CA1262904A - Pyrrolo ¬1,2-b| ¬1,2,5|triazepines, a process and intermediates for their preparation and their use as medicaments - Google Patents

Abstract

ABSTRACT

The invention relates to compounds having the general formula II

(II) where R is hydrogen, loweralkyl, loweralkylaminoloweralkyl or diloweralkylaminloweralkyl, X is hydrogen, halogen, lower alkyl triflouromethyl or nitro; Y is hydrogen, halogen or loweralkyl;
and R1 is hydrogen , or and processes for preparing the compounds.

Many of the compounds of the formula II are useful as intermediates for synthesizing compounds of the formula I

(I) where R, X and Y are defined above.

Compounds of the formulae I and II are useful as analgesic, anxiolytic and/or anticonvulsant agents.

The invention also relates to compounds of the formula III

III

wherein X and Y are as defined above and processes for preparing the compounds. Compounds of the formula III are useful as intermediates for synthesizing compounds of the formulae I and II.

Description

~z~
~rhis Application is a Divisional of Canadian Patent Application Serial No. ~85,960, Filed June 28, 1985 This invention relates to novel pyrrolo[1,2~b]l1,2,5~-triazepines of the general formuLa Y ~$

where R is hydxcgen, lcweralkyl, loweraIkylaminolcweraIkyl or diloweraIkylaminoloweralkyl; X is hydrcgen, halogen ~flw rine, chlorine, bromine or iodine) trifluoromethyl or nitrD; and Y is hydrogen, halogen or loweralkyl, or a pharmaceutically acceptable acid addition salt thereof. miS invention also relates to derivatives of l-amuno-2-benzoylpyrrole having the general formula 3x (II) R R
where R, X and Y are as def m ed above, and Rl is hydrogen, ~CCH2NH2r -CCH2N~C02C(C~3)3' O O

-CC112Br~ 1l 2Cl~ -C02E:tt {~CH2M~2 (~, O o O O
- la -~;~6Z~

o ,~x Il 2 ~ 11 2 ~ 1l 2 11 C: ~ O O

~2N~3-O O

C~rp~s I and II a~e useful as ar~algesic, ar~iolytic and/or antic~nvulsant agent~, and many of (~3s II a~e useful as inte~nediates i~or synthesizing ~s I.
q~his illvention also relates to novel ~ nds ~ ic~h are derivatives of 2-~en20yl-l-phthalimidopyrrDle having the general forn~la ~ X
N

O ~ O (III) ~D .
where X and Y are as defined above which Are useful as intermediates for synthesizing Ccmpounds I and II.
~ o the best of our knowledge the compounds of the present invention have not ~een described or 6uggested.
ThloNyhout the specification ~nd ~he appended cla~ms, unless otherwise stated or indicated, the texm halogen shall mean fluor me, chlorine, bromine ~r iodine, and the term loweralkyl shall mean an alkyl group Df 1-6 carbon atoms.

~z~

The invention also relates to a process of preparing a compound of the formula I

Y ~ ~ N

~X
where X is hydrogen, halogen, Cl-C6-alkyl, CF3 or N02; Y is hydrogen, halogen or Cl-C6-alkyl and R is hydrogen, Cl-C6-alkyl, Cl-C6-alkylamino-Cl-C6-al}cyl ( 1 C6)-alkylamino-Cl-C6-alkyl or pharmaceutically acceptable acid addition salt of a compound of the formula I, which comprises a) cyclizing a compound of the formula II

y ~N ~ X II

R ~ CCH2NH2 d ; where X, Y and R are as defined above, in the presence of an acid, or b~ cyclizing a compound of the formula ~ X
o XV
R CCH2Br -2a-where X, Y and R are as defined above, in the presence of ammonia, or first reacting a compound of the formula XV with ammonia and reacting the product formed with an acid, c) optionally halogenating a compound of the formula I
wherein Y is hydrogen to obtain a compound of the formula I wherein Y is halogen, and d) optionally converting a compound of the formula I
into a pharmaceutically acid addition salt thereof.

-2b-z~
The invention also provides a process of preparing a compound o~ the fo.rmula II

N

wherein X i5 hydrogen, halogen, Cl-C6-alkyl, CF3 or N02; Y is hydrogen, halogen, or Cl-C6-alkyl, R is hydrogen, Cl-C6-alkyl, Cl-C6-alkylamino-Cl-C6-alkyl or di~Cl-C6)-alkylamino-Cl-C6-alkyl and Rl is hyd~n, -CcH2~H2' -C~2NH02C(c~3)3 O O

~CCH2Br, -CCH2Cl, -~2Et, ~2NK~X~2 ~ ' O O O O
O ~X
~X~2-N ~ ' 1l 2 ~ N ~ , CCH2 NH-CH2~1 , -CC~2N~X~3 or a pharmaceutically acceptable ~cid addition salt of a compound of the .formula II, which comprises a) hydrolyzing a compound of the formula III

Y~3 ~ N ~ III

E 2c ` ~21~:9U4 where X and Y are as deflned above to afford a co~pound of the formula II where R and Rl are both hydrogen, or b) react.ing a compound of the formula II where R is as defined and Rl is hydrogen, with HOOCCH2NHC02C(CH3)3 to afford a compound of the formula II where Rl is the group ~ ~ ~~ ~~ ~~ ~~ ~~ ~7 2c(i) ~29~

~CCH2NYC02C(CH3)3 , and c) optionally hydrolyzing a compound of the formula II
where R is as defined and Rl is the group -ccH2NHco2c(cH3)3 to afford a compound of the formula II where Rl is the group -CCH2NH2 or d) reacting a compound of the formula II where R is as defined but is not hydrogen~ with a compound of the formulae BrCH2COBr c~rClCH2COCl to afford a compound of the formula II where Rl is -CCH2Br or -CCH2Cl and O O

-2d-9Q~
e) optionally reactlng the compound obtained with alkali metal azide and further hydrogenating the resultant azide compound ln the presence of a suitable catalyst to afford a compound of the formula II where Rl is -CCH2NH2, or o f) reacting a compound of the formula II where R
and Rl are both hydrogen with ethyl chloroformate or ethyl bromoformate to afford a compound of the formula II where Rl is the group -C02Et, or g) reacting a compound of the formula II where R
is as defined and Rl is hydrogen, with one of the compounds or ~ N CH2COOH

to afford a compound of the formula II where Rl is the group -CCH2NHCOCH2 ~ or o -CC}~2 N~3 or h) reacting a compound of the formula II where Rl is the group O

-2e~

~Z4i'~9~
with N-phenylpiperazine to afford a compound of the formula Il where Rl is the group -C CH2-N ~ ~ or i) reacting a compound of the formula II where R
is as defined except hydrogen and Rl is the group -CCH2E~r with ammonia and then reacting the resultant product with glacial acetic acid to afford a compound of the formula II where Rl is the group Y~

-c_cH2_NH_c~2_c-NR
O

where R is as defined a~ove, or j~ reacting a compound of the formula II where R is as defined except hydrogen and Rl is the group -CCH2Br with ammonia and reacting the resultant product with acetic acid to afford a compound of the formula II
where Rl is the group -CCH2NHCCH3 and C) O

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k) optionally converting a compound of the formula II so formed into a pharmaceutically acceptable acid addition salt thereof.

Another aspect of the invention provides a process of preparing a compound of the formula III

OL~ .

wherein X is hydrogen, halogen, Cl-C6-alkyl, CF3 ox N02 and Y is hydrogen, halogen or Cl-C6-alkyl, which comprises reacting a compound of the formula IV

Y~

~ N ~

wherein Y is as above defined, with a compound X~cl -2g-~Z~ 4 our~s of ~is ~'cion rnay ~e prepar~d by us~ e or more of the foll~ ~teps. Unless ot}~erwise stated or in~icated, the definitions of the g~s R, ~, X Ar~l Y ~re as described ab~ve, arx~
the ~an~ sy~rbols have the s~ ~s th~ug~ut the desc~riptions of the reaction steps given belc~.

ST~ A
Car~ III may ~ cbtairY3d by reacting a canpo~d of Forrrula ~V with X ~ 1.
,[nl - Y N t X ~3CCC1 ~ ~11 0~ ~0 ~ IV) Said reaction may be conduct~d in the presence of zinc chloride in a suitable solvent such as dichloroethane. A typical reaction condition is stirring the re~ction mixture at room temperature overnight an~
additionally at 80 for 1 hour.
Compound IV may be prepared by using the method described in Flitsch et al, Chem. Ber. I969, Vol. 102, pgs. 3268-76.
STEP B
_ Compound IIa may ~e obtained by hydr~lyzing Ccn~x~md III in a suitable nEdium such as H20/CH3NH2/DMF or H2O/CH3~H2/EtCH. A typical reaction condition is stirrin~ the reaction mixture at room temperature for several hours.

3 H2/H20 ---------~ ~ X

O

2 (~Ia) lSl~PS C thrDugh E relate to the 6ynthesis of Cbn~p~D~is Il m which R is hy~nDgen and ~ i~ loweralkyl.
C
CXn}x7und V may ~e obtained by r~acting Ccn~xYund IIa with ethyl chlorofor~ate.

Ila ~ C1002Et ~ Y ~ ~u ~ X

(~
Said reaction is conducted usually in the presen oe of an acid scavenger such as sodium bicarbonate in a suitable solvent such as dichloromet } . A typical reaction oondition is refluxing the reaction n~rture for several hours.
STEP D
CXn~on~ VI may ke obtained by reacting C~n~x~und V with a loweraIkyl halide of the formLla ~ -Hal, Hal being iodine, bromine or chlorine, pre~exably iodine, and ~ being loweralkyl.

V ~ R2-Hal ~ Y Nl ~ X

N
R2 02Et (V~) Said reaction is oDnducted usually in the presence o~ an acid scavengersuch as sodium carbonate in a suitable solvent such as DMF, A typical reaction co~dition is stirring the reaction mixture at roa~ temperature iZ9~)~
ove~ht ~r~l ~itianally ~t 70~8û~C for a ~ew ha~;.

~ E

O ~ Y ~

(VII~

Said ~action is oonducted, for instanoe, in the presenoe of ~odi~n hydroxide in a ~uitable sclven~ such as H20/ethar~l. A t~pical reactio~
oos ~ tio~ is refl ~ the reaction mixture avernight.
(STEPS F and G relate tD the synthesis of Ccmpounds II wher~ R is hydrog~n and ~ is lcweralkyl ~ oloweralkyl or diloweralkylamin~loweralkyl. In order ~D simplify the descripkion, STEPS F and G are described with specific referenoe to the ~ituation where ~ is dimethylanuu~ethyl.) STEP F
CXJ~?ound VIII may be prepared by r~actLny CbmpDund V with dimethylaminoethyl chloride.

V ~ ClCH2~H2N(Q 3)2 ~ Y ~ X

E~02C ~H2cH2N(cH3)2 ~VqII) 9~L
&id reaction i~ oonduct2d, ~or ~tan~e, Ln the pre~oe c~f sodiunn n~tl~Dcide ~n a ~ ble solvent ~h ~ ~. ~ typi~l rea~ticxn ~itio~ 16 ~ti~r~ the ~eactio~ mix~ at lOO~C ~or 30 mil~utes.
G
_u~
~3x VIII ~ ~2 ~ Y I O

H CH2a~2N (CH3) 2 (IX) Said reaction is oo~duc*~, for instanoe" in ~ presenoe of sodium hydroxide in a suitable solvent E;uch as H20/et}~l. A t~pi~al reaction oDndition is reflux~g the reacticn mixture s:nrernight.
Although the df~seription o~ 51~S F and G above are given with referenoe to 'che situation where ~ is dimethylamin~ yl, it will be cbvious to the person sJcilled ~n the art that th~ san~ p ~ is generally applicable for preparing Cbr}~unu`s X and Xl below where ~ is loweralkylaminoloweralkyl or diloweralkylaminoloweralkyl.
~ ~X ~ ~X
y N~ y N
O l O
N N

3 2~t (X) ~rom th~ foregDing descriptions of STEPS C thr~ugh G, it will be seen that corpou=d~ of the general ~ormula XII can be prepared, where R4 is X - ~ _ ~.26zg~4 loweraL~cyl, lc~æral)~lamir~loweralky~l or diloweral)yla~ loweralkyl.

~'~
O
~M~ ~XIIj R~

H
~p~ XIII may ~e obtained ~y ~eacting C~ XII with N- (tert-~ut~ycarbc>n~ l) ~ly~_ine.

XII ~ (CH3) 3 2C02H ~ yJ~3X
O

R4 ~;~ )2c (~H3) 3 o ~XIII ) Said reaction is oc~r~ducted usually is~ the presence of dicyclohex~lcarbcdiimlde which acts as a dehydrating agent in a suitable solvent such as dichlorc0ethane. A typical reaction condition is stirring the xeacti~n n~xture at room temperature for several hours.

