CA2016501C - Substituted pyrrole compounds and their applications in pharmacy - Google Patents

Abstract

The invention concerns substituted pyrrole compounds and their applications in pharmacy. The compounds of the invention are potent inhibitors of lipoxygenase and cyclo-oxygenase and therefore are suitable to treat the set of rheumatic illnesses and to prevent allergically induced ailments.
The compounds have the general formula:

Description

Professor Dr. Cerd Dannhard Konigsbergstr. 26a D-6236 Eschborn 2 Federal Republic of German Merckle GmbH
Graf-Arco-StraLie 3 7900 Ulm-Donautal SUBSTITUTED PYRROLE COMPOUNDS AND
TI-IEIR APPLICATIONS IN PHARMACY
t5 The invention concerns substituted pyrrole compounds and their applications to pharmacy and to drugs containing these compounds.
It is known that arachidonic acid metabolizes two different ways. In the cyclo-oxygenase way the cyclo-oxygenase enzyme metabolizes the arachidonic acid into xo prostaglandins. In the lipoxygenase way, the arachidonic acid affected by the lipoxygenases is metabolized into the so-called leucotrienes.
The prostaglandins take part in the generation of inflammation, fever and pain, whereas the leucotrienes are significant in the generation of asthma, inflammations and allergies. Frequently non-steroidal antiphlogisncs such as derivatives of arylacetic-x5 acid, 2-aryl-propionic-acid and anthranilic acid to fight those symptoms.
These derivatives inhibit cyclo-oxygenase and thereby prevent the formation of prostaglandins from arachidonic acid. However the use of such derivatives is questionable on account of their side effects. On the other hand, drugs inhibiting lipoxygenase are not commercially available.

Now it was found in surprising manner that certain substituted pyrrole compounds arc potent cyclo-oxygenase and/or lipoxygenase inhibitors and therefore are suitable to prevent allergically induced maladies and to treat the set of rheumatic illnesses.
Accordingly the object of the invention are substituted pyrrole compounds of the general formula I

R N
~o R
~1 where R~ denotes a Cl - C~2 alkyl group, RZ is a hydrogen atom or a C~ - C~2 alkyl group, or R' and RZ together with the carbon atom and the nitrogen atom to which ~s they are bound form a 5- to $- link ring which also may contain a sulfur heteroatom or a carbonyl group and which where called for may be substituted with one to two C, - C4 alkyl groups, each time, two of the residues R3, R4 and RS independently of each other are a hydrogen atom, a Cs-C8 cycloalkyl group, a Cl - C~Z alkyl group or an aryl group zo which may be substituted by one or two residues selected form a halogen atom, a vitro-, a C, - Ca alkoxy, hydroxy, a C,-C4 alkyl or phenoxy group, and the third of the residues R', R" and RS denotes -CI-IO, -COZI-I, -COSC,-C,,-alkyl or A-X, with A being a straight chain or branched C, - C8 alkylene group which may be interrupted by a hydrogen heteroatom or a carbonyl group, or a CZ - C8 alkenyl group, 2s and with X being COZH, S03I-I, CI-IO, OH or SH.
as well as their pharmaceutically compatible salts and esters, for application in pharmacy.

In the present case the pharmaceutically compatible salts may be salts of acid or of base addition. For acid addition :;alts, inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid are used, or such organic acids as tartaric acid, lactic acid, citric acid, malic acid, mandelic acid, ascorbic acid, malefic acid, fumaric acid, s gluconic acid and the like.
The base salts include the salts of the compounds of formula I with inorganic bases such as sodium or potassium hydroxide or with organic bases such as mono-, di- or tri-ethanolamine.
The esters of the compounds of formula I include in particular physiologi-cally easily hydrolyzed esters such as alkyl-, pivaloyloxymethyl-, acetoxymethyl-, phthalidyl-, indanyl- and methoxymethyl-ester.
The term "alkyl, alkoxy etc." covers straight-chain or branched alkyl groups such as methyl, ethyl, n- and i-propyl, n-, i- or t-butyl, n-pentyl, neopentyl, n-hexyl etc.
Unless otherwise stated, "alkyl" preferably shall denote Cl - C8 alkyl and in 95 particular Ct - C6 alkyl.
Preferably aryl shall denote naphthyl and in particular phenyl.
The expression "halogen atom" covers an atom of fluorine, chlorine, bromine or iodine, especially a fluorine or chlorine atom.
The cyclo-alkyl residue preferably denotes a cyclopentyl or cyclohexyl Zo residue.
A preferred embodiment mode are compounds of the formula Ia:

R~
R5 N ~ R4 o s A 4 ~'~ .~.. ) ~r where R3, R' and 1R5 arc the carne as stated above in relation to formula I
and where R~' and R7 independently from one another denote a hydrogen atom or a Cr - C~
alkyl group.
Especially preferred compounds of formula la are those wherein two of the residues R', R' and RS denote a phenyl group which is possibly substituted by one or two s residues selected from a halogen atom, in particular a fluorine or chlorine atom, from a Cr - C~ alkyl-, Cr - Cn alkoxy-, Irydroxy- and phenoxy-group and where the third residue denotes A - X, with A being a Cr - C$ alkylene group or a C, - Cg alkenylene group, and with X being CO21-I.
In particular AX denotes CZ - C6-alkylene-COZI-I or CZ - C6 alkenylene-,o COZI-I and in an especially preferred instance it stands for (CI-IZ)ZCO21-I, C1-IZCOzI-I or CH = CH COzH.
Preferably R6 and R' are in the 2-position of the pyrrolizine structure and in particular they designate both a hydrogen atom or a methyl group.
Especially preferred embodiment modes are the compounds of the formulas ~s R3 R3 R s 4 R
R6 N~ R R6 N~AX
dUC . _~ R4 R~

2o R6 N ~ R

where RG and R' denote a hydrogen atom or a CI - C4 alkyl group and R3 and R~ denote n phenyl group which may be substituted by one or two residues which are selected from a halogen atom, a nitro-, CI - Ca alkoxy-, C~ - Ca alkyl- or a phenoxy- group.
A-X has the same mewing as above in relation to Lhe formula I.
Preferably the substituents of the phenyl group are selected from a halogen s atom, in particular a fluorine or chlorine atom, from a C1 - C,~ alkyl-, C~ -C4 alkoxy- and phenoxy-group. Preferably the substituents shall be in the m- and/or in the p-position.
Preferably A denotes a C~ - C$ alkylene group or a C~-C$ alkenyiene group in particular, or a CZ - CG alkylene- or C2 - C6 alkenylene group and X
preferably denotes COzI-I.
Another embodiment mode are the compounds of formula I
where R~ and RZ independently of one another denote a Cl - C~2 group, with two of the residues R3, R4 and RS being a phenyl group possibly substituted by one or two residues selected from a halogen atom, a Cl - C4 alkyl-, C, - C4 alkoxy-, hydroxy-and phenoxy-group, and ,s where the third of the residues R3, R4 and RS is a hydrogen atom or A-X, with A being a Cl - C6 alkylene- or a CZ - C6 alkenylene-group and X being COZH or S03H.
Rl preferably is a Cl - Cs alkyl group, in particular a C~-C6 allyl group and especially preferred a C4-C6 alkyl group.
zo R' preferably is a Cl-Ca alkyl group and especially a methyl group.
R3 and R'' on one hand and R'~ and RS on the other preferably are a phenyl group and RS and R3 resp. are A-X, with A being preferably a C~-C,~ alkylene group or a Ci C6 alkenylene group.

Especially preferred compounds are:
(2,2-dimethyl-6,7-Biphenyl-2,3-dihydro-l I-I-pyrrolizine-5-yl)-acetic acid, and 3-(2,2-dimethyl-G-(4-phenoxyphenyl}-7-phenyl-2,3-dihydro-II-I-pyrrolizine-S-yl) propionic acid.
s Further the invention concerns the compounds of the general formula I and also the corresponding above stated preferred embodiment modes per se, where R1 and RZ together denote <~ S to 8 link ring possibly containing a sulfur hetero-atom or a carbonyl group and further possibly substituted with one to two Cr-C4 alkyl groups, and where R', R4 and R5 assr:me the above meanings but with A being a straight-chain or a ,o branched C3 C,~ alkylene group which may be interrupted by an oxygen atom or a carbonyl group, or denoting a straight-chain or a branched C3 C8 alkenyl group, or where Rr through R$ assume the meanings stated in claim 4.
Synthesis of the compounds of formula I wherein R' and RZ together form a S to 8 link ring, takes place in a first step described by the equation (1) below:
R~

+ RS - CH - C - R~
ICHZIn N
R6~ X= C1, Br n = 1 - 3 R3.
R~
(CH ~ n~ / R 9 RS~N
RS

~ ~. ~i ~ ~9 _~. ' This synthesizing; step is elucidated together with the following ones by means of the illustrative Biphenyl-substituted I>yrroiizine compounds. ~I~hc first reaction stage is explained in further detail below:
Reaction diagram (1) / \ __ Ethanol, C\ _ NaHCOy N + ~C~
BrH2C
/ ~ / \
,o Ethanol, NaHCO~, II + C
N 1 H ' ~5~ N
Br~'~
ri Ethanol, CN3 ~ NaHCOy N + \C Hue, -°-~
C1-- ' \ /' 20.30 °~
/.
The con~~o4~v~~s of r~:vtion are known and described in CI-IEM~KEId-ZEITUNG, 110, (1968) # 7/$, pp 267, 271 and in ARCH. PHARM. 321, pp 159-162 ( 1988).

do a second stage, the formyl or methylol group is introduced into the pyrrole ring and further reaction takes place into the corresponding derivatives of acetic acid and ethanol rep. as given by the reaction diagram (2) below:
Reaction diagra~r~ (2) POCi~, DMF, er~~z~r!r.~
CHO
UAIH4, THF
-Y-CHzOH
~ CHO ~ / CHzOH
/' /\
a CH~OH

