4H)-one or a pharmaceutically accoptable salt thereof.

28. The compound 7-bromo-2-[2-(dimethylamino) etllyl]-2,3-dilIydro-4-metllyl-1,4-benzoxazepine-5(4H)-tilione or a pharma-ceutically acceptable salt thereof.

29. The compound 2-[2-(dimethylamino)ethyl]-2, 3-dihydro-4-methylpyrido[3,2-f][1,4]thiazepine-5(4H)-one or a pharma-ceutically acceptable salt thereof.

30. The compound 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]thiazepine-5(4H)-thione or a pharma-ceutically acceptable salt thereof.

31. The compound 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido[3,4-f][1,4]-oxazepine-5(4H)-one or a pharmaceutically acceptable salt thereof.

32. The compound 2-[2-(dimethylamino)ethyl] 2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof.

:::

33. The compound 2-(3-aminopropyl)-2,3-dihydro-4-methylpyrido-[3,2-f][1,4]-oxazeplne-5(4H)-one or a pharmaceutically ac-ceptable salt thereof.

34. The compound 2,3-dihydro-4-methyl-2-[2-(4-morpholinyl)ethyl]-pyrido[3,2-f][1,4]-oxazepine-5(4H)-one or a pharma-ceutically acceptnble salt thereof,

35. The compound 2,3-dihydro-4-methyl-2-[2-(l-pyrrolidinyl)ethyl]-pyrido[3,2-f][1,4]-oxazepine-5(4H)-one or a pharma-ceutically acceptable salt thereof.

36. The-compound 2-[2-(dibutylamino)ethyl]-2,3-dihydro-4-methylpyrido [3,2-f][1,4]-oxazepine-5(4H)-one or a pharmaceutically acceptable salt thereof,

37. The compound 2-[2-(diethylamino)ethlyl]-2,3-dihydro-4-methlylpyrido[3,2-f][1,4]-oxazepinc-5(4H)-one or a pharmaceutically acceptable salt thereof.

38. The compound 2,3-dihydro-4-methyl-2-[2-(1-piperi-dinyl)ethyl]pyrido[3,2-f][1,4]-oxazepine-5(4H)-one or a pharmaceutically acceptable salt thereof.

39. The compound 2,3-dihydro-4-methyl-2-[2-[methyl(phenylmethyl) amino]ethyl]pyrido[3,2-f][1,4]-oxazepine-5(4H)-one or a pharmaceutically acceptable salt thereof.

40. The compound 2,3-dihydro-4-methyl-2-[2-(methylphenylamino) ethyl]pyrido[3,2-f][1,4]-oxazepine-5(4H)-one or a pharmaceutically acceptable salt thereof.

41. The compound 2-[2-(2,5-dimetl-yl-1-pyrrolidinyl) ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-one or a pharmaceutically acceptable salt thereof.

42. The compound 2,3-dihydro-4-methyl-2-[2(2-methyl-1-pyrrolidinyl)-ethyl]pyrido[3,2-f][1,4]-oxazepine-5(4H)-one or a pharmaceutically acceptable salt thereof.

43. The compound 2,3-dihydro-4-methyl-2-[2-(1H-pyrazol-1-yl)ethyl]pyrido[3,2-f][1,4]oxazepine-5(4H)-one or a pharmaceutically acceptable salt thereof.

44. The compound 2,3-dihydro-2-[2-(1H-imidazol-l-yl)ethyl]-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one or a pharma-ceutically acceptable salt thereof,

45. The compound 2- [2-(dimethylamino)ethyl]-4-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepine-5(4H)-one or a pharmaceutically acceptable salt theroof.

46. The compound 2,3-dihydro-4-ethyl-2-[2-(1-pyrrolidinyl)-ethyl]pyrido[3,2-f][1,4]oxazcpine-5(4H)-one or a pharmaceut-ically acceptable salt thereof.

47. The compound 2,3-dihydro-4-methyl-2-[2-(4-morpholinyl)ethyl]pyrido[3,2-f][1,4]oxazepine-5(4H)-thione or a pharma-ceutically acceptable salt thereof.

48. The compound 2-[2-(dibutlyamino)ethyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione or a pharmaceut-ically acceptable salt thereof.

49. The compound 2-[2-(diethylamino)ethyl]-2,3-dihydro-4-metllylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione or a pharmaceut-ically acceptable salt thereof,

50. The compound 2,3-dihydro-4-methyl-2-[2-(1-pyrrolidinyl)-ethyl]pyrido[3,2-f][1,4]oxazepine-5(4H)-thione or a pharma-ceutically acceptable salt thereof.