~Z~Z~Q~

S~ I
._ ~J~
~II ~ B20 ~ I ~

~4 1l 2~2 Said rea~ion is o~nducted, ~or inst~nce, ~y using 48% Br ~nd a suitable solvent such as e'c}~yl aoetate/n-pr~Dl. ~ t~pical re~ctic~n cc~nditio~ is st~sring the reaction mixture at r~an ~perature for ~e~eral hours.
~ As an alternative to adopting SrEPS H an~l I to prepar~ Cc~r~
XIV fran CaT~ Xll, ti2e ~olla,nng Sll~; J and K ma~ be adc~pt~d.) SrEP J
~3 ~N may ~e prepared ~y reacting CaTp~d XII with br~rD3acetyl branide.

X~l ~ BrW12Br ~ y ~rl~3X

R~ ~CCH Br o ~XV) Said reactio~ is oc>nducted usually ~r the preænc:e of an a~id ~cavenger such as sodiun bicarbonate in a sui~able sol~ent such as ~ z~z~o~
dichlorc~neth~ne. 11~ typical reactian ct~ 6t~ing tl2e r~actiu~
mixture ~t r~n t~erat~re averrlight.

Oor~ ~UV may be prepared ~y fi~st reac~ing ~pc3u~ X~

d&:r.ivative with ~dr~ gas in the presenoe c~f a ~ ble catalyst D5 platinun.
aN3 XV ~ ~ XIV
(2) Pt/H2 Said r~action wi'ch sodi~n azide May be oon~uct~d in a r~utine manner kn~n t4 the art. Said hy~rogenatio~ reaction may be ~cted, ~or instan~e, in a suitable solvent su~ as methanol at a l~n gas pressure of 15 psi. A typical hydr~genation cc~ition is shaking the reactio~ mixture for a few l~rs at ro~n tçsr~erature.
S~ L
la mEIy be obt~ined by cyclizing cq XIV.

~c Y
.~ ~?

a~

~2~:90~

~id reactiorl ifi oo~duc,~d, ior instanoe, ~ ~ px~ence t~f glaGial eloetic acid in a ~table ~olvent ~h ~ lletha~l. A typi~l neac~

~s.
(Ca~d Ib a~rrespandi~ to the situatic~ where R i~ ~ in Fo~s~la I may be prepared ~y usin~ SrEPS M ar~ N bel~w.) ST~ M
O~pc~ XVI may be pr~pared ~y reacting ~pa~ IIa with b~aoetyl br~nide.

IIa Il 2 N
O ~ ~
CQ2Br o (X~l ) &id reaction is con~ucted usually in 'che presenoe of ~n acid sca~enger ~ch as sodi~n bicax~onate in a suitable solvent ~uch as dic31loraret~. A typical reaction condition is stirring the reaction mixture at ro~n t0~erature for a ~ew l~urs.
SI'EP N
Canpow2d Ib may be prepared by cyclizing C~r~ XVI.
H

Y ,1~

>
IIb) ~
~X

-- lC --~zg~
Said ~ac~ia~ may be ~n~uct.ed ~ ~ pre~ of ~a~tio¢l ~ix~ at r~an ~erat~re cnresnight and ~itionally refl~ it ~ ~everal ha~s. Altern~tively, ~aid reacti~ m2ly ~e ~ n t~ ~teps, f~r~'c reacting C~r~ XYI wil:h ~nia in a ~uitable ~olvent ~u~h as nethanol ~It or for 10 ~utes f~r instanoe.

a ~uitable solvent sll~h as i~pr~l, and glacial aoetic acid i~ added to the solution. There~fter, the nixture i5 refluxed for several h~urs.
P O
As an a~ ~ tive to the sequen oe oonsisting of Sl~ S M and N
to prepare Ccnpound Ib, a method may be used wherein a ocmpound o~ the form~la XVII, XYIII or XIX may first be prep2red by using Fcute O(a), Onb) or O(cl below. ~ydrolysis of any of Cc~pound XVII, XVlII o~ XlX
affords Compound XX. CGmpound XX is then cyclized to af~ord Cbmpound Ib. The hydrolysis of Ccrpounds XVlI and XVIII to afford CGmpound XX is oon~ucted in substantially the same n~nner as used for ~e hydrDlysis of ~n~pound X~II t~ afford Campvund XIV w~ich is described in STEP I.
Ihe hydrolysis of Conpound XIX to afford ~bmpound XX may be conducted in substantially the same n~nner as used ~or the hydrolysis of Compound III
to afford Compcund Ila described in STEP B, The cyclization of ~X to afford Db may be conduc*ed in substantially ~he same n2nner as described in ~P L.
KII~TE O(a) ~ d IIa is reacted with N-(ter$-but~xycarb~nyl)-glycine tD afford Ccmpound XVII.

i29(~

IIn ~ ~H3~ 3~H2C~2~ ~ X

B ~ ~2~C~2C (CH ~) 3 (XVII) Said r~actian is ~ducted in the presenoe of dicyclc~yl~iilride in a suit~ble solvent such as dichlomnethane. A t~pical reaction ~n~lition is ~tirring the reacti~ mixtur~ at r~n tenperature for a few hc~urs and additiollally refluxing it for a few ~urs.
~OUI'E O(b) C~und IIa is reac~ted with c~zylo3yglycine to ~fford C~r~r~ XYIII.

Ila ~ ~H? ~2C~ Y~ X

~2~C~)2a~Z~7 (XVIII) Said rea~tion is o~nducted in the presenoe of dicyclohexylcarbodiiJnide :Ln a suitable solvent such ~s dic~hlon~re~ne. A t~pical reaction oondition is st~T~g ~e reactic~n mixture at r~n t~erature for a fe~

h~urs.

~Z6Z~
~ C) __ Canp~ ~ react~d with ~Eihthz~l~yl gly~ fford ~X.

Jla ~ H202N ~ Y
'~

~ XIX) Said reactic~n is cc)nducted in the presenoe c~f dicyclo~exylc~imide in a suitable solvent such as dichlor~retha~. A typical reaction oonditi~n is stirring the rea~tion mixtlare at roan temperature for a few hcurs and additior~lly reflux ~g it for a f~7 hl~urs.

XVI~, XV~I~ ~r XIX ~~~--~~i ~ X Ib O
N
11 12~H2 o (~) The reactions describ~d in ~Dutes ~a~, nD) and (c) ~ay also be utilized to obkain compcunds XVIIa, XVIIIa ~nd XIXa by reactLng Corpound XII with N-~tert-~utoxycarbonyl)-glycine, carbobenzyloxyglycine and N-phthaloyl glycine, respectiYely.

~2~Z~
x ,~ r~X

R4 ~ 2NH0~2C(CH3 ~ 4 ~ 2NH002CH
(XVIIa) (XVIIIa) Y~

R4 CCH2N ~

O (xIxa) ~ny of the Cb~X~l~d5 XVIIa, XVIIIa or XlXa may be hydrolyzed to afford c~und XIV.
(Cc~Qound I ~*here Y is chlorine or bromine may be prepared from Ccn~xYund Ic and N-chlorosuccLnimide or N-brcmosuccLm mide, respectively, as an alternative to adopting the foregoing steps.) SI'EP P
Conpound Id may be obtained by reacting Ca ~x~und Ic with N-chlorosuccinimlde.
R R
I ~ Cl ~? NCS 3 ~?

~ (Ic) ~ ~Id) Said reaction is conducted in the presence of a suitable solvent such as dry tetrahydrofuran. A typical reaction condition is refluxing the reaction mixture under nitrogen for several hours.

~Z6Z~
.~ ~
O~n~ le ~ay be ~Lir~d ty reacting Carp~ ~c with Ic ~ ~, _ ~>

~Ie~ ~
Said reactio~ is o~nducted usually in a su~table ~olvent ~u~h as dry tetrahydr~furan. A typical reactioll oondition is refluxir~ the reaction m.ix~ for several h~urs.
SIEP R
Cbmpound of For~ula XXI may be prep2red by reacting ~bmçound XVI with N-phenylpiperazine.

X~q ~ ~ - N NH ~ Y
o~ 3 ~3 (~u) Said reacticn is cGnducted usually Ln the presence of an acid scav2ngersuch as sodium bicarbDnate in a ~uitable solvent such 2S
dichloro~ethane. A typical reaction oondition is stirring the reaction muxture at 75 for a few hours.

~o~
~rEp s A a~ of F~rul~ ~I ~y ~e p~ared ~y xea~ing rea~ting t}~e ~esultant product with ~ cial acetic acid ~ ~ Euitable nt ~ s isopr~l.

3/Me~ ~3 X
XV ~ I O ¦ D
(2) Ha~ PrO~l R4NC-CH2~ CH2 ~jN~4 O O

~ 1) Ihe first s~ep is ~nducted, for instanoe, by stirring the reaction mlxture at room temperat~re for a few hours. Ihe seo~nd ~tep nay be oonducted by refluxing the reaction mixtuYe ~or 5-'0 hcurs.
STEP T
A oompound of Formula XXIII may be pr ~ d by reacting ~cmpound XIV with ammonia in a suitable ~olvent ~uch as ~ethanol, and then reacting the resultant product with glacial acetic acid in a suitable solven~ such as isopropanol.

ll) NH3/MeC
XV
l21 HQAc~i-PrOH
o o tXXIII) m e first step is oonducted, ~or instance, by stirring ~he reastion ~uxture for 1 hour and then xefluxing it for ~everal hours. The sec~nd ~tep n~y be o~nducted, for ins~ance, by refluxing the reacti~n mixture for several days.
_ 16 -E

~Z~ 9C)~
All ~ther ~ta~ting m~terial~ ~ abave are either kno~
readily available m~teri~ls.
~ I ~ II of the preserlt ~ticn ~re useful as ac~ivity of the m~ ~ nstrated in the 2-pheryl-1,4-benzoquinone-induced writ ~ test in ni oe , a ~tandard ~ssay ~or analgesia, ~Proc. Soc. Exptl. Biol. Med., 95, 729 (1957)]. Results ~f the analgesic activities of ~ome of the ocmpcurds of this in~ention are shcwn in Table I.
T ~ I
PNAL~C ~rIV~
P~W (% decrease) (at 20 mgtk2~s c.

[2-(2-Chlorbbenzcyl)-lH-pyrTDl-1-yl]-2- 41 [~dimethyLaminD)ethyl]carbamic acid, ethyl ester hydrobromide [2-(2-~hlorbben2Oyl)-lH-pyrr~ yl]-2- 72%
(dimethylaminD)ethylamine hydrdbromide l-[N-Methyl-(t-bu~DxycarkDnylamino)- 47%
acetam~do]-2-(2-chlorobenzoyl)pyrrole 1-[(t-ButoxycarbDnylæminD)a oe tamidD]- 49 2 ~2-chlorobenzoyl~pyrsDle 1-nN-Methyl-am~noacetami~D)-2- 42 (2-chlorobenzDyl)pyrrole hydrobromide Di-[(2-(2-fluoro~enzoyl)-5-methyl-lH- 68 pyrrol-l-yl)-2-a oe tanido~amine hydrochloride ~z~z~

LE I continu~d) ~ Ca1ixibe-zyloxyaINuno)aoetamido]-2~ 50kenzoylpyIrole 1-Aminca oe tamido-2-benzoylpyrrole 23%
hydrochloride 1-[(t-~ut3xycarbonylamino)a oe tamido]- 21 2-~2-flu~rcbenzsyl)pyrrole 5-(2-Chlorcphenyl)-l-methyl-lH-pyTrolo- 36%
11,2-b]~1,2,$)triazepin-2(3H)-one 5-Phenyl-1~-pyrrolo~1,2-b][1,2,5]- 31%
triazepin-2(3H)-one 1-~ethyl-5-phenyl-lH-pyrrolo[1,2-b]- ,26%
[1,2,5]triazepin-2~3H)-one hydrcbrcmide 5-12-Fluorophenyl)-l-~ethyl-lH-pyrrolo- 27%
[1,2-b][1,2,5]triazepin-2(3H)-one hydrcchloride 8-Chloro-S-(2-fluorophenyl)-1-methyl- 19 lH-pyrrolo[1,2-b][1,2,5]-triazepin-2(3H)-one hydrochloride Com~ounds I an~ II of the present m vention are us2ful 2s anxiolytic agents. Ihe activity of the compounds is demonstrated in the Geller-conflict paradigm with rats. See Geller, Trviny and Seifter, Psychopharmacologia Vol. 1, 482-492 (1362). ~ale rats are used as test subjects. They are housed in ividually and food and ~ter are available ad libitum until they are 300 to 400 gTams prior to the start of training. Subseq~lently they are food deprived until their bcdy weight is reduced to approxim~tely 80~ of original and it is maintained at this level by a restricted focd diet.