~~1~~~~
Pl2CHCOOC~H~, Cu°, , n -.~.~ --.~,-TULUENE
CH2 COOGzHs _ ~~HF

r~
CH2-COOC2H5 -~' / CH2-CHzOH
/~
NHS ~ CH~-CH..nH

~~~~ 1 ~.~ 10 'These reactions and their conditions are known and arc described in CI-IEMIKEIZ-LE1TUNG I10 (1968), # 7/8, pp 267-271 and in ARCI-I. PI-IAItM.
321, pp 159-162 (1988).
The preparation of the corresponding derivatives of formic acid, propionic s acid and acrylic acid is described in ARCM. I'I-IARM. 321, pp 545-549. IL
takes place according to the reaction diagrams (3) and (4).
'the preparation of the corresponding butyric-acid derivatives takes place according to the reaction diagram (5). First, using the Friedels-Crafts acylation with succinic acid anhydride (E. Berlina, ORG. REAKT. 1949, 5, pp 229-289), Lhe 4-oxo-1o butyric acids are prepared which then are reduced by means of the I-Iuang-Minion variation of the Wolff-Kishner reduction with hydrazine/KOH in diethyleneglycol. The conditions of reaction are known to the expert.
The derivatives of valeric acid can be prepared by means of the 5-oxo-valeric acids which in turn can be made from the pyrrolizine base bodies by the Friedel-1s Crafts acyiation with glutaric acid anhydride in a manner similar to the preparation of the butyric acid derivatives. In similar manner the caproic acid derivatives are obtained by the Friedel-Crafts acylation of diphenylpyrrolizine with methyl-5-(chloroformyl-valerate/AICI~) and saponification of the 6-oxocaproic-acid-methylester derivatives and subsequent reduction of the oxovaleric acid with. hydrazine/KOI-I.
zo The preparation of compounds substituted at the phenyl group takes place similarly. The hydroxy-substituted derivatives are prepared by ether splitting with BBr3 from the corresponding alkoxy derivatives ('rETRAI-IEDRON, 1968, 24, pp 2289-2292).

2fl~.~~~~
Reaction diagr:rrn (3) l~
._ CtCOSC2H~, AlCta CH,aCi2 ,. N
iC2H5 KOH, s Ethanol, D ~, ° N s cooH
s ~

~2 Itca~aion diogratia (4) ~
3.
~ ' \
-- ~.. H
I
_ '~~Ig- C-COOG2H5 Ko CHO arr,cTiotv ~ ~.- Ethanol, DD
N ~ ~ ~ \
H

i H~IPtO~, .-COOH Ethanol, - ~~ -N ~, (CHz)2 COOH
/
w COOCZHS COOH
H~~ .. --C
H C-H (CH2)~-CG
N.' reaction diagram (S) agcy cHach_ (CH2)2-COOH
HzN-NH2, NaOH, DIETHYLENEGLYCOL
(CH2)~ COON
~H2)2 COOH
.OO H (C H2 )3~ COO H

,4 The prclrrration of the compounds of formula I is described below, wherein Rr and RZ denote a C,-Crz alkyl group. The initial material for the synthesis of these compounds are the corresponding 2,3,4- and 2,3,5-substituted pyrrole compounds of which the production is described in AUST. J. CI-IEM. 19G<, 19, pp 1971-1885. The further s synthesizing steps are elucidated illustratively below starting with 2-methyl-2,3-diphenyl-pyrrole and 5-methyl-2,3-diphenylpyrrole. These reactions are shown in the diagrams (G) and (7).
The first step is an alkylation of the pyrrole nitrogen atom. This reaction is carried out in conventional manner, for instance using the corresponding alkyl halides ,o in the presence of a birse, for instance alkali-metal aicoholates such as sodium mcthylate, sodium ethylate or potassium-t-butylate, in an inert solvent such as DMSO, ethylenegiycol methylether and the like. The alkylation also can be carried out heterogeneously with the corresponding toluene sulfonic-acid alkylesters or alkyl halides using phase transfer catalysts, in conventional manner (see for instance CAN. J. CI-IEM. 1977, 55, pp 4112-~s 4116). The introduction of acid lateral chains then takes place similarly to the synthesises of the corresponding pyrrolizinyl carboxylic acids as described above.
The compounds of the invention are potent inhibitors of cyclo-oxygenase and/or lipoxygenase. Accordingly they are useful in treating the set of rheumatic illnesses and in preventing allergically induced ailments. Therefore the compounds of the 2o invention represent effective antiphlogistics, analgetics, antipyretics, anti-allergies and broncholytics and may be used in thrombosis prophylaxis and in the prophylaxis of anaphylactic shock and to treat skin diseases such as psoriasis, urticaria, acute and chronic exanthemas of allergic and non-allergic origins.

Reaction diagram (G) TOLUEfJE SULFONIC _ nCID ME'I'JIYI,ESTEI2 OR
AL(;YLI3ROMIDE
H3 N~ H3C N
H R
CH2~Ct-ICOOCH3, BFI, CHzCICH2Cl COMPOUtJD ( R
H
CH3 !~

i R
n-~H.r n-C4Hg KOH, Ethanol, D
f n-CsH9~
Si ~'CsH~3 ~I iso-C4H~
i Neoperrtyl COON
R

os ~'~.1~ ~~~~
Reaction diagrs~m (7) 'I'OGUEIJE SUI,FONIC
ACID ME'PF1YLESTEt2 OH
Alkyibromld a H
NzCHCOOCzHy COMPOUND R CUB, toluened H

F /
n-C3H7 H3C N
e_ n_CaHs R
f_ n-CSH, ~
KOH, g n-CsH,3 Elhanoi, D
h~ n-CaH»
j ISO-C4H9 Neopenfyl HOOC

The crampounds of the invention may be administered either as individual therapeutic substances or as mixtures with other active substances. They may be administered alone, but as a rule they may be administered in the form of drugs, that is as rnixtures of the active substances with suitable ;pharmaceutical carriers or diluents. The s compounds or drugs may be administered orally or parentcrally but preferably they shall be dosed orally.
The kind of drug and of pharmaceutical carrier or diluent depends on the desired method of administration. Oral drugs for instance may be in the form of tablets or capsules and may contain conventional excipienis such as binders (for instance syrup, ,o acacia, gelatin, sorbite, traganth gum or polyvinylpyrrolidane), fillers (for instance lactose, sugar, maize starch, calcium phosphate, sorbite or glycine), lubricants (for instance magnesium stearate, talcum, polyethyleneglycol or silicon dioxide), disintegrants (for instance starch) or wetting agents (for instance sodium lauryl sulfate). Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, ,s syrups, elixirs or sprays etc. or they may be in the form of dry powders to be reconstituted with water or another suitable carrier. Such liquid preparations may contain conventional additives such as suspending agents, flavorings, diluents or emulsifiers. As regards parenteral administration, solutions or suspensions with conventional pharmaceutical carriers may be used.
2o The compounds or drugs of the invention can be administered to mammals (human and animal) in doses of about 0.5 mg to about 100 mg per kg of body weight per day. They can be administered in single or multiple doses.

~~ ~~ ~4~:~ ,o The effectiveness of the compounds of the invention can be determined by means of the inhibition of S-lipoxygenase or of c:yclo-oxygenase. The research was carried out as follows:
TESTING TO DETERMINE THE INI-IIBITION OF 5-LII'OXYGENASE
The source for 5-lipoxygenase were bovine granulocytes which can form leucotrienes just as human granulocytes do. By stimulation with calcium-ionophore (see BIOCI-IEM. BIOPI-IYS. ACTA 1984, 795, pp 499 - 503), mainly LTC4 (leucotriene C4) and LTB4 (leucotriene B4) are formed from endagenous arachidonic acid. The isolation of the granulocytes and the implementation of the enzyme reaction are conventional (see ,o BIOCHEM. BIOPI-IYS. ACTH 1984, 795 pp 499 - 503). The blood protected against clotting by EDTA first is centrifuged for that purposed and the thrombotic excess is removed. Following lysis of the erythrocytes with water the lymphocytes and monocytes are separated from the granulocytes by means of a Ficoll gradient. The granulocytes are set to a specific cell number. The enzyme reaction is then begun in the presence or ,s absence of the test substances following the addition of Caz+ with calcium ionophore. The synthesis of the leucotrienes is stopped after S minutes by adding a mixture of methanol and acetonitrile containing PGB2 as the internal standard and NDGA as the anti-oxidant.
Next the samples are diluted in water and processed in the manner described in J.
CHROMATOGR. 1896, 378, pp 208 - 214. LTB4 is measured at the absorption 2o maximum at 270 nm. The arachidonic acid metabolites are observed ,present in this research in approximately quantitative manner.

~~~.~~~0~

TEST1NCG 'r0 DF,'r>rIRMINIE 'TI IE INHIII3IT10N OF CYCLO-OXYGENASE
In this test the 12-IIH'r amount of 12-hydroxyheptadecatriene acid or prostaglandin EZ amount formed by bovine thrombocytes following addition of calcium ionophore is determined by uv detection following HPLC separation. Following s centrifuging of the bovine blood, the thrombocytes are isolated from the surnatant. The enzyme reaction and the isolation of the formed metabolites take place as when determining the 5-lipoxygenase inhibitiun, however the incubation time was one minute.
The detection of 12 I-II-IT following I-IPLC separation takes place at 232 nm.
Tables 1 and 2 list the test results for the compounds of the invention, The 1o test substances were at concentrations of 10 p M.
The Examples below illustrate the invention. All temperatures are uncorrected. The it spectra -- unless noted otherwise -- are from KBr molded articles.
The NMR spectra, unless noted otherwise, are 90 Mhz spectra, recorded in CDCI3 with tetramethylsilane (TMS) as the internal standard.
1s The preparation and the properties of the compounds used as initial materials used in part for the reactions below and listed in Tables 3, 4 and 5 are described in the following literature:
ARCH. PHARM. 312, pp 896 - 907 (1979) ARCH. PHARM. 319, pp 500 - 505 (1986) zo ARCH. PHARM. 321, pp 159 - 162 (1988) ARCH. PI-IARM. 321, pp 545 - 549 (1988) CHEMIKER ZEITUNG, 110, (1986), 7/8, pp 267 - 271.

'rAI3L~ 1: INI-IIBITION OF 5-I_.,IPOXYGENASE AND OF
CYCLO-OXYGI;NASC BY PYRR,OLIZINE COMPOUNDS.

R~
R 4 ( 10 y1~5 ) R 6 Pl RS

R3 INfIIBITIO~ClppXy-Nr. ge~
a genase Phenyl (CH2)4C02H Phenyl H H 82 Phenyl (CH2)5CO2tiPhenyl H H 80 ( ~2 ) Phenyl Phenyl H ti 86 (CH2)5C~2r~Phenyl Phenyl H H 86 Phenyl Phenyl CH2~2H ~3 ~3 94 99 Phenyl Phenyl ( ta-12 CH3 CH.~91 97 ) 2C02H

( ~2 ) Phenyl Phenyl CIi3Cli393 2~2H

( ~Z ) Phenyl Phenyl CH CH 96 5~2H 3 3 Phenyl Phenyl CHZCOZH H H 91 Phenyl Phenyl CH=C~1-C02HH H 80 CH=CHC02HPhenyl Phenyl CH3 CH3 91 Phenyl C6H13 (~(=(3iC~p2HH H 82 Phenyl m-C'hl.osphenyl( (~~2 H H 89 ) 2Cp2H

Phenyl p-(hlozphenyl( ~2 ) H H 98 zCp2H

Phenyl p-Tolyl ( C7-12 H H 92 ) 2Cp2H

Phenyl p-Methoxy- (CH2)2Cp2HH H 91 phenyl Phenyl p-Phenoxy- (CHZ)ZOpzHH H 98 70 i phenyl i Phenyl a-naphthyl ( p-(2 H 11 94 ) 2pp2H

Phenyl p-Fluorphenyl(Di2)zCp2H~3 ~3 93 (3,3 yM) Phenyl p-Tolyl. (Cfi2)2C02HCH3 CN3 93 (3.3 pM) Phenyl p-Ffienoxy-( C1~2 C?-i3C~-1398 ) 2Cp2H

phenyl ( 3, ~;M

2, T ABLE 2: INI-iIBITION OI~ 5-L,IPOXYGENASE
BY 2-ME'rI-IYL-DIPLIENYLPYRROL1C-ACETIC-ACIDS

R2 ~ ~ RS ( 10 uM ) N

ir~tmamoN( R1 R2 R3 R4 RS ~Lipoxygenase~
n-CQH~ CN3 PhenylPhenyl (C7-IZ)2COZH

n-C5~111 ~3 ~enylPhenyl ( CIi2 ) 2COZH

n-C6H13 CH3 PhenylPhenyl (C7-12)ZC02H

tVeo-pentyl CH3 PhenylPhenyl (CH2)ZC02H 97 EXAMP~T
H CHs i H ~ 1~

CHO

CH2COOC2H~

(CH2)20H

(CH2)2COOCH3 (CH2)ZCOOH 27a 27~

io CH=CHCOOCZHS (E) ,~

11 CH~HCOOH (E) EXAMPLE
..._ _ ._ _.._ .~.. ~ _.. H ~ -~.c"3 13 CHO 7~ 7~1 14 CHaOH ~ lQtz 16 (CH2)20H 1~ 1 ~

1~ COSC2H~ 1~ 1~

1s COOH 21~ 21~

1~ CH2COOH 24a 24b 2o CH~HCOOC2H5 (E) 2$

21 CH~HCOOH (E) ,~Q

22 (CH2)zCOOH ~2 za EXeIMPLE
Nr. ~ ~ H I CH3 2 3 hi ,~ ~.

