Pyranenamines: A New Series of Potent Antiallergic Compounds

8 Pyranenamines: A New Series of Potent Antiallergic Compounds K. M. SNADER, L. W. CHAKRIN, R. D. CRAMER III, Y. M. GELERNT, C. Κ. ΜΙΑΟ, D. H. SHAH, Β. M. SUTTON, J. W. VENSLAVSKY, and C. R. WILLIS Research and Development Division, Smith Kline & French Laboratories, Philadelphia, PA 19101

Downloaded by UNIV OF MISSOURI COLUMBIA on May 2, 2013 | http://pubs.acs.org Publication Date: February 22, 1980 | doi: 10.1021/bk-1980-0118.ch008

1

The discovery of disodium chromoglycate (DSCG) in 1969 and its unique antiallergic activity (1) has prompted many labora tories, including our own, to search for more potent, orally active compounds with this activity (2). We reported in 1976 on a mildly active new series, the pyrantriones (I) (3).

We now report an extension of this series, the amine adducts or pyranenamines (II) which have potent, oral, DSCG-like activity

as demonstrated both in the rat PCA test system and in rat and primate in vitro systems which measure the antigen-IgE induced release of allergic mediators. Introductory Chemistry Condensation of the pyrantrione I with various aromatic and aliphatic amines gives the monopyranenamine II, whose skeletal Current address: Hercules, Inc., Central Research Department, Wilmington, DE 1

0-8412-0536-l/80/47-118-145$05.00/0 © 1980 American Chemical Society

In Drugs Affecting the Respiratory System; Temple, D.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.

DRUGS A F F E C T I N G T H E RESPIRATORY

146

SYSTEM

s t r u c t u r e and tautomeric s t a t e can be c l e a r l y demonstrated by carbon and proton nmr spectroscopy. The bisenamine can a l s o be


II

prepared under f o r c i n g c o n d i t i o n s such as elevated temperature and a z e o t r o p i c removal of water, but i n general the monoenamine i s r e a d i l y obtained i n high (50-85%) y i e l d by p r e c i p i t a t i o n from the r e a c t i o n media. The s t r u c t u r e o f I I was o r i g i n a l l y suggested by Kiang and h i s colleagues (4) but was not r i g o r o u s l y proven. Examination of the proton and carbon-13 nmr s p e c t r a s u b s t a n t i a t e the tautomeric form shown here as I I , Furthermore an x-ray c r y s t a l l o g r a p h i c examination was performed on the p-hydroxy analog, 15, and agreed with our assignment. Test

System

We use the conventional (Goose and B l a i r ) i n h i b i t i o n of antigen-IgE induced passive cutaneous anaphylaxis (PCA) r e a c t i o n i n r a t s as a p r e l i m i n a r y t e s t system ( 5 ) . Test compounds a r e administered a t the optimum pretreatment time of 0.5 minutes p r i o r to antigen challenge i n the i , v . t e s t s and 15 minutes p r i o r to antigen challenge i n o r a l t e s t s . G e n e r a l l y , s i x animals are used i n each t e s t group. In a d d i t i o n , the a b i l i t y of any t e s t compound to i n h i b i t a d i r e c t , exogenous challenge of histamine or s e r o t o n i n i s measured when there i s s i g n i f i c a n t a c t i v i t y i n the PCA system. Monosubstituted

Pyranenamines

In the search f o r improved potency, a group of simple sub~ s t i t u e n t s was f i r s t examined as shown i n Table I . In t h i s t a b l e the r e s u l t s of the PCA t e s t a r e shown as a percent i n h i b i t i o n a t the intravenous dose t e s t e d . For those compounds which were s u f f i c i e n t l y a c t i v e to t e s t s e v e r a l doses, an I D , or a dose which gives a 50% i n h i b i t i o n of the PCA r e a c t i o n , was c a l c u l a t e d . The mean percent i n h i b i t i o n was evaluated u s i n g a one-sided Student " t " t e s t and ρ i s 0.01 u n l e s s otherwise noted. The column l a b e l e d p l i s a c a l c u l a t e d v a l u e used f o r QSAR work and i s d e f i n e d as l o g ( l / I D o ) . The obvious d i f f i c u l t i e s i n e s t i m a t i n g the I D from a s i n g l e dose experiment are discussed i n the f o l l o w i n g paper. The I D of DSCG as determined i n our system i s included as compound 13^ f o r r e f e r e n c e purposes. 5 0

5 0

5

5 0

5 0


8. SNADER ET AL.

147

Pyranenamines


TABLE 1

CMPD. NO.