~;

~Z~i~"3(~

The pr~grq and test ~ert oonsist~ of solid state ~nd c~ulative reoorders. ~he cages nre ~p~ed ~ith ~ ;elight, B
singl~lever, cue-light6, a liquid diE~ær, a ~r and a grid-floc~r liquid-diE~er Eerve as the positive reinforQE~'c for all ~ubjects.

distinct respo~ reward secti~s. In the ~e~ or ~c~fli~t"
~e~r~ t, signaled ~y o~set of botl- toq~ c ~ lights, a di~ er of m~lk is delivered in response tD each l~ver-press ~CRF schedule of reinforoement). HoweYer 12ver presses during this period are alsD
a ~ ed by a 40 m ~ec pulse of aversive ~ookshock through ~he grid-floor. This creates a ~oonlict ~etween 1) easy access to ~ilk rewand and 2) the sLm~ltaneous p~esentation of a pain~ul foot-shDck.
~his ~oDnflict" period is 3 munu~es in duration.
D~rmg the other segment of this paradigm, the lever presses produoes a dipper of milk only at variable intervals of time fr~m 60 to 210 seoonds kith an averaye reward of onoe per 2 ~inu~es ~YI-2 ~in.).
~D shocks are ever administered durLng this Vl phase of test mg which is 15 munutes in duration.
me test proceduIe oonsists of ~our 15 m~nute (non-~hcck) Vl seg~en~s where re m forcement was availaDle on a limited basis. Each Vl perio~ is followed by a 3 minute ~CRFn-cDnflic~ phase w~en reLnforoement is cDnstantly available ~ut always acoompanied by an aversive foot-shock. The shock-level is titrated f~r each ~ubjec* tD redu oe the CRF responding to a to~al of less than 10 lever-presses durLng ~he entire test. The rats ~re tested f~ur days a week. Drugs 2re administered on ~he third day and the performance is compased tD the _ 19 _ ~3,zf~o~,g~

pr~viaus day~ ntrol tri~l. lhe VI reF~nse~ are u~d to ~v~luate dny e~luate ~y Vnnti~ety" effects ~ in~ y increaged respon~l~ng during tl~ ~C~nflict' ~sd.

injection in v~lumes of 10 ~c~kg and the pretreat interval l~ usually one-half hour.
CcnTrxnds I ~nd II of the present ~ tion nre useful as antio~nvul~ant agents. ThR activity of the corçcunds i~ demonstrated in supr ~ 1 electr~shcck assay. Groups of male mi oe (18-30 gra~s) are used. nrugs are prepared us m g distilled w~ter and if insDluble, a surfactant is added. CDnt~l animals receive vehicle. Drugs nre rcutinely ad~inistered intraperitoneally. The d~sage v~lume is 10 ml/kg.
Ihe ani~al'~ eyes are placed acr~ss the output ~e ~ ls of an A.C. shcckex that delivers 206 volts rms for 300 milliseconds.
Electrode paste coats the anlmal's eyes at the point o~ cantact wqth the terminals .
A oonpound is considered ~D gi~e prDtection if the mouse does nct exhibit extensor tonus. Protection is expresse~ as normaliz~d peroent inhibition relative to vehicle control.

#Rx protected ~Control pnDteCted rmalized ~ Rx tested ~C~trol Ce~ted inhibition = - X 100 # CDntrol prDtecked # Contr~l test~d A time response is carried out us mg 6 animals per group.
A~imals are tested at 30, 60 and 120 ~unutes pDstdrug. Additional time periods are tested if indica~ed by previous ~ests.

U

~:6'~

~ hen the peak activity time has been determined, a dose response is initiated, using 10 animals per group at that time period.
The ED50 and 95~ oonfidence interval are calculated by computerized probit analysis.
Results of the anxiolytlc and anticonvulsant activities of some of ~he compounds of this invention are shown in Table II.
Ta~le II also lis~s benzodiazepine binding properties of scme of the compounds o~ this invention. ~his a~say is used to determine potential anxiolytic or anticonvulsant activity vLa direct interaction with benzodiazpeine recognition sites in a m~mbrane preparation obtained from rat brain~
Ben2cdia7epine is a widely prescr~ho~ psychoactive agent. It has various pharmacological prcperties, including anti-anxiety, anticonvulsant, mLscle relaxant and hypnotic effects. The relationships ~etween the pharmacol~gical activities of this compcund and the G~eA
recep~or-chloride ionophore oomplex have been studied in the past. The values of IC50 listed in Table Il were determined in the follcwing manner. See S~uires and Braestrup, '~nzodlazepine Beceptors in Rat Brain", N~ture, 266, 732-734 (1977).
Reagents 1. T~is Eu~fer pH 6.9:
a. 78.1 g of Tris-HCl q.5. ~0 1 liter b. 60.6 g of Tris-base q.s. to 1 li~er c. Adjust pH of Tris HCl to 6.9 at 25C by adding Tris base to cbtain 0.5 M Tris bufer, pH 6.9~
d. Mbke a 1:10 dilution with dis~illed H20 bo obtain 0.05 ~ Tris bu~fer, pH 6.9 2. 0.32 M sucrose: 21,9 g o~ sucrose q.s~ to 200 ml tz~v~
3. Radioactive b~odiazepine~ marl~r oarpc~r~ is ma~e up to ~ ~t~atic~ ~f ao r~M ~ 50 1 of tlae solut~on i~ ~ed to ~ach tube, which yiel~s a final cc~oentr3tio~ of 2 nM in ~ ~ssay.

ehicle and ~erially diluted, ~uch that the f~al ~tration in ~he f 10-5 ~ 10 8 M

~ ale Wistar xats are decapitated and the brain rapidly r ~ . qhe oe rebral oortioes are removed, weighed and homoyenized with a homogenizer in 20 vDlumes of ice-cold C.32 M sucr~se~ This hLmog~nate is oontrifuged at 1,000 g ~r 10 minutes, the pellet is discarded and the supernat~nt is recentri~uged at 30,000 9 ~or 20 ninutes. ~he resulting nembrane pellet is resuspended in 40 v~lumes of 0.05 M Tris buffer, pH 6.9.
ssay 1 nl 0.05 M Tris buf~er, pH 6.9 1 0.5 M Tris buffer, pM 6.9 1 radioactive benzodiazepine solution 1 vehicle or a solution oontaininy an appropriate oDn oe n~ration of test drug 300 1 tissue suspension prepared above A tUtR oontain~ng the first five items listed abov~ is i~cubated at 0-4C in an i oe ~ath. A 300 1 aliquot ~ the tissue suspension is 2dded ~D ~he tube and the sample is then incubated for 20 ~unutes at 0-4C and thereafter vacuum,filtered using a ~uitable filter.
The filter i6 innediately rinsed with three S ml washes of ice-cDld Tris ~uffer, p~ 6.9. The radioactivity Df the filter is counted in 10 nl of ~6~

a counting cocktail. Ihe value of the radioactive ocunting obtained for a aample containing ~ test drug is c~q~ared ~o the count m g ob~ bed for the sample nct containing the test drug and the ratio between the ~wo computed. The IC50 ~alue for ~ given test drug is definsd as that ooncentration of the tes* drug at w*ich said ratio bec2mes 50~ (IC
stands for inhibitory oon oe ntrati~n).

TAQLE II
ANXIOLYTIC AND^ANTIccrN~n~suN~ ACTIVITIES

Bz BindingGeller SES
( 50~ )dose/CRF ED50 /kg~l.p.~ kg) 5-Phenyl-lH-pyrrolo[1,2-b~- 6.73xlO 6 [1,2,5]triazepin-2(3H)-one l-Methyl-5-phenyl-lH-pyrrolo- 3.40x10 740/22.6 [1,2-b][1,2,5]-triazepin-2(3H)-one hydrobromide 5-l2-Fluorophenyl)-lH-pyrrolo 5.86xlO40/2.4 l1,2-b][1,2,5]triazepin-2(3H)-one 8-Chloro-5-~2-fluor~phenyl)-1- 6.99xlO 36.1~i.p.
methyl=lH-pyTrolo[1,2 b]ll,2,5]-triazepin-2(3H)-one hydrochloride $-(2~Chlorophenyl)-lH-pyrrolo- 2.04~10 60~15 [1,2-b~[1,2,5~triazepin-2(3H)-one 5-(2-Chlorophenyl)~1-methyl-lH- 2.27xlO 8 40/1.4 17.9 i.p.
pyrrolo l 1, 2-b] 11, 2, 5] triazepin-2(3H)-one 90~

(TABLE II oontinued) 1 nN-Methyl- ~ oe tanid~)- less ~han 40/11.2 8.2 i.p.
2-(2-flu~robenzoyl~pyrrDle 1~0K10 5 ~drab~amide 5-(2-FluDrophenyl~ methyl-lH- 6.21x10 8 ~3.6 i.p.
pyrrolo[1,2-b][1,2,5]triazepin-2(3~)-one hydrochloride Effecti~e 9uantities of the oo~poucds of the inventi~n may be ~dministered to a patient by any of the various methods/ for example, orally as in capsules or tablets, parenterally in ~he form of ~terile solutions or suspensions, and in some cases intraven~usly m the form of sterile solutions. m e free base final products, while effective themselves, may be formulated and administered in ~he form of their phaIma oe utically ac oe ptable ad~ition salts for Furposes o stability, oonvenien oe of crystallization, increased solubility and the like.
Acids ~seful for preparing the pharma oe utic~lly acceptable acid additi~n salts of the ~nvention include Lnorganic acids such as hyd~ochloric, hydrcbromic, sul~uric, nitric, ph~s ~ ric and perchloric acids, as well a~ organic acids such as tartaric, citric, aoetic, 6uccinic, maleic, fumaric and oxalic acids.
1$~ active oompounds of the present invention may be orally administercd, for example, with an i~ert diluent or with an edible carrier, or they may be enclosed in gelatin ~apsules, ~r th2y nay be compressed into tablets. For the puxpose of oral th2rapeutic administration, the active cc0pcqnds of the invention may be incorp~rated with e~cipients and ussd in the form ~f tabl~ts, troches, capsules, elixirs, suspensions, syrups, wafers, chew ~ gum and the like. m ese preparati~ns shDuld ODntain ~t least 0.5~ of active compound, but may be varied dependiny upon the particular form and may - 24 ~

~L2~ f~99L
conven1ently be bet~3en 4~ to about 70~ of the weight of the u m t. The ~m3unt of ~ctive c~x~m d in ~uch compc~ition~ i~ such that ~ suit~bie d~sage will be ot~L~3d. PIeferred oompositions ~nd preparations ~ccordin~ to the present Lnvention are prepaled so that an oral dosage unit form oontains between 1.0-300 milligrams of active crn~x~md.
The ~ablets~ pills, capsules, ~ s ~nd the like may also contain the following m gredients: a bin~er such as m~crD-crystalline oellulose, gum tragacanth or gelatin; ~n excipient 6uch as starch or lactose, a dis m tegrating agent uch as algLnic acid, PrimDgel, cornstarch and the like; a lubricant such as magnesium stearate or Sterotex; a glidant such as colloidal silioon dioxide; and a sweetening agent such as sucro~e or ~accharin may be added or a ~lavoring agent such as peppermunt~ methyl salicylate, or orange flavoring. ~hen the d3sage unit fonm is a capsule, it may contain, in addition to materials of the ~bove type, a liquid carrier such as a fatty oil. O*her dosage unit fonms may oontain other various ~aterials which m~dify the physical form of the dos~ge unit, for example, as ooatings. Thus t~blets or pills may ~e coa W with sugar, shellac, or other enteric o~at m g agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, colorings and flavors. Materials used in preparing these various ccrpositions should be pharmaceutically pure and non-toxic in the amounts used' For the p~rposes of parenteral therapeutic administration, the active ccn~x~l~ds of the invention may be inoorporated into a solution or suspension. These preparations ~hould oontain at least 0.1~ of active ccmpound, but may be varied to be between 0 5 and about 30~ of ~he w~ight thereof. m e amount of active oompound in such oampositions is such that a sNitable dosage will ~e obtained. Preferred oompositions and preparations according to the present invention are prepared so that t~S ~ k -25-g~

p~renter~l d~fia~e unit cc~t~ 2~een 0.5 to 100 milligral!roe of ~ctive c~
~he @olutians or ~:sion ~y al~ lr3clus~e t~ ollo~ir~
terile diluent ~UC31 ~s water for ~njecticin, Daline ~olution, fix3d oil~, polyetl~ylene glyc~l~, glyoer~, pr~lene glyoc)l or methyl psra~; antia~cidan~s ~uch ~s asco~ic acid or 30diun bisulfite; ~helatin~ ag~nts E;uch ~s ethylenedi~ni~tetraaoetic acid;
buffers ~uch as aoetates, citrates or ~spllates ~ agents ~or tl~e adjus~t of tonicity such as ~odi~n ~:hlc~ride or dextrose. Ihe par~teral preparation can be enclosed in di~;posable liyrir~es or multiple ds~se vials made of glass or plastic.