24 CHO $.~ $~2 25 CH~OH 11~, 11~

26 CH2COOC2H5 L4,~ ~i4 a~ (CHz)20H 1?~

2 8 COSC~-IS ~ 2_Qt~

2 ~ COOH

3o CHaC00H ,~ 2~, 3i CH~HCOOC2H5 (E) 2~ ,2~

32 CH~HCOOC2H5 (Z) 29b' 33 CH~HCOOH (E) ~ i~

34 CH=CHCOOH (Z) ~11~' 35 (CH2)2COOH

Gl=:NERAI_ l'h.OCEDUIZI: hOR I'IZEE'ARING 'I'IIE 4-(DIPI-IENYL-2,3-DII-IYDRO-lI-I-I'YRROLIZINYL)-4-OXOI3UTYRIC ACIDS
With ice cooling and stirring, 8.8 mmoles (1.17 g) of A1C13 are added in batches over five minutes to a solution of 4 mmoles of Biphenyl-2,3-dihydro-1H
s pyrrolizine and 4 m~xr (0.40 g) of succinic acid anhydride. Then agitation continues for 4S minutes at room temperature. Thereupon the batch is poured into 1S0 ml ice water.
After adding 4 ml of 8 % I-I~PO,,, extraction is performed three times with CI-ICh, the organic phases are dried with Na2S04 and the solvent is distilled. Product isolation is by means of column chromatography (silica gel, 1st ether, 2nd ether/THF 1+1). The ,o product fractions are concentrated, the residue is dissolved in a little CI-ICl3. After adding n-hexane and new concentration, the product is precipitated.
GENERAL PROCEDURE FOR PREPARING TI-IE 4-(DIPI-IENYL-2,3-DIHYDRO-1H-PYRROLIZINYL)-IiUTRYIC ACIDS
15 O.S mmoles of 4-(Biphenyl-2,3-Bihydro-1H-pyrrolizinyl)-4-oxobutyric acid are mixed with 10 ml of diethyleneglycol, SO mmoles (2.8 g) of KOH and 30 mmoles (1.S
g) of hydrazine hydrate. The batch is heated 1 hour till reflux (bath temperature 170 ° C).
Next the reflux condenser is replaced by a distillation bridge and the temperature is raised until the inside is at about 210 ° C. This temperature is then maintained for 2 h.
2o Following cooling, the batch is poured into 1S0 ml I-I20, acidified with 8 % I-I3P0,, and extraction is carried out three times with ether. The extracts are washed with HzO, dried and concentrated. The product is isolated with column chromatography (silica gel, ether/TI-iF 4 + 1 in 39, diisopropylether in 4Q, ether in 41a and ether/n-hexane 4 + 1 in 4~) and is precipitateB using n-hexane.

~~~~~3~~
2s GENERAL 1'ItOCEDURE rOR PREPARING TI-IE S-(DII'I-IENYL-2,3-DIi-IYDRO-li-I-PYRROI_IZINYL)-5-OXOVALER1C ACIDS

4 mmoles of Biphenyl-2,3-dihydro-lI-I-pyrrolizine are reacted in lf~ ml of absolute CIIZCI2 with 4 mmoles (O.~IG g) of glutaric acid anhydride and 8.8 mmoles (1.17 s g) of AlCl3 similarly to the procedure for rnaking the 4-(Biphenyl-2,3-dihydro-1H-pyrrolizinyl)-4-oxobutyric acid ("s.S." 222). In deviation, the batch is poured into ice water immediately after the addition of AICI~ and then is processed further.
Product purification takes place by column chromatography (silica gel/ether).
GENERAL PROCEDtJRE FOR PREPARING TI-IE 5-(DIPI-IENYL-2,3-DIHYDRO-,0 1H-PYRROLIZINYL)-S-VALERIC ACIDS
0.5 mmoles of 5-(Biphenyl-2,3-dihydro-lI-I-pyrrolizinyl)-S-oxovaleric acids are reacted similarly to the procedure for making the 4-(Biphenyl-2,3-dihydro-pyrrolizinyl)-4-oxobutyric acids. The product is isolated by column chromatography (silica gel, ether) and precipitated by means of n-hexane.
,s GENERAL PROCEDURE FOR PREPARING THE 6-(DIPI-IENYL-2,3-DII-IYDRO-lI-I-PYRROLIZINYL)-6-OXOCAPROIC-ACID METHYLESTERS
With ice Gaoling and while stirring, 22 mmoles (2.93 g) of A1CI3 are added aver 5 minutes and in batches to the solution of 10 mmoles of Biphenyl-2,3-dihydro-1H-pyrrolizine and 10 mmoles (1.79 g) of methyl-5-(chloroformyl)-valerate in 50 ml of 2o absolute CHZC12. Immediately thereafter the batch is poured into 150 ml of ice-cooled % NaCI solution. Upon addition of 4 ml of 8 % h13P04, extraction with ether is carried out three times, the organic phases are dried with NazS04 and the solvent is distilled. The product is isolated by means of column chromatography (silica gel, 1st n-hexane/ether 3-+~2, 2nd n-hexane/ether 1 + 4 in 48, 50a and SOb, or 1st toluene, 2nd 2s hexane/ether 1+4 in 49). First the eluates are concentrated to about 100 ml, then they are washed twice with 0.05 n NaOI-I and twice with 10 % NaCI solution and lastly they are dried with Na2S0,,. When the solution is concentrated, the products precipitate or, following distillation of the solvent, crystallize.

~~ ~ ~'.v~~

GENERAI_ PROCEDURE FOR PREPARING 'I'I-iE 6-(DII'IIENYL-2,3-DII-IYDRO-lI-I-PYRROLIZINYL)-G-CAI'ROIC ACIDS
The solution of 1 mmole of 6-(Biphenyl-2,3-dihydro-lI-I-pyrrolizinyl)-6-oxocaproic-acid methylester in 10 ml of ethanol is heated to boiling. S ml of 10 % KOH
s previous degassed by boiling are dripped into that solution and heating continues another 1S minutes with reflex. Following cooling the batch is poured into 100 ml of S
°lo NaCI
and then is acidified with 8 % H3P0,~ and extraction is carried out three times with ether.
The organic phases are dried by means of Na2S04 and concentrated. The residue is reacted with SO mmoles (2.8 g) of KOI-I and 30 mmoles (1.S g) of hydrazine hydrate in ,0 10 ml of diethyiene glycol similarly to the preparation procedure for the 4-(Biphenyl-2,3-dihydro-1H-pyrrolizinyl)-butyric acids and is purified by column chromatography with silica gel.
The compounds so prepared and several physical properties of theirs are listed in the Tables 6 through 8 below.
,s GENERAL PROCEDURE FOR PREPARING THE 2-(DIPI-IENYL-2,3-DIHYDRO-lI-I-PYRROLIZINYL)-PROPIONIC-ACID ETHYLESTERS
S mmoles of Biphenyl-2,3-dihydro-1H-pyrrolizine dissolved in 4 ml of absolute toluene are reacted with 7.5 mmoles (0.96 g) of 2-diazopropionic-acid ethylester dissolved in 2 ml of absolute toluene similarly to the procedure for preparing the 2o diphenyl-2,3-dihydro-1H-pyrrolinyl acetic-acid ethylesters. I-Iowever the time of reaction is 2 h. Purification is column chromatography (A1ZO3, n-hexane/ether 9+1). The products are precipiated with ethanol.
GENERALPROCEDURE FOR SAPONIFYING THE 2-(DIPHENYL-2,3-DIHYDRO-1H-PYRROLIZINYL) PROPIONIC-AICD ETHYLESTERS
2s S mmoles of 5~i or O.S mmoles of 55a and SSb, dissolved in 12 ml or 9 ml resp. of ethanol are reacted with 8 mI or 2.S ml resp. of 10 °~o aqueous KOI-I similarly to the procedure for saponifying the Biphenyl-2,3-dihydro-lI-l:-pyrrolizinyl-acetic-acid ethylesters. The time of saponification is 1S min in 54, 60 min in 55a, and 55b.
Purification is by column chromatography (silica gel, 1st n-hexane/ether 1+ 1, 2nd ether).
ao After the eluates have been concentrated, the products are precipitated with n-hexane.
The compounds so prepared together with some of their properties are listed in Table 6 and the Table 9.

Tabie 6 % ~ ~
. .. . ,y. .
EXAMPLE-. ,. , MEL'I'IC~GjRl J
ppyNZ~
tdr. ~ C

6 COOH ,~ 187-188 1710, 1635 ) CO(CH

g 37 (CH2)gCOOH ~ 166-167 1705 CO(CH2)3COOH 42 142-143 1710, 1635 3 $

3~ (CH2)aCOOH 4~ 146 1710 40 CO(CH2)4COOH ~ 9~ 1740, 1630 41 (CH2)~COOH ~.~.

CH (CH3)COOC2H5 ,;~_4, - 17 30 43 CH(CHg)COOH ~ 173 1705 1, (C=O) hand ~H-NMR: b (ppr'~) = 1.06-1.78 (m, 6H, -(~)3-CHz-CO-), 2. i0-2.40 (rn, 2H, ...CH~p-), 2.40-2.76 (rn, 4H, f'yr-CH2 ~a :.-2), 3.02 (t, 2H, J=7 Hz, C-1), 3.94 (t, 2H, J=7 Hz, C-3), 6.97-7.31 (m, 10H. Arom.) Table 7 G:,AMPLG MELTING 1 ) ' NZ,. R POINT IR
.
e~

44 CO(CH2)2COOH s~ 231-234 1715, 1680 45 (CH2)3COOH ~ 176-178 1715 46 CO(CHZ)3COOH ~ 128 1710, 1660 47 (CH2)4COOH ~ 126-127 1?00 48 CO(CHa)4COOCH3 ~ 112 17d5, 1658 49 (CHp)gCOOH ~ 63 1710 1~ (C=O) Band G~ '~ a i"' 4 Table 8 I
EXAMPLE ~~ ~ MCi.TING
N_r. H CT.
R - C
~ I
_ R1 a ~
b_ a b , ~ '~15, 166 1715.-CO(CH2)2COOH ~ 190-191187-1881 1645 51 (CH2)3COOH 41 a 41 146-148192-194 17051U
b 7 ' 52 CO(CH2)3COOH 44a 44~' 109 167 172 715, 0 .

53 (CH2)4COOH 47a 47~ 111-1121705 129-1301715 54 CO(CH2)4COOCHg ~ ~ 92 1735, 1740, 55 (CH2)SCOOH ~ ~b 123 1710 122 1710 v.

~0 1~

ai 'I'ablc 9 2p~.~ ~ fly.
10 ~- - I - -_ _ EXnMPLE R'= MELTING FT. lf~ (C-=O) I
Nr. R H CH.t a b a b 56 CH(CH3)COOC2H5 55a 55b X33 136 1730 1740 57 CH(CH3)COOH ~ 57a I 57b i 190 1705 ~ 226 1710 is 5-( 1-(DIPf-IENYL-2,3-DI I-IYDRO-1 ~I-PYRROLIZINE-7-YL)-ETI-IYL)-2,2-DIMETI-IYLr 1,3-DIOXAN-4,6-DIONE (59a) The solution of 4 mmoles (1.04 g) of 3a, 4 mmoles (0.58 g) of 2,2-dimethyl-zo 1,3-dioxan-4,6-dione (Meldrum's acid) and 8 mmoles (0.35 g) of freshly distilled acetaldehyde in 40 ml of acetonitrile is made to stand for 24 h at 30 °
C. Following cooling in the ice bath, the precipitated product is evacuated.
Yield: 0.44 g (2G %) melting point: 169 ° C (with dissociation) zs IR: v ",~x = 1790 (C=O), 1605 (C=C)~cm S-(1-(2,2-DIMETIIYL-5,6-DIPIIINYI; 2,3-DIE-IYDRO-lI-I-PYRROLIZINE-7-YL)-ETIIYL)-2,2-DIME~I'IfYL-1,3-DIOXAN-4,6-D~fONE (59b) 4 mmoles ( 1. IS g) of 3b are reacted in the manner described in relation to s 59a with acetaldehyde and Meldrum's acid.
Yield: 1.35 g (74 °lo) Ir: v max = 1700 (C =O), 1755 (C=O), 1605(C=C)/cm 3-(5,6-DIPHENYL-2,3-DII-IYDRO-lI-I-PYRROLIZINE-7-YL) BUTYRIC-ACID
