320187 2.3-Diarylindoles 407

Arch. Pharm. (Weinheim) 320,407-417 (1987)

Synthesis and Estrogen Receptor Affinity of 2,3-Diarylindoles

Josef Strohmeier and Erwin von Angerer*

Institut fur Pharmazie, Lehrstuhl Pharmazeutische Chemie 11, Universitat Regensburg, Universitatsstra- Be 3 1, D-8400 Regensburg Eingegangen am 30. Mai 1986

2-Phenylindoles with aromatic substituents at C-3 and hydroxy functions at the aromatic rings were syn- thesized and tested for their binding affinity for the calf uterine estrogen receptor. Most of these indoles bind to the estrogen receptor. The highest binding affinity (1,25 % of estradiol) was found with 3-(4-hy- droxyphenyl)-2-phenylindole (3b). The acetate of 3b was studied in vivo. It was devoid of estrogenic or antiestrogenic activity in the mouse and inhibited only weakly the growth of hormone-dependent DMBA- induced rat mammary tumors.

Synthese und 6strogenrezeptoratZt von 2,3-Diarylindolen

2-Phenylindole mit aromatischen Substituenten an C-3 und Hydroxylgruppen an den aromatischen Rin- gen wurden synthetisiert und auf ihre Affinitat zum 6strogenrezeptor aus Kalbsuteri gepriift. Die meisten dieser Indole binden an den 6strogenrezeptor. Die hochste Bindungsaffnitat (1,25 % von Ostradiol) wur- de beim 3-(4-Hydroxyphenyl)-2-phenylindol(3b) gefunden. Das Acetat von 3b wurde auch in vivo unter- sucht. Es besalj keine ostrogene oder antiostrogene Aktivitat in der Maus. Das Wachstum des hormonab- hangigen DMBA-induzierten Mammacarcinoms der Ratte wurde nur schwach gehemmt.

Non-steroidal compounds having estrogenic and antiestrogenic activity are of interest for controlling estrogen-dependent neoplasms1- 2). Recently, we found that 2-phenylindole is a suitable structure for the development of new agents for the treatment of estrogen-responsive mammary tumors. Some derivatives show high binding affinities for the estrogen receptor and inhibit the growth of experimental mammary tu- mors3-5). These findings prompted us to extend our studies onto 2-phenylindoles bearing a phenyl, benzyl or benzoyl group at C-3. These compounds are structurally related to the triphenylethylene antiestrogens but lack the basic side chain of these compounds. We showed previously that the amino function is not a prerequisite for estrogen antagonistic activity@. The structural variations of the 1,2-diarylindoles concern- ed the number and positions of aromatic hydroxy groups and the substituent at the nitrogen. The objec- tive of this work was the search for new compounds with binding affinity for the estrogen receptor and higher activity against hormone-dependent tumors than compounds that are presently in use.

,R3

x

\ R l

R 2

R' = H,CH3,C2H5

R2= H,OH

R3= H,OH

R ~ = ti, 5- or6-OH

X = - , CH2, C O

0365-6233/87/0505-407 $02.50/0

0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1987

408 19. Angerer and Strohriieier Arch. Pharm.

Chemistry

The indoles 3a-7a and 13a were synthesized according to Fischer7! The hydrazones obtained by the reaction of phenyl hydrazine hydrochlorides 1 with the aromatic keto- nes 2 and 12 were not isolated but directly converted into the 2,3-disubstituted indoles by treatment with HCI (Fig. 2). The 2.3-diphenylindoles 10a and l la were prepared according to ref.’) by heating anisidine (8) with benzoin (9) in the presence of HCl. The Fischer synthesis of the 3-benzylindole 15 failed. Therefore, the Bischler method was applied in this case: Reaction of 3-methoxy aniline (8a) with the bromo ketone 14 af- forded 15. Indole 17 with a 4-methoxybenzoyl group was obtained by the reaction of 4- methoxybenzoyl chloride with the Grignard reagent prepared from 2-phenylindole (16) and methyl magnesium iodide.