EKanples of the ~ :r~s of this im~ention include:
5-~2-Fluorophenyl)-LH-pyrrDlo[1,2-b][1,2,5]triazepin-2~3H)qone;
5-Phenyl-lH-pyrrDloll,2-b]l1,2,5]triazepin-2~3H)-one;
l-Methyl-5--phRnyl-lH-pyrrolol1,2-b][1,2,5]triazepin-2(3H)-one hydrQbrom1de;
5-(2-Chlorophe~yl)-l~methyl-lH-pyrrolo[1,2-b]¦1,2,5]triazepin-2(3H)-D~e;
5-(2-Chlorophenyl)-lH-pyrrolo~1,2-b][1,2,5]triazepLn-2(3H)~c~e, .
8-Chloro-5-(2-fluorophenyl)-l~methyl-lH-pyrrolo[1,2-bJ[1,2,5~triazepin-2(3H)-one hydrochloride;
5-(2-Fluo~ophenyl) 1-methyl-lH-pyrrolo[1,2-b][1,2,5]triazepin-2(3H)-one hy~roc~loride;
5-(2-FluDrophenyl)-8~methyl-lH-pyrr~1~[1,2-~J I 1, 2,5Jtriazepin-2(3H)-one;
1-(N-Methyl-aminoacetamidD)-2-benzoylpyrrole fu~arate;
l-(N-Methyl-aminoa oetamido)-2-(2-chlorDbenzoyl)pyrrDle hydrcbrcmide;
l-(N-Methyl-~mlnoaoe tamido)-2 t2-fluorobenzoyl)pyrrDle hydrobrcmide;

Z9~
l-~N-Methyl-(t~butoxycarbonylamino)a oe tamudo]-2-(2-chlorcbenzoyl)-pylrole;
l~[lt-~utoKycarbonyl~mino)~ oe tamido~-2-~2-chlo ~ yl)pyrr~le;
l-[N-Methyl-(t-butoxycarbonylan~o)a oe tamido]-2-(2-fl~orobenzoyl)-pyrlole;
l-~(t-Butcxycarbonylam m 3)a oe tamido~-2-(2-fluDrobenzoyl)pyrrole;
l-Brcmoacetamidc-2-(2-fluorbben2cyl)pyrrole;
l~Bromcacetamido-2-ben20ylpyrrDle;
l-~N-~ethyl-brcmcaoetamido)-2-ben2cylpyrr~1e;
l-Chloroacetanldc-2-~2-fluorobenzcyl)pyrrole;
l-Brcnca oe tamiac-2-(2-fluorobenzoyl)-5-methylpyrrole;
1- ~N-~ethyl-brom3a oe tamido)-2-t2-chlorc~enzoyl)-5-methylpyrrole;
1-Amino-2-(2-fluorobenzoyl)pyrrDle;
l-Amino-2 benzoylpyrrole;
l-Aminc,2-(2-chlorobenzcyl)pyrrole;
1-Pmino-2-t2-chloro~enzoyl)-5-methylpyrr~1e;
1-Amino,2-(2-fluorbbenzcyl)-5-methylpyrrole;
2-Benzcyl-l-methylaminopyrrole hydrobromide;
2-(2-Chlorobenzoyl)-l-~ethylacLIi~7yrr~1e;
2-(2-Chlorobenzoyl)-l-methylam m o,5-~ethylpyrrDle;
(2-Benzoyl-lH-pyrrol-1-yl)-methyl-carbamic acid, ethyl ester;
[2-(2-Chlorobenzoyl~-lH-pyrrol-l-yll-methyl-carbamic aciA, ethyl ester;
[2-(2-Fluoroben2oyl)-lH-pyrrol-l-yl]-methyl-c2~txanic acid, ethyl ester;
(2-Ben~oyl-lH-pyrrol-l-yl)-carbamic acid, ethyl ester;
[2-(2-Chl~robenzoyl)-lH-pyrrol-l-ylJ-carbamic acid, ethyl ester;
[2-(2-Fluorcbenzoyl)-lH-pyrrol-l-yl]-carb~mic acid, ethyl ester;
[2-(2-Chlorokenzoyl)-5-methyl-lH-pyrrol-l-ylJ-c~L~bamic acid, ethyl ester;
2-(2-Fluorobenzoyl)-l-phthalimidop)~rrole;
2-Benzoyl-l-phthaliTidopyrrole;

~2~
2-(2 Chlorobenzc~ Fhthal~m~ole;

12- q2~o~z~1) -lH~1-1-y1]-2- E l~ine~yl~oTino)ethyl3csr~nic acid, e~l ester hydr~nide;

~2~ lH-E~yrrol-1~1~-2-~dinEthylamir~ethylanine ~ydrwhloride;
l-Anin~oe~mid~2-ber.zc~yl~r~le hydr~loride;
l-Aninoa oe tamido-2-(2-ri~3rob~:~0yl~pyrr~1e hydrcbromide;
l-(Phthaloyl ~ oetamido) 2-~en20ylpylTole;
1-[(Carbcbenzyloxy~mino)a oe tamidol-2-~en20ylpyrrDle;
2-(2-Fluorobenzoyl)-1-(4-phenylpiperazin-1-yla oe tamido)pyrrole;
Di- ~ (2- (2 fluDrcbenzoyl~-5-met~yl-lH-pyrr~l-l-yl)-2-a oe tamido]amine hydrochloride; and 1-nN-Methyl-a oe tylaminoaoetylamido)-2-(2-chlorobenzoyl)-5~methylpyrrDle.

The following examples are give~ for illustrative purposes and ~re not to be o~nsidered as limitlng the invention disclosed herein.

EK~E 1 2-12-Fluorobenzoyl)-l-phthalLml ~ le TD a mixture of N-phthalinidopyrrDle ~10 g, 47 nnDle) and fused zinc chloride ~10 g, 73 nmDle) in 80 n~ dichloroethane wa~ added o-fluoro~en20yl chloride (7.5 9, 47 nmD~e). The reaction mixture was ~tirred at ambient temperature for twenty hours and at 80 f~r one hour~
Thereafter, it was oooled, poured ln~D water and extracted with dichloromethane. The organic extract was washed with water and with saturated sodium chloride solution, and dried over magnesium sulfate.

The s~lution was filtered and evaporated to an oil which yielded a solid ~z~
up~ trituratio~ with ethanol ~yield 11 g, m.p. lB0-190). ~his hlo~ethane) to gi~re 3 g ~lid. Ihis m~ter~l was re~ tallized fran i~opr~l to gi~le 2.Ç g ~17~ tals, m.p. 202-203''.
P~LYSIS:
_ __ Calculated for Cl~ 11 2 3 68.26~C 3.32gH 8.38%N
F~: 69.53~C 3.27%H 8.i3%N

~ 2 l-Amir,~2- l2-flue~rcbenz~yl) Py2:Tole T~ a su~sian of 2-(2-f}u~robenzoyl)-1-Eihthal~-rQd~r~ole (12.5 9, 27 ~r~,le) in 40 ml ~F was add~d 40 ml nethylamine (40~
æolu*ion in watex). After stirr ~ one hour at ambient temperature, the reaction ~ix*ure was diluted with water 3nd extracted wlth ether. Ihe organic extract was washed with water and with saturated NaCl solution, dried over anhydrDus MgSO~, filtered and evaporated to 9 g oil, half of which was ~ ified by ~ugelrDhr distillation (120-130 at 0.2 mm Hg) to give 3.5 9 (93~) s~lid, m.p. 44-47.
ANhLYSIS:
--Calculated for C11HgFN2O 64.70~C 4.44%H 13.72~N
Four>~: 64.69%C 4.64~H 13.53%N

EW~ 3 l~Chl roaoe~mid~2- (2-fluorc~enz 1) le _ _ . C~Y F~' ~ o a sDlutio~ of 1-~m~r~2-(2-fluor~benzoyl)F~rr3le (7 g, 34 mnDle) ~n 100 ml dichlorane~ane cDntaining 5.5 g (55 mT~le) ~di~n biQ~Dr~te was sl~ly added dr~ise a ~olution of chl~roaoetyl chloride (4.2 g, 38 ~le) in 15 ml dichlorarethane.

~z~
After 6tirriJ 9 or~ t ~ient t~Tperature, the ~c~ic~

aver ~s ~gSO4, filtered and e~ orated to yield 10 g ~olid. ~is material ~as recrystallized f~n }~canes/e~r t~ give 6 g ~63%) ~olid, m.p. 110-112.
AN~LYSIS:
C~lculated for C13~10CL~N2O2 55.63~C 3.59P6H 9.9B~N
Fo~: 55 . 59~C 3 . 71%H 9 . 94BN

E~AI~ 4 l-Br~moace~id~2- (2-fluorobenz~l) ~le T~ a soluti~n of 1-~2-~2-fluor~enzc~l)~rr~le (19 q, 93 n~Dle) in 2S0 ml dichlorc~ret~e oontair~ng 16 g lO.l9 n~le) s~diun bicar~nate was sla"ly ad~ed dr~wise a solutio~ of brc~aoetyl brcanide (22 g, 0.11 mDle) in 50 ml di~ rar~thane.
After Sti~T~ng two ~ rs at alribient t~rçerature, tlbe reaction nixture was evaporated, dissolved in ether, washed with water and ~aturated NaCl solution, dried over anhydrous MgSD4, filtered and evaporated to 31 g solidu This material was recrystalliz~d from hexanes/ether to give 25 g (83%) needles, m.p. 112-114.
ANALYSIS:
_ Calculat~d ~or C}3HlO~r~202 4B.024C 3.10%H 8.6~%N

Found: 48.02~C 3.13~H 8~66~N

EXAMPL~ 5 5-(2-Fluoro~Enyl)~ yrrDlo[1,2-b]~1,2,51triazepLn-2_3~)-one l-Bromca oe t~mid~-2-t2-flu~roben~oyl)pyrrole (15 g, 46 mmDle~
was added to ~00 ml cold saturated ammonia-methanol solution. A~ter stirrlny t~enty hcurs at ambient temperatuLe, the nuxture was evaporated, stirr æ with water and extracted with eth~l aoet~te. The organic extract was washed with water and saturated NaCl solution, dried over anhyd~7us Y~304, filtered and evaporated to yield an oil. This oil was p~rified ~y HPIC (silica gel, 10~ lethanol/dichloro~ethane) and then by column chlcn~tography (silica gel, ethyl a oe tat~) to give 1.9 g waxy solid. This n~terial was recrystailized from a oe tone to give 0.8 g (7%) solid, d 189-190.
A~ULYSIS:
Calcula~ed for C13HloFN30: ~4.19~C 4.14%H 17.28%N
Found: 64.10~C 4.17%~ 17.44UN

E A~T,F: 6 2-(2-Fluoro~enzoyl)~ 4-phenylpiperazin-l-ylacetamido)pyrrole A m ~xture of 1-bromoa oe tamido-2-(2-fluoro~nzoyl)pyrr~lle (3.5 g, 11 ~mole), N'phenylpiperazine (2.2 g, 14 ~ ole) and sodium bicarbonate (1.8 9, 22 m~ole) in 120 ml dichloromethane was stirred at 75 for two hours.
The re~ction nuxture was cooled, con oe ntrated to an oil, stirred with water and extracted with ether. The organic extract was washed with water and saturated ~aC1 so~ution, dried over anhydrous ~ySO4, filtered and evaporated to a solid which was recrystallized twice from isopropanol to give 2.6 g (59%) solid, m.p. 124-125.

P~LYSIS:
Calculated for C23H23FN402 67.96~C 5.7~H 13.79%~' ~ound: 67.87~C 5.78~H 13.58~t -3l-9(~
,~ 7 ~ a ~ixt:ure ~ l~thalin~i~yr~le (37 g, 0.17 ~le) d b~zcyl dlloride ~24 9, 0.17 ~le) in 400 ml 1,2-dic3l10roethane was zldded zinc ~loride ~ ed, 36 g, 0.26 ~le).
After ~tirr~ vigorously for falr hours ~t 70~C, 'che mixture c~rg~n~c ext:ract was WaS~led with atura ~ d NaCl ~olutio~, dried over anhydrous MgS04, fil~ered and evaporated to 60 g waxy sDlid. This material was purified by HPlC (silica gel, dichlorcmet ~ ) to give 38 g ~69~) sDlid. A 3 g sample was reGrystallized from iscpropanol to give 2.9 g crystals, m.p. 150-152.
PN~LYSIS:
Calculated for ClgH1 ~ 203 72.14~C 3.82~H 8.86~N
Found: 72.45%C 3.93~H 8.93~N

. ~ 8 1-~mino-2-benzoylpyrrole T~ a suspension of 2-benzoyl-1-phthalimidopyrrDle 135 g, 0.11 ~Dle) in 350 nl ethanol was slowly added 45 nl methylamine (40% ~olution in water). After stirring tWD hours at ambient temperature, the mixture was diluted with 40 n~ water ~nd extracted wnth ether. Ihe ether extract was washed with water and saturated NbCl solution, dried over anhydr~us Mg5D4, filter~d and evaporated t~ 28 9 oil which upon trituration wnth hexanes ga~e 21 9 (99~) 6~lid, m.p. 65-69~o 3.5 g of ~Z~'~9~
this materi~l was purifisd ~y ~C (~ilica gel, 4~ ethyl aoet~te/
lo~æ~ tD give 2.,B g eolid, ~i~h was recry~alLi~ ~n ~anes to give 2.4 9 K~lid, m.p. 65~67~.
~LYSIS:
Calculated ~ 0 2 70~959~C 5.41?~H 15.05~N
Fa~l: 71.11~C 5.2796H 14.98~N

~I~ 9 1 -Brar~aoe~id~2-benzo~lpyrrole lo a stirred ~ y of 1-~min~2~ zoyl~yrrole ~14.2 9, 59.4 m~l, 78~) and ~di~n bicar~onate (13 9, 158 ~1~ in 200 ml of dichlor~thane was added a solutiod~ of brc~aoetyl branid~ ~lB.l g, 90 mrol) in 50 ml dic~ runethane aver five minutes. After ~tirring for tw~ ha}rs at roaln ~rature 1:he volatiles ~ere evaporated an~ the residue Wcen ~p in 200 ml ether. fflis was wa~d with water and brine, dri~d aver anhydrous MgSO4, filt~red, and evapc~rated. Ihis ma~erial was purified by ~LC (silica gel/DC~q) to give 13.08 g (7196) r~eedles, Tn.p. 80-83 .
A~LYSIS:
Caluclated for C13HllBrN202: SO.B3P6C 3.613H 9.12~N
~ound: 51.16%C 3.61%H 9.16U~