51. The compound 2,3-dihydro-2-[2-(1H-imidazol-1-yl)ethyl]-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione or a pharma-ceutically acceptable salt thereof.

52. The compound 2-[2-(dimethylamino)ethyl]-4-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepine-5(4H)-thione or a pharma-ceutically acccptable salt thereof.

53. The compound 2,3-dihydro-4-methyl-2-[2-[methyl(phenylmethyl) amino]ethyl]pyrido[3,2-f][1,4]oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof.

54. The compound 2,3-dihydro-2-[2-(methylamino) ethyl]-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione or a pharmaceutic-ally acceptable salt thereof.

55. The compound 7-chloro-2,3-dihydro-4-methyl-2-[2-(1-pyrrolidinyl)ethyl]pyrido[3,2-f][1,4]oxazepine-5(4H)-one or a pharmaceutically acceptable salt thereof.

56. The compound 7-chloro-2-[2-(dimethylamino) ethyl[-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one or a pharmaceutically acceptable salt thereof.

57 The compound 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-phenylmethylpyrido[3,2-f][1,4]oxazepine-5(4H) one or a pharma-ceutically acceptable salt thereof.

58. The compound 2-[2-(dimethylamino)ethyl]-2,3 dihydropyrido[3,2-f][1,4]oxazepine-5(4H)-one or a pharmaceutically accept-able salt thereof.

59. The compound 2-[3-(dimethylamino)propyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one or a pharmaceut-ically acceptable salt thereof.

60. The compound 2-[3-(dimethylamino)propyl]-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione or a pharma-ceutically acceptable salt thereof.

61. The compound 7-chloro-2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido(3,2-f][1,4]
oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof.

62. A process for the preparation of an aromatic or hetero-cyclic oxazepine or thiazepine of the formula (I) wherein A represents an aromatic ring having two of its carbon atoms held mutually with the oxazepine or thiazepine moiety selected from the group consisting of benzene, naphthalene or a pyridine in any of its four positions, any of the rings optionally substituted by one or two Y radicals selected from the group consisting of halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
B & E are selected from oxygen or sulfur and may be the same or different;

R is selected from the group consisting of hydrogen, loweralkyl, cyclo-alkyl, or phenyl-loweralkyl of which phenyl may be optionally substituted by one or two radicals selected from halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
n is 1, 2 or 3;
Z is selected from the group consisting of -NR1R2, 1H-pyrazol-l-yl or 1H-imidazol-l-yl, R1 and R2 are selected from the group consisting of hydrogen, loweralkyl, cycloalkyl and phenyl-loweralkyl of which phenyl is unsubstituted or substituted by 1 or 2 radicals selected from halo, lower-alkyl, loweralkoxy, nitro, trifluoromethyl or cyano or R and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consisting of l-pyrrolidinyl, 2,5-dimethyl-pyrrolidin-l-yl, 2-methylpyrrolidin-1-yl, l-piperidinyl, 4-substituted piperidine-l-yl, 4-morpholinyl, l-piperazinyl, 4-substituted piperazin-l-yl and 1,2,3,6-tetrahydropyridin-1-yl and the pharmaceutically acceptable salts thereof with the proviso that when R is hydrogen, Z is never a primary or secondary amine and a further proviso that when n=3, Z is not lH-pyrazol-l-yl, 2,5-dimethylpyrrolidin-1-yl, 2-methyl-pyrrolidin-1-yl or 1,2,3,6-tetrahydropyridin-l-yl, which process comprises;
i) reacting a compound of the formula wherein A, B, E and Y are as defined above, R is as defined above except for hydrogen, n is 1 or 2, X is chlorine or bromine, with an amine of the formula ZH