R3

1 2 3a-7a R = H , O C H 3

8

rn

CHL a - /

l a + H 2 c

‘co -Q

OCH3

9 H

10a , Ila

H2C x.3 OCH3

\ H

12 13a

32018 7 2.3-Diarylindoles 409

14 15

’. tbCflg1 Z.H$OCgHqCOCI

H H !

16 17a

m R 2

1.NaNH2

2. R’ I 3a-5a,lla,15

R4

’R1

18a-23a R1= CH3,C2H5

R2,R3,R4= H,OCH3

N-Alkylated indoles were synthesized from the parent indole by treatment with NaNH2 followed by addition of methyl or ethyl iodide. Demethylation of the methoxy compounds was readily effected with BBr, in CH2CI2. The mono-hydroxy indoles lob, 13b, 17b, and 18b were purified by column chromatography. All of the other hydroxy derivatives had to be converted into the acetates in order to separate them from oxida- tion products and boric acid. After chromatography, the free hydroxy compounds were obtained by alkaline hydrolysis in methanol.

410 v. Arigerer and Strohrneier Arch. Pharm.

Estrogen Receptor Binding Affinity

The binding affinities for the estrogen receptor were measured by a competitive binding assay with 17P-[3Hlestradiol. Calf uterine cytosol was used as receptor source and the dextran coated charcoal (DCC) method was applied'). The relative binding af- finities (RBA) are given as the ratio of the molar concentrations of 17P-estradiol and indole required to decrease the receptor bound radioactivity by 50 %, multiplied by 100. All of the phenyl indoles with free hydroxy groups were tested for their binding af- finity; the RBA values are reported in Table 1.

Tab. 1: Estrogen Receptor Binding Affinities of compounds 3b-23b

compd. R' R2 R3 R4 X R B A ~ ) ~~

3b H H OH H - 1.25 4b H OH H 6-OH - 0.22 5b H H OH 6-OH - 0.30 6b H OH OH H - <0.04 7b H OH OH 6-OH - 0.22

lob H H H 5-OH - < 0.04 l l b H H H 6-OH - 0.18 13b H H OH H CH2 0.04 17b H H OH H c=o 0.45 18b CH3 H OH H - 0.82 19b C2H5 H OH H - 0.78 2Ob C2H5 H H 6-OH - <0.04 2lb c2 H5 OH H 6-OH - 0.22 22b C2H5 H OH 6-OH - 0.12 23b CH3 OH H 6-OH CH2 0.20

a) Relative binding affinities for the calf uterine estrogen receptor = ratio of molar concentrations of 17pestradiol (E2) and inhibitor required to decrease the amount of bound 3H E2 by 50 % x 100.

Most of the compounds show binding affinities less than 1 % of that of 17p-estra- diol. These values are much lower than those obtained with 2-phenylindole derivatives bearing an alkyl substituent or hydrogen instead of an aromatic group at C-33). Re- garding the monohydroxy derivatives, the highest binding affinities are observed with the 3-(4-hydroxyphenyl)-2-phenylindoles 3b, 18b and 19b. The RBA values are ab- out 1. In contrast to the 3-alkyl series, the receptor binding ist not influenced by an al- kyl substituent at the nitrogen. Similar observations are made in the dihydroxy series (4b, 21b, 5b, 22b). Introduction of additional hydroxy functions into the monohydro- xylated derivatives did not improve the receptor binding. Since the unexpectedly low receptor affinity of the 2,3-diphenyl indoles might be due to the rather rigid arrange- ment of the three aryl groups compared to acyclic triphenyl butenes, we introduced a CH,- and a CO-fragment, respectively, between C-3 and the phenyl ring. A similar structural modification exists in the antiestrogens trioxifenel') and keoxifene"). These structural alterations did also not increase the affinity.

320187 2.3-Diarylindoles 41 1

Biological Properties

The diphenylindole 3c was selected for in vivo studies since its hydroxy derivative 3b that is thought to be the active metabolite showed the highest affinity in this series.

Estrogenicity and antiestrogenic activity was determined in the mouse uterine weight test (Table 2)12). The indole 3c was devoid of significant uterotrophic activity. A weak antagonistic effect was observed at a dose of 125 pg/animal.