EK~ 10 (2-Benzoyl-lH-pyrrol l-yl)-carbamic acid, ethyl ester 1~ a mixture of l-amir~2~ zoylpyr~le (12.3 g, 66 am~l) and sodi~n bicar~ate (13.9 g, 165 mrol) in 250 ml of di~hlomrethane was added a ~olution of ethyl chlt)roformate ~8.2 g, 75 mr~l) ~n 50 ml of dichl~thane. lhis mixture was stirred ~t reflux for 5 haurs and then quenched with 150 ml of ice ffle dichlor~ne~ane layer was ~eparated, wa.shed w:Lth water, dried crver anl~rdrous ~a2S&, filtered eva~ratesl to an oil. qhis oil solidified up~n triturati~ with hexar~
to give 16.3g (96~) of ~r, m.p. 68-70.
AN~LYSIS:
Calculated for C14H14N203 65.10~C 5.4696H 10.84~1, ~ound: 65.11~C 5.374H lO.B4%N

~ 11 Ib a viqorously stirred mixture of 1~phthal~midc~yrrole (45 g, 0.212 mol) and o ~ lor~benzoyl chloride ~37 g, 0.212 n~l) ~n 500 ml of 1,2-dichl~rceth~une was added freshly pulverized, fused zinc chloride (43.3 g, 0.318 mol) in one portion. The reaction mixture was heated at gentle reflux for 4.5 hours and then quenched with 700 ml of cr~hed i oe and 500 ~ of dichloro~ethane. The organic layer was separated and washed with water (2x 500 ml), dried over anhydrous MgSO4, filtered, and eva~orated to give 92 g of an oil. This oil was purified by column chromatography (silica gel/dichloromethane) to give 33.8 y (454) of needles, m.p. 158-160C.
P~I~LYSIS:
Calculated for ClgHllCIN203 65.05~C 3.16~H 7.98UN
Found: 65.32~C 3.40~ 7.94~N

EX~D~LE 12 5-Phenyl-lH-pyrrololl,2-b][1,2,5]triazepLn-2(3H)-one 220 ml of an i oe cold saturated ammonia-methanol solution was addcd dropwise cver 15 nunutes to an ice oold solution of 12.9 g (42 ol) of l-bro~oacetamido-2-benzoylF3~mDle m 70 m~ of meth3nol. The reaction mixture was stirred at ro~m temperature for 18 hours, refluxed ~ z~Z~4 for 3.5 ~; ~r~ ev~or~ted ~der n3duoed pres~ure. me re5i~e WZ15 17.5~ o~ p~, ~.p. ~97-199 ~.
fflis n~a~eri~l ~5 bin~d wi~h 1.15 g fx~n an e4rlier reactio31 ~nd rec~stalliz0d iEran aoet~e to gi~e 2.6 g cl~bes, m.p.
198-~û0C d~c.
ANALYSIS:
Calculated for C13~11N30: 69.3196C ~a.929~H 18.65~N
69.37~C 4.9296H 18.84%N

~ 13 t2-~zovl-lH-~l-l-y~ ne~c acid, et}~l ester (2-~enzoyl-lH-pyrml-l-yl)-car~nic ~cid, e~yl ester (18.5 g, 71.6 mT~l) was car~in~d with s~di~n car~onate (16.û g, ~57 mr~l) and ~thyl iodide (13.2 g, 93 mr~l) in 100 ml of dim2t~ylformamide. The resulting slur~y was stirred at a~bbieJIt ~erature for 20 h~urs and t}~ ~t 75~C for 2 Ix~urs. miS reaction mixture was p~ured in~o 3ûO ml of crushed i oe and extracted w~th four 20û nl portions of ether. The combined ex*racts were washed with water, dried over MgS04, filtered and evaporated to an oil which was purified by HPLC (silica gel, 15~ hexanetDCM). The resultLng n~terial ~as recrystallized from ether-hexane tD give lB.4 g (94~) of cubes, m.p.
5n_520.
ANALYSIS:
Calculated for C15H16N203: 56.15~C 5.9~UH 10.29~N
Found: 66.28~C 6.05~H 10.26~N

=~
~ a ~olutian ~t~ning 1~1.9 g (59 nn~l) of (2~1-lH
E~yrr~l-l-yl)-netlyl~nic acid, ethyl ester in 60 ~1 o 95~ et~l dded a ~oluti~ oa taining 10.9 g ~273 n~l) of ~odiun ~ide ~n 40 ml of water an~ the resulting ~lur~y was ~tirnsd un~er refl~K gc)r 18 hcurs. ffl e ethar~l was re~ ~der ~ uo~d pressure ~nd the residue w~s diluted w~th 100 nl of water and then extracted with ~hree 125 nl portions of ethyl ~ oe tate. Ihe oombined ex*racts were washed with water, dried cver An~ydrcus k~ 4, filtered and ~vaporated to an oil which was distilled in ~ K~gelrohr apparatus at 120 tO.l nmH~) to give 9.1 g (B4~) of an oil. 1.9 g of this oil was ~reated with 100 ml of HBr-saturated ether and the xesult ~ precipitate was ~Dllected on a filter. miS material was recrystallized frQm 2-propan~l tD give 2.1 g ~Df solid, m.pO 180-182 (d~c1.
AN~LYSIS:
Calculated for C12H13BrN20 51.~6%C 4.66~H 9.96~N
Found: 51.39%C 4.77~H 9.91~N

E~LE 15 l-lN-Methyl-bromoacetamido)-2-benzoylpy~
A sDlution of bromDa oe tyl brcnude (8.47 g, 42 D 1) in 30 ml of dichloromethane was added over 30 ~u~utes t~ a stirrsd ~lurry oDntaining 2-ben~oyl-1-methyldni~Y~frDDle ~ydrobromlde ll4.9 gt 54.7 n~Dl) and ~cdium bicarbDnate (5.9 g, 71 mm~l) in 150 nl of dichlorometh2ne. After 22 hours at room temperature the ~Y*ure was quen~hed with 150 nl of ~rushed i oe and the layers ~ere separatÆd. The organic layer wa5 washed wnth water, dried ~ver snhydrous MgS04, ered and evapDrated. The residual oil was flash chromatographed i2~
(6~ el, 5~ h~ne~ethyl aOet~te) ~CO g~ .0 ~ l9~ Vf cry~ B~
.P~ 76-78. A 2.2 9 POrtit~n of ~i8 mater~ W2~ xe~ry~all~zed fran ether h~Xane tO affOrd 2.1 g Of c~ibe~, m.P. 76-78"

P~L~IS:
, Calculatet fOr C14H13ES~a2O2 52'3S~C ~.07~6H 8.72~N
FC~ 52 . 22~C 4 . 01~H 8 . 65%;N

~ 16 1-Panj~2- ~2~h1C>~enZOY1) T~le 2-(2~ Or~enZOY1)-1-PI1tha1~midC~rrO1e ~40 g, 0.114 m:~l) was su~ded in 350 ml of 95% ethanol. 1~ this rapidly stirred ~lur~ was ad~3ed 50 ml of a 40% aq~us ~olutioa~ of m~thylamine aver 10 ~tes.
A~ter 2.5 halrs of rapid st~rrir~ t~ mixture was diluted with 400 ml of water an~ extracted w~th four 200 ml portio~s c~f ether. ~e ocsnibin~d e~rtracts were washed with water, dri~d over arilyd~ MgSO4, filtered and evapc~rated to an oil ~i~h ~olidified upon ~tanding. ~rituration of this solid with hexane and oDllection upon a filter yielded ~3.6 g (94~) of solid, m.p. 76-78.
SIS:
Calculated for Cl1HgClN2O 59.87%C 4.11%H 12.69~N
Faund: 59 . 91~sC 3 . 97~H 12 . 74~N

~ 17 1- ~N~ethyl-aminoacetamido)-2-benzo~lpy3:~le f~r~rate Platin~ axide (250 ~7) was added under ni~r~gen t~ a ~luti~n of N-srethyl-l azidoaoe~nid~2-~nzoylE~yrrole ~B.2 g, 29 n~l) ~1 cocalic acid ~2.7 9, 30 n ~ l) in 200 ml of nethanol, and this slurry was hydrogenated at 15 psi for 2 hDurs. miS muxture was diluted with an additional 200 nl of meth3nol, filtered and evaporated. The xesulting ~2~9()4 resi~ue was tIeat~d with 100 ml of ~aturated ~odiun bicar~ate ~lutiw~
ted with thr0e 150 ml Eortion~ of e~hyl aoetate~ T~ cc~ribinsd tr~ated with ~ ~luticn of f~aric ~cid (3.S g, 30 m~l) ~n 100 ml of meth~l. Eva~ratiw~ under r~duced pressure left a ~olid ~ic~h was ~ystallized f~m PbC~H-ether to give 5.2 g (48%) of pow;~er, m.p.
168-- 16g .
~YSIS:

14H15N302 C4H40~: S7.90%C 5.13~H 11 25~N
Fcn~d:57.59%C 5.134H 11.11~N

E~E 18 1- [ (Car~enzyla?~ no? aoetarnido] -2-~enzc~le N,N'-Di~ycl~hexylcarbodiimide (2.32 g, 11.2 nn~l) was ad~d in one portion tD a st~rred sollltion of 1-amin~2-b~zoyl~ le (2.1 g, 11.2 mr~l) and carboben~lcoyglyc~e (2.36 g, 11.2 .,~,,)1) ~n 70 rnl of dichloraTethane. The reaction mixture was ~tirred rapidly for 2.5 l~urs at roan t~r~erature an~l thereafter fil~ered to reT~ve the precipitated dicyclohexylurea. Evaporatio~ of the filtrate left 4.7 g of a ~r~-solid whic~h was flash c~r~tograp~ed (silica gel, 1:1 ethyl aoetate-hexane) to give 3.75 g (B8~) of pad~er, m.p. 96-98.
P~LYSIS:
Calculated for C21 19 3 4 66.83%C 5.û74H 11.13~N
Fourld: 66.5496C 4.88%H 11.34~N

~z~
~ l9 (2.1 g, 11.2 mr~ thaloylgly~ne (2.3 g, ~ m~l) an 70 nl of dic~hlom~thane wa~ d dicycloh~ylc~nide (2.3 9, 11.2 nn~l~ in cne pc>rtion. me sesultant 61urry was 6tirred at ~bient t~erature for 3 hours and t}2en a~ reflux ~or 3 additi~al ~laurs. ~he oooled reaction mixture was filtered and the filtrate evaporated to give 3.2 9 of a 601id. ~s solid was flash chr~atograp~ed (silica gel, 60 ~exane:ethyl acetate) to afford 3.1 g ~73~] of pDw~er, m.p. 207-209~, PNAL~SIS:
Cal~ulated for C21H15N304: 67.55P6C 4.04~H 11.25%N
Found: 67.64~C 4,.32%H 11.46~N

E~A~E 20 1-A~oaoetanid~2-benzc~yl~yrrole ~d~chl~ride 1~ an ether solution o~nt~ini ~ 1-1(t-buto~ycar~onyl~nino)-aoetamid~-2-benzoylpyrrDle (18.5 g, 53.8 mmol) was added dlopwise 150 ml of 4 M anhydrcus HCl ~aturated ether solution at -10. The reaction mlxture was stirred at ambient temçerature for 1 hour. The precipitated amine ~alt was oollec*ed ~n a ~ilter tD give 14.2 g sf pow~er. 1his psw~er was recrystallized from isopropanol to give 11.2 g ~74%) of pcwder, m.p. 218 ~dec).
ANALY~IS:
Calcula C13 13 3 2 55.8~4C 5.04~H 15.02UN
Found: 55.51%C 5.11~H 15O19UN

E~A~ 21 T~ a ~luti~n oontainir~ 1-~2-~2-~luor~yl)E~yr~le (25~8 g~ 0.126 mDl) ~nd t~(tert~utoo~rcz~r~or~yl)glycine i22.4 g, 0.1~8 mD13 in 3~0 ~1 of di~hlo~netha~e was aa~d dicyclo~e~ylca~odiilTide (26.~ ~, 0.128 nnDl) in t~ pc)rtio~s over 3 minutes. I~æ raactic~ mixture Wa5 ~ti~Ted at ~ient tenperatuse for 2 h~rs and th~ filter~d. q~ filtrate was evapc~rated to an oil ~ic3~
was purified ~y HPIC ~silica gel, 4:3 hexar~thyl aoetate) to gi~e 37.2 g (82~) of cryst2lls, m.p. 114-116.
PNALYSIS:
Calculated for C18H20F~304 59.8296C 5.574H 1ï.62~N
F~d: 59.9896C 5.85~ 11.64%N

