AU637098B2 - Substituted pyrrole compounds and their applications in pharmacy - Google Patents

Description

COMMONWEALTH OF AUSTRALIA Patent Act 1952 1 v0- COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number Lodged Complete Specification Lodged Accepted Published Priority 11 MAY 1989.

Related Art Name of Applicant Address of Applicant Actual Inventor/s Address for Service :PROF. Dr.GERD DANNHARDT and MERCKLE GmbH KONIGSBERGERSTR. 26a D-6236 ESCHBORN 2 :BUNDESREPUBLIK

DEUTSCHLAND.

and GRAF-ARCO-STR.3.

D-7900 ULM-DONAUTAL BUNDESREPUBLIK

DEUTSCHLAND.

respectively.

GERD DANNHARDT, LUDWIG STEINDL and MATTHIAS LEHR.

RICE CO., Patent Attorneys, 28A Montague Street, BALMAIN 2041.

C6mplete Specification for the invention entitled: "SUBSTITUTED PYRROLE COMPOUNDS AND THEIR APPLICATIONS IN PHARMACY" The following statement is a full description of this invention including the best method of performing it known to us/me--- *It is known that arachidonic acid metabolizes two different ways. In the laavailable.

The invention concerns substituted pyrrole compounds and their

*.SS

S. o 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 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 antiphlogistics such as derivatives of arylacetic- 25 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.

2 Now it was found in surprising manner that certain substituted pyrrole compounds are 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

3

R

4 R2/

\R

R2 R

R

where

R

1 denotes a C, C 12 alkyl group,

R

2 is a hydrogen atom or a C C 12 alkyl group, or R' and R 2 together with the carbon atom and the nitrogen atom to which they are bound form a 5- to 8- 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, C 4 alkyl groups, each time, two of the residues R 3

R

4 and R 5 independently of each other are a hydrogen atom, a C 5

-C

8 cycloalkyl group, a C t

C

12 alkyl group or an aryl group which may be substituted by one or two residues selected form a halogen atom, a nitro-, a C, C 4 alkoxy, hydroxy, a C-C 4 alkyl or phenoxy group, and i* the third of the residues R 3

R

4 and R 5 denotes -CHO, -CO 2 H, -COSC 1

-C

4 alkyl or A-X, with A being a straight chain or branched C, C 8 alkylene group which may be interrupted by a hydrogen heteroatom or a carbonyl group, or a C 2

C

8 alkenyl group, and with X being CO 2 H, SO3H, CHO, OH or SH.

as well as their pharmaceutically compatible salts and esters, for application in pharmacy.

3 In the present case the pharmaceutically compatible salts may be salts of acid or of base addition. For acid addition salts, 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, maleic acid, fumaric acid, 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- 000*1o cally easily hydrolyzed esters such as alkyl-, pivaloyloxymethyl-, acetoxymethyl-, 0« 0' phthalidyl-, indanyl- and methoxymethyl-ester.

a0 The term "alkyl, alkoxy etc." covers straight-chain or branched alkyl groups °such as methyl, ethyl, n- and i-propyl, i- or t-butyl, n-pentyl, neopentyl, n-hexyl etc.

Unless otherwise stated, "alkyl" preferably shall denote C, Cg alkyl and in 15 particular C, C 6 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 residue.

A preferred embodiment mode are compounds of the formula Ia: 4 where R 3

R

4 and R 5 are the same as stated above in relation to formula I and where R 6 and R 7 independently from one another denote a hydrogen atom or a C, C4 alkyl group.

Especially preferred compounds of formula la are those wherein two of the residues R 3

R

4 and R 5 denote a phenyl group which is possibly substituted by one or two residues selected from a halogen atom, in particular a fluorine or chlorine atom, from a

C

1 C4 alkyl-, C 1

C

4 alkoxy-, hydroxy- and phenoxy-group and where the third residue denotes A X, with A being a C, C 8 alkylene group or a Ct C 8 alkenylene group, and with X being COzH.

In particular AX denotes C 2

C

6 -alkylene-COH or C2 C 6 -alkenylene- 0io CO 2 H and in an especially preferred instance it stands for (CH 2 2

CO

2 H, CH 2 COH or 0 CH=CH COH.

Preferably R 6 and R 7 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 15 R 3

R

3

A

7 7 R R AX R

RR

3

AX

0 N where R 6 and R 7 denote a hydrogen atom or a C 1

C

4 alkyl group and R 3 and

R

4 denote a phenyl group which may be substituted by one or two residues which are selected from a halogen atom, a nitro-, C 1

C

4 alkoxy-, Ci C 4 alkyl- or a phenoxy- group.

A-X has the same meaning as above in relation to the formula I.

Preferably the substituents of the phenyl group are selected from a halogen atom, in particular a fluorine or chlorine atom, from a C 1

C

4 alkyl-, C I

C

4 alkoxy- and phenoxy-group. Preferably the substituents shall be in the m- and/or in the p-position.

Preferably A denotes a C, C 8 alkylene group or a C 1 alkenylene group in particular, or a C 2

C

6 alkylene- or C 2

C

6 alkenylene group and X preferably denotes

COH.

Another embodiment mode are the compounds of formula I e* where R' and R 2 independently of one another denote a C 1

C

1 2 group, with two of the residues R 3

R

4 and R 5 being a phenyl group possibly substituted by one or two residues selected from a halogen atom, a C 1

C

4 alkyl-, C 1

C

4 alkoxy-, hydroxyand phenoxy-group, and ,is where the third of the residues R 3

R

4 and R 5 is a hydrogen atom or A-X, 0 with A being a C 1

C

6 alkylene- or a C 2

C

6 alkenylene-group and X being CO 2 H or

SO

3

H.

R' preferably is a C, C, alkyl group, in particular a Ci-C 6 alkyl group and especially preferred a C4-C 6 alkyl group.

R

2 preferably is a C-C 4 alkyl group and especially a methyl group.

R

3 and R 4 on one hand and R 4 and R 5 on the other preferably are a phenyl group and R 5 and R 3 resp. are A-X, with A being preferably a C 1

-C

4 alkylene group or a C 2

-C

6 alkenylene group.

Especially preferred compounds are: (2,2-dimethyl-6,7-diphenyl-2,3-dihydro-1H-pyrrolizine-5-yl)-acetic acid, and 3-(2,2-dimethyl-6-(4-phenoxyphenyl)-7-phenyl-2,3-dihydro-lH-pyrrolizine-5yl) propionic acid.

Further the invention concerns the compounds of the general formula I and also the corresponding above stated preferred embodiment modes per se, where R 1 and

R

2 together denote a 5 to 8 link ring possibly containing a sulfur hetero-atom or a carbonyl group and further possibly substituted with one to two C 1

-C

4 alkyl groups, and where R 3

R

4 and R 5 assume the above meanings but with A being a straight-chain or a branched C 3

-C

8 alkylene group which may be interrupted by an oxygen atom or a s carbonyl group, or denoting a straight-chain or a branched C3-C 8 alkenyl group, or where R 1 through R 5 assume the meanings stated in claim 4.

9o Synthesis of the compounds of formula I wherein R' and R 2 together form a 5 to 8 link ring, takes place in a first step described by the equation below: 79 7 3 3 2 O 2 n N x

R

6 X= Cl, Br n 1 3 R 3.

R

nN R/ R

R

7 This synthesizing step is elucidated together with the followin'g o-nes by means of the illustrative diphenyl-substituted pyrrolizine compounds. The first reaction stage is explained in'further detail below: Reaction diagram (1) *00.10 0 BrH 2

C

0 Ethanol, NaHC03,

H

2 0 E than~ol, NaHCC) 3

H

2 0 9999 99..

9 9 *9 9 9.

99 9 9 OI' H 3 Ethanol, NaHCO 3

H

2 0. A 20-30%0/ C N 9.

The conditions of reaction are known and described in CH-EMIKER- ZEITUNG, 110, (1968) 7/8, pp 267, 271 and in ARCH. PHARM. 321, pp 159-162 (1988).

In 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 below: Reaction diagram (2) P003. DMF,

BEN\ZENE.A

I \C

CHO

9G99

S

0*OO

S

@9 4 0S* S 9 9@@e 99 0 9 *59 0 LiAiH 4

THF

CH

2 0H

S.

S

S~~S

4 S 90 50 5 5 0S9 S

S.

9 599

-CH

2 0H CHO CH 2 0H C

N/\

UAJH

4

THF

cu 0

A

TOLUENE

CN/\

CH

2 -0H 2 0 H

OSOS

S

0**S *00@

OS

S S @0 0

OS@@

S S 1*s 0

OSOS

S

006e 0@*S 0e

S

S 0 0 *0.

a so.

CH

2 -COQf'H

N/\

CH

2

-CH

2

OH

These reactions and their conditions are known and are described in CHEMIKER-ZEITUNG 110 (1968), 7/8, pp 267-271 and in ARCH. PHARM. 321, pp 159-162 (1988).

The preparation of the corresponding derivatives of formic acid, propionic acid and acrylic acid is described in ARCH. PHARM. 321, pp 545-549. It takes place according to the reaction diagrams and The preparation of the corresponding butyric-acid derivatives takes place according to the reaction diagram First, using the Friedels-Crafts acylation with succinic acid anhydride Berlina, ORG. REAKT. 1949, 5, pp 229-289), the 4-oxo- 1 butyric acids are prepared which then are reduced by means of the Huang-Minlon o variation of the Wolff-Kishner reduction with hydrazine/KOH in diethyleneglycol. The *0 conditions of reaction are known to the expert.

The derivatives of valeric acid can be prepared by means of the valeric acids which in turn can be made from the pyrrolizine base bodies by the Friedel- Crafts acylation 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 valerate/A1C1 3 and saponification of the 6-oxocaproic-acid-methylester derivatives and subsequent reduction of the oxovaleric acid with hydrazine/KOH.

The preparation of compounds substituted at the phenyl group takes place similarly. The hydroxy-substituted derivatives are prepared by ether splitting with BBr 3 from the corresponding alkoxy derivatives (TETRAHEDRON, 1968, 24, pp 2289-2292).

Reaction diagram (3)

CICO-SC

2

H.

AYCI

3

.CH

2

CI

2 0 000.

0000 0 0000 00 0 0 0* .000 0 0000 *0 0 0 000 0 000.

0 00..

0000 00 0 00 O 0 0 000 0 00 0 000

KOH.

Ethanol, A 0001- Reaction diagram (4) Wrtg-

REACTION

KOH.

S

S.

SO

S S .5

S

55 S S 555 5 Hi/PtO 2 Ethanol,

THF

*5S*

S

55.5 5.55

S*

55 5* 0 S 555 S

S

S..