DOSE

R

3

% INHia

b

P|50 -0.70

1

H

10

76

2

2-Cl

10

36

-1.20

3

3-CI

10

74

-0.70

4

4-CI

10

84

-0.60

5

4-F

10

54

6

4-Br

7

4-N0

8

2-COOC H

0.5 2

2

4-COOC H

9

2

5

5

0(NS)

-1.00 c

-1.50

10

17(NS)

-1.34

5

18(NS)

-0.50

5

6(NS)

-1.50

10

3-S0 NH

2

0.5

45

0.31

11

4-S0 NH

2

0.5

12(NS)

0.00

12

4-CH

13

DSCG

2

2

3

10 0.9t

33

-1.15

50

a. dose in mg./kg.; b. p=0.01 except where noted; c. NS=Not significant;

t=calculated IDQ 5



148

DRUGS A F F E C T I N G

T H E RESPIRATORY

SYSTEM

The analogs were prepared from r e a d i l y a v a i l a b l e a n i l i n e s . Halogen s u b s t i t u t i o n as w e l l as s u b s t i t u t i o n with other e l e c t r o n withdrawing groups d i d not s u b s t a n t i a l l y improve potency i n the PCA assay. Simple a l k y l s a l s o had only minor impact on potency. More s i g n i f i c a n t improvements were made with hydroxyl f u n c t i o n s and t h e i r d e r i v a t i v e s , as shown i n Table I I . The phenol e s t e r s were prepared by conventional methods from the phenoxide and a s u i t a b l e a c i d h a l i d e or anhydride. The PCA a c t i v i t y of the v a r i o u s e s t e r s reached a maximum with the v a l e r a t e (19) but even t h i s was not s i g n i f i c a n t l y more potent than the parent 4-hydroxy d e r i v a t i v e , 15, which was our e a r l y lead candidate. Another s i g n i f i c a n t improvement was obtained with amine s u b s t i t u e n t s and t h e i r d e r i v a t i v e s as shown i n Table I I I , The amines were prepared by r e d u c t i o n of the corresponding n i t r o pyranenamine. Amide d e r i v a t i v e s , I I I , were prepared from the corresponding n i t r o - a n i l i n e IV and then condensed f o l l o w i n g r e d u c t i o n as shown i n Scheme I. Two i n t e r e s t i n g compounds were the sulfamides .56 & 57_ which were prepared from sulfamyl c h l o r i d e and the corresponding n i t r o aniline. The para s u b s t i t u t e d compound was s t r a i g h t f o r w a r d but the meta isomer produced equal amounts of the sulfamide and the d i s u l f a m i d e intermediate. One of the d r i v i n g f o r c e s i n our s e l e c t i o n of d e r i v a t i v e s was the QSAR s t u d i e s being performed and two choices made e a r l y i n the s e r i e s were the guanidine 36. * the glyceramide 6i0 both of which were q u i t e a c t i v e i n the PCA assay. The most a c t i v e d e r i v a t i v e s i n t h i s s e r i e s were the oxamic a c i d 59^ and the glyceramide 60. The 3-amido analogs were examined i n more d e t a i l and other isomers were prepared as shown i n Table IV. The benzylamido analog 6>1 was prepared from the benzylamino compound V which i n turn was e a s i l y made from m-nitrobenzaldehyde as shown. The v a r i o u s amides, i n c l u d i n g the barbituramide 66, were prepared from m-nitrobenzoyl c h l o r i d e . PCA t e s t i n g of these v a r i o u s analogs c l e a r l y showed a decrease i n a c t i v i t y when the amine f u n c t i o n i s d i s p l a c e d from the aromatic r i n g (see Scheme I I . ) The importance of N - a l k y l a t i o n was determined by a short s e r i e s of d e r i v a t i v e s as shown i n Table V. P r e p a r a t i o n of the N - a l k y l d e r i v a t i v e s i s accomplished i n the u s u a l manner by condensation of the p y r a n t r i o n e with an N - a l k y l a n i l i n e but f o r c i n g c o n d i t i o n s are necessary. Comparison of 67_ & 68^ with t h e i r corresponding u n a l k y l a t e d parents show no s i g n i f i c a n t improvement. In a d d i t i o n , the corresponding morpholino analog and the unsubs t i t u t e d amide show no s i g n i f i c a n t a c t i v i t y . a n (

M u l t i p l y S u b s t i t u t e d Pyranenamines Based on the observed a c t i v i t y , the assembly of m u l t i p l e groupings was a c l e a r pathway to improved potency. Once again the QSAR study helped our decision-making process by reducing the l a r g e number of p o s s i b l e permutations to some workable



SNADER ET AL.

Pyranenamines

χΟ HO

IV PCA CMPD. NO. 1

R

DOSE

H

1 0

3

,

% INHIB.

b

P"50

76

-0.70

DOSE

PO PCA % INHIB.

b

3

13

2-OH

2.8t

50

-0.45

25

-12(NS)

14

3-OH

1.6t

50

-0.20

25

0(NS)

15

4-OH

1.3t

50

-0.11

29t

50

16

4 O C O C H 3

0.5

41

0.22

17

4-0C0CHCH

0.5

16

-0.06

18

4-0C0(CH ) CH

1.5t

50

-0.19

19

4-0C0(CH ) CH

0.5

34

0.16

25

36

20

4-0C0(CH ) CH

12.1t

50

-0.83

21

4-0C0(CH ) CH

0.5

21

22

4-0C0C(CH)

0.5

3(NS)

-0.45

23

4-0C0CgH

0.5

10(NS)

-0.18

24

4-0C0NH

0.5

19

-0.01

25

4-0C0NH-CH

0.5

22

0.03

26

4-0CH

5

27

-0.92

27

3-0CH C00H

0.5

28

4-0CH C00H

0.5t

50

29·

4-SH

1.9t

50

2

3

2 2

3

2 3

3

2 4

3

2 5

3

33

5

2

7

3

2

2

?