~ 22 l-Aminoaoetanido 2-(?-fluorabenz~l)~rrole ~obranide A stirred susp~sion oontaining 1-[ (t-h~to~car~nylamino)-aoet~mido]~2-~2-fluc)ro~nzc~ le ~25.2 9, 69 m~l) ~n 300 ml of ether was treated with 160 ml of a 0.6 M ethereal hydr~g~n bramiae solution. The mixture was stin~ed at anibient ten~erature for 1 hour and the resultant precipitate ~ollected on a filter. mis solid was ta~en up in isopr~panol and evaporated to a foam, wllich was sl~bsequently recn~stallized frain isoprc~anc~ ether to give 20~2 g (86%) of pc~er, n~.p. 114-116.
LYSIS:
Calculated fc>r C13H13Br~d32 45.62%C 3.82%H 12.284N
Found: 45.20%C 4.14~H 12.04~N

_ 40 -~2~29~4 EK~LE 23 -Methyl~ enyl-lH~lot1!2~ ll ,2,~triaze~in-2 (3H)~#
~LLde A ~olution prepared ~r~n 1- ~methyl-Amin~aoetami~) -2-benzo~lpy~Tole f~narate ~ 6 g, 7.24 m~}), 2 ml of qlacial ~oetic acid an~ 110 ~1 of Iretl~l was refl-Ked ~er nitr~n for S h~r5.
Eva~or~ti~ of the v~latiles left an oil which was chranatogra~d lsilica gel, et ~ l a oe tate) to give 1.3 g (74%) of an oil. q~is oil was oombined wi~h 1.0 ~ from an ~arlier reaction. Ihe oily materi21 ~as t2ken up in ether &nd treated with an excess of ethereal HBr whereup~n a precipi~ation occurred. Ihe precipitate was oollec*ed upon a filter and washed with ether to give 2.7 g (6S~ overall) of crystals, m.p~ 280 (dec) .
AN~LYSIS:
Calculated 14 14 3 52.51%C 4.40%H 13.12%N
Found: 52.57~C 4.55~ 13.01%N

~ 24 [2-(2-Chlorbbenzoyl)-lH-pyrrol-l~yl]-carbamic acid, ethYl ester ~ Lno-2-(2-chlo~benzoyl)pyrrole t32 g, 0.145 mDll was combined with sodium bicarbonate (30.2 9, 0.36 mDl) in 400 ~1 of dichloronethane. ~D this rapidly ~tirred nixture was added ethyl chlorof~rmate ~18.6 9, 0.172 ~ol) ouer 2 munutes and the resultant ~lurry heated under reflux for 2.5 hcurs. m e reaction mixture was guenched with 300 Fl of H20, separated, wash~d with H20, dried (MgS04), filtered, and evaporated to give 51 9 of an oil. qhis Dil ' ~a2629~
was purifi~d by HPLC ~silica, 10:1 DCM-ethyl a oe tate) to give ~fter evaporation 32.a g (77~) of cry6t~1~, m.p. 90~92".
AN~LYSIS:
Calculated for C14H13CLN2 3 57.44~C 4.47~H 9.57~N
Fcund: 57.36~C 4.51UH 9.56~N

EXP~n~LE 25 ~2-(2-Chlorbbenzoyl)-lH-p~rrol~ l]-methyl-c~u~bamic acld, ethyl ester ~ 2-~2-Chlorobenzoyl)-lH-Fyrrol-l-yl] ~ ic acid, ethyl ester (22 g, 75.1 mmDl), scdium carbonate (16.0 g, 0.112 m~l) and methyl iodide (13 g, 0.122 mol) ~ere added to 100 ml of dry nM~ and the mlxture stirred at ambient tenç~rature for 78 hours. 'rhe reaction was q~ h3d with 1 liter of H20 an~ extracted w~th five 200 ~1 portio~s of diethyl ether. The co~bined e racts were washed with water and brine, dried ~S04), filtered, ~nd evaporated to give 15 g of solid. This solid was purified by HPIC (silic~ gel, DCM) to give 13.1 g (57%) of crystals, m.p. 54-56.
P~Z~LYSIS:
Calculated for C15H15ClN203: 58.73~C 4.93~H 9.13%N
Found: 58.62%C 4.92%H 9.07~N

[2-~2-Chloroben2oyl)-lH-F~lrrvl-l-yl]-2-[(dimethylamino~ethyl]cau~x~mic acid, ethyl es~er hydr3bromide l2-(2-Chlorcbenzoyl)-lH-pyrrol-1-yl]-carb~mic acid, ethyl ester (24.8 g, 85 ~m~l) was dissolved in 110 ml of rP~ with sodi~m methoxide (4.8 g, 8g mnal) and the solution heated at 100 for 30 nu~utes. To this solution was added the free base of dimethylamunoethyl chloride hydrochloride (12.8 g, 89 nmDl) in 100 ml of toluene and the solution stirred at reflux. After 2 hours, the toluene was evaporated K

G;2~

~3 t~ rea~tio~ ~llixtllre pc~u~ i~ltO 1.5 literB o$ H2C~. Fa~extract~ ~th 20D 3nl p~ o~ of ~et3ylene *ll~ri~e, and w~in~ ~rith H20 and br~ lef* ~ ~oluticn whic~h was d~ied ~MgSO4) ~nd evaporated 0 ~ o~ ~n oil. ~his oil was purifi~ LC (silica, 3 E~a~/D~I) t~ Slive 30.2 g (97%1 of ~n oil.
lq~e ~robramide alt was p~pared fran 3.4 g sf ~his oil ~nd ~ecrystallized fr~r is~r~panol-ether to give 2.6 g of pow&r, m.p.
154-156~ .
P~LYSIS:
____ cal~ulated for C13~22 33 48.6096C 5.219~1 9.44%N
Found: 48 . 32%C 5 .17P~H 9 . 49~N

~_27 [ 2- (2~hlorc~en~ yl~ -2- tdi~thylamir~) eth~lamine h~ ranide ~ 2- (2~hlorobenzoyl)-lH-pyrr~ yl]-2~ nethylarninolethyl~-car}~nic acid, 2thyl ester (26.3 g, 0.07 mol) was dissolved in S0 ml of ethanol and 70 n~ of H20 c~ntaining sodi~n hydroxide ~8.6 g, 0.216 nLl).
The reaction ~ixture was hea W at reflux for 19 hcurs followed ~y evaporation of the ethanol. Ihe aqueous solution was extracted wlth four 100 nl portions of ethyl acetate, washed with water and brine, dried ~MgSQ4), filtered, and evaporated to give 14.3 9 of an oil.
m is oil was distilled ~ia a Kugelrohr apparatus at 150 (0,1 ~Hg) to give 13.B g ~69%) of a ~iso~us oil. 1.9 g of this oil was trea~ed with ~;

ne~Lhan~lic HE~r ~nd ev~orated to a pc~der. ffli6 pCh~ wa5 recryst~ d fr~n ~ th2r ~ give 2.3 g t~f r~sette~, ~.p.
15~1~2~
~YYSIS:
or C15~18ClP~30-HBr: 48.33~C 5.13%H 11 27~N
~ound: 48.124C 5.32%H 11.15%N

~ 28 2- (2~hlorobenzc~ 1~rethyl~nir~r~le ~ 2-(2~hl~robenz~y1)-lH-~yrTol-l-yl]~thyl-car~c acid, ethyl ester ~39.2 g, .127 m)l) was dissol~ed in 100 ml of ethanol and 200 ml c)f H20 cantaining sodiun hide ~25 q, 0.625 nol,~. me reaction ~as refluxed for 18 Ix)urs foll~ed ~y evap~ration OI the ethanol. lhe aqlleous solution was extracted ~ith three 300 ml portions of ethyl acetate, dried ~MgSO4), filtered, and 2vaporated to give 28 9 of an c~il. q~his oil was distilled via Kugelrohr apparatus 125 (0.15 n~3g) to yive 26.3 9 of a ~olid. mis solid was triturat~3d with hexane to give 25.5g IB5%) of crystals, m.p. 56-58.
AN~LYSIS:
c~l ted for C12HllClN2O: 61.40%C 4.724H 11.944N
Four~: 61.4396C 4.86%H 11.91~N

~ 29 1- EN-Methyl- ~t-~utoxyu~r~ylamino)ac_amido~-2- (2-chlc~roi~enzoyl)~ole 2~ (2{:111Or~enzGyl)-l~thylamir~rrrole (23.7 g, 0.10 n~l~
and tert-buto~carbonyl glycine (19.26 g. 0.11 mol~ aQnibined in 250 ml of dichlornethane follawed by ~qitio¢~ of dicyclohe~ylcar~odiim~de (23.7 g, 0.115 nLl) over 3 minutes. me mixture wa5 stirred at ~bi~t erature for 5 hours and thereafter filtered and evapt)rated to give ~L2~2~4 35 9 c~f oil. Ihis oil was puri~ ilica, 2:1 hexa~t~yl ~oetate) to give ~8 g of ~olid. fflis mate~iP~l wzls re~y~talliz~d ~Eran r t~ give 26.5 g (68~) of cul~es, m.p. 131-133D.
AI~LYSIS:
c~lcula~d for ~19 22 3 4 58.239~C 5.66~H 1û.72 ~d: S~,25~C 5.99~H 10.61~N

~ 30 1-Amino-2-~2-chlor~enzoq~ 1e ~24.3 g, 0.12 mol) and t-~uto~ yl glycine ~22.7 g~ 0.13 nDl) were dissolved in 300 ml of di~hlo~ e. Dicyclo~lca~diin~ide ~26.8 q, 0.13 n~l) was a~3ded a~er 3 ~utes and the reactic~n mixture stirred at ~bient te~rature for 4 hc~rs. q~he resultant slur~y was filtered, and the the filtrat evaporated tc~ gi~re 65 g of oil. Ihis oil was purified }~y flash s~ ography (5ilica, 2:1 hexa~thyl aoetate) to give 21.9 g ~48~6) of ~ystals, m.p. 156-158~.
~LYSIS:
Calculated for C18N20ClN3O4: 57.21%C 5.3396H 11.12~
~o~d: 57. 334C 5. 58Q~H 11. 03%N

. ~ 31 1-nN-Methyl-aminoacetamido~-2-(2-chlorbbenzoyl~pyrrDle hydrDbromide l-~N-Methyl-(t-butoxycarbonyla~ino)aoetamido]-2-(2-chlorvbenzoyl~pyYrole (24 g, 61.2 mmDl) was dissolved in 10~ nl ~f ethyl a oe tate, and 60 ~1 of n-propan~l solution oDntaining 12 ~1 of 48%
HBr was added thereto with stirrLng. After 1 hour at 35 the solution was evaporated and the residue triturated with ether tD give 23.2 9 of ~LZ6~
~r. Ihi~ der was recrys~lliz~d f~m isc~r~1-ether to give 22 g l96%) of flocculent ~ryE;t~16, m.p. 193-195.
~SIS:
Calculat~ C14~14 3 2 11. 27%N
F~d: 44 . 75~C 4 . 05~H 11. lB~N

E~ 32 5-(2 Chlor~Phenyl)-l~ret~l-l~rrolo[1,2-b] ~lt2,5]triazepin-2(3H)~e A solution co~t~ini~ 1-l~thyl-an~noaoetamido)-2-(2-chlorcbenzoyl)pyrn:~le h~r~mnide (12.6 g, 43.4 mrol) and glacial aoetic acid (15 g, 0.25 n~l~ in 100 ml of isc~ anol was refluxed under ni~en for 12 ~urs and thereafter evaporated t~ an oil. This oil was flash chranatograp~ (silica, 4:} ethyl aoetate-hexane) t~ give 3.2 g (27~) of crystals, m.p. 132-134. miS was oarbined ~ith 0.5 g f.~"
an earlier run an~ recrystallized fr~n aoetone to give 3.5 g of c~stals, m.p. 132-133.5.
AN~LYSIS:
CalcUlated for C14 12 3 61.42~C 4.42%H 15.35~N
Found: 61.5796C 4.43%H 15.75%N

~ 33 [? (2-Fluorobenz~l)-lH-Pyrrol-l-yl] carbamic acid, ethyl ester 1-Amin~ 2-(2-~luoro~er~oyl)pyrrole (41 g, 0.20 mol) and sodi~n bicar~onate (39 g, 0.46 ~ol) were oombined in 400 nl of dichloromethane.
To this stirred slurry was added ethyl chlorDfonma~e ~24 g, 0.22 mol) over 3 munutes and the reaction nuxture was refluxed for 5 hours, whereupon it ~as quenched with 200 ml of H2O and the organic layer separated. The organic extract was washed wnth H2O and brine, dried (MgSO4), filtered, and evaporated ~o an oil which crystallized upon ~6Z~
tritura~ n with h~xane. Filtratic~n yielded 50.8 9 (92~) of CryBtalE;, m.p. 7B-80~.
~LYSIS:
, Calculated for C14~13P~203 60.~6~C 4.74~H 10.14 Fc~d: 61.2196C 4.B2%H 10.57 ~ 3~
12- (2-Fll~or~nzoyl)-lH-pyrrol-l-yl]~ret~ryl car~amic acid, ethyl ester Sodi~n ca~onate (22.4 g, 0.21 n~l), meth~rl iodide (30 g, 0.21 n~l), and [2-(2-fluorcbenzoyl)-lH-pyrrol-l-yl] car~nic acid, ethyl ester (25.4 g, 0.09 mD1) were ~,ibined in 100 ml of dry ~MF w~th stirring at ambient temperature. After 72 hours, the nLx~lre was poured into 800 ml of H20 and extracted with three 250 ~1 portions of DCM. The ccmbined extracts were washed with H20 and brine, dried ~SO4~, filtered and evaporated to an oil. This oil was purified by HP1C
(silica, DCM) to give 26 g (97%) of crystals, m.p. 64-66.
~LYSIS:
Calculated for C15H15FN2 3 62.05%C 5.20%H 9.65~N
Found: 62.11~C 5.19~H 9.65%N

5-(2~Chlorophen~ lH~pyrrolo[1,2-b][1,2,5]~riazepin-2(3HI-one A suspension of l-aminoa oe tamido-2-(2-chlor ~ oyl)pyrrole hydrcbromide (4.9 g, 13.0 nmDl) in 100 ml of ethyl acetate was treat æ
with triethylamine (4.9 g, 48.4 m~Dl), filtered, and evaporated t~ give 3.8 g tlO0~ of the free kase. m is oily material was taken up in 70 ml of isopropanol containing glacial acetic acid (4.6 g, 76.6 nmDl) and the solution was refluxed under nitrogen for 7 hours. Evaporation of the volatiles left an oil which wa5 flash chrcmatographed (silica gel, 4:1 ~L2~Z9(~g~
ethyl ~cetate-hexane) to give 0.19 g ~5.3~) of powder, m.p. 21S-217D
(dec). ~his ~ateria} was ccnbined with other cyclization product6 (total ~eight, l.lg) Drd recrystallized f~u~ a oe tone to give 0.87 g (79%) of pohder, m.p. 215-216 (dec).