COCH

N/

(0H 2

)Z-CC

N/\

reaction diagram

AJCI

3

CH

2

CI

2 -(0H 2 2

-OOOH

H

2

N-NH

2 NaCH,

DIETH-YLENEGLYCOLA

(CH

2 3

-COOH

*see *0000 0 0 0 0 59S

S

55.5 5O55 S S 0* C *5 S S

S

55

'S.

5 555 (0H 2 3

-COOH

N/\

14 The preparation of the compounds of formula I is described below, wherein

R

x and R 2 denote a C 1

-C

12 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. CHEM. 1966, 19, pp 1971-1885. The further synthesizing steps are elucidated illustratively below starting with 2-methyl-2,3-diphenylpyrrole and 5-methyl-2,3-diphenylpyrrole. These reactions are shown in the diagrams (6) and 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 it in the presence of a base, for instance alkali-metal alcoholates such as sodium methylate, 0** sodium ethylate or potassium-t-butylate, in an inert solvent such as DMSO, ethyleneglycol methylether and the like. The alkylation also can be carried out heterogeneously with Al the corresponding toluene sulfonic-acid alkylesters or alkyl halides using phase transfer catalysts, in conventional manner (see for instance CAN. J. CHEM. 1977, 55, pp 4112- 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 g c 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 invention represent effective antiphlogistics, analgetics, antipyretics, anti-allergics 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 (6)

H

3 5 NF

H

TOLUENE SULFONIC ACID METHYLESTER

OR

ALKYLBRO141DE

H

3 0 N

R

ICH

2

-CHCOOCH

3 8F 3

CH

2

CICH

2

CI

69 9 044 COMPOUNDh 2 H b

OH

3 _Q C 2

H

5 d n-C 3

H

7 .111 00 a n-0 4

H

n-0 H 1 n-qCH 13 i'O-CAH Ne opentyl H 3 NE COOOH 3

R

{KOH,

Ethanol, A

H

3 N COCH Ia i Reaction diagram (7) TOLUEN4E SULFONIC/ ACID METRYLESTER

OR

Ajkylbromid e

H

3 N H 3 C N N

N

N

2

CHCOOC

2

H

5 COMPOUND R cu tolueneA

CH

3

H

60000

C

2

H

5 5 2 0

R

e n-0 4

H

9 f nlCSH 11

KM

gn-0 6

H

1 3 IEthanol, A h n-CBH 17 iSO-C 4

H

i Neopentyl HO- 17 The compounds 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 mixtures of the active substances with suitable pharmaceutical carriers or diluents. The compounds or drugs may be administered orally or parenterally 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 excipients such as binders (for instance syrup, acacia, gelatin, sorbite, traganth gum or polyvinylpyrrolidone), fillers (for instance lactose, sugar, maize starch, calcium phosphate, sorbite or glycine), lubricants (for instance

*C*

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, 1"75 syrups, elixirs or sprays etc. or they may be in the form of dry powders to be reconstituted "6 with water or another suitable carrier. Such liquid preparations may contain conventional C C additives such as suspending agents, flavorings, diluents or emulsifiers. As regards parenteral administration, solutions or suspensions with conventional pharmaceutical carriers may be used.

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.

18 The effectiveness of the compounds of the invention can be determined by means of the inhibition of 5-lipoxygenase or of cyclo-oxygenase. The research was carried out as follows: TESTING TO DETERMINE THE INHIBITION OF The source for 5-lipoxygenase were bovine granulocytes which can form leucotrienes just as human granulocytes do. By stimulation with calcium-ionophore (see BIOCHEM. BIOPHYS. ACTA 1984, 795, pp 499 503), mainly LTC 4 (leucotriene C 4 and LTB 4 (leucotriene B 4 are formed from endogenous arachidonic acid. The isolation of the granulocytes and the implementation of the enzyme reaction are conventional (see BIOCHEM. BIOPHYS. ACTA 1984, 795 pp 499 503). The blood protected against S• 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 0 0.15 absence of the test substances following the addition of Ca" with calcium ionophore. The 0 synthesis of the leucotrienes is stopped after 5 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. LTB 4 is measured at the absorption maximum at 270 nm. The arachidonic acid metabolites are observed present in this research in approximately quantitative manner.

TESTING TO DETERMINE THE INHIBITION OF CYCLO-OXYGENASE In this test the 12-HHT amount of 12-hydroxyheptadecatriene acid or prostaglandin E 2 amount formed by bovine thrombocytes following addition of calcium ionophore is determined by uv detection following HPLC separation. Following 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 inhibition, however the incubation time was one minute.

The detection of 12 HHT following HPLC separation takes place at 232 nm.

Tables 1 and 2 list the test results for the compoinds of the invention, The 0 test substances were at concentrations of 10 L M.

o.

The Examples below illustrate the invention. All temperatures are uncorrected. The ir spectra unless noted otherwise are from KBr molded articles.

The NMR spectra, unless noted otherwise, are 90 Mhz spectra, recorded in CDCI 3 with tetramethylsilane (TMS) as the internal standard.

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) 0* ARCH. PHARM. 319, pp 500 505 (1986) ARCH. PHARM. 321, pp 159 162 (1988) ARCH. PHARM. 321, pp 545 549 (1988) CHEMIKER ZEITUNG, 110, (1986), 7/8, pp 267 271.

S

TABLE 1: INHIBITION OF 5-LIPOXYGENASE AND OF CYCLO-OXYGENASE BY PYRROLIZINE COMPOUNDS.

R

3 R (10 jiM) CO MPO N 6 R'7 INHIBITION Lipoxy- Cyclooxyqenase genase 4- 4 99.

*9* :.9 o 9

S.

9 Phenyl Phenyl

(CH

2 4

CO

2

H

(CH 2 5 2

H

Phenyl Phenyl

(CH

2 2

CO

2

H

(CH

2 5

CO

2

H

Phenyl Phenyl CH=CHCO 2 Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl (G 2 4

CO

2

H

(a 2 5 Co 2

H

Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl CH1 c6 H13 m-Chlorphenyl p-0ilorphenyl p-Tolyl p-Methoxyphenyl p-Phenoxyphenyl a-naphthyl p-Fluorphenyl p-Tolyl p-Phenoxyphenyl Phenyl Phenyl Phenyl Fenyl (CH 2)2 co 2 Phenyl Pheny.

Phenyl O=CHCO H Q-lHQ-I-CO H (CH2)CO 2

H

(02)CO2 H

(CH

2 2 O 2 (OH 2 2 co2H

(CH

2 2 O 2 (OH 2 2 2H (OH 2 2 co2H (OH 2 2 co2H

H

H

H

H

CHI

CH 3 CH 3

H

3

H

H

H

H-I

H

H

H

H

H

CH

CH

3 C H 3

H

H

H

H

CH 3 CH 3 CH 3

H

3

H

H

H

H

H

H

H

H

H

H

H

3

CH

3

CH

3 91 82 89 98 92 91 98 94 (3,3 tiM) (3,3 pM) (3,3 N L -I TABLE 2: INHIBITION OF BY 2-METHYL-DIPHENYLPYRROLE-ACETIC-ACIDS R3 R4

R

2 /5 ~10 JIM)

N

Al 1 2 4 5 INHIBITIONIk%) R R R R (Lipoxygenas') n-C H 9 CH- Phenyl Phenyl (CH 2 2 co 2 H 94 9 3 9:.n-C 5

H

1 1 acH 3 Phenyl Phenyl (0- 2 2 CO2H 99 n-C H 13 CH-i 3 Phenyl Phenlyl (CHi 2 2 o2H9 pentyl CH3Penyl P hey (H22COR2 97 TABLE 3 F

EXAMPLE

'64,Nr. R H CH 3 *es 1 H 1-2 2

CHO

0 sees see 3 CH 2 0H 9 4 CH 2

COOC

2

H

5 1a 12b

(CH

2 2 0H 1a 0056 COGH iu 18b 7 CH 2 COOH 23a 23 5558(CH 2 2

COOCH

3 2a 26b 9 (CH 2 2 COOH 27a M7

CH=CHCOOC

2

H

5

I

11 CH=CHCOOH 3 TABLE 4

R

EXAMPLE

.Nr.H 3 6 12 H 2 13 CHO i 14 CH 2 OH -1-Qa lob

CH

2 C000 2

H

5 ia

(CH

2 2 0H a 16 *17 COSCA H 5 19 18 COCH 21 a 21 :*19 CH 2 COOH 24a 24b

CH=CHCOOC

2

H

5 2 21 CH=CHCOOH I 22 (CH 2 000H 3 24 TABLE

RR

EXAMPLER

RH

OH

3 23 H 3 24 CHO

CH

2 OH ll~a llb 26 CH 2 0000 2

H

5 14a~ 14b (CH29 2 OH 1a 17b .28 COSC 2

H

5 20 0 .29 COOH 2a 22b

CH

2 000H25 b 31.. CH=CHCoOC 2

H

5 2a 29b 32 CH=OHCOOC 2

H

5 29b' 33 CH=CHCOOH 31 31b 34 CH=CHCOOH 31b'

(CH

2 2 C00H3a m GENERAL PROCEDURE FOR PREPARING THE 4-(DIPHENYL-2,3-DIHYDRO- 1H-PYRROLIZINYL)-4-OXOBUTYRIC ACIDS With ice cooling and stirring, 8.8 mmoles (1.17 g) of AlCl 3 are added in batches over five minutes to a solution of 4 mmoles of diphenyl-2,3-dihydro-lHpyrrolizine and 4 mm (0.40 g) of succinic acid anhydride. Then agitation continues for minutes at room temperature. Thereupon the batch is poured into 150 ml ice water.

After adding 4 ml of 8 H 3

PO

4 extraction is performed three times with CHCI 3 the organic phases are dried with Na 2

SO

4 and the solvent is distilled. Product isolation is by means of column chromatography (silica gel, 1st ether, 2nd ether/THF The .0 product fractions "re concenitrated,-the residue is dissolved in a little CHC1 3 After 0 0 adding n-hexane and new concentration, the product is precipitated.

S*

GENERAL PROCEDURE FOR PREPARING THE 4-(DIPHENYL-2,3-DIHYDRO- 1H-PYRROLIZINYL)-BUTRYIC ACIDS 0.5 mmoles of 4-(diphenyl-2,3-dihydro-lH-pyrrolizinyl)-4-oxobutyric acid are mixed with 10 ml of diethyleneglycol, 50 mmoles (2.8 g) of KOH and 30 mmoles g) of hydrazine hydrate. The batch is heated 1 hoi r till reflux (bath temperature 1700 C).

Next the reflux condenser is replaced by a distillation bridge .nd the temperature is raised until the inside is at about 210 C. This temperature is then maintained for 2 h.

20 Following cooling, the batch is poured into 150 ml HzO, acidified with 8 H 3

PO

4 and extraction is carried out three times with ether. The extracts are washed with H 2 0, dried and concentrated. The product is isolated with column chromatography (silica gel, ether/THF 4 1 in 39, diisopropylether in 40, ether in 41a and ether/n-hexane 4 1 in 41b) and is precipitated using n-hexane.