Tab. 2: Estrogenic and Antiestrogenic Activity of 3c in the Mouse Uterine Weight Test

uterotrophic test antiuterotrophic test compd dose,”) effectb) dose,aib) effect’) inhibn

rg r g %

control 14.4 2 3.0 14.4 k 3.0 3c 5 11.9 f 2.3 5 43.5 f 5.5

25 13.8 f 4.9 25 45.3 k 6.2 125 13.0 * 3.0 125 41.6k1.4 1 8d) 625 19.0 f 5.0

estrone 0.4 41.4 k4 .2 0.4 41.6 2 4.2

a) Dose per animal, administered at 3 consecutive days sc. b) Uterus dry weight (milligrams)/body weight (grams) X 100, determined 24 h after the last injec-

c) Simultaneous administeration of 0.4 pg of estrone per animal and day. d) Significant (p < 0.05).

tion; mean of 10 animals + SD.

For evaluation of the antineoplastic activity of 3c, the 7,12-dimethylbenz[aIanthra- cene (DMBA) induced mammary tumor of the Sprague-Dawley rat was used. This tumor shows a marked sensitivity towards ovarian hormones by regressing following the surgical removal of the ovaries5). In this and other respects, the rat tumor resembles the human hormone-dependent breast cancer13!

Treatment of rats bearing DMBA-induced mammary carcinomas with 6 x 6 mg 3c/ kg and week led only to a non-significant inhibition of tumor growth. The change of tumor area after 4 weeks was + 334 % (control: + 5 15 %). This effect was mainly due to an increased fraction of static tumors (31 % vs. 14 %).

Discussion

Many investigators have shown that the arrangement of three aryl groups - one of which bearing a hydrophilic residue - around a double bond leads to a class of endocri- nely active compounds generally described as antiestrogens. The most prominent ex- ample is tamoxifen, a drug that is widely used for the treatment of estrogen dependent breast cancer. Studying the pharmacological effects of one representative of the struc- turally related 2,3-diphenylindoles we found a considerably reduced endocrine and an- tineoplastic activity. Compound 3c with an RBA-value of 1.25 for the deacetylated de-

412 13. Arinerer arid Strohrneier Arch. Pharm.

rivative showed no estrogenic activity in the mouse uterus and only a weak inhibition on hormone-dependent rat tumors. The lack of activity of 3c can only partly be ex- plained by the rather low receptor affinity. For comparison, the acyclic triphenyl bu- tene with an oxygen function at the corresponding position has only a marginally higher affinity but it shows a strong antitumor effect6). A similar decrease of activity after cy- clisation to indoles was observed in a series of cyclofenil analogsL4).

The authors thank R. Brunner, A. Schmitz-Seitz and G. Seidl for technical assistance and the Deutsche Forschungsgemeinschaft (SFB 234) for financial support.

Experimental Part MP: Biichi 5 10 apparatus (uncorr.). - 'H-NMR Spectra: Varian EM 360 L spectrometer. - Column Chromatography: Kieselgel60 (Merck). - Elemental Analyses: Mikroanalytisches Laboratorium, Univ. Regensburg.

General Procedure for the Preparation of Methoxy-substituted 2.3-Diarylindoles (3a-7a)

A mixture of 1,2-diphenylethanone 2 (0,l mol) and 2,O ml of glacial acetic acid was added to the pertinent phenylhydrazine 1 (0,l mol) in 100 ml of dry benzene. The mixture was kept boiling for 1 h while the wa- ter formed distilled off. After cooling, the solvent was removed i. vac. The residue was redissolved in 100 ml of glacial acetic acid, saturated with HCI and refluxed for 1,5 h. The cold mixture was poured onto ice and extracted with CH,CI,. The org. layer was dried (MgSO,). After evaporation, the residue was pu- rified by column chromatography (SiO,; CH,CI,) and recrystallized from EtOH: colorless crystals, 20-46 % yield. 3a7), 6a7), 7a7) have been described previously.