,o E'1'I-IYLESTERS (GOa) 1 mmole of 59a is dissolved in a mixture of S ml of absolute pyridine and 1.0 ml of absolute ethanol. After adding some copper powder, the batch is heated to reflex for 3 h. The copper power is evacuated and the solvent is distilled in vacuum. The product is isolated from the residue by column chromatography (silica gel, n-hexane/
,s CI-IZC1Z 1 + 2).
Yield: 96.5 mg (25 °lo); IR: v,nax- 1735 (C=O), 1605 (C=C)/cm.

3-(2,2-DIMETHYL-S,6-DIPI-IENYL-2,3-DIHYDRO-1I-I-PYRROLIZINE-7-YL)-BUTYRIC-ACID ETI-IYLESTER (GOb) 20 2.5 mmoles of 59b are dissolved in a mixture of 20 ml absolute pyridine and 2 ml of absolute ethanol and upon addition of some copper powder the batch is reacted as described for 60a. Purification is by column chromatography (silica gel, n-hexane/-CHzCIZ 2+ 1) in isolation. , Yield: 0.68 g (68 %) IR: vmax = 1745 (C=O), 1605 (C=C)/Cm 2s EXAMPLE 62 -3-(5,6-DIPI-iENYL-2,3-DII-IYDRO-lI-I-PYRROLIZINE-7-YL)-BUTYRIC ACID (61a) The eluates are concentrated. The product is made to crystallize using a little ether and then is made to precipitate extensively by aclding n-hexane.
so Yield: 63 mg (36 %); melting point: 157 ° C (with dissociation) IR v max = 3300 - 2400 (OI-I), 1710 (C=O), 1605 (C=C)/cm 3-(2,2-DIMETi-lYL-5,G-DIP1-iENYL-2,3-DIi-IYDRO-1 i-I-PYRROLiZINE-7-YL) 13U'I'1'RIC-ACID (61b) The product precipitates when the eluates are concentrated.
s Yield: 0.26 g (46 %); melting point: 202 - 208 ° C (with dissociation) GENERAL PROCEDURE POR PREPARING TIE TItIMETI-IYLPiIENYL-2,3-DIHYDRO-1-i-I-PYRROLIZINES
0.05 moles (5.6 g) of 2,4,4-trimethyl-0lpyrroline, dissolved in 25 ml of absolute ethanol, are reacted with 0.05 moles (10.7 g) of 1-bromo-1-phenylacetone (in G3) io or a-bromo-propiophenone (in G4) in a manner analogous to the synthesis of 3a. In deviation from that reference, here, following addition of the NaI-IC03 solution (0.06 motes in 40 ml of i-Iz0) are heated only 4 h to reflex. Purification is carried out by means of column chromatography (A1203, n-hexane/ether 9+ 1). Oil remains following concentration of the eluate.
is . GENERAL PROCEDURE FOR PREPARING TI-IE TRIMETI-IYLPHENYL-2,3-Dii-IYDRO-1I-I-PYRROLIZINYL-ACETIC-ACID ETi-IYLESTERS
mmoles (1.13 g) of G3 or of 64, dissolved in S ml of absolute toluene, are reacted with 7.5 mmoles (0.86 g) of diazo-acetic-acid ethylester dissolved in 4 ml of absolute toluene similarly Lo the procedure for preparing the Biphenyl-1,2,3-dihydro-1I-I-2o pyrrolizinyl acetic-acid ethylesters. The products are obtained as oils following column chromatography (A1203, 1st n-hexane/ether 9+ I, 2nd n-hexane/ether 3+2).
SAPONIFICATION OF THE TRIMETI-IYLPI-IENYL-2,3-DII-IYDRO-1I-I-PYRROZINYL-ACETIC-ACID ETI-IYLESTERS
1.5 mmoles of 65 or 0.5 mmoles of GG, dissolved in 4m1 or 12 ml resp. of is ethanol are reacted with 2.5 ml or 7.5 mi resp. of 10 % aqueous KOi-I
similarly io the procedure for saponifying the Biphenyl-2,3-dihydro-lI-I-pyrrolinyl-acetic-acid ethylesters.
Purification is by column chromatography.
The compounds and several of their properties are listed in the Tables 10 and 11 below.

'('able 10.
H
Ha H

R MELTING P'r. IR
64 ti 63 -- 1605 66 CH2CO0rt 67 168 1715 Table 11 R

CHI
as 1) R MELTING ~ I R
PT.

67 H 64 58-6U 1595 (C=C) 68 CHZCOOCZFiS 66 1740 as 1) (C=0~ band, unless stated otherwise 5-(n-IIL:XYL)-7-I'I-IENYL-2,3-DII-IYDRO-lI-I-PYRIZOLIZ(NE (G9) In order to dissolve 35 mmoles of n-octanal in 15 ml of ether and S ml of dioxan, a solution of 35 mmoles (5.6 g) of bromine in 5 ml of CI-1ZC12 is slawly added s while stirring. This batch then is mixed with 50 rnl ether and to neutralize I-IBr, the mixture is washed carefully twice with a 5 % NaI-IC03 solution. The organic phase is dried by means of NazSO,, and concentrated. The residue is dissolved in SO ml ethanol and added to a mixture of 35 mmoles of 2 benzyl-Q 1-pyrroline~, SO ml of ethanol and 50 ml of 10 % NaLICO~ solution. After stirring for 24 at room temperature, the batch is ,o poured into 500 ml of 10 % NaCI and extraction is carried out twice with ether. The organic phases are dried by means NazSO~, the solvent is distilled and the pyrrolizines so obtained, 69 and 70, are isolated by column chromatography (A.IzO~, n-hexane/ether 9+1).
The two isomeric pyrroiizines then are dissolved in SO ml of dichloroethane ,s and are mixed a total of four times, 15 minutes apart, each time with 17 mmoles of acrylic-acid methylester and 1.0 ml of BF3 etherate. Following addition of 200 ml of 5 NaCI solution, the batch is extracted twice with ether. Following drying by means of Na2S04, the solvent is distilled and the unconverted G9 is isolated by means of column chromatography (A1203, n-hexane/ether 9+ 1). The eluates are concentrated. The 2o remaining oil solidifies after some time.
Yield: 1.23 g (16 %); Melting point: 46-47 ° C
C»H~N (224.1) IR: vn,ax= 1610 (C=C)/cm tH-NMR: 8 (ppm) ~ 0.73-1.06 (m, 3H, -CFA), l.Ofri.76 (m, 8H, -CHz-), 2.33-2.72 (m, 4H, C-2 and Pyr-CHr), 3.04 (t, 2H, J=7 Hz, C-1), 3.83 (t, 2H, J=7 Hz, C-3), 6.20 (s, 1H, C-5), 6.~5-7.56 (m, 5H, Aran.) 5-(S-(n-I-II~XYL)-7-PI-IENYL-2,3-DIHIYDRO-11-I-PYRROLIZINE-6YL)-5-OXOVALERIC ACID (71) s 5 mmoles of 5-(n-hexyl)-7-phenyl-2,3-dihydro-11-I-pyrrolizine G9 are reacted in 20 ml of ChIZCI2 with 5 mmoles (0.5 g) of glutaric acid anhydride and 11 mmoles (1.47 g) of A1CL~ similarly to the procedure far preparing the 5-(Biphenyl-2,3-Bihydro-lI-I-pyrrolizinyl)-5-oxovaleric-acids. The product is purified by column chromatography (silica gel, 1st n-hexane/ether 1+ 1, 2nd ether). After the eluates are concentrated, 71 remains 1o as an oil.
Yield 0.40 g (21 %) C2aH3tN03 (381.5) tH-NMR: a (ppm) = 0.69-1.07 (m. 3H, -CH3), 1.07-1.98 (m, 10H, -CHr), 1.98-2.65 (m, 6H, C-2 and -CO-~1- -CHz-~-CO-), 2.65-2.95 (m, 4H, G1 t.uid Pyr-CH2-), 3.91 (t, 2H, J=7 Ha, C-3), 7.07-7.47 (m, 5H, Arom. ) 5-(5-(n-HEXYL)-7-PHENYL-2,3-DII-IYDRO-1I-I-PYRROLIZINE-6YL)-VALERIC
ACID (72) 1 mmole of 71 is reacted in 10 ml of Biethyleneglycol with 50 mmoles (2.8 2o g) of KOI-I and 30 mmoles (1.5 g) of hydrazine hydrate similarly to the procedure for reducing the 4-(Biphenyl-2,3-Bihydro-lII-pyrrolizinyl)-4-oxobutyric acids.
Product purification is by means of column chromatography (silica gel /
Biisopropylether). After concentrating the eluates, 72 remains as an oil.
Yield 0.20 g {54 %) C2aH33N02 (367.5) IR: vrt,~ = 3600-2400 (OH), 1710 (C~). 1605 (C~) cm-t tH-NMR: b (pprn) a 0.72-1.12 (m, 3H, -Cl-~), 1.12-1.78 (m, 12H, -CHr), 2.08-2.70 (m, 8H, C-2, -CHz-CO- tmd 2x pyr..CH2-), 2.90 (t, 2H. J=7 Ha, 61 ),3.87 (t, 2H, J=7 Hz, C-3), 6.95-7.44 (m, 5H, Arum. ) CXAMI'I_ES 73, 74 5-(n-I1~;XYL.)-7-I'IIENYL-2,3-DII-IYDRO-ILI-PYRROLIZINE-6-YL-CARBAL-DGI iYDE (73) AND b-(n-I-IEXYL)-7-P~ICNYL-2,3-DII-IYDRO-11-i-PYRROLIZ1NE-5-YL-CARBALDRI-IYDE (74) s 35 mmoles of octanal, bromine and 2-benzyl-D 1-pyrroline arc reacted each time similarly to the preparation for 69 and 70. The isolated pyrrolizines then are absorbed in 35 ml of absolute benzene and reacted with 105 mmolcs (7.7 g) of absolute DMF and 35 mrnoles (5.4 g) of POCK similarly to the procedure of the Vilsmeier formylation of the Biphenyl-2,3-dihydro-lI-I-pyrrolizines. The two products are separated ,o by column chromatography with silica gel, first elution taking place with n-hexane/diiso-propylether 73 and then with diisopropylether 74. Both products will be in the form of oils after the eluates have been concentrated.
Proof of structure for 73: the same product is obtained in the Vilsmeier formylation of 69.
15 73 Yield 1.74 g C2oH2sN~ (295.4.
IR: vr"~ a 1660 (C~7), 1610 (C~) c;m-~
~H-NMR: b (ppm) = 0.73-1.07 {m, 3H, -Ct-~), 1.07-1.86 (m, 8H, -CHr), 2.30-2.70 (m, 2H, C-2), 2.74-3.05 (m, 4H, C-1 a~a Pyr-CHZ-), 3.91 (t, 2H, J=7 Hz, C-3), 7.05-7.46 (m, 5H, Aran.), 9.87 {s, 1H, -CHO) 20 74 Yield 2.13 g C2ort25N0 (295.4) IR: v~ = 1655 {C~), 1610 (C~) cm-t ~H-NMR: 8 (ppm) = 0.68-1.01 (m, 3H, -CH3), 1.01-1.74 (m, 8H, -CHr), 2.30-2.67 (m, 2H, C-2), 2.67-3.00 (m, 4H, C-1 ~d Pyr-CHr), 4.32 (t, 2H, J=7 Hz, C-3), 7.19-7.4& (m, 5H, Aran.), 9.67 (s, 1H, -CHO) CXAMPLI'75 3-(fi(n-I iEXYL)-7-1'f-IENYI: 2,3-DII-IYDRO-lI-I-PYRROLIZINE-5-YL)-ACRYLIC-ACID EThIYLES'hCRs (75) mrnoles ( I.48 g) of 74 are reacted similarly to the procedure for preparing s the Biphenyl-2,3-dihydro-I HI-pyrrolizinyl-acrylic-acid ethylesters.
Purification is by column chromatograpi~y (silica gel, petroleum ether SO-70/acetic-ester 7+'l).