26 GENERAL PROCEDURE FOR PREPARING THE 5-(DIPHENYL-2,3-DIHYDRO-

ACIDS

4 mmoles of diphenyl-2,3-dihydro-1H-pyrrolizine are reacted in 16 ml of absolute CH 2 Cl 2 with 4 mmoles (0.46 g) of glutaric acid anhydride and 8.8 mmoles (1.17 g) of AIC1 3 similarly to the procedure for making the 4-(diphenyl-2,3-dihydro-1Hpyrrolizinyl)-4-oxobutyric acid 222). In deviation, the batch is poured into ice water immediately after the addition of A1C13 and then is processed further. Product purification takes place by column chromatography (silica gel/ether).

GENERAL PROCEDURE FOR PREPARING THE 5-(DIPHENYL-2,3-DIHYDRO- ,oW. 1H-PYRROLIZINYL)-5-VALERIC ACIDS 0.5 mmoles of 5-(diphenyl-2,3-dihydro-1H-pyrrolizinyl)-5-oxovaleric acids are reacted similarly to the procedure for making the 4-(diphenyl-2,3-dihydro-1H-

*SS@

pyrrolizinyl)-4-oxobutyric acids. The product is isolated by column chromatography (silica gel, ether) and precipitated by means of n-hexane.

GENERAL PROCEDURE FOR PREPARING THE 6-(DIPHENYL-2,3-DIHYDRO- 1H-PYRROLIZINYL)-6-OXOCAPROIC-ACID

METHYLESTERS

With ice cooling and while stirring, 22 mmoles (2.93 g) of AlCl1 are added over 5 minutes and in batches to the solution of 10 mmoles of diphenyl-2,3-dihydro-1Hpyrrolizine and 10 mmoles (1.79 g) of methyl-5-(chloroformyl)-valerate in 50 ml of absolute CH,C 2 Immediately thereafter the batch is poured into 150 ml of ice-cooled 10 NaC1 solution. Upon addition of 4 ml of 8 H 3

PO

4 extraction with ether is carried out three times, the organic phases are dried with Na 2

SO

4 and the solvent is distilled. The product is isolated by means of column chromatography (silica gel, 1st nhexane/ether 3+2, 2nd n-hexane/ether 1 4 in 48, 50a and 50b, or 1st toluene, 2nd hexane/ether 1+4 in 49). First the eluates are concentrated to about 100 ml, then they are washed twice with 0.05 n NaOH and twice with 10 NaCl solution and lastly they are dried with NaSO4. When the solution is concentrated, the products precipitate or, following distillation of the solvent, crystallize.

27 GENERAL PROCEDURE FOR PREPARING THE 6-(DIPHENYL-2,3-DIHYDRO- 1H-PYRROLIZINYL)-6-CAPROIC ACIDS The solution of 1 mmole of 6-(diphenyl-2,3-dihydro-lH-pyrrolizinyl)-6oxocaproic-acid methylester in 10 ml of ethanol is heated to boiling. 5 ml of 10 KOH previous degassed by boiling are dripped into that solution and heating continues another minutes with reflux. Following cooling the batch is poured into 100 ml of 5 NaC1 and then is acidified with 8 H 3

PO

4 and extraction is carried out three times with ether.

The organic phases are dried by means of Na 2

SO

4 and concentrated. The residue is reacted with 50 mmoles (2.8 g) of KOH and 30 mmoles (1.5 g) of hydrazine hydrate in 10 ml of diethylene glycol similarly to the preparation procedure for the 4-(diphenyl-2,3dihydro-lH-pyrrolizinyl)-butyric acids and is purified by column chromatography with silica gel.

S The compounds so prepared and several physical properties of theirs are listed in the Tables 6 through 8 below.

GENERAL PROCEDURE FOR PREPARING THE 2-(DIPHENYL-2,3-DIHYDRO- •1H-PYRROLIZINYL)-PROPIONIC-ACID ETHYLESTERS 5 mmoles of diphenyl-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 diphenyl-2,3-dihydro-1H-pyrrolinyl acetic-acid ethylesters. However the time of reaction is 2 h. Purification is column chromatography (A1 2 0 3 n-hexane/ether The Sproducts are precipiated with ethanol.

GENERAL PROCEDURE FOR SAPONIFYING THE2-(DIPEENYL-2,3-DIHYDRO- 1H-PYRROLIZINYL) PROPIONIC-AICD ETHYLESTERS .25 5 mmoles of 54 or 0.5 mmoles of 55a and 55b, dissolved in 12 ml or 9 ml resp. of ethanol are reacted with 8 ml or 2.5 ml resp. of 10 aqueous KOH similarly to the procedure for saponifying the diphenyl-2,3-dihydro-1H-pyrrolizinyl-acetic-acid ethylesters. The time of saponification is 15 min in 54, 60 min in 55a, and Purification is by column chromatography (silica gel, 1st n-hexane/ether 1+ 1, 2nd ether).

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.

0

S

.a S 0

S.

B

0 S S

S

0 *000 S 5 00 S 0* S. S Table 6 EXAMPLE '.MELTING IR' Nr. R

PON

36 CO(0H 2 2 COOH 187-188 1710, 1635 37 (CH 2 3 COOH 166-167 1705 38 CO(CF1 2 3 COOH 42 142-143 1710, 1635 39 (CH 2 4 COOH 45 146 1710

CO(CH

2 4 COOH 48 99 1740, 1630 41 (CH 2 5 000H 5j.. 42 CH(CH 3

)COOC

2

H

5 54 1730 43 CH(CH 3 )COOH 56 173 1705 :0.

00se 1) Band 1H-NMR: 5 (PPM) 1.06-1.78 (in, 6H, -(QH5 2 3 -0H 2 2.10-2.40 (in, 2H, 2.40-2.76 (in, 4H, Pyr-0H 2 and 3.02 2H, J=7 Hz, C- 3.94 2H, J=7 Hz, 6.97-7.31 (in, 1 OH, Aroin.) Table 7 0** IzAPL MELTING POINT I1) Mr.R

IR

44:. CO(CH 2 2 000H 231-234 1715, 1680

(CH

2 3 000H A 176-178 1715 46 CO(CH2 3 COOH 4 12 1710, 1660 0 0 47 (CH 2 4COOH 46 126-127 1700 48 CO(CH 2 4

COOCH

3 43. 112 1745,165B 49 (CH 2 )000H 263 1710 1) Band S Table 8 EL< AMP L Nr.

b51 I52 R, H MELTING rPT. C H_ I lb I

IR

1 ab

CO(CH

2 2 000H

(CH

2 3

COOH

CO(CH

2 3 000H

(CH

2 4 000H

CO(CH

2 4 0000H 3

(CH

2 5 000H m8 41a 44a 47a 41b 44b 47b 190- 19 1 146-148 109 111-112 92 123 187-188 192-194 167 1705 1735, 1645 1710 L715,1665 {1715-.

1645 ~1645 1705 1710) 1720, 17 1660 1660 129-130 1715 1740, 1655 122 1710

U.

U. 4.

II

.5

U

U LbS S 4 I -4a Band Table 9

R

EXAMPLE R= MELTING PT. IR Nr. R H CH. a b a b 56 CH(CH 3 )COOC H 5 5 55b 1 33 136 1730 1740 3 2 5 57 CH(CH 3 )COOH 57a 57b 190 1705 226 1710 C a EXAMPLE 58 f. G 5-(1-(DIPHENYL-2,3-DIHYDRO .1H-PYRROLIZINE-7-YL)-ETHYL)-2,2-DIMETHYL- 1,3-DIOXAN-4,6-DIONE (59a) C 0 dThe solution of 4 mmoles (1.04 g) of 3a, 4 mmoles (0.58 g) of 2,2-dimethyl- 1,3-dioxan-4,6-dione (Meidrum's acid) and 8 mmoles (0.35 g) of freshly distilled 0 .111 acetaldehyde in 40 ml of acetonitrile is made to stand for 24 h at 30 0 C. Following cooling in the ice bath, the precipitated product is evacuated.

*Yield: 0. 44 g (2 6 melting point: 169 0C (with dissociation) IR: V ma 1790 1605 (C =C)/cm EXAMPLE 59 5-(1-(2,2-DIMETHYL-5,6-DIPHENYL-2,3-DIHYDRO-1H-PYRROLIZINE-7-YL)- ETHYL)-2,2-DIMETHYL-1,3-DIOXAN-4,6-DIONE (59b) 4 mmoles (1.15 g) of 3b are reacted in the manner described in relation to 59a with acetaldehyde and Meldrum's acid.

Yield: 1.35 g (74 Ir: max 1790 1755 1605(C=C)/cm EXAMPLE 3-(5,6-DIPHENYL-2,3-DIHYDRO-1H-PYRROLIZINE-7-YL) BUTYRIC-ACID ETHYLESTERS 1 mmole of 59a is dissolved in a mixture of 5 ml of absolute pyridine and ml of absolute ethanol. After adding some copper powder, the batch is heated to ea" reflux 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/- O1. CHC1, 1+2).

Yield: 96.5 mg (25 IR: v=max 1735 1605 (C=C)/cm.

EXAMPLE 61 3-(2,2-DIMETHYL-5,6-DIPHENYL-2,3-DIHYDRO-1H-PYRROLIZINE-7-YL)- BUTYRIC-ACID ETHYLESTER 2.5 mmoles of 59b are dissolved in a mixture of 20 ml absolute pyridine and 2 ml of absolnte ethanol and upon addition of some copper powder the batch is reacted 0 as described for 60a. Purification is by column chromatography (silica gel, n-hexane/-

CH

2 Cl 2 2+1) in isolation.

Yield: 0.68 g (68 IR: v max 1745 1605 (C=C)/cm W EXAMPLE 62 3-(5,6-DIPHENYL-2,3-DIHYDRO-1H-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 adding n-hexane.

Yield: 63 mg (36 melting point: 157 C (with dissociation) IR vmax 3300- 2400 1710 1605 (C=C)/cm EXAMPLE 63 3-(2,2-DIMETHYL-5,6-DIPHENYL-2,3-DIHYDRO-1H-PYRROLIZINE-7-YL) BUTYRIC-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 FOR PREPARING THE TRIMETHYLPHENYL-2,3- DIHYDRO-1-H-PYRROLIZINES 0.05 moles (5.6 g) of 2,4,4-trimethyl-A Ipyrroline, dissolved in 25 ml of absolute ethanol, are reacted with 0.05 moles (10.7 g) of 1-bromo-l-phenylacetone (in 63) or a -bromo-propiophenone (in 64) in a manner analogous to the synthesis of In deviation from that reference, here, following addition of the NaHCO 3 solution (0.06 moles in 40 ml of H 2 0) are heated only 4 h to reflux. Purification is carried out by S means of column chromatography (A1 2 0 3 n-hexane/ether 9+ Oil remains following o concentration of the eluate.