wherein Z is -NR1R2 wherein R1 and R2 are each hydrogen, loweralkyl, cycloalkyl or penyl-loweralkyl of which phenyl is unsubstituted or substit-uted with 1 or 2 radicals selected from halo, loweralkyl, loweralkoxy, nitro, trifluoromethyl or cyano or R1 and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consisting of 1H-pyrazol-1-yl, 1H-imidazol-1-yl, 1-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, 1-piperidinyl, 4-substituted piperidin-1-yl, 4-morpholinyl, 1-piperazinyl, 4-substituted piperazin-1-yl and 1,2,3,6-tetrahydropyridin-1-yl, to obtain a compound of the formula wherein A, B, E, Y and Z are as defined above, and R and n are as defined in process i), or ii) reducing a cyano compound of the formula wherein A, E and Y are as defined above, and R is as defined above except for hydrogen, to obtain a primary amine of the formula wherein A, E and Y are as defined above, and R is as defined in process ii), or iii) reacting a compound prepared in step i) or ii) of the formula wherein A, E, Y, Z and n are as defined above, and R is as defined above except for hydrogen, with a sulfurizing agent to obtain a compound of formula wherewherein A, E, Y, Z and n are as defined above, and R is as defined in process iii), or iv) reacting a primary amine prepared in process i) or ii) of the formula wherein A, E, Y and n are as defined above, and R is as defined above except for hydrogen, with one of the following reactants or sets of reactants, a) formaldehyde and formic acid to give a tertiary dimethylamine, b) a dihalide to give a heterocyclic amine, c) a dialdehyde and sodium cycanoborohydride to give a heterocyclic amine, d) equal molar amounts of an aldehyde or ketane and sodium cyano-borohydride with large excess of above primary amine to give a secondary amine, e) equal molar amounts of the primary amine and sodium cyanoboro-hydride with at least two equivalents of aldehyde or ketane to give a tertiary amine, f) in sequence: trifluoroacetyl chloride, alkyl or phenylalkyl halide, potassium hydride and potassium hydroxide to give a secondary amine, to obtain a product of the formula wherein A, E, Y, and n are as defined above, Z is as defined above except for -NH2, and R is as defined above in process iv), or v) reacting a compound prepared in process i) or ii) of the formula wherein A, E, Y and n are as defined above, Z is as defined above except for primary or secondary amino group, and "phenyl" is unsubstituted or substituted with halo, loweralkyl, lower-alkoxy, nitro or trifluoromethyl, with sodium and ammonia to obtain a compound of the formula wherein A, E, Y and n are as defined above, and Z is as defined in process v), and vi) if desired, converting the resulting free base or a salt thereof prepared in process i) to v) to a pharmaceutically acceptable salt thereof by reacting with a pharmaceutically acceptable acid or quaternary forming halide or sulfate.

63. A process for the preparation of an aromatic or heterocyclic oxazepine of the formula:

(II) wherein;
A is selected from an aromatic or heterocyclic ring system having two of its carbon atoms held mutually with the oxazepine or thiazepine moiety selected from benzene, a naphthylene, a pyridine in any of its four pos-itions, any of which ring systems are optionally substituted by one or two Y radicals selected from the group consisting of halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
B and E are selected from oxygen or sulfur and may be the same or different;
R is selected from the group consisting of loweralkyl, cycloalkyl or phenyl-loweralkyl wherein phenyl is optionally substituted by one or two radicals selected from halo, loweralkyl, loweralkoxy, nitro or trifluoro-methyl;
n is 1 or 2;
X is chlorine, bromide or cyano or an acid addition salt thereof, which comprises the steps of Step 1) halogenating a compound of the formula wherein A, E, R, n and Y are as defined above except the two carbon atoms of A are not bound by oxazepine or thiazepine rings and R3 is hydrogen or an acid salt neutralizing ion, to give an acid halide of the formula or its free base wherein X is chlorine or bromine and A, E, n, R and Y are as defined above, Step 2) fusing the compound prepared in Step 1 to give an oxazepinone or thiazepinone of the formula wherein A, E, R, X, n and Y are as defined above in Step 1 and A now has 2 of its carbon atoms held mutually with the oxazepine or thiazepine moiety, Step 3) when required, reacting the compound prepared in Step 2 with a sulfurizing agent to obtain an oxazepine-thione or thiazepinethione of the formula wherein A, E, R, X, Y and n are as defined above, Step 4) when required, reacting a compound prepared in Step 2 with an alkali-metal cyanide to obtain a compound of the formula wherein A, E, Y and R are as defined in Step 2, Step 5) in the alternate halogenating a compound prepared in Steps 2 or 4 having the formula wherein E and R are as defined above and x is chlorine, bromine or cyano with sulfuryl chloride in a suitable solvent to give a compound having tile formula wherein E and R are as defined above and X is chlorine, bromine-or cyano.

64. A process for the preparation of a compound having the formula wherein;
A represents an aromatic or heterocyclic ring system selected from benzene, a naphthalene or a pyridine in any of its four positions, any of which rings systems are optionally substituted by one or two Y radicals selected from the group consisting of halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
R is selected from the group consisting of loweralkyl, cycloalkyl or phenyl-loweralkyl wherein phenyl is optionally substituted by one or two radicals selected from halo, loweralkyl, loweralkoxy, nitro or trifluoro-methyl;

n is 1 or 2;
X is selected from chlorine, bromine or fluorine and E is selected from sulfur or oxygen, which process comprises halogenating a compound of the formula wherein A, E, R, n and Y are as defined above and R3 is hydrogen or an acid salt neutralizing ion.