Following concentration of the eluate, the product is obtained as an oil Yield 0.45 g (25 °lo) C2aN3tN02 (365.5) IR: vr"~ x 1705 (C~), 1610 (C~) Cm-t tH-NMR: 8 Cpprn) = 0.62-1.02 (m, 3H, -CH3), 1.02-1.76 (m, 11 H, -CH2- and -O-CH~t- ), 2.23-3.01 (m, 6H, C-2, Pyr-CH2- ~a C-1), 3.93-4.39 (m, 4H, G3 and -0-CHr), 5.89 (AB, 1 H, J=16.1 Hz. =CH-CO-), 7.04-7.48 (m, 5H, Arum.), 7.68 (AB, 1H, J=16.1 Hz, Pyr-CH=) is EXAMPLE 76 3-(6-(n-HEXYL)-7-PI-IENYL-2,3-DIHYDRO-1I-I-PYRROLIZINE-5-YL)-ACRYLIC
ACID (75) 1.0 mmole (0.37 g) of 75 is reacted similarly to the procedure for saponifying the Biphenyl-2,3-dihydro-lI-I-pyrrolizine-acrylic-acid ethylesters.
2o Yield 0.20 g (59 %) melting point 140 ° C (with dissociation) C22H27N02 (337.5) iR: vr"~ = 3300-2200 (OH), 1670 (C~), 1595 (C~) cart tH-NMR (c!u-DM50): 5 (ppm) = 0.58-0.96 (m, 3H, -CH3), 0.96-1.60 (m, SH, -CHz-), 2.18-2.73 (m, 4H, C-2 ana Pyr-CHr), 2.86 (t, 2H, J=7 Hz, C-1), 4.15 (t, 2H, J=7 Hz, C-3), 5.85 (AB, 1H, J=15.8 Hz, ~H-CO-), 7.02-7.53 (m, 5H, Arum.), 7.50 (AB, 1H, J=15.8 Hz, Pyr-CH=) 6-CYCLOI-II;XYL-7-I'1IENYL-2,3-DIIIYDRO-11I-PYRROLIZINE (77) SO mmoles of I3rz, dissolved in 10 ml of CCI,,, are slowly dripped into the solution of 50 mrnolcs (G.3 g) of cyclohexylmethylketone in 40 ml of CCI4 with stirring and s shielding from light. Tl2is batch is then mixed with 50 ml of CI-lzClz and carefully washed twice with a S % NaI-ICO~ solution to neutralize the hIbr. The organic phase is dried by means of NazSOa and concentrated. The residue is dissolved in 30 ml of ethanol and reacted with the solution of 50 mrnoles of 2-benzyl-~ 1-pyrroline in 20 ml of ethanol.The batch is stirred for 24 h at room temperature. After adding 25 ml of a saturated NaI-IC03 io solution, stirring proceeds for another 24 h. Then 500 ml of 10 % NaCi are added and extraction with ether is carried out twice. The organic phases are dried (Na2S04). The solvent is distilled and the product is isolated by column chromatography (A1203, n-hexane/ether 9+1). The oil (3.0 g) remaining after the eluate was concentrated is impure. It is further reacted without any purification.
,s EXAMPLE 78 6-CYCLOI-IEXYL-7-PI-IENYL-2,3-DII-IYDRO-1H-PYRROLIZINE-SYL-CARBAL-DEI-IYDE (78) 3.0 g of impure 77 are dissolved in S ml of absolute benzene and reacted zo with 12 mmoles of absolute DMF (0.88 g) and 4 mmoles (0.61 g) of POC13 similarly to the procedure for the Vilsmeier formylation of the Biphenyl-2,3-dihydro-lI-I-pyrrolizines.
Purification is by column chromatography (silica gel, ether/n-hexane 3+ 1).
Then the product is precipitated with ethanol Yield O.C6 g (4.S % referred to the cyclohexylmethyl ketone) 2s Melting point 135 ° C
C2pHg3NO2 (293.4) IR: vr,,,e"~ = 1645 (C~), 1610 (C~C) cm-j ~H-NMR: g (ppm) = 1.01-2.13 (m, 10H, -CH~-of the cyclohexyl ring), 2.24-3.03 (m, 5H, C-1, C-2 and Pyr-CH<), 4.35 (t, 2H, J=7 Hz. C-3), 7.07-7.51 (m, 5H, Arcxn.), 9.93 (s, 1H, CHO) EXAM I'L.L: 79 3-(G-CYCLOI-iEXYL-7-PI-iENYL-2,3-DII-iYDRO-lI-I-PYRROLIZINE-5-YL)-ACRYLIC-ACID ETI-IYLES'I'I?RS (79) s 2 mmoles of 78, dissolved in 4 ml of absolute CI-IZC12, are reacted with a solution of 2 mmolcs (0.86 g) of ethoxycarbonyl triphenyl phosphoniurn bromide in 3.5 ml of absolute ethanol and with a solution of Na-ethanolate prepared from b mmoles (0.14 g) of sodium and 3 ml of absolute ethanol in a manner similar to the procedure for preparing the Biphenyl-2,3-dihydro-lI-I-pyrrolizinyl acrylic-acid ethylesters.
The ~o purification takes place by column chromatography (silica gel, petroleum ether 50-70/acetic-ester 7+2). The oil remaining after concentration solidifies after some time.
Yield: 80 mg (I1 %); melting point: 190 ° C
C2~H~N02 (363.5) IR: v~ ~ 1715 (0),1605 (C~) crn-I
~H-NMR: 8 (ppm) ~ 0.99-1.99 (m, 10H, -CHr of the cyclohpxyl ring), . 1.31 (t, ,s 3ti, J= 7 Hz, -O-CHI), 2.27-2.93 (m, 5H, C-1, C-2 and Pyr-CH<), 4.17 (t, 2H, J=7 Hz, C-3), 4.23 (q, 2H, J=7 Hz, -O-~CHr), 5.85 (AB, 1H, J=16.2 Hz, ~H-CG), 7.04-7.48 (m, 5H, Arom.), 7.91 (AB, 1 H, J=16.2 Hz, Pyr-CH=) 3-(6-CYCLOI-IEXYIr7-PHENYL-2,3-DII-IYDRO-lI-I-PYRROLIZINE -S-YL)-ACRYLIC
2o ACID (80) 0.22 mmoles (80 mg) of 79 dissolved in S ml of ethanol are reacted with 3 ml of 10 % adueous KOH similarly to the procedure for saponifying the Biphenyl-2,3-dihydro-lI-I-pyrrolizine acrylic-acid ethylesters (see p 219).
Yield 37 mg (SO %) 2s melting point 201 ° C (with dissociation) C22H25N02 (335.4) IR: vm~ = 3200-2400 (OH), 1660 (C~), 15$5 (C~) crtrt ~H-NMR: 5 (ppm) = 0.98-2.05 (m, tOH, -CH2- of the cycloheuyl rmp, 2.29-2.98 (m, 5H, G1, C-2 ur~d Pyr--CHo), 4.21 (t, 2H, J=7 Hz, C-3), 5.87 (AB, 1H, J=16.0 Hz, ~H-CO-), 7.02-7.55 (m, 5H, Arorn.), 8.01 (AB, 1H, J=16.0 Hz, Pyr-CH=) 6'S n'~7 r A, . / ~ .4, ~' .,) ~ . s 41 GENERAL PROCEDURE FOR 'I'I-IE N-ALKYLATION OF 2-METHYL-3,4-DIPI-iENYLPYRROLE
2 I11I11(lleS (0.47 g) of 2-methyl-3,4-Biphenyl-pyrro(e (AUS'r.,d. CI-IEM.
1966, 19, pp 1871-1885) (and] 2.2 mmoles of p-toluene sulfonic-acid rnethylester (in 81b) or s alkylbromide (for the remaining compounds) and 1 mmole (0.32) g) of tetrabutyl-ammonium bromide are mixed with 10 ml ether and 5 m1 of 50 °lo aqueous NaOI-I.
While agitating strongly, the mixture is heated for 8 h to slow boiling.
Thereupon the batch is poured into 100 ml of I-IZO acrd extracted twice with ether. The ether phases are washed with 1 °lo II~i'O,, and I-1Z0, dried by means of Na2S04 and concentrated. The 1o product isolation takes place by column chromatography (A1203, n-hexane/ether 9+ 1).
The compounds so obtained and their physical properties are listed in Table 12 below.

1-NEOPENTYL-2-METHYL-3,4-DII'I-IENYLPYRROLE (81i) The above compound cannot be synthesized. I-lowever it may be prepared as follows:
2 mmoies (0.46 g) of 2-methyl-3,4-Biphenyl-pyrrole, 2.6 mmoles of potassium-t-butylate and 3 mmoles (0.45 g) of neopentyl bromide in 6 ml of absolute zo DMSO are heated for 45 minutes to 130 - 140 ° C. Following cooling, 100 ml Hz0 are added, acidification with dilute I-I3P04 and next double extraction with ether are carried out. The ether phases are washed with I-h0, dried by means NazSO4, and concentrated.
The product is isolated from the residue by column chromatagraphy (A12O3, n-hexane/ether 9+ 1) and precipitated with ethanol (similarly to the case for 81h).
zs YielB: 0.31 g (51 °~o); melting point: 132 ° C.
Cz2H~N (303.4) COMPUTED C 87.1 I-I 8.30 N 4.6 MEASURED C 86.9 H 8.21 N 4.5 IR: vr"~= 1605 (C~) cart MS: m/z (rel.lnt.) = 303 (89°/°, M+~), 288 (9%, M+-CH3, °
273.74), 247 (58°I°, M+-C4H8, ' 201.34), 246 (100%, 247-H) tH-NMR: b (ppm) = 1.02 (s, 9H, -CH3), 2.19 (s, 3H, Pyr-CHI), 3.66 (s, 2H, >N-CHz-), 6.75 (s, iH, C-5), 7.06-7.33 (m, 10H, Arom.) ~0~.~~0~.
Table 12;

R
EXAMPLE R ; I R ( C=C
MELTING ) POINT

IJr. C

811 CH3 81b 82 C2H5 81c I 1600 83 n-C3H7 81d 80 1605 I
i 84 n-C4H9 81e~ 1610 ~

852 n-C5t111 81f ) 1 862 n-C6H13 81g 87 iso-C4H9 8lta; 1605 1) Tetrahedron Lett. 1969, 55, 4875-4878 Chem. Pharm. Bull. 1974, 22, 61-69 2) mixture with alkyl bromide; it is reacted withwt further purification GENERAL I'ItOCEDURE FOIZ PREPARING 'I'I-IE 3-(5-ME'rI-iYL-3,~-DIPI-IENYL-I'YRROLE-2-YL)-PROPIONIC-ACID METI-IYLES'1'ERS
1 mmole of 2-methyl-3,4-diphenylpyrrole or of 1-alkyl-2-methyl-3,4 diphenylpyrrole 82b-i and 1.5 mmoles (0.13 g) of acrylic-acid methylester are dissolved s in 4 ml of dichlorocthane. Following addition of O.OG mi of BF3 ethylether complex, the batch is stirred for 1 h at room temperature and after 15 minutes in each case again the same amounts of acrylic-acid methylcster and BF3 ethylester complex are added.
Then the batch is mixed with 50 ml of I-IZO and extraction with ether is performed twice. The ether phases are washed with I-IzO, dried by means of NazS04 and concentrated.
The ~o product is isolated from the residue by column chromatography (A1203, n-hexane/ether 1+4 (82a) or 1+1 (82b,c) or 3+2 (remaining compounds)). After the eluate has been concentrated, an oil remains.
The compounds so obtained and several of their physical properties are listed in Table 13 below.
is GENERAL PROCEDURE FOR THE SAPONIFICATION OF TI-IE 3-(5-METHYLr3,4-DIPI-IENYLPYRROLE-2-YL)-PROPIONIC-ACID METIIYLESTERS
The solution of 0.4 mmoles of 3-(2-methyl-3,4-diphenylpyrrole-5-yl)-propionic-acid methylester 82a or 3-(1-alkyl-2-methyl-3,4-diphenylpyrrole-5-yl)-propionic-2o acid methylester 82b-i in 3 ml of ethanol is heated to boiling. 2 m1 of 10 % aqueous KOH previously degassed by boiling are dripped into the batch which then is heated with reflux for another 5 minutes. Following cooling, the batch is poured into 100 ml of 5 %
NaCI solution and is washed twice with 50 ml of ether. The aqueous phase is acidified with dilute I-I3P04 and extracted twice with 50 ml of ether. The ether phases are washed is with 100 ml of I-Iz0 and dried by means of NazS04. The solvent is distilled, and where called for the product is precipitated with hexane.