GENERAL PROCEDURE FOR PREPARING THE TRIMETHYLPHENYL-2,3- S DIHYDRO- 1H-PYRROLIZINYL-ACETIC-ACID ETHYLESTERS mmoles (1.13 g) of 63 or of 64, dissolved in 5 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 to the procedure for preparing the diphenyl-1,2,3-dihydro-lHpyrrolizinyl acetic-acid ethylesters. The products are obtained as oils following column chromatography (A1 2 0 3 1st n-hexane/ether 9+1, 2nd n-hexane/ether 3+2).

SAPONIFICATION OF THE TRIMETHYLPHENYL-2,3-DIHYDRO-1H- PYRROZINYL-ACETIC-ACID

ETHYLESTERS

mmoles of 65 or 0.5 mmoles of 66, dissolved in 4ml or 12 ml resp. of ,25 ethanol are reacted with 2.5 ml or 7.5 ml resp. of 10 aqueous KOH similarly to the procedure for saponifying the diphenyl-2,3-dihydro-1H-pyrrolinyl-acetic-acid ethylesters.

Purification is by column chromatography.

The compounds and several of their properties are listed in the Tables and 11 below.

Table 0 00 0 0 0 0 0 -i.

009 0 Table 11 *me

R

H

3 C

H

3 0

CH

3 T r R MELTING PT. IR 67 H 64 58-60 1595 (C=C) 68 CH 2 COOC 2 H 5 66 1740 69 CH 2 COOH 68 141 1710 1) band, unless stated otherwise EXAMPLE 5-(n-HEXYL)-7-PHENYL-2,3-DIHYDRO-1H-PYRROLIZINE (69) In order to dissolve 35 mmoles of n-octanal in 15 ml of ether and 5 ml of dioxan, a solution of 35 mmoles (5.6 g) of bromine in 5 ml of CH 2 Cl 2 is slowly added S while stirring. This batch then is mixed witl 50 ml ether and to neutralize HBr, the mixture is washed carefully twice with a 5 NaHCO 3 solution. The organic phase is dried by means of Na 2

SO

4 and concentrated. The residue is dissolved in 50 ml ethanol and added to a mixture of 35 mmoles of 2 benzyl-A 1-pyrroline 9 50 ml of ethanol and ml of 10 NaHCO 3 solution. After stirring for 24 at room temperature, the batch is

O*S

'e*a poured into 500 ml of 10 NaCl and extraction is carried out twice with ether. The 0*So organic phases are dried by means Na 2

SO

4 the solvent is distilled and the pyrrolizines so obtained, 69 and 70, are isolated by column chromatography (A 2 03, n-hexane/ether 9+1).

The two isomeric pyrrolizines then are dissolved in 50 ml of dichloroethane is 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 BF 3 etherate. Following addition of 200 ml of 5 NaCI solution, the batch is extracted twice with ether. Following drying by means of Na2SO 4 the solvent is distilled and the unconverted 69 is isolated by means of column chromatography (Al 2 0 3 n-hexane/ether The eluates are concentrated. The 20 remaining oil solidifies after some time.

Yield: 1.23 g (16 Melting point: 46-47 C

C

9 ,HsN (224.1) IR: vmax= 1610 (C=C)/cm 1 H-NMR: 5 (ppm)- 0.73-1.06 3H, -CH3), 1.06-1.76 8H, -CH 2 2.33- 2.72 4H, C-2 und Pyr-CH 2 3.04 2H, J=7 Hz, 3.83 (t, 2H, J=7 Hz, 6.20 1H, 6.95-7.56 5H, Arom.) EXAMPLE 71 5-(5-(n-HEXYL)-7-PHENYL-2,3-DIHYDRO- OXOVALERIC ACID (71) W 5 mmoles of 5-(n-hexyl)-7-phenyl-2,3-dihydro- 1H-pyrrolizine 69 are reacted in 20 ml of CH 2

CI

2 with 5 mmoles (0.5 g) of glutaric acid anhydride and 11 mmoles (1.47 g) of ALCL, simiflarly to the procedure for preparing the 5-(diphenyl-2,3-dihydro-IH- The product is purified by column chromatography (silica gel, 1st n-hexane/ether 1 1, 2nd ether). After the eluates are concentrated, 71 remains as an oil.

Yield 0.40 g (21

C

24

H:

31 N0 3 (381.5) 1 H-NMR: 6 (ppm) 0.69-1.07 (in, 3H, 1.07-1.98 (mn, 10H, -CH 2 1.98- 2.65 (in, 6H-, C-2 und -CO-QFLz-CH2-Cjj.'-CO-), 2.65-2.95 (mn, 4H, C-1 un~d Pyr-CHz-), 3.91 2H, J=7 Hz, 7.07-7.47 (in, Arom.) EXAMPLE 72 (5-(n-I-EXYL)-7-PHENYL-2,3-DLHYDRO- 1H-PYRROLIZINE-6YL)-VALERIC ACID (72) 1 mmole of 71 is reacted in 10 ml of diethyleneglycol with 50 mmoles (2.8 g) of KOH and 30 mmoles (1.5 g) of hydrazine hydrate similarly to the procedure for reducing the 4-(diphenyl-2,3-dihydro-1H-pyrrolizinyl)-4-oxobutyric acids. Product purification is by means of column chromatography (silica gel diisopropylether). After concentrating the eluates, 72 remains as an oil.

Yield 0.20 g (54 C2 4 H33NO 2 (367.5) IR: VMax 3600-2400 1710 1605 a-r 1 l 'H-NMR: 6 (ppm) 0.72-1.12 (mn, 3H, -OH 3 1. 12-1.78 (in, 12H, -OH 2 2.08- 2.70 (mn, 8H, C-2, -CH 2 -CO- ur)d 2x PYr-CHz-), 2.90 2H, J=7 Hz, C-10,.87 2H, J=7 Hz, 6.95-7.44 (mn, 5H, Arom.) eg S.

0595

S*

S S

S

S.

o a S 55 0 5

S

*SS

EXAMPLES 73, 74 5-(n-HEXYL)-7-PHENYL-2,3-DIHYDRO-IH-PYRROLIZINE-6-YL-CARBAL- DEHYDE (73) AND 6-(n-HEXYL)-7-PHENYL-2,3-DIHYDRO-1 YL-CARBALDEHYDE (74) 35 mmoles of octanal, bromine and 2-benzyl-A 1-pyrroline are 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 mmoles (7.7 g) of absolute L'Va, 1 35 mmoles (5.4 g) of POCI 3 similarly to the procedure of the Vilsmeier formyiation of the diphenyl-2,3-dihydro-1H-pyrroliziries. The two products are separated by column chromatography with Silica gel, first elution taking place with n-hexane/diisopropylether 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 samt product is obtained in the Vilsmeier formylation of 69.

73 Yield 1.74 g

C

20

H

2 5 N0 (295.4) I R: vmax =1660 (C00). 1610 (C0C) crn- 1 IH-NMR: 6 (Ppm) 0.73-1.07 (in, 3H, -OH 3 1.07-1.86 (mn, 8H, 2.30- 2.70 (in, 2H, 2.74-3. 05 (in, 4H, C-i1 and Pyr-0HZ-), 3.91 2H, J=7 Hz, 7.05-7.46 (in, 5H, Aroin.), 9.87 1H, -CHO) 74 Yield 2.13 g 2 5 N0 (295.4) IR: yma 1655 1610 cm-1 1 H-NMR: 8 (ppm) 0.68-1.01 (in, 3H, -OH 3 1.01-1.74 (in, 8H, 2.31)- 2.67 (in, 2H, 2.67-3.00 Cm, 4H, C-1 -nd Fyr-0HL 2 4.32 2H, J=7 Hz, 7.19-7.46 (mn, SH, Arom.), 9.67 Cs, 1H, -CHO) EXAMPLE 3-(6(n-HEXYL)-7-PHENYL-2,3-DIHYDRO- 1H-PYRROL17ZINE-5-YL) -ACRYLIC- ACID ETHYLESTERs mmoles (1.48 g) of 74 are reacted similarly to the procedure for preparing the dip henyl-2,3-dihydro- 1H-pyrrolizinyl-acrylic-acid ethylesters. Purification is by column chromatography (silica gel, petroleum ether 50-70/acetic-ester 7+ Following concentration of the eluate, the product is obtained as an oil Yield 0.45 g (25 0 24

H

3 1 N02 (365.5) I R: vmal 705 1610 T- 1 H-NMR: 6 (ppm) =0.62-1.02 3H-, -CH 3 1.02-1.78 (in, 11 H, -CH- und 0 O-CHr-QU 3 2.23-3.01 (in, 6H, C-2, Pyr-CH 2 nd 3.93-4.39 (in, 4H, C-3 und -0-OH 2 5.89 (AB, 1H, J=16. 1 Hz, =CH-CO-) ~.7.04-7.48 (in, 5 H, Arom.), 7.68 (AS, 1 H, J =16. 1 H z, Pyr-C H) EXAMPLE 76 3-(6-(n-HEXYL)-7-PHENYL-2,3 -DIHYD RO- IH-PY RRO LLZINE-5 -YL) -ACRYLIC ACID (76) mrnole (0.37 g) of 75 is reacted similarly to the procedure for saponifying the diphenyl-2,3-dihydro-1H-pyrrolizine-acrylic-acid ethylesters.

Yield 0.20 g (59 melting point 140 0 C (with dissociation) C22H 27 N0-2 (337.5) IR: vmax =3300-2200 1670 1595 aCir 1 1 H-NMR (d 6 -OMSO): 6 (ppm) =0.58-0.96 (mn, 3H, -OH 3 0.96-1.60 (Mn, 8H,

-OH

2 2.18-2.73 (mn, 4H, 0-2 and Pyr-OH 2 2.86 2H, J=7 Hz, 4.15 2H, J=7 Hz, 5.85 (AS, 1H, J=15.8 Hz, =CH-CO-), 7.02-7.53 5H, Aron.), 7.50 (AB8, 1H, J=15.8 Hz, Pyr-0H=) EXAMPLE 77 6-CYCLOHEXYL-7-PHENYL-2,3-DIHYDRO-1H-PYRROLIZINE (77) mmoles of Br 2 dissolved in 10 ml of CC1 4 are slowly dripped into the solution of 50 mmoles (6.3 g) of cyclohexylmethylketone in 40 ml of CCI 4 with stirring and shielding from light. This batch is then mixed with 50 ml of CH 2 CI, and carefully washed twice with a 5 NaHCO 3 solution to neutralize the Hbr. The organic phase is dried by means of Na 2

SO

4 and concentrated. The residue is dissolved in 30 ml of ethanol and reacted with the solution of 50 mmoles of 2-benzyl-A 1-pyrroline in 20 ml of ethanol.The batch is stirred for 24 h at room temperature. After adding 25 ml of a saturated NaHCO 3 solution, stirring proceeds for another 24 h. Then 500 ml of 10 NaCI are added and e. extraction with ether is carried out twice. The organic phases are dried (NazSO 4 The solvent is distilled and the product is isolated by column chromatography (Al 2 0 3 n-hexane/ether The oil (3.0 g) remaining after the eluate was concentrated is impure. It is further reacted without any purification.