6-Methoxy-2-(4-methoxyphenyl)-S-phenylindole (4a): mp. 17 1-1 73O; C,,H,,NO, (329.4), Calcd. C 76.9 H 5.89 Found C 76.7 H 5.79.- 'H-NMR(d,-DMSO):6(ppm)3.77(s;3H,OCH,),3.80(s;3H,OCH3), 6.63-7.46 (m; 12H, ArH).

6-Methoxy-3-(4-methoxyphenyl)-2-phenylindole (5a): mp 198- 199"; C,,H,,NO, (329.4), Calcd. C 76.9 H 5.89 Found C 76.9 H 5.83.- 'H-NMR(d,-DMSO):6(ppm)3.78(s;3H,OCH,),3.80(s;3H,OCH3), 6.62-7.50 (m, 12H, ArH).

5-Methoxy-2,3-diphenylindole ( 1 Oa)

A mixture of 0.08 mol4-methoxyaniline, 0.024 mol benzoin and 1 ml of conc. HCI was heated to 200'for 5 h with stirring. The cold mixture was treated with 100 ml of 2N HCI and extracted with CH,CI,. The org. layer was dried (MgSO,). After evaporation, the residue was recrystallized from EtOH. Yield 40 %; mp. 155-156'; C,,H,,NO (299.4), Calcd. C 84.3 H 5.72 Found C 84.5 H 5.81. - 'H-NMR (CDCI,): G(ppm) 3.78 (s, 3H, OCH,), 6.78-7.40 (m, 13H, ArH), 8.22 (s, lH, NH). Compound 1 la has been described*).

3-(4-Methoxybenzyl)-2-phenylindole (1 3a)

0,023 mol3-(4'-methoxyphenyl)-l-phenyl-l-propanone in 100 ml of EtOH was added slowly to a boiling mixture of phenylhydrazin (0,023 mol) and 15 ml of conc. HCI in 200 ml of EtOH. After addition boiling was continued for 12 h. The cold mixture was poured onto ice and extracted with CH,CI,. The org. layer was washed (sat. NaCl solution), dried (MgSO,) and the solvent stripped off. The residue was purified by chromatography (SO,; CH,CI,) and recrystallized from EtOH. Yield 17 96; mp 153-155'; C,,H,,NO (299.4), Calcd. C 84.3 H 5.47 Found 84.0 H 5.73. - 'H-NMR (CDCI,) 6 3.71 (s; 3H, OCH,), 4.16 (s; 2H, -CH,-), 6.66-7.40 (m; 13H, ArH).

320/87 2.3- Diarylindoles 413

3-(4-Methoxybenzoyl)-2-phenylindok (17a)

A suspension of 0,02 mol MeMgI in 30 ml of dry Et,O was added slowly to a stirred solution of 0.015 mol 2-phenylindole in 80 ml of dry Et,O. After an additional I h of stirring, 2 ml of 4-methoxybenzoylchloride was added dropwise at 0' with stirring. After addition, the mixture was treated with KHCO, solution. The org. layer was dried (MgSO,) and evaporated. The residue was chromatographed (SiO,). At first, with CH,CI, 2-phenylindole was isolated. The second fraction with CH,CI,/Et,O (1 :1) contained the product. After evaporation, recrystallization from EtOH afforded 24 %of 19; mp 151-153"; C,,H,,NO, (327.4), Calcd. C 80.7 H 5.23 Found C 80.5 H 5.39. - 'H-NMR (CDCI,) 6 (ppm) 3.77 (s, 3H, OCH,), 6.68,7.70 (AB, J = 7 Hz, 4H, ArH), 7.06-7.90 (m, 9H, ArH), 9.52 (s, IH, NH).

3-Benzyl-6-methoxy-2-(4-methoxyphenyl)indole (15)

0,06 mol of 2-bromo-1-(4'-methoxyphenyl)-3-phenyl- 1-propanone in xylene was added slowly to a boiling mixture of 3-methoxyaniline (0,2 mol) and 35 ml of N,N-dimethylaniline with stirring. After addi- tion, the mixture was kept at 170Ofor 3 h. After cooling, EtOAc was added and the mixture extracted with 2N HCI. The aqueous layer was extracted several times with EtOAc. After washing with 2N HCI and wa- ter, the org. layer was dried (MgSO,) and evaporated. The oily residue was alkylated without further puri- fications. Yield 37 %. -lH-NMR (CDCI,) 6 (ppm) = 3.80 (s; 3H, OCH,), 3.86 (s; 3H, OCH,), 4.20 (s; 2H, -CH,-), 6.63-7.60 (m; 12H, ArH), 8.25 (s; lH, NH).