65. A process for the preparation of a compound having the formula:

(IVa) wherein;
A represents an aromatic or heterocyclic ring system selected from a naphthalene or a pyridine in any of its four positions, any of which ring systems are optionally substituted by one or two radicals selected from the group consisting of halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl, R is selected from the group consisting of loweralkyl, cycloalkyl, or phenyl-loweralkyl wherein phenyl is optionally substituted by one or two radicals selected from halo, loweralkyl, loweralkoxy, nitro or tri-fluoromethyl;
n is 1 or 2;
Q is selected from the group consisting of ?NH2 , cyano, ?R3 wherein R3 is H, an acid neutralizing ion or an esterifying radical, and E is oxygen or sulfur, which process comprises:
I) reacting a compound of the formula wherein A, E, Y and Q are as defined above, and M is an acid neutralizing ion, with a compound of the formula wherein R and n are defined above, and W is an aryl sulfonate, alkyl sul-fonate, chlorine or bromine, or II) reacting a compound of the formula wherein A, Y and Q are as defined above, and "halo" is a halogen atom, with a compound of the formula wherein R and n are as defined above.

66. An aromatic or heterocyclic oxazepine or thiazepine of the formula:
where in;
A represents an aromatic ring having two of its carbon atoms held mutually with the oxazepine or thiazepine moiety selected from the group consisting of benzene, naphthalene or a pyridine in any of its four positions, any of the rings optionally substituted by one or two Y
radicals selected from the group consisting of halo, lower-alkyl, loweralkoxy, nitro or trifluoromethyl, B and E are selected from oxygen or sulfur and may be the same or different:
R is selected from the group consisting of hydrogen, loweralkyl, cycloalkyl or phenyl-loweralkyl, of which phenyl may be optionally substituted by one or two radicals selected from halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl:
n is 1, 2 or 3;
z is selected from the group consisting of -NR1R2, 1H-pyrazol-1-yl or 1H-imidazol-1-yl;
R1 and R2 are selected from the group consisting of hydrogen, loweralkyl, cycloalkyl and phenyl-loweralkyl, of which phenyl may be optionally substituted by 1 or 2 radicals selected from halo, loweralkyl, loweralkoxy, nitro, trifluoromethyl or cyano, or R1 and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consisting of l-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2 -methylpyrrol idi n-l -yl, l-piperidinyl, 4-substituted piperidine-l-yl, 4-morpholinyl, l-piperazinyl, 4-substituted piperazin-l-yl and 1,2,3,6-tetrahydropyridin-l-yl, or a pharmacuetically acceptable salt thereof, with the proviso that when R is hydrogen, Z is never a primary or secondary amine and a further proviso that when n=3, Z is not lH-pyrazol-l-yl, 2,5-dimethylpyrrolidin-1-yl, 2-methylpyrrolidin-1-yl or 1,2,3,6-tetrahydropyridin-1-yl.

67. A compound having the formula:

( I I ) wherein;
A is selected from an aromatic or heterocyclic ring system having two of its carbon atoms held mutually with the oxazepine or thiazepine moiety selected from benzene, a naphth-ylene, a pyridine in any of its four positions, any of which ring systems are optionally substituted by one or two Y radicals selected from the group consisting of halo, loweralkyl, lower-alkoxy, nitro or tirfluoromethyl;
B and E are selected from oxygen or sulfur and may be the same or different;
R is selected from the group consisting of loweralkyl, cycloalkyl or phenyl-loweralkyl wherein phenyl is optionally substituted by one or two radicals selected from halo, lower-alkyl, loweralkoxy, nitro or trifuloromethyl;
n is 1 or 2;
X is chlorine, bromide or cyano or an acid addition salt thereof.

68. A compound of the formula:

(III) wherein;
A represents an aromatic or heterocyclic ring system selected from benzene, a naphthalene or a pyridine in any of its four positions, any of which rings systems are optional-ly substituted by one or two Y radicals selected from the group consisting of halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
R is selected from the group consisting of lower-alkyl, cycloalkyl or phenyl-loweralkyl wherein phenyl is optionally substituted by one or two radicals selected from halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
n is l or 2;
X is selected from chlorine, bromine or fluorine and E is selected from sulfur or oxygen.

69. A compound having the formula:

(IVa) wherein;

A represents an aromatic or heterocyclic ring system selected from a naphthalene or a pyridine in any of its four positions, any of which ring systems are optionally substituted by one or two radicals selected from the group consisting of halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
R is selected from the group consisting of lower-alkyl, cycloalkyl, or phenyl-loweralkyl wherein phenyl is optionally substituted by one or two radicals selected from halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
n is 1 or 2;

Q is selected from the group consisting of -?-NH2 cyano, -?-R3 wherein R3 is H, an acid neutralizing ion or an esterifying radical, and E is oxygen or sulfur.