C

EXAMPLE 78 6-CYCLOHEXYL-7-PHENYL-2,3-DIHYDRO-1H-PYRROLIZINE-5YL-CARBAL- DEHYDE (78) g of impure 77 are dissolved in 5 ml of absolute benzene and reacted 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 diphenyl-2,3-dihydro-lH-pyrrolizines.

Purification is by column chromatography (silica gel, ether/n-hexane Then the product is precipitated with ethanol Yield 0.66 g (4.5 referred to the cyclohexylmethyl ketone) Melting point 135 C

C

20

H

23 N0 2 (293.4) IR: max 1645 1610 cn- 1 1 H-NMR: 6 (ppm) 1.01-2.13 10H, -CH 2 -of the cyclohoxyl ring), 2.24- 3.03 5H, C-1, C-2 und Pyr-CH<), 4.35 2H, J=7 Hz, 7.07- 7.51 5H, Arom.), 9.93 1H, CHO) EXAMPLE 79 3-(6-CYCLOHEXYL-7-PHENYL-2,3-DIHYDRO-1H-PYRROLIZINE-5-YL)-ACRYLIC- ACID ETHYLESTERS (79) 2 mmoles of 78, dissolved in 4 mln of absolute CH 2

CI

2 are reacted with a solution of 2 mmoles (0.86 g) of ethoxycarbonyl. triphenyl phosphonium bromide in ml of absolute ethanol and with a solution of Na-ethanolate prepared from 6 mmoles 10.14 g) of sodium and 3 ml of absolute ethanol in a manner similar to the procedure for preparing the diphenyl-2,3-dihydro-1H-pyrrolizinyl acrylic-acid ethylesters. The 12 purification takes place by column chromatography (silica gel, petroleum ether 0...0 70/acetic-ester The oil remaining after concentration solidifies after some time.

$*so Yield: 80 mg (ii melting point: 1900' C

C

24 H29NO2 (363.5) IR: vmax1715 (C=O).1605 cm1 1H-NMR: 6,(ppm)=0.99-1.99(in, 1OH, -OH 2 of the cyclohexyl ring), 13 t 3H, J= 7 Hz, -0-0H-CH2ff), 2.27-2.93 5H, C-1, 0-2 und Pyr-CH<), 4.17 (t 2H, J--7 Hz, 4.23 2H, J=7 H;z, -0-OH 2 5.85 CAB, 1H, J=16.2 Hz, =CH-C0-) 7.04-7.48 (in, 5H, Arom.), 7.91 C (AS, 1H, J=16.2 Hz, Pyr-CH=) .EXAMPLE 3-(6-CYCLOHEXYL-7-PHENYL-2,3-DIHYDRO-IH-PYRROLIZINE ACID 0 Sze0.22 mmoles (80 mg) of 79 dissolved in 5 ml of ethanol are reacted with 3 ml of 10 aqueous KOH similarly to the procedure for saponifying the diphenyl-2,3dihydro- iR-pyrrolizine acrylic-acid ethylesters (see p 219).

Yield 37 mg (50 melting point 2010' C (with dissociation)

C

22

H

25 N0 2 (335.4) IR: vmax 3200-2400 1660 1585 crTrl 1 H-NMR: 6 (ppm) =0.98-2.05 (in, 10H, -CHZ of the cyclohexyl ring), 2.29- 2.98 Cm, 5H, C-1, 0-2 und Pyr-C 4.21 (t 2H, J=:7 Hz, 5.87 (AB, 1H, J--16.0 Hz, 7.02-7.55 (mn, 5H, Arom.), 8.01 (AB, 1 H, J--16.0 Hz, Pyr-CH=) 41 GENERAL PROCEDURE FOR THE N-ALKYLATION OF 2-METHYL-3,4-

DIPHENYLPYRROLE

2 mmoles (0.47 g) of 2-methyl-3,4-diphenyl-pyrrole (AUST. J. CHEM. 1966, 19, pp 1871-1885) [and] 2.2 mmoles of p-toluene sulfonic-acid methylester (in 81b) or S alkylbromide (for the remaining compounds) and 1 mmole (0.32) g) of tetrabutylammonium bromide are mixed with 10 ml ether and 5 ml of 50 aqueous NaOH.

While agitating strongly, the mixture is heated for 8 h to slow boiling. Thereupon the batch is poured into 100 ml of HzO and extracted twice with ether. The ether phases are washed with 1 H 3

PO

4 and HO 2 dried by means of NazSO 4 and concentrated. The product isolation takes place by column chromatography (Al 2 0 3 n-hexane/ether 9+1).

The compounds so obtained and their physical properties are listed in Table 12 below.

EXAMPLE 88 1-NEOPENTYL-2-METHYL-3,4-DIPHENYLPYRROLE (81i) The above compound cannot be synthesized. However it may be prepared as follows: 2 mmoles (0.46 g) of 2-methyl-3,4-diphenyl-pyrrole, 2.6 mmoles of potassium-t-butylate and 3 mmoles (0.45 g) of neopentyl bromide in 6 ml of absolute DMSO are heated for 45 minutes to 130 140 C. Following cooling, 100 ml H,O are added, acidification with dilute H 3

PO

4 and next double extraction with ether are carried out. The ether phases are washed with H20, dried by means Na 2

SO

4 and concentrated.

The product is isolated from the residue by column chromatography (AlzO 3 nhexane/ether 9+1) and precipitated with ethanol (similarly to the case for 81h).

Yield: 0.31 g (51 melting point: 132 C.

C

22 H2N (303.4) COMPUTED C 87.1 H 8.30 N 4.6 MEASURED C 86.9 H 8.21 N IR: vmax 1605 (C=C)cm 1 MS: m/z (rel.lnt.) 303 288 M'-CH3,. 273.74), 247 (58%.

M+-C4H, 201.34), 246 (100%, 247-H) 1 H-NMR: 5 (ppm) 1.02 9H, -CH 3 2.19 3H, Pyr-CH3), 3.66 2H, 6.75 1H, 7.06-7.33 10H, Arom.) Table 12 H 0 *0* *000 0 *5 SeWS 0

S@

C

C

EXAMPLE

1 r1) 82 83 84 2) 86 2) 87 MELTING POINT

OC

IR (C=C) CH 3 n-C 3 H 7 n-C 4 H 9 n-C 5H 1 iso-C4H9 81b 81C 81d 81e 81f 81g~ s0 116 1600 1605 1610 1605 see 0 1.4 0 se Tetrahedron Lett. 1969, 55, 4875-4878 Chern. Pharm. Bull. 1974, 22, 61-69 2) mixture with alkyl. bromide; it is reacted without further purification 43 GENERAL PROCEDURE FOR PREPARING THE 3-(5-METHYL-3,4-DIPHENYL- PYRROLE-2-YL)-PROPIONIC-ACID METHYLESTERS 1 mmole of 2-methyl-3,4-diphenylpyrrole or of 1-alkyl-2-methyl-3,4diphenylpyrrole 82b-i and 1.5 mmoles (0.13 g) of acrylic-acid methylester are dissolved in 4 ml of dichloroethane. Following addition of 0.06 ml of BF 3 -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 methylester and BF 3 -ethylester complex are added. Then the batch is mixed with 50 ml of HO and extraction with ether is performed twice. The ether phases are washed with H20, dried by means of NazSO 4 and concentrated. The product is isolated from the residue by column chromatography (A1 2 0 3 n-hexane/ether I* 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 S* listed in Table 13 below.

GENERAL PROCEDURE FOR THE SAPONIFICATION OF THE 3-(5-METHYL-3,4- DIPHENYLPYRROLE-2-YL)-PROPIONIC-ACID METHYLESTERS The solution of 0.4 mmoles of 3-(2-methyl-3,4-diphenylpyrrole-5-yl)- S* propionic-acid methylester 82a or 3-(1-alkyl-2-methyl-3,4-diphenylpyrrole-5-yl)-propionicss a acid methylester 82b-i in 3 ml of ethanol is heated to boiling. 2 ml 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 H 3

PO

4 and extracted twice with 50 ml of ether. The ether phases are washed with 100 ml of H 2 0 and dried by means of Na2SO 4 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

H

3 N 0001-3 e.

t g.e.

S.

go SoOg 0 6eSb S.

S

".4 b S S QE S SEE S a geE

R

H

CH 3 n-C 4H9 n-C 5H 1 n-C 6H 1 iso-C 4H9 Neopentyl I R(C=O) 82a 1730 82b 1740 82c 1740 82d 1740 82e 1745 82f 1740 82g j1740 82h I1740 82i j1740 Table 14

H

3 NE GOOH

R

0 U~o EXAMPLE R MELTING POINT IR (C=O Nr. o 98 H 60 1710 99 CH 3 108 1710 10c2 H5 157 1715 101 n-C 3H7128 1705 102 n-C 4 H 9 >49C s 1715 104 n-C 5 H 1 1 1715 105 n-C 6H 131715 106 iso-C 4

H

9 50 1715 107 Neopentyl 48 1710 46 GENERAL PROCEDURE FOR THE N-ALKYLATION OF 5-METHYL-2,3-

DIPHENYLPYRROLE

mmoles (1.17 g) of 5-methyl-2,3-diphenylpyrrole (AUST. J. CHEM. 1966, S 19, pp 1871-1885), 5.5 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 ml of 10 aqueous NaOH. 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 shown in Table GENERAL PROCEDURE FOR PREPARING THE (5-METHYL-4,5-DIPHENYL- PYRROLE-3-YL)-ACETIC-ACID ETHYLESTERS.

2.5 mmoles of methyl-2,3-diphenylpyrrole (AUST. J. CHEM. 1966, 19, pp 1871-1885) or of 1-alkyl-5-methyl-2,3-diphenylpyrrole 84b-j, dissolved in 2 ml of absolute toluene, are reacted similarly to the procedure for preparing the diphenyl-2,3-dihydro-1Hpyrrolizine-acetic-acid ethylesters. Following column chromatography (silica gel, nhexane/ether 1+1 in Example 117 or Al203, 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 data relating to them are o, shown in Table 16.

Table 0 0 SO S.6.

Go, see EXAMPLE 1 R MELTING PT. IR(C=C) Nr. I 108 109 110 ill 112 113 114 115 116 CH 3 n-C 3H7 n-C 5H1 n-C 6 H 13 iso-C 4 H 9 Neopentyl.