General Procedure for the Alkylation of 2.3-Diarylindoles

Sodium (1,44 g; 0,06 mol) was added in portions to 200 ml of liquid ammonia. After the disappearance of the blue color, 0,035 mol of the indole in 100 ml dry THF was added at -70". After stirring for additional 30 min, 0,042 mol of the alkyl iodide in dry THF was added slowly. After 30 min, the cooling bath was re- moved to allow the ammonia to evaporate. The residue was treated with water and extracted with Et,O. The org. layer was washed with NaHSO, solution and water, and dried (MgSO,). The residue obtained after evaporation was purified by chromatography (SiO,; CH,CI,) and recrystallized from EtOH. The yields ranged from 75 % to 81 %.

General Procedure for the Ether Cleavage and Acetylation

8,O mmol of the methoxy substituted 2,3-diarylindole in 50 ml dry CH,CI, was cooled to -60' under N, and BBr, (3,a ml; 0,035 mol) was added. After 30 min, the cooling bath was removed and the mixture stirred over night. With cooling, the mixture was poured into an aqueous solution of NaHCO,. The org. layer was separated and the aqueous phase was extracted with EtOAc. The combined org. layers were washed with water and dried (MgSO,). After the solvent was removed, the dark residue was treated with 6,O g Ac,O and 6,O ml pyridine. After refluxing for 2 h, the mixture was poured onto ice and extracted with CH,CI,. The org. layer was washed with 2N HCI and water, and dried (MgSO,). After evaporation, the remaining residue was chromatographed (SiO,; CH,CI,). The product was usually obtained as a solid and recrystallized from EtOH. The yields ranged from 57 to 72 %. The hydroxy-substituted 2.3-diarylin- doles lob, 13b, 17b, and 18b were not converted to the acetates but purified by column chromatography (SiO,) using CH,CI, as solvent.

General Procedure for the Hydrolysis of the Acetates

The acetoxy indole (0.3 g) was suspended in 20 ml of MeOH. Under N,, 4 ml2N NaOH were added and the mixture was stirred for 2 h at room temp. The clear solution was acidified with 2 N HCI and the MeOH was removed under reduced pressure. The aqueous mixture was extracted with CH,CI,. After drying (MgSO,) the solvent was evaporated. The residue crystallized after treating with a small volume of CH,Cl,. The yields were between 75 and 90 %.

Tab.