'the compounds so obtained and several of their physical properties are shown in Table 14.

Table 13 I
R
cnnMYLE R

Nr.
IR(C=0) 89 H 82a CH3 82b 1790 C2H5 82c 1740 n-C3H 82d n-C4H9 82e 1745 , n-C5H11 82f 1740 95 n-C6H13 82g 1740 ~

96 i.so-C4 82h 1740 H9 j Neopentyl 82i. 1740 I

Table 14 COOH
i R
-.-ExnMPLE R

Nr.
MELTIMG POINT

IR (C=O
C

98 H . .

n-C H

n-C H

>4~CctiSS~c lU4 n-C H ..,l 1715 5 11 _ 105 n-C H 1715 6 13 _ 106 iso-C
H

Neopentyl ~Q1~~ ~~-GENERAL PROCEDURE FOR Tf-1E N-ALKYLATION OF 5-METHYL-2,3-DIPI-IENYLPYRROLE
S mmoles ( 1.17 g) of 5-methyl-2,3-diphenylpyrrole (AUST. J. CI-1EM. 1966, s 19, pp 1871-1885), S.S mmoles of toluene sulfonic-acid methylester or of alkyl bromide and 1 mmole (032 g) of tetrabutyl ammonium bromide are mixed with 10 ml ether and S ml of 10 % aqueous NaOI-I. The reaction henceforth is carried out in the manner of the procedure for the N-alkylation of 2-methyl-3,4-diphenylpyrrole.
The compounds so obtained and some of their physical properties are ~o shown in Table 15.
GENERAL PROCEDURE FOR PREPARING 'r1-IE (5-METI-IYL-4,5-DIPI-IENYL-PYRROLE-3-YL)-ACETIC-ACID ETF-IYLESTERS.
2.5 mmoles of methyl-2,3-diphenylpyrrole (AUST. J. CI-IEM. 1966, 19, pp 1871-1885) or of 1-alkyl-5-methyl-2,3-diphenylpyrrole 84b-j, dissolved in 2 ml of absolute 15 toluene, are reacted similarly to the procedure for preparing the Biphenyl-2,3-dihydro-1H-pyrrolizine-acetic-acid ethylesters. Following column chromatography (silica gel, n-hexane/ether 1 + 1 in Example 117 or AIZO3, n-hexane-ether 9+ 1 in the remaining compounds), the products are obtained in the form of oils The compounds so obtained and the infra-red Bata relating to them are zo shown in Table 16.

Table IS
H
R MELTING P'r.1R(C=C) EXAMPLC C
~o Nr.

108 CH3 84b 149 1605 109 84c 68-69 1605 110 n-C3H~ 84d - 1605 H 84e _ 1605 n-C

84f 1605 112 n-C5H11 1s 84g 1605 113 n-C6H13 114 1) 84h n-C8H17 115 iso-C4H9 84i 107 1600 116 Neopentyl 84J 89 1605 20 1) mixture with n-CBH~~Br, reacted without further purification ~fl.~ ~~~.~
T:~ble IG
H~C20 EXAMPLE R ~ I R ( C=O
Nr.

117 H 85a 1730 118 CH3 85b ~ 1740 119 C2H5 85c 1735 120 n-C3H7 B5d 1740 121 n-C4H9 85e 1735 122 n-C5H11 85f 1740 123 n-C6H13 85g 1740 124 n-C8H17 85h 1740 125 iso-C4H9 85i 1735 126 Neopentyl 85j 1735 GENERAL PROCEDURE FOR SAPONIFYING THE (2-METHYL-4,5-DIPHENYL-PYRROLE-3-YL)-ACETIC-ACID ETHYLESTERS
The solution of 0.6 mmoles of (2-methyl-4,S-diphenylpyrrole-3-yl)-acetic-acid ethylester or of (1-alkyl-2-methyl-4,5-diphenylpyrrole-3-yl)-acetic-acid ethylester in zo 5 ml of ethanol is heated to boiling. Then 3 ml of 10 % aqueous KOI-I
previously degassed by boiling are dripped into the batch which is further heated for 1 h with reflux.
Following cooling the batch is poured into 100 ml of S °Jo NaCI
solution and the mixture is then acidified with 8 % I-I3P04 and extracted three times with ether. The organic phases are dried by means of NaZS04 and concentrated. Product purification takes place zs by column chromatography (silica gel, 1st n-hexane/ether 1+1 in the Examples 127-131, fl16~~~
or 2-H 1 in Examples 132-136, 2nd ether). The eluates are concentrated down to a few ml. After adding n-hexane and concentrating again, the product precipitates.
The compounds so obtained and their physical data are shown in Table 17.
Table 17 HOC
EXAMPLE R MELTING POINT IR(C=O) Nr. C

127 H 86a 110 1710 128 CH3 86b 161 1710 129 C2H5 86c 177 1705 130 n-C3H7 86d 172 1700 131 n-C4H9 86e 129 1705 132 n-C5H11 86f 121 1710 133 n-C6H13 86g 127 1710 134 n-C8H17 86h 45 1715 135 iso-C4H9 86i 168 1710 136 Neopentyl 867 163 1710 ~fli~~~Q~
GENERAL PROCEDURE FOR PREI'ArIING 1'I-IE 6-ARYL-7-PI-IENYL-2,3-DII-IYDRO-IN-PYRROLIZINES OR TI-IE 6-PI-IENYL-7-ARYL-2,3-DIHYDRO-1H-PYRROLIZINES
20 mmoles of aromatics-substituted' or unsubstituted a-bromo-acetophe-s none dissolved in 25 ml of CI-IzClz are mixed with the solution of 20 mmoles of unsubstituted or aromatics-substituted" resp. 2-benzyl-b, l-pyrroline in 50 mI
of ethanol and are stirred for 24 h aL room temperature. lfien 20 ml of saturated aqueous NaI-IC03 solution are added and the batch is stirred for another 24 h at roam temperature. The batch is poured into 500 ml of 5 % NaCI solution and is extracted three times each time io with 100 ml of ether/CI-IzClz 3+ 1. 'Ifie organic phases are dried by means of NaZS04 and processed in the manner discussed below.
* a-bromo-3-chloroacetophenone, a-bromo-3,4-dimethoxyacetophenone, a-bromo-3,4-d9chloroaceto ~s phenone and a-bromo-4-phenoxyacetophenone are not available commercially.
They are prepared as follows:
A solution of 20 mmoles (3.2 g) of bromine In 10 ml of CI-hCta is slowly dripped into the solution of 20 mmoles of 3-chloroacetophenone, 3,4-dimethoxyacetophenone, 3,4-dichloroacetophenone or 4-phenoxyacetophenone in 15 ml of CHtCt~ and 20 ml of dioxan. Thereupon the batch is mixed with 20 50 ml of CI-tlCtZ and carefully washed twice with 5 °,6 NaHCO, solution to remove the Hbr. The organic phase is dried by means of NaZ SO, and concentrated. The residue is reacted directly as described above with 20 mmoles of 2-berrzyl-D 1-pyrroline.
** 2(4-chlorobenzyl}-A1-pyrrollne The preparation Is similar to that for 2-benzyl-D 1-pyrroline (J. AMER. CHEM.
SOC. 1932, 2s 54, pp 3971-3976) ** 2-(4-methylb~nzyl}-d1-pyrrollne A Grignard reagent is prepared from O.i5 moles (3.6 g) of Mg and 0.15 moles (21.1 g) of methylbenzyl chloride in 150 ml of absolute ether. After dripping 0.15 moles (15.5 g) of 4-chlorobutyronitrile dissolved in 100 ml absolute ether into the batch, same is heated for 2 h to reBux. Next so the ether is distilled and 200 ml of absolute xylene are added. After further boiling with reflux for 2 h, the batch is mixed with 100 ml of H~ 0 while being ice-cooled and is acidified with dilute H, PO,. The aqueous phase is made alkaline with concentrated NH, and ice-cooling and the generated precipitate is evacuated.
The filtrate is extracted three times with 50 ml of Cf-~Ct~ and the precipitate is washed with 100 ml of ~~~~~~i~ ~ 51 CFi~ Ct~. The CFis Cll solutions are combined, dried by means of Na; SO, and concentrated. The product Is Isolated from the last residue by distillation (boiling point 117 °
C at 0.1 torr).
Yield 3.7 g (14 96) C,iH,sN (173.3) Ir: vmax = 1640 (C=N), 1605 (C=C)/cm ** 2-(4-melhoxybenzyl~-G1-pyrrollne 4-methoxybenzyl magnesium chloride Is prepared from 3.0 moles (72.9 g) of Mg and 0.15 moles (23.5 g) of 4-methoxybenzylchlorlde fn 500 ml of absolute ether. The product is reacted further with 0.'15 moles (15.5 g) of 4-chlorobutyronitrile and is purified by distillation (boiling point 142 C at 0.1 1o torr).
Yield 2.4 g (8 °~6) C,aFi,sNO (189.3) Ir: v,°d" = 164~ (C=N), 1610 (C=C)/Cm GENERAL PROCEDURE FOR PREPARING 3-(6-CHLOROPHENYL- AND 6-NITROPHENYL-7-PHENYL,~2,3-DIl-IYDRO-1H-PYRROLIZINE-S-YL)-PROPIONIC-ACID METHYLESTERS
4 mmoles of 6 chloro- or 6-nitrophenyl-7-phenyl-2,3-dihydro-1H-pyrrolizine 2o and 6 mmoles (O.S2 g) of acrylic-acid methylester are dissolved in 16 ml of absolute dichloroethane. After adding 0.24 ml of BF3 ethylene complex, the batch is stirred for 1 h at room temperature, and the same amounts of acrylic-acid methylester and ethylether complex are added in each case again after 15 minutes. Thereupon the batch is poured into 100 mi of 10 % NaCI solution and is extracted twice with ether/CHzCI2 is 3+1. The organic phases are dried by means of Na2S04 and concentrated. The residue then is processed in the manner discussed below.
GENERAL PROCEDURE FOR SAPONIFYING THE 3-(6-CHLOROPI-IENYL-AND 6-NITROPHENYL-7-PHENYL-2,3-DII-iYDRO-1H-PYRROLIZINE-6-YL)-PROPIONIC-ACID METHYLESTERS
ao The solution of 1 mmole of the corresponding pyrrolizinyl-propionic-acid methylester in 10 ml of ethanol is heated to boiling. S ml of 10 % aqueous KOI-I solution previous degassed is dripped into the batch which is then heated another 5 minutes with 5z reflux. Following cooling the batch is poured unto 100 ml of 5 % NaCI solution and acidified with 8 % I-I~P04 and extracted three times with ether/CI-IZC12 3+1.
The organic phases are dried by means of Na2S04, concentrated, and processed in the manner described above.
s GENERAL PROCEDURE FOR THE VILSMEIER FORMYLATION OF
AROMATICS-SUBSTITUTED G,7-D1PHENYL-2,3-DIHYDRO-1H-PYRROLIZINES
6 mmoles of the corresponding pyrrolizine dissolved in 6 ml of absolute benzene are reacted with 18 mmoles (1.32 g) of absolute DMF and 6 mmoles (0.92 g) of POCl3 similarly to the procedure far the Vilsmeier formylatian of the Biphenyl-2,3-,o dihydro-lI-I-pyrrolizines.