~L~S~S:
13 10 3 60.12%C 3.88~H 16. le%N
Found: 60.47%C 4.00~H 16.39~N

EX~ LE 36 l-~N-Methyl-(t-butoxycarbonylaTino)a oe tamudo]-2-~?-fluorobPnzoyl)pyTrole Tc a solution containing l-~N-methyl-(t-~utoxycarbonyl~mino)-a oe tamido]-2-(2-fluorobenzoyl)pyrrole (28 g, 0.128 mol) and, N-t-butoxycarbonyl glycine (24.5 g, 0.14 1) in 300 ~1 o~
dichlorometh~ne was added dicyclohexylcarbodiimide (28.8 g, 0.14 mol) over 1 minute. The reaction mixture was stirred at ambient temperature for 4 hcurs and thereafter cooled and filtered. The filtrate was evaporated to an oil which was purified by HPLC (silica, 2:1 hexane ethyl a oe tate) to give 28.8 g of solid. miS material was recrystallized fnom ether-petroleum ether to give 27 g (~6%) of crystals, m.p. 112-114.
AN~LYSIS:
Calculated for C1gH22FN3O4: 60.78%C 5.90%H ll.l9~N
Found: 60.79%C 5.69~H 11.13~N

EXU~IPLE 37 1-nN-Methyl-amunoacetamidol-2-(2-fl~orDbenzo~l)pyrrole hydrobrcnude A slurry preFxi~ed from l-[N-meth~l-(t-b~'oxyc~rbonylamino)-acetamido]-2-(2-fluoroben2o~1)pyrr~le (20 g, 53.2 mm~1) and 100 ml of methanol solution containing 12 ml of 48% HBr (0.106 moll was stirred at roc~ temperature for 6 hours. The resultant solution was evaporated to lZ629~

~olid which wa5 r~crystallized from iscpropanol-ether to give 18 g ~95~) o~ pchder.
ANALYSIS:
Calculated for C14~1~FN30 ~r: 47.20~C 4.24~H 11.79UN
Found: 47.32%C 4.33~H 11.95~N

EXP~IPLE 38 2-(2-Chlorobenzoyl)-5-methyl-1-phthalimidcpyrrole Tb a suspension of 1-phthalimido-2imethy1F~rn~1e (105 g, 0.46 mol) and o-chlorotenzoyl chlorid~ (162.5 g, 0.93 ~Dl) in 1.5 liters of dichloromethane at 0~ was added tin(rV) chloride (243 g~ 0.94 m~l) cv~r 15 nunutes. The resultant moxture was warmed to rocm temperature cver 30 munutes and then quenched with 2 liters of H20. m e organic layer was washed with H20 and brine, dried ~MgSO4), charooaled and filtered.
Evaporation of the volatiles left an oil which w~s purified by flash chrcmatography (silica, dichloro~ethane) to give 126 g of pawder. m is powder was recrystallized frcm ether-petroleum ether to give 82 g (4B~) of pcwder, m.p. 260-262.
ANALYSlS:
Calculated for C20H13ClN2O3: 65.84~C 3.59%H 7.684N
Found: 65.64~C 3.63~H 7.59~N

5-(2-Flu~rcphenyl)-l-methyl-lR-pyrrolo~1,2-b)[1,2,5~triazep m-2(3H)-one hydrochloride m e free base from l-~N-methyl-aminoacetamido)-2-~2-fluorbbenzoyl)pyrrole hydrobromide (13.7 g, 38.4 ~mol) was refluxed with glacial acetic acid (13.1 g, 218 mmol) in 200 ml of isopropanol for 5 hours under a nitrogen blanket. Evaporation of the volatiles left an 2~04 oil which wa5 purified ~ HPIL (I;iliCa, 3:1 ethyl aoetate hexar~) ts give 8.4 g ~85~) of ~n oil. ~liB oil was tr~ated with ~n exoess of ~sW.lize~ fmm e~ol~ther to give 8.6 g (764 averall) of p~er, m.p. 210 (d~c).
A~ALYSLS:
Calculated for Cl~H12FN30-K:1: 57.24~C 4.45~H 14.30%N
Four~d: 56.87%C 4.62%H 14.12~N

E~LE 40 l-A~nin~2-(2 chlo~oyl)-5~ethyleyrrole . A suspension o~ 2-(2 chlorobenzoyl)-5qrethyl-1-phthalimidopyrrDle (48 g, 0.13 mol) in 200 ~1 of 95% ethYux~l was treated with B0 ml of 40% aq~eous solution of methylamine and stirred at rocm temperature for 6 hours. The reaction was quenched with 1.5 l;ter of H2O and extracted with three 400 ml portions of ether. The ocmbined ether extracts were washed with H20, dried OMgs~4)~ filtered, an~
evaporated to an oil. This oil crystallized from hexane to give 22.7 g (74~) of cubes, m.p. 84-8$.
ANhLYSIS:
Calculated for C12HllC1N2O: 61.40%C 4.72%H 11.93~N
Found: 61.66~C 4.72~H 12.08~N

EXI~D~LE 41 2-t2-Chlorobenzoyl)-5-~eth~l-lH-Fq~rrol-l-yl)-cau~amic acid, ethyl ester To a stirr~d slurry containing 1-amino-2-(2-chlorobenzoyl)-5-methylpyrrole (27.1 g, 0.115 ~Dl) and sodium bicarbonate (16.8 g, 0.20 mol) in 300 ml of dichloromethane was added ethyl chloroformate t21.7 g, 0.20 mol) over 5 munutes. lhe r~action mlxture was stirred at room lZ629Q~

t~perature ~ght ~nd thereafter quen~ with 50û ml of H~O. qhe ~ er w~s wa*~d wi'ch brine, ~kied ~04), ~a~

whi~h was recry~tallized fran et~ler-hexane to give 31.9 q (~) of ~wder, m.p. B2-84~.
ANPLYSIS:
Cal~te~ r C15H15ClN203 58.73~6C 4.929~H 9.13~N
Fc~ 58 . 6996C 4 . 91~6H 9.19%N

~ 42 8{~hlor~5- (2-fluor~phenyl) -l~rethyl-lH-~lo [ 1, 2-b~ [ 1, 2, 51 ~
triazepin-2 ~3H) ~ e h~lorlde A sc>lutia~ o~tain~ng 5-(2-fluor~enyl)-1-sretl~yl-lH~yrrol~
[1,2-b] I1,2,S]triazepin-2 (3H)-one Iydroc~loride (3.3 g, 12.9 mrol) and N-chlon~succ~nimide (1.87 g, 14 mr~l) isl 100 ml of dry tetraly~rc~furan was refluxed under N2 for 3 hc~urs. me resultant solutia~ was evaporat~d and ~e re5i~ual oil was taken ~p in 20û ml of Et~c, washed ~ith H20, dried 1MgS04), filtered, and evap~rated to an oil. qhis oil was purified ky flash chrcmatcgraphy (silica, 4:7 hex2ne-eth~r) to ~ive an oil ~2.1 g). Ihis oil was treated wlth ethereal H~l and the resultant solid was recrystallized from isoprapanol-ether to give 2.36 g (55%~ of pcwder, m.p. 218 dec.
R~LYSIS:
Calculated for C14HllCLF~30-HCl: 51.23~C 3.68~H 12.8ûUN
Found: 51.11~C 4.0û%H 12.75%N

~Z6Z~O~

E~A~E 43 2-(2~1oro~nz~y1)-1 metl~yl~mir~S~ethyl~role A Eolutic~n containir~ 12-(2~hlor~1)-lH~yr~l-l-yl]-nethyl-ca~nic acid, ~st}~l ester (29.4g, 91 ~ ul) an~ ~diuT hydr~ide (11 g, 275 ~r~l) ~n 50~ ~s ethanol was heated un~r reflwc for 16 ~urs. me excess ethanol was ev~porat~d ~nd tl~ solutic~ was ~just~d to p~l 7 ~ h 10~ ~Cl. Ihe result~nt ~lurTy was extracted w~th thr~e 100 ml portions of DCM, dried ~gSO4), filtered, and evaporated to give 22 g of solid. This solid ~as charooaled and recrystallized fr ether-hexane to give 21 g 193%) of powder, m.p. 107-108.
ANALYSIS:
Calcuiated for Cl3Hl3CIN2 62.77~C 5.26~H 11.26~N
Found: 62.98%C 5.20%H 11.06%N

.
l-tN-Methyl-br ~ cetamido~-2-12-chlorobenzoyl)-5-methylpyrrole A stirred slurry of 2-(2-chlorobenzoy1)-l-methylamino,5-nethylpyrrole 118.7 g, 75 mmol) and sodium bicarbonate (14.2 q, 170 mmol) in lO0 ml of dichlorometh~ne was treated with a s~lution of bromoacetyl brcmide (15.2 g, 90 mn~l) in 30 ml of dichloromethane over 30 ~lnutes and stirred at room temperature overnight. The reaction mixture ~as quenched wqth lOO ml of H20, separated, washed wnth ~2 and brire, dried ~gS04), filtered, and evaporated. The resultant oil was purified ~y HPLC (silica, l:l ethyl acetate-hexane) to give an oil which crystallized f~om ether to give 22.7 9 (82~ of needles, m.p.
108-109~.
AN~LYSIS:
Calculated for C15H14BrClN202 48.72~C 3.01~H 7.57%N
Found: 48.B9~C 3.82%H 7.50~N

~26~
~ 45 1- ~Me~yl-aoe~yl~ni~oetyl~nnids) -2- ~2~hlo~nz~5~et~yl~rrole (2~hlor~r~1)-5~et~ yrro1e (20.1 9, 54.5 ~nDl) ~n 150 ~nl of t ~30~ wa6 ~d 250 ml of ~0~6 w/~3 ~1 ~lution ~r 5 mi~utes. Iq~ solutioT~ was wanE~d ~ ~an ~perature cr~rer 1 h~ur and then ~eated ~o r~lux for 4 l~r~. ~he reaction n~ct~ was eva~rated to give 10.5 9 of an oil. miS oil was dissol~red in 200 ml of isopr~yl alco~ol coqltainir~ glacial aoetic acid ~:L8.3 g, 0.305 n~l) and refluxed under s~i~n. After 72 ht~urs the reaction mixture was eva~orated an~ the residue was purified ~ ilica, 4:1 etl~yl acetate-hexar~e) to give 4.2 9 (22~) of a white pawder, m.p. 139-141DC.
P~L~SIS:
Calculated for C~ B 3 3 58.70~6C 5.21~H 12.08U~
Found: 58.52~C 5.29UH 11.98~N

EXAMP~E 46 1-Amino-2-(2-fluoxobenzoyl) 5-methylpyrrole A rapidly ~tirred suspensicn of 2-(2-fluorokenzoyl)-5~methyl 1-phthalimidapyrrDle (137 g, 0.39 mDl) in 500 n~ of 95% ethanol was treated with 230 nl of 40% w/w solution of methylamine and ~he mixture was further stirred at ambient temperature for 5 hours. Ihe mixture was diluted with 300 ~1 of H20 and extracted ~ith three 400 nl portions of dichlorometh3ne. ~he combined extracts were dried ~gSO~, filter~d, and evapDrated to an oil which ~as purified by HPLC ~silica gel, DCM) tD
give 71 g (83%) of an oil w~ich sDlidified upon seeding. A three gram p~rtion of this naterial was distilled at 120D ~O.~mmHg) to give 2.9 9 of sDlid, m.p. 45-q8D.