70. A compound according to claim 66, wherein E is oxygen.

71. A pharmaceutical composition comprising an anti-histamic effective amount of a compound of formula (I) as defined in claim 66 or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable carrier or excipient.

CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE

72. A process for the preparation of an aromatic or heterocyclic oxazepine or thiazepine of the formula (I) wherein A represents an aromatic ring having two of its carbon atoms held mutually with the oxazepine or thiazepine moiety selected from the group consisting of benzene, naphthalene or a pyridine in any of its four positions, any of the rings optionally substituted by one or two Y radicals selected from the group consisting of halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
B & E are selected from oxygen or sulfur and may be the same or different;
R is selected from the group consisting of hydrogen, loweralkyl, cycloalkyl, or phenyl-loweralkyl of which phenyl may be optionally substituted by one or two radicals selected from halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
n is 1, 2 or 3;
Z is selected from the group consisting of -NR1R2, 1H-pyrazol-1-yl or 1H-imidazol-1-yl, R1 and R2 are selected from the group consisting of hydrogen, loweralkyl, cycloalkyl and phenyl-loweralkyl of which phenyl is unsubstituted or substituted by 1 or 2 radicals selected from halo, loweralkyl, loweralkoxy, nitro, trifluoromethyl or cyano or R1 and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consisting of 1-pyrrolidinyl, 2,5-dimethyl-pyrrolidin-l-yl, 2-methylpyrrolidln-1-yl, 1-piperidinyl, 4-substituted piperiaine-l-yl, 4-morpholinyl, l-piperazinyl, 4-substituted piperazin-l-yl and 1,2,3,6-tetrahydropyridin-l-yl and the pharmaceutically acceptable salts thereof with the proviso that when R is hydrogen, Z is never a primary or secondary amine and a further proviso that when n=3, Z is not lH-pyrazol-l-yl, 2,5-dimethylpyrrolidin-1-yl, 2-methyl-pyrrolidin-1-yl or 1,2,3,6-tetrahydropyridin-1-yl, which process comprises:
i) reacting a compound of the formula wherein A, B, E and Y are as defined above, R is as defined above except for hydrogen, n is 1 or 2, X is chlorine or bromine, with an amine of the formula ZH
wherein Z is -NR1R2 wherein R1 and R2 are each hydrogen, lower-alkyl, cycloalkyl or phenyl-loweralkyl of which phenyl is unsubstituted or substituted with 1 or 2 radicals selected from halo, loweralkyl, loweralkoxy, nitro, trifluoromethyl or cyano or R1 and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consist-ing of lH-pyrazol-l-yl, lH-imidazol-l-yl, l-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, l-piper-idinyl, 4-substituted piperidin-l-yl, 4-morpholinyl, l-piper-azinyl, 4-substituted piperazin-l-yl and 1,2,3,6-tetrahydro-pyridin-l-yl, to obtain a compound of the formula wherein A,B,E,Y and Z are as defined above, and R and n are as defined in process i), or ii) reducing a cyano compound of the formula wherein A, E and Y are as defined above, and R is as defined above except for hydrogen, to obtain a primary amine of the formula wherein A, E and Y are as defined above, and R is as defined in process ii), or iii) reacting a compound prepared in step i) or ii) of the formula wherein A, E, Y, Z and n are as defined above, and R is as defined above except for hydrogen, with a sulfurizing agent to obtain a compound of formula wherein A, E, Y, Z and n are as defined above, and R is as defined in process iii), or iv) reacting a primary amine prepared in process i) or ii) of the formula wherein A, E, Y and n are as defined above, and R is as defined above except for hydrogen, with one of the following reactants or sets of reactants, a) formaldehyde and formic acid to give a tertiary dimethylamine, b) a dihalide to give a heterocyclic amine, c) a dialdehyde and sodium cycanoborohydride to give a heterocyclic amine, d) equal molar amounts of an aldehyde or ketane and sodium cyanoborohydride with large excess of above primary amine to give a secondary amine, e) equal molar amounts of the primary amine and sodium cyanoborohydride with at least two equivalents of aldehyde or ketane to give a tertiary amine, f) in sequence: trifluoroacetyl chloride, alkyl or phenyl-alkyl halide, potassium hydride and potassium hydroxide to give a secondary amine, to obtain a product of the formula wherein A, E, Y, and n are as defined above, Z is as defined above except for -NH2, and R is as defined above in process iv), or v) reacting a compound prepared in process i) or ii) of the formula wherein A, E, Y and n are as defined above, Z is as defined above except for primary or secondary amino group, and "phenyl"
is unsubstituted or substituted with halo, loweralkyl, lower-alkoxy, nitro or trifluoromethyl, with sodium and ammonia to obtain a compound of the formula wherein A, E, Y and n are as defined above, and Z is as defined in process v), or vi) cyclizing a compound of the formula:

wherein A, Y, R, Z and n are as defined above, and R3 is H, a cation or an esterifying radical, to obtain a compound of the formula:

wherein A, Y, R, Z and n are as defined above, or vii) cyclizing a compound of the formula:

wherein A, Y, R, Z and n are as defined above, and X is halogen, to obtain a compound of the formula:

wherein A, Y, R, Z and n are as defined above, and viii) if desired, converting the resulting free base or a salt thereof prepared in process i) to vii) to a pharmaceutic-ally acceptable salt thereof by reacting with a pharmaceutically acceptable acid or quaternary salt forming halide or sulfate

73. A process according to claim 72, wherein E is oxygen.

74. A process for the preparation of 2-[2-(dimethylamino)-ethyl]-2,3-dihydropyrido[3,2-f]-1,4-oxazcpin-5(4H)-one or a pharmaceutically acceptable salt thereof, which process comprises:
(1) cyclizing 2-chloro-N-[4-(dimethylamino)-2-hydroxy-butyl]-3-pyridinecarboxamide, and (2) if desired, converting the cyclization product into a pharmaceutically acceptable salt thereof.

75. A process according to claim 74, wherein the cyclization is carried out using potassium hydride.

76. A process according to claim 74 or 75, wherein the cyclization product is converted to its fumarate.

77. 2-[2-(Dimethylamino)ethyl]-2,3-dihydropyrido[3,2-f]-1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof.

78. A process for producing 2,3-dihydro-4-methyl-2-[2-(methylamino)ethyl]-pyrido[3,2-f]-1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof, which process comprises:
(1) reacting 2-(2-chloroethyl)-2,3-dihydro-4-methyl-pyrido[3,2-f]-1,4-oxazepin-5(4H)-one with monomethylamine, and (2) if desired, converting the reaction product into a pharmaceutically acceptable salt thereof.

79. A process according to claim 78, wherein the reaction product is converted to its oxalate.

80. 2,3-Dihydro-4-methyl-2-[2-(methylamino)ethyl]-pyrido[3,2-f]-1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof.

81. A process for the preparation of 2-(2-aminoethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof, which process comprises:
(1) reducing 2,3-dihydro-[1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-ethyl]-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one with hydrazine, and, (2) if desired, converting the reduction product into a pharmaceutically acceptable salt thereof.

82. A process according to claim 81, wherein the reduct-ion product is converted to its fumarate.

83. 2-(2-Aminoethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof,

84. A process for the preparation of 2-(2-aminoethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-thione or a pharmaceutically acceptable salt thereof, which process comprises:
(1) reducing 2-[2-(2,3-dihydro-5(4H)-thioxopyrido[3,2-f]-1,4-oxazepin-2-yl)ethyl]-lH-isoindole-1,3(2H)-dione with hydrazine, and, (2) if desired, converting the reduction product into a pharmaceutically acceptable salt thereof.

85. A process according to claim 83, wherein the reduction product is converted to its fumarate.

86. 2-(2-Aminoethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-thione or a pharmaceutieally acceptable salt thereof.

87. A process for the preparation of 2,3-dihydro-4-methyl-2[2-[(l-methylethyl)amino]ethyl]pyrido[3,2-f-]-1,4-oxazepin-5(4H)-one or a pharmaceutieally acceptable salt thereof, which process comprises:
(1) reacting 2-(2-aminoethyl)-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4-oxazepin-5(4H)-one with acetone in the presence of sodium cyanoborohydride, and (2) if desired, converting the reaction product into a pharmaceutically acceptable salt thereof.

88. A process according to claim 87, wherein the reaction product is converted to its fumarate.

89. 2,3-Dihydro-4-methyl-2{2-[(1-methylethyl)amino]-ethyl}pyrido[3,2-f]-1,4-oxazepin-5(4H)-one or a pharmacutically acceptable salt thereof,

90. A process for the preparation of 2-{2-[bis(phenyl-methyl)amino]ethyl}-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof, which process comprises:
(1) reacting 2-(2-aminoethyl)-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4-oxazepine-5(4H)-thione with benzaldehyde in the presence of sodium cyanoborohydridc, and (2) if desired, converting the reaction product into a pharmaceutically acceptable salt thereof.