GENERAL PROCEDURE FOR PREPARING AROMATICS-SUBSTITUTED 6,7-DIPHENYL-2,3-DII-IYDRO-lI-i-PYROLLIZINYL-ACRYLIC-ACID ETHYLESTERS
2.5 mmoles of the corresponding carbaldehyde dissolved in 5 rnl of absolute CI-i2C12 are reacted with the solution of 2.5 mmoles (1.08 g) of ethoxycarbonyl-,a methyltriphenyl-phosphonium bromide in 4 ml of absolute ethanol and with a solution of Na-ethanolate prepared from 7.5 mmoles (0.I7 g) of sodium and 3 ml of absolute ethanol in a manner similar to the procedure for preparing the Biphenyl-2,3-dihydro-lI-I-pyrrolizinyl-acrylic-acid ethylesters.
GENERAL PROCEDURE FOR SAPONIFYING AROMATICS-SUBSTITUTED 3-(6 zo 7-DIPHENYL-2,3-DII-IYDRO-1H-PYRROLIZINE-5-YL)-ACRYLIC-ACID ETHYL
ESTERS.
1.2 mmoles of the corresponding pyrrolizinyl-acrylic-acid ethylesters dissolved in 50 ml of ethanol are reacted with 10 ml of aqueous KOH similarly to the procedure for saponifying the 3-(Biphenyl-2,3-dihydra-lI-I-pyrrolizine-5-yl)-acrylic-acid zs ethylesters.

GGNf~RAL. I'ROC1-~DURC FOR HYDROGENATING AROMATICS-SUBSTITUTED
3-(6,7-DII'f IENYfd 2,3-DII~IYDRO-Ifd-PYRROLIZINE-5-YL) ACRYLIC ACIDS
0.9 mmoles of the corresponding pyrrolizinyl acrylic acid are dissolved in 30 ml of absolute TI-IF. After adding 10 ml of absolute ethanol and a spatula tip-ful of s PtOz (alternatively, palladium also may be used), hydrogenation is carried out in the autoclave for about 4 h at 15 bars. Several times a spatula tip-ful of fresh Pt02 (or palladium) is added. Upon complete reaction (thin-layer chromatography: silica gel, TI-IF), the catalyst is evacuated, the solvent is distilled and the product is isolated.
GENERAL PROCEDURE FOR SPLi'I~I'ING THE ARYLME'I'f-IYLETHERS
~0 0.5 mmoles of the corresponding methyl compound dissolved in 5 ml of absolute CHZCIz are dripped into the solution of 0.20 ml of BBr3 in 3 ml of absolute CHzCIz at -80 ° C. The mixture is allowed to rise to room temperature in about 8 h.
After adding 30 ml of HZO, extraction is carried out three times with ether.
The organic phases are washed twice with a saturated NaCI solution, dried by means of NazS04 and is are processed.
The compounds so obtained and their physical properties are shown in the Tables 18 through 27 below.

2f~~.~ ~~~
Table 18 Jtd ~p8(8 H
FXAt4PLE ' I R ( C=C
Nr. Rmeta ~para vLo~. ) R para P.r.

1391) H C1 H

1~ Chemiker-Zeitung 1986, 110, 267-271 ~0~~~~~~
Table 19 ~I nars ~t8 af8 EXAMPLER R R ~ MELTING j R ( C=O
Nr. meta para para E'T ) C

Table 2Q~
Sara R~~
N
H2~2-CQOH
GXAMPL!: Rmeta Rpara R~para M~;T. IR(C=O) Nr. QT.
C

144 H C1 ti 98 1730 Table Z1 EXAMPLE MELT. IR
Nr. R PT. (C=O) C

(C=C) 154 CHO >84 1650 155 CFi=CtiCOOC2H5 122 1715 ( E ) 156 CH=CHCOOf-I (E) 229 1660 157 (CH2)z OOH 157 1710 Table 22 ~o r ~~a ~, io ~xNr ~'c Rmeta Rpara R~ para MeLm. OR( C=C
p~r. ) 'C

1611) H OCH3 H

1621) OCH3 OCH3 H

1632) H O-C6H5 H

1) Chemiker-Zeitung 110, 2) the product is impure; it is made to react without further purification Table 23 ?~
EXN~PLERmeta Rpara R~para M~oC' IR(C=O
~~w 173 Cl CZ H 162 1640 174 H H CFi3 102 1645 l) Chemiker-teitung 1986 110, 267-271 Table 24 ~para E?(APIPLERmeta H ara R~ ara MELT, IR(C=O) Nr. p p eT.
C

177 OCH3 Fi H 119 1710 COOCZHS

~rlr~ee Zs EXAMPLLE2 t'. R' MELTING IR(C=O) ((~~td ~uI'u ~7dra PT.
Nr. C

190 H ti CH3 118 1665 ,..
H~~~
~GOH

sz 1'f1Af11 '1('able 2G
AW
a cx.~MPLrRmeta Rpara ~~para M~L~r. I~(C=O) Nr. ~T.
C

(CH2)2-COOH

Table 27 a GXAt~iPLER R MELT I R ( N.r. p~r~ . PT C=O ) 'C

io 202 tl C1 118 1605 ( C=C:
) 203 (Ctf2)2COOCH C1 113 1735 204 (CH2)2COOH C1 207 1710 sa ~s EXAMPLE 205 2,2-DIMETI-IYL-6-(4-FLUORO)-7-PHENYL-2,3-DII-IYDRO-1H-PYRROLIZINE (lv) 20 mmoles of a -chlorine-4-fluoroacetophenone dissolved in 25 rnl of CI-IZCIz are mixed with the solution of 20 mmoles of 2-benzyl-4,4-dimethyl-D 1-pyrroline [inj 25 ml zo of ethanol and the batch is stirred for 24 h at a bath temperature of 70 ° C. Thereupon 20 ml of saturated aqueous NAI-IC03 solution is added and agitation continues for another 24 h at the same temperature. The batch is poured into S00 ml of S
°~o NaCI
solution and is then extracted three times each time with 100 ml of ether/CI-IZC12 3-h 1.
The organic phases are dried by means of Na2SOa. The product is precipitated by column zs chromatography (AhO~, n-hexane/ether 9+1) in the form of an oil Yield 3.1 g (S1 %) C2~H2oFN (305.x) IFi: v~ = 1605 (CaC) cm-~
1H-PlMR: b (p~m) = 1.28 (s, 6H, -CHI), 2.78 (s, 2H, C-1), 3.71 (s, 2H, C-3), 6.64 (s, 1H, C-5), 6.75-7.60 (tn, 9H, ~.~rom.) ExAMPI-.E 20(~
2,2-D1 ME'I'I-lYL-G-(~1-IvLL10It0)-7-PI IENYL-2,3-DII-IYDRO-II-I-I'YltROI.OZINE-5-YI,-CAItt3ALDEIIYDE (Gv) 19 mmolcs of iv dissolved in 9 ml of absolute benzene are reacted with 27 mmoles (1.97 s g) of absolute DMP and 9 mmoles (1.38 g) of I'UCh in a manner similar to the Vilsmeier forrnylation of the Biphenyl-2,3-dihydro-11-I-pyrrolizines. Purification is by means of column chromatography (silica gel, n-hexane/ether 2-H 1). When the eluates are concentrateB, the product precipitates.
YielB: 0.9 g (30 %) melting point: 186 ° C
C22H2pFN0 (333.4) ,o 1R: vr,.,~ = 1645 (C~), 1610 (C~) cm-1 1H-NMR: a (ppm) = 1.33 (s, 6H, -CH3), 2.83 (s, 2H, C-1 ), 4.18 (s, 2H. C-3), 6.90"7.44 (m, 9H, Arum.), 9.38 (s, 1H, -CHO) ,s EXAMPLE 207 3-(2,2-DIMETI-IYL-6-(4-PLUORO)-7-PI-IENYL-2,3-DII-IYDR~-lI I-PYRROLIZINE-5-YL)-ACRYLIC-ACID ETI-IYLESTERS (34v) 2 mmoles of Gv Bissolved in 15 ml of absolute CI-IzClz are reacted with the solution of 2 mmoles (0.8G g) of ethoxycarbonyl methyltriphenylphosphonium bromide in Zo 4 ml of absolute ethanol and a solution of Na-ethanolate prepared from 6 mmoles (0.14 g) sodium and 3 ml absolute ethanol in a manner similar to the procedure for preparing the Biphenyl-2,3-Bihydro-lI-I-pyrrolizinyl acrylic-acid ethylesters.
Purification is by column chromatography (silica gel, CI-IzCl2}. After the eluates have been concentrateB, the product remains in the form of a foam.
2s Yield 0.33 g (41 %) melting point 152 ° C
C26H26FN02 (403.5) IR: vm~ = 1715 (C~), 1620 (C~) an-1 ~H-NMR: b (ppm) = 1.27 (t, 3H, J=7 Hz, -O-CHI), 1.33 (s, 6H. -CH3), 2.86 (s, 2H, C-1 ), 4.00 (s, 2H, C-3), 4.19 (q, 2H, J=7 Hz, -0-~H~-CH3), 5.90 (AB, 1H, J=16.4 Hz, ~H-GU-), 6.87-7.34 (m, 9H, Arom.), 7.48 (AB, 1 H, J=16.4 Hz, Pyr-CH=) ss EXAMI'I_I? 208 3-(2,2-DIML'I'11YL-6(4-PLUORO)-7-PI-IENYL-2,3-DIHIYDRO-lI-I-I'YRROLIZINE-S-YL) ACRYLIC-ACID (35v) 0.6 mmoles c~f 34v dissolved in 30 mt of ethanol are reacted with 6 ml of s 10 °lo aqueous KOI-d in a manner similar to the saponification of the Biphenyl-2,3-dihydra-lI-d-pyrrolizinyl acrylic-acid esters.
Yield 0.20 g (89 %; melting point: 242 ° C
IR: vrr,~ ~- 3300-2200 (OH), 1685, 1670 (C~), 1600 (C~) ar-t 1H-NMR (ds-DMSO): b (ppm) = 1.27 (s, 6H, -CH3), 2.84 (s, 2H, C-1 ), 4.06 (s, 2H, C-3), 5.92 (AB, 1 H, J=16.4 Hz, =CH-GO-), 6.87-7.41 (m, 9H, ,o Arum. ~~ Pyr-~H=) EXAMPLE 20~
3-(2,2-DI M ETI-IY1J6-(PLUORO)--PI-IENYLr2,3-DII-IYDRO-lI-I-PYRROLIZINE-5-YL)-~s PROPIONIC ACID (27v) 0.3 mmoles of 27v are reacted in the manner of the procedure for hydrogenating the aromatics-substituteB 3-(6,7-Biphenyl-2,3-dihydro-lI-I-pyrrolizine-5-yl)-acrylic-acids. Palladium is used as the catalyst. The product is precipitated by means of hexane.
zo Yield: 0.08 g (71 %) melting point: 182 ° C
C~,HZ4FNOZ (377.5) COMPUTED: C 76.4 I-I 6.41 N 3.7 MEASURED: C 75.8 H 6.56 N 3.3 IR: v",~ = 3300-2400 (OH), i 710 (C~), 1605 (G=C) crrr-t ~H-NMR: b (pprn) = 1.30 (s, 6H, -CH3), 2.28-2.58 (m, 2H, -CHI-CO-), 2.73-3.03 (m, 2H, Pyr-CHr), 2.81 (s, 2H, C-1 ), 3.68 (s, 2H, C-3), 6.76-7.28 (m, 9H, Arom.) se 2,2-DIMETI-IYL-C-(4-I'IIENOXYPI-IENOL)-7-PHENYL-2,3-DIHYDRO-1H-PYRROLIZINE (lw) 20 mmoles of 2 bcnzyl-4,4-dimcthyl-d I-[pyrroline lb~ are reacted with 20 s mmoles of a -bromo-4-chloroacetophenone in 50 ml of ethanol similarly to the procedure for preparing the f-aryl-7-phenyl-2,3-dihydro-11-I-pyrrolizines. Purification is by column chromatography (AI20~, n-hexane/ether 9+ 1). Following concentration of the eluates, Iw remains in the form of oil Yield 2.7 g (36 °lo) io C27H25NO (379.5) IFt: v~ - 1605 urxi 1595 (C~) cm's 'H-NMR: b (ppm) = 1.28 (s, 6H, -rCH3), 2.78 (s, 2H, C-1 ), 3.71 (s, 2H, C-3), 6.65 (s, 1 H, C-5), 6.78-7.57 (m, 14H, Arom.
,s EXAMPLE 211 2,2-DIMETI-IYL: 6-(4-PI-IENOXYPHENYL)-7-PI-IENYL-2,3-DII-1YDR0-II-I-PYRROLIZINE-S-YL-CAItBALDEHYDE (Gw) S mmoles of lw dissolved in 6 ml of absolute benzene are reacted with 18 mmoles (1.32 g) of absolute DMF and 6 mmoles (0.92 g) of POC13 similarly to the Zo procedure for the Vilsmeier formylation of the Biphenyl-2,3-dihydro-lI-i-pyrrolizines.
Purification is by column chromatography (silica gel, CI-IZCIz). The product is precipitated by ethanol.