~26Z~O~

AUL~LYSIS:
___ Calculated for C~ FN~O: 66.0~C 5.08UH 12.83~N
Fb~D~d: 66.05~C 5.13~H 12.78~N

EXU~i~LE ~7 5-~2-Fluorophenyl)-8-methyl-lH~E~rolo[1,2-b~1,2~5]triszel~Ln 2(3H)-one To an i oe cold ~lution of l-bramGa oe tamidb-2-(2-fluorbbenzoyl)-5-nethylpyrrole ~42.3 g, 0.124 m~ol) in 100 ml Qf methanol was added 200 ~1 of 10~ w/w NH3/methanol ~olution over 10 munutes. m e vDlatiles were evaporated under vacuum at 30 ~nd the residue was ta~en up in 300 ml of isopropanol. TD this solution was added glacial a oe tic acid ~40 g, 0.60 mol) and t~e DL~ture heated under reflux for 7 h~urs. Evaporation of the ~Dlatiles left an oil which was purified by flash chrc~atography (silica gel, 4:1 E~IY4c-hexane) to give 2.9 g of an oil~ This oil was f ~ r purified by HPLC ~silica, 2:1 EtOAc-hexane) to give 1.1 g of solid. This solid was recrys ~ lized from ether-a oe tcne to give 0.81 g (2.4%) of pcwder, m.p. 214-216.
P~LYSIS:
Calculated for C14H12FN30: 65.35~C 4.704H 16.33~N
Found: 65.50%C 4.934H 16.42UN

EXAMPL~ 43 1-8rcmoacetamido-2-(2-fluorDbenz 1)-5imethylpyrrole ~ D a stirred slurry oDnt ~ g l-a~inK-2 (2-fluorDbenzoyl~-5-methylpyrrD1e (65 g, 0.29 mol) and sodium bicarbonate (52 g, 0.62 mDl) in 500 nl of dichloromethane was added bromoacetyl b ~ de (76.7 g, 0.38 mDl) over 30 minutes. After the initial peric~, the reaction exotherm subsided. The reactian muxture was stirred for 3 hours and thereafter quenched wnth 100 ml of H20. The organic layer was separated and ~LZtj2~3~4 w~d ~ br~, dried ~O4~, filtersd, ~nd evap~r~ olid.
~ id w purified ~y ~C (~iL~c~ yel, DC~) to give 7~ g (73P~) of p~wder, ~.p. 1~111.
~LYSIS-. .
Calc~u~ted f~r C14Hl~rFN202: 49.57%C 3.56~H 8.26~3 9 . 524C 3. 50~H 8. 31~N

E~UU~ 49 .
Oi- [ ~2- 52-f1UC)~TIZO~1) -5~rethyl~ 1-yl)-2-aoet~nido]amine ~ydro~lc)ride To an i oe oold solutio~ of l-br ~ a oet~unid ~ 2-(2-fluor ~ oyl)-5-methylpysr~le ~42.3g, 0.124 1) in 75 ~1 of methanol was added 200 nl of 104 w/w amm~nia-nethan~l ~oluticn over 20 ~unu~es. The nuxture was w~rmed tv room temperature and maintaLned at that terperature for 2 hcurs. Evaporation of khe vDlatiles unker reduced pre55Ure at 35 left a semisolid which was tak~n up in 300 nl of i~opropan~l and the solution was filtered. The filtrate was treated with glacial a oetic acid 540 g, 0.60 mDl) nnd refluxed for 7 ho~rs.
Evaporation of the volatiles left an ~il which was purified by f~ash chramatcgraphy t~ilica, 4:1 EtOhc-hRxane) tD give 5 g of an oil. Ihis oil was taken up in ether and treated wi~h ethereal ~C1. The ~esultant precipitate wa5 oollected and recry5talliz~d fr~m ethanol tD give 4.9 9 (6.9~) of powder, m.p. 171-174D.
ANALYSIS-Cal~ulated $or C28H25F2N5o~-~cl: 58.99~C 4.59~H 12.28~N
~ound: 58.46%C 4.74%~ 12.05~N

- 5~ -~ 50 A ~luti~ prepar~ fmm [2-(2-benzoyllFyr~l-l-yl]-2-[5din~thyl~mi~)ethyl]car~nic ~cid, ethyl e~ter (51.2 g, 0.174 11 ~nd ~odiun hyd~ide ~28 g, 0.70 n~1) and 260 ml of sa~
refl~ r 16 ~rs~ She exoess ethanol w~s evaporated and thR
resid~e diluted with 200 ml of H20 ~ ~tracted ~th three lO0 ~1 porti~ns of D~l. The organic p~ase was dried (~SO4), filter~d, ~
~va~rated to an oil. Ihis oil was distilled in a R~gelrohr z~paratus (150, 0.1 nn~g) to give 30.3 g (67.8~) of a li~d. A 3.û g portiorl of this li~uid was talce~ up in ether an~ treated with ethereal HCl. q~e resultant precipitate was oc~ll~ ar~ recrystalliz~d fmn ethanol-ether t~ give 2.1 of p~wder, m.p. 149-151~.
ANPlYSIS:
Calculated for C15HlgN30 ~ 61.32%C 6.86~H 14.30~1 ~ound: 61.23%C 6.82%H 14.41~N

~`

Claims (33)

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

1. A process of preparing a compound of the formula II

II

wherein X is hydrogen, halogen, C1-C6-alkyl, CF3 or NO2; Y is hydrogen, halogen, or C1-C6-alkyl, R is hydrogen, C1-C6-alkyl, C1-C6-alkylamino-C1-C6-alkyl or di(C1-C6)-alkylamino-C1-C6-alkyl and R1 is hydrogen, or a pharmaceutically acceptable acid addition salt of a compound of the formula II, which comprises a) hydrolyzing a compound of the formula III

III

where X and Y are as defined above to afford a compound of the formula II where R and R1 are both hydrogen, or b) reacting a compound of the formula II where R is as defined and R1 is hydrogen, with HOOCCH2NHCO2C(CH3)3 to afford a compound of the formula II where R1 is the group and c) a compound of the formula II where R is as defined and R1 is the group may be hydrolyzed to afford a compound of the formula II
where R1 is the group or d) reacting a compound of the formula II where R is as defined but is not hydrogen, with a compound of the formulae BrCH2COBr or ClCH2COCl to afford a compound of the formula II where R1 is and e) the compound obtained with alkali metal azide may be reacted and the resultant azide compound may be further hydrogenated in the presence of a suitable catalyst to afford a compound of the formula II where R1 is or f) reacting a compound of the formula II where R
and R1 are both hydrogen with ethyl chloroformate or ethyl bromoformate to afford a compound of the formula II where R1 is the group -CO2Et, or g) reacting a compound of the formula II where R
is as defined and R1 is hydrogen, with one of the compounds to afford a compound of the formula II where R1 is the group h) reacting a compound of the formula II where R1 is the group with N-phenylpiperazine to afford a compound of the formula II where R1 is the group or i) reacting a compound of the formula II where R
is as defined except hydrogen and R1 is the group with ammonia and then reacting the resultant product with glacial acetic acid to afford a compound of the formula II where R1 is the group where R is as defined above, or j) reacting a compound of the formula II where R is as defined except hydrogen and R1 is the group with ammonia and reacting the resultant product with acetic acid to afford a compound of the formula II
where R1 is the group and k) optionally converting a compound of the formula II so formed into a pharmaceutically acceptable acid addition salt thereof.

2. The process as claimed in claim 1 wherein the procedure is conducted in accordance with step (a) and may also include step (k).

3. The process as claimed in claim 1 wherein the procedure is conducted in accordance with step (b) and may also include step (c) or step (k).

4. The process as claimed in claim 1, wherein the procedure is conducted in accordance with step (d) and may also include step (e) or step (k).

5. The process as claimed in claim 1, wherein the procedure is conducted in accordance with step (f) and may also include step (k).

6. The process as claimed in claim 1 , wherein the procedure is conducted in accordance with step (g) and may also include step (k).

7. The process as claimed in claim 1 , wherein the procedure is conducted in accordance with step (h) and may also include step (k).

8. The process as claimed in claim 1 , wherein the procedure is conducted in accordance with step (i) and may also include step (k).

9. The process as claimed in claim 1 , wherein the procedure is conducted in accordance with step (j) and may also include step (k).

10. A compound of the formula II

II

where X is hydrogen, halogen, C1-C6-alkyl, CF3 or NO2: Y is hydrogen, halogen or C1-C6-alkyl; R is hydrogen, (C1-C6)-alkyl, (C1-C5)-alkylamino-(C1-C6)-alkyl, di(C1-C6)-alkyl-amino(C1-C6)-alkyl;
and R1 is hydrogen, or a pharmaceutically acceptable acid addition salt thereof.

11. The process as claimed in claim 1, wherein, in a compound of the formula II or a compound of the formula III, X is hydrogen or halogen, Y is hydrogen or C1-C6-alkyl, and R is hydrogen or C1-C6-alkyl.

12. A compound of the formula II wherein X is hydrogen or halogen, Y is hydrogen, or C1-C6-alkyl, R is hydrogen or C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

13. The process as claimed in claim 1, wherein, in a compound of the formula II or a compound of the formula III, X is hydrogen, fluorine or chlorine, Y
is hydrogen or methyl and R is hydrogen, methyl or dimethylaminoethyl.

14. A compound of the formula II wherein X is hydrogen, fluorine, chlorine, Y is hydrogen or methyl, R is hydrogen, methyl or dimethylaminoethyl, or a pharmaceutically acceptable salt thereof.

15. The process as claimed in claim 1, wherein [2-(2-chlorobenzoyl)-1H-pyrrol-1-yl]-2-[(dimethylamino)ethyl]
carbamic acid, ethyl ester is hydrolyzed to produce [2-(2-chlorobenzoyl)-1H-pyrrol-l-yl)-2-(dimethylamino) ethylamine.

16. The process as claimed in claim 15, wherein the hydrolyzing step is conducted with sodium hydroxide in ethanol with heating.

17. [2-(2-Chlorobenzoyl)-1H-pyrrol-1-yl]-2-(dimethylamino) ethylamine.

18. The process as claimed in claim 1 , wherein 2-(2-chloro-benzoyl)-1-methylaminopyrrole is reacted with tert-butoxycarbonyl glycine in the presence of dicyclohexyl-carbodiimide to form 1-[N-methyl-(t-butoxycarbonylamino) acetamido]-2-(2-chlorobenzoyl-pyrrole.

19. The process of claim 18, wherein the reaction is conducted in dichloromethane at ambient temperature.

20. 1-[N-Methyl-t-butoxycarbonylamino)acetamido]-2-(2-chlorobenzoyl)-pyrrole.

21. The process as claimed in claim 1, wherein 1-amino-2-(2-chlorobenzoyl)pyrrole is reacted with t-butoxycarbonyl glycine in the presence of dicyclohexylcarbodiimide to form 1-[(t-butoxycarbonylamino)acetamido]-2-(2-chlorobenzoyl)-pyrrole.

22. The process as claimed in claim 21 , wherein the reaction is conducted in dichloromethane at ambient temperature.

23. 1-[(t-Butoxycarbonylamino)acetamido]-2-(2-chlorobenzoyl)-pyrrole.

24. The process as claimed in claim 1, wherein 1-bromo-acetamido-2-(2-fluorobenzoyl)-5-methyl pyrrole is reacted with ammonia and the resulting product is then reacted with glacial acetic acid to form di-[(2-(2-fluorobenzoyl)-5-methyl-1H-pyrrol-1-yl)-2-acetamido)amine.

25. The process as claimed in claim 24, wherein an ice cold solution of 1-bromoacetamido-2-(2-fluorobenzoyl)-5-methylpyrrole in methanol is reacted with ammonia and methanol while warming to room temperature, and the resulting product is then reacted with glacial acetic acid under reflux.

26. Di-[2-(2-fluorobenzoyl)-5-methyl-1H-pyrrol-l-yl)-2-acetamido]amine.

27. The process as claimed in claim 1 , wherein 1-amino-2-benzoylpyrrole is reacted with carbobenzyloxyglycine in the presence of N,N'-dicyclohexyl-carbodiimide to form 1-[(carbobenzyloxyamino)acetamido]-2-benzoylpyrrole.

28. The process as claimed in claim 27, wherein the reaction is conducted in dichloromethane at room temperature.

29. 1-[(Carbobenzyloxyamino)acetamido]-2-benzoylpyrrole.

30. A compound of the formula II as defined in claim 10 or a pharmaceutically acceptable acid addition salt thereof, for use as one or more of an analgesic, anxiolytic and anticonvulsant agent.

31. Use of the compound of the formula II as defined in claim 10 or a pharmaceutically acceptable acid addition salt thereof as one or more of an analgesic, anxiolytic and anticonvulsant agent.

32. A pharmaceutical composition containing a compound of the formula II as defined in claim 10 or a pharmaceutically acceptable salt thereof in admixture with one or more of a pharmaceutically acceptable diluent, carrier and excipient, for use as an analgesic, anxiolytic and anticonvulsant agent.

33. The pharmaceutical composition as claimed in claim 32, which further contains one or more of an antibacterial agent, an antioxidant, a chelating agent, a buffer, and an agent for the adjustment of tonicity.