91. A process according to claim 90, wherein the reaction product is converted to its fumarate.

92. 2-{2-[Bis(phenylmethyl)amino]ethyl]-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutic-ally acceptable salt thereof.

93. A process for the preparation of 2,3-dihydro-4-methyl-2-[2-(4-methyl-1-piperazinyl)ethyl]pyrido[3,2-f]-1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof, which process comprises:
(1) reacting 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4-oxazepin-5t4H)-one with N-methylpiperazine, and (2) if desired, converting the reaction product into a pharmaceutically acceptable salt thereof.

94. A process according to claim 93, wherein the reaction product is converted to its fumarate.

95. 2,3-Dihydro-4-methyl-2-[2-(4-methyl-1-piperazinyl)-ethyl]pyrido[3,2-f]-1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof,

96. A process for the preparation of 2,3-dihydro-4-methyl-2-[2-(4-methyl-1-piperazinyl)ethyl]pyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof, which process comprises:
(1) reacting 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4-oxazepine-5(4H)-thione with N-methylpiperazine, and (2) if desired, converting the reaction product into a pharmaceutically acceptable salt thereof.

97. A process according to claim 96, wherein the reaction product is converted to its fumarate.

93. 2,3-Dihydro-4-methyl-2-[2-(4-methyl-l-piperazinyl)-ethyl]pyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutic-ally acceptable salt thereof.

99. A process for the preparation of 2,3-dihydro-4-methyl-2-[2-(methylphenylamino)ethyl]pyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof, which process comprises:
(1) reacting 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4-oxazepine-5(4H)-thione with N-methylaniline, and (2) if desired, converting the reaction product into a pharmaceutically acceptable salt thereof.

100. 2,3-Dihydro-4-methyl-2-[2-(methylphenylamino)ethyl]-pyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof.

101. A process for the preparation of 2-(3-aminopropyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof, which process comprises:

(1) sulfurizing 2-(3-aminopropyl)-2,3-dihydro-4-methyl-pyrido[3,2-f]-1,4-oxazepin-5(4H)-one in which the amino group may be protected, with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide, removing the amino protective group if any, and (2) if desired, converting the reaction product into a pharmaceutically acceptable salt thereof.

102. A process according to claim 101, wherein the amino group in the starting material is protected by reacting the starting material with di-tert-butyl dicarbonate, and after the sulfurization reaction, the protective group is removed by treating with trifluoroacetic acid.

103. A process according to claim 101 or 102, wherein the product is converted to its fumarate.

104. 2-(3-Aminopropyl)-2,3-dihyro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceuticallly acceptable salt thereof.

105. A process for the preparation of 2-[2-(dimethyl-amino)ethyl]-2,3-dihydropyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptahle salt thereof, which process comprises:
(1) sulfurizing 2-[2-dimethylamino)ethyl]-2,3-dihydro-pyrido[3,2-f]-1,4-oxazepin-5(4H)-one with phosphorus penta-sulfide, and (2) if desired, converting the sulfurized product into a pharmaceutically acceptable salt thereof.

106. A process according to claim 105, wherein the sulfurized product is converted to its dihydrochloride.

107. 2-[2-(Dimethylamino)ethyl]-2,3-dihydropyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof.

108. A process for the preparation of 2,3-dihyro-4-methyl-2-[2-(lH-pyrazol-l-yl)ethyl]pyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof, which process comprises:
(1) reacting 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4-oxazepine-5(4H)-thione with pyrazole, and (2) if desired, converting the reaction product into a pharmaceutically acceptable salt thereof.

109. 2,3-Dihydro-4-methyl-2-[2-(lH-pyrazol-l-yl)ethyl]-pyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof.

110. A process for the preparation of 2-[2-(dimethylamino)-propyl]-2,3-dihydro 4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof, which process comprises:
(1) reacting 2-(2-chloropropyl)-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4-oxazepin-5(4H)-one with dimethylamine, and (2) if desired, converting the reaction product into a pharmaceutically acceptable salt thereof.

111. A process according to claim 110, wherein the reaction product is converted to its dihydrochloride.

112. 2-[2-(Dimethylamino)propyl]-2,3-dihydro-4-methyl-pyrido[3,2-f]-1,4-oxazepin-s(4H)-one or a pharmaceutically acceptable salt thereof.

113. A process for the preparation of 2,3-dihydro-4-methyl-2-[2-(2-methyl-1-pyrrolidinyl)ethyl]pyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof, which process comprises:
(1) reacting 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4-oxazepine-5(4H)-thione with 2-methylpyrrolidine, and (2) if desired, converting the reaction product into a pharmaceutically acceptable salt thereof.