84b 84c 84d 84e 34f 8 4g 84h 84i 8 4j 149 68-69 1605 1605 1605 1605 1605 1605 1600 107 89 1605 .1 1) mixture with n-C 8

H

17 Br, reacted without further purification Table 16 00 0 0 0 *000a :9.

200 EXAMPLE R IR(C=O) Nr.

117 H 85a 1730 118 CH 3 85b 1740 119 C 2 H 5 85c: 1735 120 n-C 3 H 7 85d 1740 121 n-C 4

H

9 85e 1735 122 n- 185f 1740 123 n-C 6

H

13 85g 1740 14 nC8 H17 85h 1740 125 iso-C 4 H 9 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-4,5-dip henylpyrrole-3-yl) -ace ticacid ethylester or of (1-alkyl-2-methyl-4,5-diphenylpyrrole-3-yl)-acetic-acid ethylester in ml of ethanol is heated to boiling. Then 3 ml of 10 aqueous KOH previously degassed by boiling are dripped into the batch which is further heated for 1 h with reflax.

Following cooling the batch is poured into 100 ml of 5 %Y NaCl solution and the mixture is then acidified with 8 H 3 P0 4 and extracted three times with ether. The organic phases are dried by means of Na 2

SO

4 and concentrated. Product purification takes place by column chromatography (silica gel, 1st n-hexane/ether 1 I in the Examples 127-13 1, a a 00000 0 a. a$ 49 or 2 +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

HOOC

EXAMPLE R MELTING POINT IR(C=O) Nr. 0 127 H 86a 110 1710 128 C H 86b 161 1710 129 C 2H 586c: 177 1705 130 n-C 3H 786d 172 1700 131 n-C 4H 986e 129 1705 132 nC5 H11 86f 121 1710 133 nC6 H13 86g 127 1710 134 z 8 C H 1 7 86h 45 1715 135 iso-C 4H 9 86i 168 1710 136 Neopenty. 86j 163 1710 GENERAL PROCEDURE FOR PREPARING THE 6-ARYL-7-PHENYL-2,3- DIHYDRO-1H-PYRROLIZINES OR THE 6-PHENYL-7-ARYL-2,3-DIHYDRO-1H-

PYRROLIZINES

mmoles of aromatics-substituted* or unsubstituted a -bromo-acetophe- S none dissolved in 25 ml of CH 2 C1L are mixed with the solution of 20 mmoles of unsubstituted or aromatics-substituted** resp. 2-benzyl-A 1-pyrroline in 50 ml of ethanol and are stirred for 24 h at room temperature. Then 20 ml of saturated aqueous NaHCO 3 solution are added and the batch is stirred for another 24 h at room temperature. The batch is poured into 500 ml of 5 NaCl solution and is extracted three times each time So with 100 ml of ether/CH 2 Cl1 3+1. The organic phases are dried by means of Na 2

SO

4 and processed in the manner discussed below.

S*

o a -bromo-3-chloroacetophenone, a -bromo-3,4-dimethoxyacetophenone, a -bromo-3,4-dichloroacetophenone 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 CH CI 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 CHCl and 20 ml of dioxan. Thereupon the batch is mixed with 20 50 ml of CHCICl and carefully washed twice with 5 NaHCOQ solution to remove the Hbr. The organic phase is dried by means of Na, SO 4 and concentrated. The residue is reacted directly as described above with 20 mmoles of 2-benzyl-A 1-pyrroline.

2-(4-chlorobenzyl)--A-pyrroline The preparation is similar to that for 2-benzyl-A 1-pyrroline AMER. CHEM. SOC. 1932, 2 1as 54, pp 3971-3976) 2-(4-methylbenzyl)-A1-pyrroline A Grignard reagent is prepared from 0.15 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 4chlorobutyronitrile dissolved in 100 ml absolute ether into the batch, same is heated for 2 h to reflux. Next 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 I-1O 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 CHICL and the precipitate is washed with 100 ml of

O

51

CH

2 CI6. The CHFCI, 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

C

1 2 ,,HN (173.3) Ir: 1640 1605 (C=C)/cm 2-(4-methoxybenzyl)-A -pyrroline 4-methoxybenzyl magnesium chloride is prepared from 3.0 moles (72.9 g) of Mg and 0.15 moles (23.5 g) of 4-methoxybenzylchloride in 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 torr).

Yield 2.4 g (8

C

2 Hs NO (189.3) Ir: 1640 1610 (C=C)/cm GENERAL PROCEDURE FOR PREPARING 3-(6-CHLOROPHENYL- AND 6- NITROPHENYL 7-PHENYL-2,3-DIHYDRO-1H-PYRROLIZINE-5-YL)-PROPIONIC- ACID METHYLESTERS 4 mmoles of 6 chloro- or 6-nitrophenyl-7-phenyl-2,3-dihydro-1H-pyrrolizine and 6 mmoles (0.52 g) of acrylic-acid methylester are dissolved in 16 ml of absolute dichloroethane. After adding 0.24 ml of BF 3 ethylene complex, the batch is stirred for 1 h at room temperature, and the same amounts of acrylic-acid methylester and BF 3 ethylether complex are added in each case again after 15 minutes. Thereupon the batch is poured into 100 ml of 10 NaCl solution and is extracted twice with ether/CH 2 Cl1 3+1. The organic phases are dried by means of Na 2

SO

4 and concentrated. The residue then is processed in the manner discussed below.

GENERAL PROCEDURE FOR SAPONIFYING THE 3-(6-CHLOROPHENYL- AND 6-NITROPHENYL-7-PHENYL-2,3-DIHYDRO-1H-PYRROLIZINE-6-YL)- PROPIONIC-ACID METHYLESTERS The solution of 1 mmole of the corresponding pyrrolizinyl-propionic-acid methylester in 10 ml of ethanol is heated to boiling. 5 ml of 10 aqueous KOH solution previous degassed is dripped into the batch which is then heated another 5 minutes with 52 reflux. Following cooling the batch is poured into 100 ml of 5 NaCl solution and acidified with 8 H 3

PO

4 and extracted three times with ether/CH 2 C1 2 3 1. The organic phases are dried by means of Na 2

SO

4 concentrated, and processed in the manner described above.

GENERAL PROCEDURE FOR THE VILSMEIER FORMYLATION OF AROMATICS-SUBSTITUTED 6,7-DIPHENYL-2,3-I)IHYDRO-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 POC1 3 similarly to the procedure for the Vilsmeier formylation of the diphenyl-2,3dihydro-1H-pyrrolizines.

GENERAL PROCEDURE FOR PREPARING AROMATICS-SUBSTITUTED 6,7- DIPHENYL-2,3-DIHYDRO- 1H-PYROLLiZINYL-ACRYLIC-ACID ETHYLESTERS 2.5 mmoles of the corresponding carbaldehyde dissolved in 5 ml of absolute

CH

2 C1, are reacted with the solution of 2.5 mmoles (1.08 g) of ethoxycarbonylmethyltriphenyl-phosphonium bromide in 4 ml of absolute ethanol and with a solution of S: Na-ethanolate prepared from 7.5 mmoles (0.17 g) of sodium and 3 ml of absolute ethanol in a manner similar to the procedure for preparing the diphenyl-2,3-dihydro-1Hpyrrolizinyl-acrylic-acid ethylesters.

GENERAL PROCEDURE FOR SAPONIFYING AROMATICS-SUBSTITUTED 3-(6- 7-DIPHENYL-2,3-DIHYDRO-1H-PYRROLIZINE-5-YL)-ACRYLIC-ACID ETHYL-

ESTERS.

1.2 mmoles of the corresponding pyrroliziny: -rylic-acid ethylesters dissolved in 50 ml of ethanol are reacted with 10 ml of aqueous KOH similarly to the procedure for saponifying the 3-(diphenyl-2,3-dihydro-1H-pyrrolizine-5-yl)-acrylic-acid ethylesters.

53 GENERAL PROCEDURE FOR HYDROGENATING AROMATICS-SUBSTITUTED 3-(6,7-DIPHENYL-2,3-DIHYDRO-1H-PYRROLIZINE-5-YL) ACRYLIC ACIDS 0.9 mmoles of the corresponding pyrrolizinyl acrylic acid are dissolved in ml of absolute THF. After adding 10 ml of absolute ethanol and a spatula tip-ful of S PtO 2 (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 PtO 2 (or palladium) is added. Upon complete reaction (thin-layer chromatography: silica gel, THF), the catalyst is evacuated, the solvent is distilled and the product is isolated.

GENERAL PROCEDURE FOR SPLITTING THE ARYLMETHYLETHERS 0.5 mmoles of the corresponding methyl compound dissolved in 5 ml of absolute CH 2 Cl 2 are dripped into the solution of 0.20 ml of BBr 3 in 3 ml of absolute

CH

2 C1, 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 Na 2 zO 4 and are processed.

The compounds so obtained and their physical properties are shown in the Tables 18 through 27 below.

S* o Table 18

C

S.

S S

S.

55S0

S.

5 5 SSC S 5*5

S

55.5

.SSS

S S S. S

S.

S S

S

P.X AtI P LE R t I R( C=C) Nr.

138C.

139 1)

H

140NO 141H 142H R meta c 1

H

NO 2

H

H

para paaMELT. PT.

IR(C=C)

H

C).

H

NO 2

H

117 132 156 1600 1605 1595 1605 1 0 1 Chemiker-Zeitung 1986, 110, 267-271 Table 19 Rpara 0*0*

S

*SSe 0S S 0 0S 0

OSS*

S.

S S See S @5*S

S

SOSS

SOSO

S S 0* S S S 555 5 EXAMPLE MELTING yr.

Nr. OC IR(

C~O)

143 144 145 146 147

R

meta cl

H

NO 2

H

H

MELTING PT.

oc para para

IR(C=O)

-t 4 4.

H

Cl

H

NO 2

H

99 98 111.

1735 1730 1740 1740 1730 a. *g Table pant Rpar

(CH

2 2

-COOH

see* be..

*s 0

OS

EXAMPLE RR R MELT. PT. IR(C=O) Nr. Rmeta para para 0 c 143 Cl H H 99 1735 144 H Ci H 98 1730 145 NO 2 H H 1740 146 H NO 2 H 1740 147 H H CI ill 1730 Table 21 0000 o SOS 0 0.00 0.

0 0 0S

OSOS

0 0000 50 0 S 000 0 0090 6 0S50 0000 S S 55 S 55 0 500 0 EXAMPLE MELT. PT. I R Nr. R oC (C=O) 153 H 1605

(C=C)

154 CHO >84 1650 155 CH=CHCOOC 2 H 5 122 1715 156 CH=CHCOOH 229 1660 157 (CH )ZCOOH 157 1710 to0 Table 22 para 0 S goo: *0 a 1 0 0 see S4..

e 05 0 EXAMPLE RR R MELT. PT. OR(C=C) Nr. Rmeta para para 0 158 CH 3 H H 1605 159 H CH 3 H 1605 160 OCH 3 H H 1605 161 1) H OCH 3H 162 1) OCH 3 OCH 3

H

163 2) H 0-C 6H 5 H 164 Ci. C1 H 119 1605 165 H H CH 3 104 1610 166 H H OCH 3 1605 Chemiker-Zeitung 1986 110, 267-271 2) the product is impure; it is made to react without further purification Table 23 'mut *sess *000 0.55 0 5 a a .4a.