Yield: 0.94 g (38 %) melting point: 139 ° C
C2eH25N02 (~7.5) IR: v,n~ = 1645 (C~), 1605 and 1590 (C~) curl 1H-NMR: 8 (ppm) a 1.30 (s, 6H, -CH3). 2.81 (s, 2H, C-1). 4.17 (s, 2H, C-3), 6.84-7.47 (m, 14H, Arum.), 9.40 (s, 1H, -CHO) I:xnMl'I_r 212 3-(2,2-D I M E'r1-I Y I_-li-(4-PI-I ENOXYPI-IENYL)-7-PI-I ENYL-2,3-DII-IYDRO-PYItI~,OLIZINC.-5-YL.)-ACRYLIC-nCID ETI-I'YLESTERS (34w) 2 mmolcs of Gw dissolved in S ml of absolute CI-I3C12 are reacted with the solution of 2 mmoles (0.86 g) of ethoxycarbonyltrimethyltriphenylphosphonium bromide in 4 ml of absolute ethanol and a solution of Na-ethanolate prepared from 6 rnmoles (0.14 g) of sodium and 3 ml of absolute ethanol in a manner similar to the procedure for preparing the Biphenyl-2,3-dihydro-11-I-pyrrolizinyl acrylic -acid esters.
Purification is by column chromatography (silica gel, CI-IZCIZ). The product remains in the form of foam ,o after the eluates have been concentrated.
Yield: 0.33 g (35 %) melting point: from 69 ° C
C32H3~N03 (477.6) iR: v,r,~ = 1705 (C~), 1610 (C~) crrr-t 1H-NMR: a (ppm) = 1.28 (t, 3H, J=7 Hz, -O-CHI), 1.33 (s, 6H, -CH3). 2.86 (s, 2H, C-1 ), 4.00 (s, 2H, C-3), 4.19 (q, 2H, J=7 Hz. -0~H3).
5.92 (AB, 1H, ,k~16 Hz, ~CH-CO-), 6.83-7.44 (m, 14H, Arum.), 7.56 'S (AB, 1H, J=16 Hz, Pyr-CH=) 3-(2,2-DIMETHYL-6-(4-PI-IENOXYPI-IENYL)-7-PHENYL-2,3-DIHYDRO-1I-I-PYRROLIZINE-5-YL) ACRYLIC ACID (35w) zo 0.6 mmoles of 34w dissolved in 30'ml of ethanol are reacted with 6 ml of % aqueous KOI-I in a manner similar to the procedure for saponifying the diphenyl-2,3-dihydro-1H-pyrrolizine-5-yl acrylic-acid ethylesters.
Yield: 0.23 g (85 %) . Illeltlrlg polllt: 198 ° C
C~hZ~N03 (449.5) COMPUTED C 80.2 I-I 6.05 N 3.1 2s MEASURED C 79.9 I-I G.07 N 2.7 IR: vr"~ = 3304-2200 (OH), 1675 (C~), 1590 (C=-C) atr~
~H-NMR (ds-DMSO): b (ppm) ~ 1.27 (s. 6H, -CH3), 2.83 (s, 2H, C-1), 4.06 (s, ao 2H, C-3)> 5.92 (AB, 1H, J=16.2 Hz, ~H-CO-), 6.86-7.57 (m, 15H, Arum. ~,a Pyr-CH=) 3-(2,2-DIME'i'IIYL-fi-(4-I'I-IENOXYPIIENYL)-7-PHENYL-2,3-DII-IYDRO-lI-I-I'YRROLIZINE-5-YL) I'ROPIONIC ACID (2fw) 0.3 mmoles of 35w are reacted in the manner of the procedure for s hydrogenating the aromatics-suUstituted 3-(6,7-Biphenyl-2,3-dihydro-lI-i-pyrrolizine-S-yl) acrylic acids. Palladium is used as the catalyst. The product is precipitated by n-hexane.
Yield: 0.10 g (74 %) melting point: 149 ° C
CSI i~,,NO~ (451.6) COMPUTED C 79.8 I-I 6.47 N 3.1 MEASURED C 79.5 H 6.61 N 2.7 ,o IR: v",~ = 3300-2400 (OH), 1710 (C=O), 1605 ,r,a 1595 (C=C) crrt-t ~H-NPvIR: b (ppm) = 1.29 (s. 6H, -CH3), 2.34-2.63 (m, 2H, -CH2-CO-), 2.77-3.06 (m, 2H, Pyr-CH2-), 2.83 (s, 2H, C-1), 3.69 (s, 2H, C-3), 6.85-7.47 (m, 14H, Arom.) ~s 2-(2,2-DIMETI-IYL-6-(4-PI-IENOXYPF-IENYL)-7-PI-IENYL-2,3-DII-I1'DRO-lI-I-PYRROLIZINE-5-YL) PROPIONdC-ACID ETI-IYLESTERS (54a) 2.5 mmoles of 6-(4-phenoxyphenyl)-7-phenyl-2,3-Bihydro-lI-I-pyrrolizine 1bv dissoiveB in 3 ml of absolute toluene are reacted with 4 mmoles (0.51 g) of 2-Biazopropionic-acid ethylesters BissolveB in 3 ml of absolute toluene in a manner similar zo to the procedure for preparing the Biphenyl-2,3-Bihydro-li-I-pyrrolizinyl acetic-aciB
ethylesters [ "s.S."201]. Isolation is by means of column chromatography (A1203, n-hexane-/ether 9+ 1). The oily product (0.45 g) remaining after concentration of the eluates is impure. It is reacteB further without aBBitionai purification.

~~3~ ~~ ~

2-(2,2-D1M~T1-IYL-6-(4-PI ICNOXYI'FICNYL)-7-PI-ICNYL-2,3-DII-IYDRO-lI-I-PYRROLIZINE-5-YL) PROPIONIC ACID (5Ga) s The impure S4a (0.45 g) dissolved in 10 ml of ethanol is reacted with 5 ml of 10 °lo aqueous KOI-I in a manner similar to the saponification procedure for the tliphenyl-2,3-dihydro-ll-I-pyrrolizinyl acetic-acid ethylesters. The time of saponification is 90 minutes. Purification is by column chromatography (silica gel, diisopropylether).
Yield: 90 mg melting point: 186 ° C
C3pH2gN03 (451.6) IR: v".,~,r = 3300-2400 (OH), 1710 (C~), 1605 ,~,~ 1595 (C=C) cm-t 1H-NMR: b (ppm) s 1.23 (s, 3H, -Chi), 1.32 (s, 3H, -CH3), 1.48 (d, 3H, J=7 Hz, CH3-CH<), 2.72, 2.91 (A8, 2H, J=15.5 Ha, C-1 ), 3.81 (s, 2H, C-3), 3.96 (q, 1H, J=7 Hz, -CH<), 6.81-7.50 (m, 10H, Arom.)

Claims (11)

1. A substituted pyrrolizine compound of the formula (I):

as well as the pharmaceutically compatible salts or esters thereof; wherein two of the residues R3 and R4 and R5 independently from one another represent a phenyl or naphthyl group wherein at least one of said phenyl or naphthyl groups is substituted by one or two residues selected from a halogen atom, a nitro-, a C1-C4 alkoxy-, a hydroxy, a C1-C4 alkyl- or phenoxy-group and wherein the third of the residues R3, R4 and R5 denotes CO2H, -COSC1-C4-alkyl or A-X, with A being a straight chain or a branched C1-C8-alkylene group which may be interrupted by an oxygen heteroatom or a carbonyl group or said A being a C2-C8 alkenylene group with the proviso that A is not -CH2- when X is OH; and said X being CO2H, SO3H, CHO, OH or SH;
and R6 and R7 independently from one another represent a hydrogen atom or a C1-C4 alkyl group.

2. The compound defined in claim 1 wherein two of the residues R3, R4 and R5 represent a phenyl group, and at least one of said phenyl groups is substituted by one or two residues selected from a halogen atom, a C1-C4 alkyl, C1-C4 alkoxy-, hydroxy-, phenoxy and nitro group and the third residue represent A-X, whereby A denotes a C1-C8 alkylene group or a C2-C8 alkenylene group and X represent CO2H.

3. The compound of claim 2 wherein the halogen is fluorine or chlorine.

4. The compound defined in claim 1 having the formula:
wherein R6 and R7 denote a hydrogen atom or a C1-C4-alkyl group, R3 and R4 independently from one another represent a phenyl group which may be substituted by a halogen atom, A represents a C1-C8-alkyl group and X represents CO2H.

5. The compound defined in claim 4 where R3 and R4 independently from one another represent a phenyl group or a p-chlorophenyl group and where AX represents CH2CO2H.

6. The compound defined in claim 5 where R6 and R7 represent a C1-C4-alkyl group.

7. The compound of claim 6 wherein R6 and R7 are a methyl group.

8. A pharmaceutical composition containing at least one compound defined in claim 1 together with an effective amount of conventional pharmaceutically-compatible inactive substances and/or additives.

9. A process for preparing a substituted pyrrolizine compound of the formula (I):
as well as the pharmaceutically compatible salts or esters thereof, wherein two of the residues R3 and R4 and R5 independently from one another represent a phenyl or naphthyl group wherein at least one of said phenyl or naphthyl groups is substituted by one or two residues selected from a halogen atom, a nitro-, a C1-C4 alkoxy-, a hydroxy, a C1-C4 alkyl- or phenoxy-group and wherein the third of the residues R3, R4 and R5 denotes CO2H, -COSC1-C4-alkyl or A-X, with A being a straight chain or a branched C1-C8-alkylene group which may be interrupted by an oxygen heteroatom or a carbonyl group or said A being a C2-C8 alkenylene group with the proviso that A is not -CH2-when X is OH; and said X being CO2H, SO3H, CHO, OH or SH;
and R6 and R7 independently from one another represent a hydrogen atom or a C1-C4 alkyl group, which comprises reacting a compound of the formula (II):

with a compound of the formula (III):

wherein R6 and R7 are as defined above, X is Cl or Br, and two of R3', R4' and R5' independently are phenyl or naphthyl wherein at least one of said phenyl or naphthyl is substituted by one or two residues selected from hydrogen atoms, a nitro-, a C1-C4 alkoxy-, a hydroxy, a C1-C4 alkyl- or a phenoxy group, and wherein the third of R3', R4' and R5' is hydrogen, to obtain a compound of the formula IV:

wherein R3' to R7 are as defined above; and converting said third of R3', R4' and R5' to a group R3, R4 or R5 to obtain a compound of the formula (I).

10. A process according to claim 9 which comprises converting a compound of the formula IV, wherein two of R3', R4' and R5' are phenyl, naphthyl or phenyl substituted by one or two residues selected from nitro-, Cl, methyl, phenoxy, methoxy and hydroxy, to obtain a compound of the formula (I) wherein two of the residues R3, R4 and R5 are phenyl, naphthyl or phenyl substituted by one or two residues selected from nitro-, Cl, methyl, phenoxy, methoxy and hydroxy and wherein the third of the residues R3, R4 and R5 is as defined above.

11. A process according to claim 9 or 10 wherein the step of converting a compound of the formula (IV) to obtain a compound of the formula (I) comprises a reduction, ester cleavage, Wittig-reaction or hydrogenation or a combination thereof.