3: A

naly

tical

and

'H-N

MR

Dat

a of

Com

poun

ds 1

8a-2

3a

~~~

mP.

'H

-NM

R (

CDC1

3) 6 (

ppm

)=

OC

com

pd.

Form

ula

Cal

cd.

(mol

. wt.)

Fo

und

C

H

18a

128-

129

3.53

(s;

3H, N

CH

3), 3

.75

(s; 3

H, O

CH

s),

6.74

-7.7

6 (m

; 13H

, ArH

)

OC

H3)

, 4.0

9 (q

, J =

7 H

z; 2

GC

&C

H3)

, 6.

72-7

.82

(m; 1

3H, A

rH)

OC

H3)

, 4.0

4 (4

, J =

7 H

z; 2

H,-C

&C

H3)

, 6.

74-7

.69

(m; 1

3H, A

rH)

OC

Hs)

, 3.8

8 (s; 3

H, O

CH

3), 4

.04

(q, J

= 7

Hz;

-C

&C

H3)

, 6.

74-7

.70

(m; 1

2H, A

rH)

OC

H3)

, 3.8

8 (s

; 3H

, OC

H3)

, 4.0

4 (q

, J =

7 H

z;

2H,-C

&C

H3)

, 6.

70-7

.70

(m; 1

2H, A

rH)

23a

157

3.43

(s;

3H,N

CH

3),

3.80

(s;3

H,O

CH

3),

3.86

(s

; 3H

, OC

HJ)

, 4.2

0 (s

; 2H

,-CH

2-),

6.63

-7.6

0 (m

; 12H

, ArH

)

1 9a

91 -9

3 1.

25 (

t, J

= 7

Hz;

3H

,-CH

2CH

3), 3

.75

(s;

3H,

20a

93-9

5 1.

24 (

t, J

= 7

Hz;

3H

,-CH

2CII

3), 3

.89

(s;

3H,

21a

114

1.25

(t,

J =

7 H

z; 3

H,-C

HzC

kI3)

, 3.8

0 (s; 3

H,

22a

150-

151

1.25

(t,

J =

7 H

z; 3

H,-C

HzC

_H3)

, 3.7

4 (s

; 3H

,

C22

Hl9

NO

(3

13.4

)

(327

.4)

c2 3

H2 l

NO

c2 s

H2 1 N

O

(327

.4)

c2 4H

2 3N

02

(357

.5)

C24

H23

N02

(3

57.5

)

c2 4H

Z 3N

02

(357

.5)

84.3

6.

11

84.4

6.

10

84.4

6.

47

84.4

6.

54

84.4

6.

47

84.3

6.

57

80.6

6.

49

80.3

6.

63

80.6

6.

49

80.4

6.

73

80.6

6.

49

80.6

6.

57

P

P

Y

Tab.

4: A

naly

tical

and

'H-N

MR

Dat

a of

Com

poun

ds 3

c-23

c

mP.

OC

IH

-NM

R (C

DC1

3) 6 (p

pm)

=

com

pd.

Form

ula

Cal

cd .

(mol

. wt.)

C

H

3c

4c

5c

6c

7c

1 lc

19c

20c

21c

22c

23c

173-

175

223-

225

172-

174

226-

228

189-

191

189 -

190

141-

143

142 -

144

163-

164

196 -

1 98

159

2.26

(s; 3

H, C

OC

Hs)

, 7.0

0-7.

67 (m; 13

H, A

rH)

2.27

(s; 3

H, C

OC

H3)

, 7.0

0-7.

67

(m; 1

3H, A

rH)

2.26

(s;

6H, C

OC

H3)

, 6.7

6-7.

56

(m; 1

2H, A

rH)

2.30

(I;

6H

, CO

CH

3), 6

.79-

7.72

(m

; 12H

, ArH

) 8.

24 (s;

IH, N

H)

(s; 3

H, C

OC

H3)

, 6.7

5-7.

53 (m

; 11H

, ArH

), 8.

47

(s; l

H, N

H)

2.30

(s; 3

H, C

OC

H3)

, 6.7

3-7.

60

(m; 1

3H, A

rH),

8.41

(s; I

H, N

H)

2.27

(s; 3

H, C

OC

Hj)

, 2.2

9 (s

; 3H

, CO

CH

3), 2

.31

1.25

(t;

J =

7 H

z; 3

H,-C

HzC

_H3)

, 2.2

3 (s

; 3H

, C

OC

Hj),

4:0

9 (9

, J =

7 H

z; 2

H,-C

_H2C

H3)

, 6.

87-7

.79

(m; 1

3H, A

rH)

1.22

(t,

J =

7 H

z; 3

H,-C

H2C

_H3)

, 2.3

2 (s

; 3H

, C

OC

H3)

, 4.0

5 (4, J

= 7

Hz;

2H,-C

&C

H3)

, 6.

81-7

.75

(m; 1

3H, A

rH)

1.25