114. A process according to claim 113, wherein the reaction product is converted to its fumarate.

115. 2,3-Dihydro-4-methyl-2-[2-(2-methyl-1-pyrrolidinyl)-ethyl]pyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof.

116. A process for the preparation of 2,3-dihydro-4-methyl-2-[2-(1-piperidinyl)ethyl]pyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof, which process comprises:
(1) reacting 2-(2-chloroethyl)-2,3-dihydro-4-methyl-pyrido[3,2-f]-1,4-oxazepine-5(4H)-thione with piperidine, and (2) if desired, converting the reaction product into a pharmaceutically acceptable salt thereof.

117. A process according to claim 116, wherein the reaction product is converted to its fumarate.

118. 2,3-Dihydro-4-methyl-2-[2-(1-piperidinyl)ethyl]pyrido-[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof.

119. A process for the preparation of 6-chloro-2,3-dihydro-4-methyl-2-[2-(dimethylamino)ethyl]-4-methylpyrido[4,3-f]-1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof, which process comprises:
(1) reacting 6-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f]-1,4-oxazepin-5(4H)-one with dimethylamine, and (2) if desired, converting the reaction product into a pharmaceutically acceptable salt thereof.

120. A process according to claim 119, wherein the reaction product is converted to its fumarate.

121. 6-Chloro-2,3-dihydro-4-methyl-2-[2-(dimethylamino)-ethyl]-4-methylpyrido[4,3-f]-1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof.

122. A process for the preparation of 2,3-dihydro-4-meth 6-dimethylamino-2-[2-(dimethylamino)ethyl]-4-methylpyrido[4,3-f]
1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof, which process comprises:
(1) reacting 6-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f]-1,4-oxazepin -5(4H)-one with dimethylamine at an elevated temperature, and (2) if desired, converting the reaction product into a pharmaceutically acceptable salt thereof.

123. A process according to claim 122, wherein the reaction is carried out in a sealed vessel at about 100°C.

124. A process according to claim 122, or 123, wherein the reaction product is converted to its fumarate.

125. 2,3-Dihydro-4-methyl-6-dimethylamino-2-[2-(dimethyl-amino)ethyl]-4-methylpyrido[4,3-f]-1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof.

126. A process for the preparation of 2-[(dimethylamino)-methyl]-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof, which process comprises:
(1) cyclizing 2-chloronicotinamide of l-dimethylamino-3-methylamino-2-propanol, or (2) reacting 2-chloromethyl-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4-oxazepin-5(4H)-one with dimethylamine, and (3) if desired, converting che product of process (1) or (2) into a pharmaceutically acceptable salt thereof.

127. A process according to claim 126(1), wherein the cyclization is carried out by heating the nicotinamide in the presence of sodium hydride.

128. A process according to claim 126(1), wherein the starting nicotinamide is prepared by reacting 2-chloronicotinic acid with l-dimethylamino-3-methylamino-2-propanol.

129. A process according to claim 128, wherein the amidation reaction is carried out using dicyclohexylcarbodiimide.

130. A process according to claim 128 or 129, wherein the starting amine is prepared by reacting substantially equal molar amounts of epichlorohydrin and dimethylamine, and then reacting the reaction product with methylamine.

131. A process according to claim 126, 127 or 128, wherein the final reaction product is converted to its fumarate.

132. 2-[(Dimethylamino)methyl]-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof.

133. A process for the preparation of 2-[(dimethylamino)-methyl]-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof, which process comprises:
(1) sulfurizing 2-[(dimethylamino)methyl]-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one with a sulfurizing agent, and (2) if desired, converting the sulfurized product into a pharmaceutically acceptable salt thereof.

134. A process according to claim 133, wherein Lawesson reagent is used as the sulfurizing agent.

135. A process according to claim 133, or 134, wherein the sulfurized product is converted to its fumarate.

136. 2-[(Dimethylamino)methyl]-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4-oxazepine-5(4H)-thione or a pharmaceutically acceptable salt thereof.

137. A process for the preparation of 2-[2-(dimethylamino)-ethyl]-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one or a pharmaceutically acceptable salt thereof, which process comprises:
(1) cyclizing 2-chloro-N-[4-(dimethylamino)-2-hydroxybutyl]-N-methyl-3-pyridinecarboxamide, and (2) if desired, converting the cyclization product into a pharmaceutically acceptable salt thereof.

138. A process according to claim 137, wherein the cyclizat-ion is effected by heating the starting material in the presence of sodium hydride.

139. A process according to claim 137 or 138, wherein the starting material is prepared by reacting 2-chloronicotinic acid with l-dimethylamino-4-methylamino-2-butanol.