660 0 a 4. 550 EXAM4PLE Nr.

167 168 169 170'1) 171 1 172 173 174 Rmeta

H

OCH 3

H

OCH 3

H

C'

H

R para I Ipara RC0METP.

.c

IR(C=O

H

CH 3

H

OCH 3 OCH 3 0-C 6H5

H

H

H

H

H

H

H

H

CH 3 128 142 117 135 162 102 1645 1645 1635 1635 1640 1645 1) Chemiker-Zeitung 1986 110, 267-271 Table 24 EXAMPLE R R R MELT. PT. IR(C=O) Nr. meta para para cc 175 CH 3 H H 142 1710 gO 176 H CH 3 H 158 1710 050 b3 177 OCH 3 H H 119 1710 178 H OCR 3 H 164 1705 179 OCR 3 OCR 3 H 133 1705 180 H O-C 6 H 5 H 173 1705 181 Cl Cl H 122 1715 182 H H CH 3 222 1705 Table ILPMr I me ta I cJH H 00011 fi 0 4 00.

06 0

Q

00o *00 a~ EXAMPLE R PR MELTING PT. IR(C=O) Nr. meta para o 183 CH 3 H H 216 1660 184 H CH 3 H 221 1680 185 OCH 3 H H 205 1670 186 H OCH 3H 216 1675 187 OCH 3 OCXJ3 H 216 1660 188 H 0-C 6

H

5 H 221 1660 189 CI Cl H 229 1660 190 H H CH 3118 1665

SO

o 0

**B

Table 26

(CH

2 2

-OOOH

0*Se *0@

S

S.

S S S 5.55

S.

S S 5 *5S* 0e 55 S

S.

S S

S

55u EXAMPLE R R R'MELT. PT. IR(C=O) Nr. meta para para o 191 CH 3 H H 125 1710 192 H CH 3 H 122 1710 193 OCH 3 H H ill 1710 194 H OCH 3H 73 1710 195 OCH 3 OCH H 152 1725 196 OH H H 87 1710 197 H OH H 187 1700 198 OH OH H 76 1710 199 H 0-C bH 5H 178 1705 200 CI C2. H 144 1710 201 H H CH 3 182 1705 Table 27 EXAMPLE R R MELT. PT IR(C=0) Nr. para 0 goo* 000f 202 H C1 118 1605(C=C) 0 0 6203 (CH 1) COOCH C1 113 1735 204 (CH2)COOH 3 Ci 207 1710 .0 EXAMPLE 205 (4--FLoP-EAJyL) 2,2-DIMETHYL-6-4 P64@ -7-PHENYL-2,3-DIHYDRO-IH-PYRROLIZINE (1v) 20 rnmoles of a -ch Iori ne-4-fluoroace tophe none dissolved in 25 ml of CH 2 Cl 2 00 S are mixed with the solution of 20 mmoles of 2-benzyl-4,4-dimethyl-A 1-pyrroline [in] 25 ml 020 of ethanol and the batch is stirred for 24 h at a bath temperature of 70 0 C. Thereupon 20 ml of saturated aqueous NAHCO 3 solution is added and agitation continues for another 24 h at the same temperature. The batch is poured into 500 ml of 5 NaCi solution and is then extracted three times each time with 100 ml of ether/CH 2

C

2 3 +1.

The organic phases are dried by means of Na 2

SO

4 The product is precipitated by column chromatography (A 2 0 3 n-hexane/ether 9+ 1) in the form of an oil Yield 3.1 g (51

C

2 jH 20 FN (305.4) 1 R: va 1605 a'n- 1 IH-NMR: (ppm) =1.28 6H,-CH 3 2.78 2H, 3.71 2H, 0-3), 6.64 1 H, 6.75-7.60 (in, 9H, Nc4"n.) EXAMPLE 206 (.f_7(IjqOpfe~tJYL_) 2,2-DIMETHYL-6 -igW@-7-PHENYL-2,3-DIHYDRO-l-PYRROLOZIN-5-YL- CARBALDEHYDE (6v) 19 mmoles of iv dissolved in 9 ml of abs -)lute benzene are reacted with 27 mmoles (1.97 g) of absolute DMF and 9 mmoles (1.38 g) of POCI 3 in a manner similar to the Vilsmeier formylation of the diphenyl-2,3-dihydro-1H-pyrrolizines. Purification is by means of column chromatography (silica gel, n-hexane/ether When the eluates are concentrated, the product precipitawes.

Yield: 0.9 g (30 melting point: 186 0 C C22H 2 OFNO (33~3.4) 1 vmax 1645 IV,: '3 (CC) crr- 1 Soso 0000 I 1 H-NMR: 6 (p~pm) -1.33 6H, -OH 3 2.83 2H, 4.18 2H, C-3).

0000 6.90-7.44 (in, 9 H, Arom.), 9. 38 1 H, -COHO) EXAMPLE 207 C4-_FLUOgOetI~j~yL) 3-(2,2-DIMETHYL-61( 96P&-7-PI-ENYL-2,3-DIHYDRO- YL)-ACRYLIC-ACID ETHYLESTERS (34v) 2 rnmoles of 6v dissolved in 15 ml of absolute CH 2

C

1 are reacted with the solution of 2 mmoles (0.86 g) of ethoxycarbonyl methyltriphenylphosphonium bromide in 020. 4+ ml of absolute ethanol and a solution ofN-thanlat prepared fo6 mnoles (0.14+ .00. g) sodium and 3 ml absolute ethanol in a manner similar to the procedure for preparing the diphenyl-2,3-dihydro-1H-pyrrolizinyl acrylic-acid ethylesters. Purification is by column chromatography (silica gel, CH 2

CI

2 After the eluates have been concentrated, the product remains in the form of a foam.

Yield 0.33 g (-A1 melting point 152 0 C

C

26 1- 26 FN0 2 (403.5) IR: vmax =1715 (C0O), 1620 (C0C) cn-1 1 H-NMR: 6 (ppm) =1.27 3H, J=7 Hz, -O-CH 2 -Q j 3 1.33 6H, -OH 3 2.86 2H, 4.00 2H, 4.19 2H, J=7 Hz, -O-Q j 2

H

3 5.90 (AS, 1H, J--16.4 Hz, 6.87-7.34 (in, 9H, Arom.), 7.48 (AS, 1 H. J= 16.4 Hz, Pyr-OH=) EXAMPLE 208 (4--RFLU0 ROPH FJ e) 3-(2,2-DMETHY L-6 -7-PHENYL-2,3-DIHYDRO-H-PYRROLZINE-5- YL) ACRYLIC-ACI 0.6 mmoles of 34v dissolved in 30 ml of ethanol are reacted with 6 ml of 10 01 aqueous KOH in a manner similar to the saponification of the diphenyl-2,3-dihydro- 1H-pyrrolizinyl acrylic-acid esters.

Yield 0.20 g (89 melting point: 242 C IR, vma-3 3 O-22OO(OH),1685. 167O(C=O). 1600(C=C)crm 1 i 1 H-NMR 6 -CMSO): 6 (ppm) 1.27 6H, -OH 3 2.84 2H, 4.06 (s, 2H, 5.92 (AS, 1IH, J=1 6.4 Hz, 6.87-7.4 1 (in, 9H, Ai-cMr ad Pyr-CH=) EXAMPLE ,209 (4-LUWOg~PMEW/.) 3-(2,2-DIMETHYL-6- PeOR@--PHENYL-2,3-DIHYDRO-1H-PYRROLIZINE-5-YL)- PROPIONIC ACID (27v) 0.3 mmoles of 27v are reacted in the manner of the procedure for hydrogenating the aro matics-substituted *diphenyl-2,3-dihydro- *get acrylic-acids. Palladium is used as the catalyst. The product is precipitated by means of hexane.

Yield: (0.08 g (71 melting point: 182 0 C

C

2 4

H

24 FN0 2 (377.5) COMPUTED: C 76.4 H 6.41 N 3.7 MEASURED: C 75.8 H 6.56 N 3.3 IR: Vmax =3300-2400 1710 1605 (0C)a Cil 1 H-NMR: b (ppm)=1.30 (s,6H, -OH 3 228-2.58 (in,2H, -CH 2 2.73- 3.03 (mn, 2H, Pyr-0HZ-), 2.81 2H. 3.68 2H. 6.76- 7.28 (mn, 9H, Aroin.) EXAMPLE 210 2,2-DIMETHYL-6-(4-PHENOXYPHEN Y L)-7-PHENYL-2,3-DIHYDRO- 1H- PYRROLIZINE (1w) mmoles of 2 benzyl-4,4-dimethyl-A 1-[pyrroline lb 3 are reacted with mmoles of a -bromo-4-chloroacetophenone in 50 ml of ethanol similarly to the procedure for preparing the 6-aryl-7-phenyl-2,3-dihydro- lH-pyrrolizines. Purification is by column chromatography (A1 2 0 3 n-hexane/ether 9 Following concentration of the eluates, 1w remains in the form of oil Yield 2.7 g (36

C

27

H

25 N0 (379.5) I R: 1605 und 1595 (C=C)aml 1 H-NMR: 6 (ppm) 1.28 6H. -OH 3 2.78 2H, 3.71 2H, C-3), *99* 6.65 1H, 6.7&-7.57 (in, 14H, Arom.) EXAMPLE 211 2,2-DIMETHYL-6-(4-PHENOXYPL-ENYL)-7-PH-ENYL-2,3-DIHYDRO-1H- PYRROLIZLNE-5-YL-CARBALDEHYDE (6w) mnmoles of 1w 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 POCd 3 similarly to the procedure for the Vilsmeier formylation of the diphenyl-2,3-dihydro-IH-pyrrolizines.

Purification is by column chromatography (silica gel, CH 2

CI

2 The product is see.

precipitated by ethanol.

Yield: 0.94 g (38 melting point: 139 C

C

2 sH 25 -N02 (407.5) I R: "'max =1645 (C00), 1605 ufld 1590 cflTl 1 H-NMR: 6 (ppm) 1.30 6H, -OH 3 2.81 2H, 4.17 '2H, 0-3), 6.84-7.47 (mn, 14H, Aron,.), 9.40 1H, -CHO) EXAMPLE 2171 3-(2,2-DIMETHYL-6-(4-PHENOXYPHENYL-7-P-AHENYL-2,3-DIHYDRO-I- ETHYLESTERS, (34w) 2 mmoles of 6w dissolved in 5 ml of absolute CH 3

CI

2 are reacted with the solution of 2 mmoles (0.86 g) of ethoxycarbonyltrimethyltriphenyiphosphonium bromide in 4 ml of absolute ethanol and a solution of Na-ethanolate prepared from 6 mmoles (0.14 g) of sodium and 3 ml of absolute ethanol in a manner similar to the procedure for preparing the diphenyl-2,3-dihydro-1H-pyrrolizinyl acrylic -acid esters. Purification is by column chromatography (silica gel, CH 2 C1 2 The product remains in the form of foam after the eluates have been concentrated.