(t,

J =

7 H

z; 3

H,-C

H2C

_H3)

, 2.2

7 (s

; 3H

, C

OC

H3)

, 2.3

1 (s

; 3H

, CO

CH

3),4

.06

(q, J

= 7

Hz;

2H

,-C_H

2CH

3), 6

.80-

7.74

(m

; 12H

, ArH

) 1.

25 (t

, J =

7 H

z; 3

H,-C

HzC

_H3)

, 2.2

4 (E;

3H

, C

OC

H3)

, 2.3

2 (s

; 3H

, CO

CH

3), 4

.05

(9, J

= 7

Hz;

2H

,-C&

CH

3),

6.80

-7.7

5 (m; 12

H, A

rH)

2.27

(s;

3H, C

OC

Hs)

, 2.3

0 (s

; 3H

, CO

CH

3),

3.46

(s;

3H, N

CH

3), 4

.23

(P; 2

H,-C

H2-

), 6.

77-7

.67

(m; 1

2H, A

rH)

C22

H17

N02

(3

27.4

)

(385

.4)

(385

.4)

C24

H19

N04

(3

85.4

)

(443

.5)

C24

H1 g

N04

C24

Hl9

N04

C26

H2 l

N06

C22

H17

N02

(3

27.4

)

(355

.4)

c2 4

H2 1

NO

2

C24

H2 1

N02

(3

55.4

)

c2 6

H2 3

N04

(4

1 3.5

)

c2 6

H2 3

N04

(4

13.5

)

c2 6

H2 3

N04

(4

13 .5

)

80.7

80

.7

74.8

75

.2

74.8

74

.4

74.8

74

.9

70.4

70

.6

80.7

80

.6

81.1

80

.9

81.1

81

.3

75.5

75

.4

75.5

75

.5

75.5

75

.5

5.23

5.

09

4.97

5.

31

4.97

5.

11

4.91

5.

09

4.77

5.

12

5.23

5.

07

5.96

6.

08

5.96

5.

96

5.61

5.

56

5.61

5.

70

5.61

5.

91

416 11. Angerer and Strohrneier Arch. Pharm.

Tab. 5: 'H-NMR Data and Melting Points of Compounds 3b-23b

compd .

3b

4b

5b

6b

7b

1 Ob

l l b

13b

17b

18b

19b

20b

21b

22b

23b

Formula (mol. wt.)

153-154

86-88

227-230

258-261

201 -204

148-150

144-147

I85 -1 87

224-226

176-177

170-172

169-171

200-203

201 -203

72-75

6.76-7.52 (m; 13H, ArH)

6.57-7.40 (m; 12H, ArH)

6.53-7.46 (m; 12H, ArH)

6.36-7.12 (m; 12H, ArH)

6.50-7.39 (m; 11H, ArH)

6.66-7.40 (m; 13H, ArH)

6.85-7.47 (m; 13H, ArH)

4.10 (s; 2H,-CH2-), 6.57 (d, J = 9 Hz; 2H, ArH), 6.77-7.53 (m; 11H, ArH)

6.57, 7.52 (AB, J = 9 Hz; 4H, ArH), 7.08-7.80 (m; 9H, ArH)

3.63 (s; 3H, NCHs), 6.68-7.68 (m; 13H, ArH)

1.12 (t, J = 7 Hz; 3H,-CHzC_H3), 4.05 (q, J = 7 Hz; 2H,-C&CH3), 6.60-7.67 (m; 13H, ArH)

2H,-C_H2CH3), 6.60-7.50 (m; 13H, ArH)

2H,-CEI2CH3), 6.60-7.50 (m; 12H, ArH)

2H,-C&CH3), 6.59-7.47 (m; 12H, ArH)

6.57-7.37 (m; 12H, ArH)

1.12 (t, J = 7 Hz; 3H,-CHzC_H3), 3.98 (1, J = 7 Hz;

1.13 (t, J = 7 Hz; 3H,-CHzC_H3), 3.96 (q, J = 7 Hz;

1.15 (t, J = 7 Hz; 3H,-CH2C€I3), 4.00 (4, J = 7 Hz;

3.33 (s; 3H, NCH3), 4.08 (s; 2H,-CH2),

C20H15N0 (285.4)

(30 1.4)

C2QHl SN02 (301.4)

(301.4)

(317.5)

C20H1 !jNO (285.4)

(285.4)

(299.4)

(3 13.4)

(299.4)

(3 13.4)

(3 13.4)

(329.4)

c2 2H1 gN02 (3 29.4)

(329.4)

C2QH 1 sN02

C2QH1 SN02

C2QH15N03

C2QH1 5N0

c2 1 H17NO

c2 1 1 sN02

c2 1 1 7 N 0

C22H19N0

c2 2H19NO

C22H 19N02

C22H19N02

Estrogen receptor binding assay, immature mice uterine weight test, and the DMBA-induced rat mamma- ry tumor model have been described)).

References

1 R. L. Sutherland, V. C. Jordan, Eds. ,,Nonsteroidal Antiestrogens", Academic Press, Sydney (1981). 2 0. H. Pearson, A. Manni, and B. M. Arafah, Cancer Res. (Suppl.) 42, 3424s (1982). 3 E. von Angerer, J . Prekajac, and J. Strohmeier, J . Med. Chem. 27, 1439 (1984). 4 E. von Angerer, J. Prekajac, and M. Berger, Eur. J . Cancer Clin. Oncol. 21, 531 (1985).

320/87 Trichomonazide Wirkstoffe 417

5 E. von Angerer, J . Prekajac, M. R. Schneider, and M. R. Berger, J . Cancer Res. Clin. Oncol. fl0,216

6 M. R. Schneider, E. von Angerer, H. Schonenberger, R. Th. Michel, and H. P. Fortmeyer, J . Med.

7 J. Szmuskovicz, E. M. Glenn, R. V. Heinzelmann, J . B. Herter, and G. A. Youngdate, J. Med. Chem.

8 R. N. Iyer and R. Gopalchari, Indian J. Chem. 4, 520 (1966). 9 G. Kranzfelder, R. W. Hartmann, E. von Angerer, H. Schonenberger, and A. E. Bogden, J . Cancer

10 A. Manni, B. Arafah, and 0. H. Pearson in ,,Non-Steroidal Antiestrogens"; R. L. Sutherland and V.

11 L. J. Black and R. L. Goode, Endocrinology 109, 987 (1981). 12 B. C. Rubin, A. S. Dorfman, L. Black, and R. I. Dorfman, Endocrinology 49,429 (1951). 13 H. H. Fiebig and D. Schmahl, Recent Res. Cancer Res. 71,80 (1980). 14 J. Strohmeier and E. von Angerer, Arch. Pharm. (Weinheim) 318,421 (1985).

(1985).

Chem. 25, 1070 (1982).

9, 527 (1966).

Res. Clin. Oncol. f03, 165 (1982).

C. Jordan (Eds.), Academic Press, Seydney (198 1).

[Ph 2191

Arch. Pharm. (Weinheim) 320,417-424 (1987)

Trichomonazide Wirkstoffe, 3. Mitt.')

Aryloxy-chlor- 1,3,5 -triazine

Alfred Kreutzberger') und Ulrich Rose**) ***)

Institut fur Pharmazie der Johannes Gutenberg-Universitat Mainz, SaarstraOe 21, 6500 Mainz Eingegangen am 2. Juni 1986

Die Umsetzung von 2,4-Dichlor-6-(dihexylamino)-1,3,5-triazin (1) mit Phenolen (2) fiihrt bei niedrigen Temperaturen zu den Monoaryloxy-chlor- 1,3,5-triazinen (3a-c), unter drastischeren Reaktionsbedin- gungen zu den Bis-(aryloxy)-1,3,5-triazinen (4c-d). Fur die neuen Verbindungstypen ist besonders cha- rakteristisch die rnassenspektroskopische Abspaltung der Aryloxygruppen, beispielsweise in 4c der Uber- gang von m/z 504 nach m/z 383. Auffallende trichomonazide und blutzuckersenkende Wirkungen ver- mag insbesondere 3b auszulosen.

*) Als Teil eines Referats vorgetragen im Wissenschaftlichen Kolloquium der Faculty of' Pharmacy,

'9 Aus der Dissertation U. Rose, Universitat Maim 1985. "') Herrn Prof. Dr. H. Oelschluger, Universitat Frankfurt am Main, mit den besten Wiinschen zum 65.

University of Manitoba. Winnipeg (Manitoba) Kanada. September 1985.

Geburtstag gewidmet.

0365-6233/87/0505-417 IE 02.50/0

0 VCH Verlagsgesellschaf? mhH, D-6940 Weinheim, 1987