0~*Yield: 0.33 g (35 melting point: from 690' C

C

32

H

3 1 N03 (477'.6) I R: vma 1705 16 10 crrr' see IH-NMR: 6 (ppm) =1.28 3H, J=7 Hz, -0-CH2-QH3), 1.33 6H, -0H3), 2.86 2H, 4.00 2H, 4.19 2H, J=7 Hz, -0-CH2-CH3), 5.92 (AB, 1H, J=16 Hz, 6.83-7.44 (in, 14H, Arcoi.), 7.56 (AS, 1 F, J= 16 Hz, Pyr-CH=) EXAMPLE 213 3-(2,2-DIMETHYL-6-(4-PHENOXYPHENYL)-7-PHENYL-2,3-DIHYDRO-lH- ACRYLIC ACID 0.6 mmoles of 34w dissolved in 30 ml of ethanol are reacted with 6 ml of 10 01 aqueous KOH in a mariner similar to the procedure for saponifying the diphenyl- 2,3-dihydro- 1H-pyrrolizine-5-yl acrylic-acid ethylesters.

Yield: 0.23 g (85 melting point: 198 C 27

NO

3 (449.5) COMPUTED C 80.2 H 6.05 N 3.1 MEASURED C 79.9 H 6.07 N 2.7 IR: vmax 3300-2200 1675 1590 a~rl 1 H-NMP (d 6 -DMSO): 6 (ppm)- 1.27 6H, -CH 3 2.83 2H, 4.06 (s, 2H, 5.92 (AB, 1H, J16.2 Hz, 6.86-7.57 (in, iH, Arorn. and Pyr-CH=) EXAMPLE 214 3-(2,2-DIMETHYL-6-(4-PHENOXYPHENYL)-7-PHENYL-2,3-DIHYDRO-1H- PROPlONIC ACID (27w) 0.3 rnmoles of 35w are reacted in the manner of the procedure for hydrogenating the ar-)matics-substituted 3-(6,7-diphenyl-2,3-dihydro-1H-pyrr zine-5-y1) acrylic acids. Palladium is used as the catalyst. The product is precipitated by n-hexane.

Yield: 0.10 g (74 melting point: 149 'C

C

30

H-J

9 N0 3 (451.6) COMPUTED C 79.8 H 6.47 N 3.1 MEASURED C 79.5 H 6.61 N 2.7 I R: vmax 330 0 2 400 1710 1 6 05 nd 1595 CM_ 1 IH-NMR: 6 (ppm) =1.29 6H, -CHA) 2.34-2.63 (in, 2H, -0HZ-CO-), 2.77- 3.06 (in, 211I, Fyr-CHZ-), 2.83 2H, 3.69 2H, 6.85- 7.47 (in, 14H, Arom.) EXAMPLE 215 2 IMETHYL- 6 -PH ENO XYPH-ENYL) PH ENYL-2,3-DIHYDRO- IH- PROPIONIC-ACID ETHYLESTERS (54a) so.. *2.5 mmoles of 6-(4-phenoxyphenyl)-7-phenyl-2,3-dihydro-IH-pyrrolizine 1w dissolved in 3 ml of absolute toluene are reacted with 4 mnmoles (0.51 g) of 2- *0 diazopropionic-acid ethylesters dissolved in 3 ml of absolute toluene in a manner similar to the procedure for preparing the diphenyl-2,3-dihydro-IH-pyrrolizinyl acetic-acid ethylesters Isolation is by means of column chromatography (AbO- 3 n-hexane- /ether 9+ The oily product (0.45 g) remaining after concentration of the eluates is impure. It is reacted further without additional purification.

EXAMPLE 216 2-(2,2-DIMETHYL-6-(4-PHENOXYPHENYL)-7-PHENYL-2,3-DIHYDRO-lH- PYRROLIZINE-S-YL) PROPIONIC ACID (56a) The impure 54a (0.45 g) dissolved in 10 ml of ethanol is reacted with 5 ml of 10 aqueous KOH in a manner similar to the saponification procedure for the dip he nyl-2,3 -dihyd ro-1IH-pyrro lizinyl acetic-acid ethylesters. The time of saponification is 90 minutes. Purification is by column chromatography (silica gel, diisopropyl ether).

Yield: 90 mg melting point: 186 0 C 030H 29 N0 3 (451.6) IR: vma 3300-2400 1710 1605 and 1595 cm-1 1H-NMR: 8 (ppm) 1.23 VH, -OH 3 1.32 3H, -CH 3 1.48 3H, J=7 Hz, CH 3 2.72, 2.91 (AS. 2H, J=15.5 Hz, 3.81 2H, 3.96 1H, J=7 Hz, 6.81-7.50 (in, 10H, Atom.,) *fee

W'

09..

69a Exampl~e 217 [2 ,2-DIMETHYL-6- (4-CHLOROPHENYL) -7-PHENYL-2, 3-DIHYDRO-1H-

ACID

The method as mentioned in example 7 is repeated with w-bromo-4-chlorophenylacetophenone instead of o-bromoacetophenone as starting product. Herewith the title compound is obtained with a melting point of 1600C.

IR (KBr): 1710 cm-1 IH-NMR: (ppm): 1,28 6H, CH 3 2,83 2H, CH 2 3, 53 2H, -CH 2 -COOH) 3, 72 2H,-CH2-N); 6,97-7,32 (in, 9-H, Arom.) The 1C 5 0 -value for the inhibition of 5-lipooxgenase is 0.18 jimol and for the inhibition of the cyclooxygenase the 1C 5 0 -value is 0. 21 jimol.

0te. es C C C C C C CCC C C *C *C*C CC C* C C CC C* C C C* C CC C CSCCC. CC C *C C CC Table: Percentage Inhibition of Lipoxygenase and of Cyclooxygenase Inhibition

AM)

R'R4R' R 6 R7 LO Co Phenyl p-C1-Phenyl CH 2 -COOH CH 3

CH

3 100 70(1) Phenyl p-OCH 3 -Phenyl CH 2 -COOH CH 3

CH

3 85(l) 62(1) Phenyl p-N0 2 -Phenyl CH 2 -COOH OH 3

OH

3 92(3,3) 95(1) In- -Phenyl m-Cl-Phenyl CH 2 -COOH OH 3

OH

3 75(3,3) vent-- Phenyl o,p-C1-Phenyl CH 2 -COOH CH 3

CH

3 72, Phenyl m,p-Ci-Phenyl CH 2 -COOH CH 3

OH

3 74 Phenyl 2,3,4-Ci-Phenyl CH 2 -COOH OH 3

CH

3 79(3,3) -Phenyl p-C1-Phenyl CH 2 -COOH H H 85(3,3) 50(1) Phenyl Phenyl CH 2 -COOH CH 3

CH

3 44(3,3) 82(1) Prior Phenyl Phenyl (CH 2 2 -COOH H H 68(10.1 55(10) Phenyl p-C1-Phenyl CHO H H 14(10) 71(10) Art -Phenyl p-CH 3 O-Phenyl CHO H IH 46(10) 174(10) Phenyl p-C1-Phenyl CH 2 -OH H H 19(10) 51(10)

Claims (8)

1. Substituted pyrrolizin compounds of the general formula I: R R 4 N 6 N (I) R wherein any two of the residues R R and R independently represent an aryl group, with at least one aryl group substituted by one or two residues selected from a halogen atom, a nitro, a C 1 -C 4 alkoxy, a hydroxy, a C 1 -C 4 alkyl or phenoxy group, and the third residue denotes CO 2 H, COSC 1 -C 4 alkyl or A-X, with A being a straight-chain or a branched C 1 -C 8 alkylene group which may include an ether or a carbonyl group or being a C 2 -C 8 alkenylene group, X being CO 2 H, SO3H, CHO, OH or SH with the proviso that A is not CH 2 R 6 7 when X is OH, and where R and R independently represent a hydrogen atom or a C 1 -C 4 alkyl group, and their pharmaceutically compatible salts and esters.

2. Compounds defined in claim 1 wherein two of the 3 4 5 S 25 residues R R and R represent a phenyl group, optionally substituted by one or two residues selected from a halogen atom, a C1-C4 alkyl, C 1 -C 4 alkoxy, hydroxy, phenoxy and nitro group, and the third residue represents A-X, where A denotes a C 1 -C 8 alkyl group or 30 a C2-C8 alkenyl group and X represents CO 2 H.

3. Compounds defined in claim 2, wherein the halogen atom is selected from the group consisting of fluorine and chlorine.

4. Compounds defined in claim 1 of the general formula II: -72-- R 3 R 7 4 AX (II) wherein R and R 7 denote a hydrogen atom or a 3 4 C1-C 4 alkyl group, R and R independently represent a phenyl group which may be substituted by a halogen atom, A represents a C 1 -C 8 alkyl group and X represents CO2H. 3 4 Compounds defined in claim 4 wherein R and R independently represent a phenyl group or a p-chlorophenyl group and where AX represents CH 2 CO 2 H.

6. Compounds defined in claim 5 wherein R 6 and R represent a C 1 -C 4 alkyl group.

7. Compounds defined in claim 6 wherein the C1-C 4 S: 20 alkyl group is a methyl group.

8. Pharmaceutical compositions containing at least one compound defined in any one of claims 1 to 7, together with pharmaceutically compatible inactive substances and/or additives.

9. Process for preparing the compounds defined in any one of claims 1 to 7, which comprises reacting A) a compound of the general formula III: SCH 2R (III) -73- wherein R 6 and R 7 independently represent a hydrogen atom or a C 1 -C 4 alkyl group, with a compound of the general formula IV: R 5 CH C R 4 (IV) x wherein X represents chlorine or bromine, where two of the residues R R and R are as defined in claim 1 and the third residue represents a hydrogen atom, to obtain a compound of the general formula I: R 4 1 R Swherein the residues R to R are as defined above, and B) introducing into the obtained compounds a hydroxymethyl group, acid ester group or formic acid 25 thioester group and, optionally, converting to the desired o• 3 4 5 residues R R and R by reduction, ester cleavage, Wittig-reaction, hydrogenation or a combination thereof. DATED this 26th day of November 1992 PROFESSOR DR GERD DANNHARDT AND MERCKLE GmbH Patent Attorneys for the Applicant: F.B. RICE CO.