6(NS)

0 . 0 1

0 . 1 0 0.30

25

2(NS)

.

a. dose in mg./kg.; b. p=0.01 except where noted; c. NS=not significant; t calculated I D Q &


C

DRUGS

150

TABLE

AFFECTING

T H E RESPIRATORY

SYSTEM

III


HO

IV P C A -

r CMPD. NO. 1

R

DOSE

Η

30

2-NH

31

3-NH

32

3-NHCH3

33

4-NH

34

4-N(CH )

35

3-NHC(NH)-NH

36

3-NHC(NH)NH

2

2

3

3

76

-0.70

50

-1.00

0.3t

50

100

2

P»50

10

-

0.5

2

% INHIB.

27.5t

0.5

J

-PO PCA b

DOSE '

% INHIB.

b

0.68

8(NS) 58

C

-0.30 0.40

25

0.30

25

23

11 (NS)

d

0.5

2(NS)

TOS 0.9t

2

50

37

2-NHCHO

0.5

52

38

3-NHCHO

0.5

22{NS)

39

4-NHCHO

40

2-NHCOCH

0.5 0.5

3

0.32 C

49

-12(NS)

41

3-NHCOCH3

0.25

65

42

4 -NHCOCH3

5

19(NS)

-

25

7(NS)

31

0.03 0.29

25

- 6(NS)

-0.50 0.73

25

53

-0.18

43

3-NHCONH

2

0.5

45

0.25

25

6(NS)

44

4-NHCONH

2

0.5

38

0.19

25

-17(NS)

0.2t

50

0.79

25

70

1.6t

50

0.04 46

45

3-NHCOCH CH

46

4-NHCOCH CH

2

2

3

3

47

3-NHCOCH(CH )

2

0.5

72

0.51

25

48

4-NHCOCH(CH )

2

0.5

64

0.42

25

450

DOSE

3

% INHIB.

-1.50 -0.50 25

-3(NS)

40

1.70

25

4(NS)

47

-0.50

50

2-OH-5-NHCOCH3

0.5

2-NH -5-OH

5.0

2

b

0.40

0.4t

3

C

a. dose in mg./kg.; b. p=0.01 except where noted; c. NS=not significant; t calculated ID^Q


b

DRUGS A F F E C T I N G T H E RESPIRATORY

156

SYSTEM

t h i s t e s t i s the p h y s i c a l l i m i t a t i o n of water s o l u b i l i t y which the compound must have i n order to be t e s t e d . The r e s u l t s of i n v i t r o r a t lung t e s t i n g of some of our most promising candidates are shown i n Table IX. As a p o i n t of r e f e r e n c e , DSCG i n t h i s system has an I D o (that i s the dose which causes an i n h i b i t i o n of 50% of the amount of histamine l i b e r a t e d by non-drug t r e a t e d c o n t r o l s ) of approximately 10~** molar. Examination of the v a r i o u s d e r i v a t i v e s t e s t e d , i n d i c a t e that our PCA data c o r r e l a t e very w e l l with the i n v i t r o data i n the same s p e c i e s . For example, the rank order f o r i n c r e a s i n g potency i n the r a t PCA t e s t i s 15, 73 and 82^ which have IDso's of 1.3, 0.7 and 0.2 mg/kg r e s p e c t i v e l y . They a l s o have the same rank order i n the i n v i t r o assay with I D o s of 10"" , 3 x l 0 " and 10 respectively. These r e s u l t s are comforting from a theor e t i c a l viewpoint but they do not c o n t r i b u t e any a d d i t i o n a l i n f o r m a t i o n to a i d i n the s e l e c t i o n and e v a l u a t i o n of compounds and so we turned to the primate system. In Table X are shown both the i n h i b i t i o n of histamine r e l e a s e and SRS-A r e l e a s e from Rhesus monkey lung t i s s u e . Our observat i o n s with t h i s system i n d i c a t e that i n h i b i t i o n of both mediators does not u s u a l l y f o l l o w the same dose r e l a t e d p a t t e r n and that f r e q u e n t l y a compound w i l l be more e f f e c t i v e at i n h i b i t i n g histamine r e l e a s e than i t w i l l be at i n h i b i t i n g SRS-A r e l e a s e . For example, i n t h i s system DSCG has an ID o a g a i n s t histamine r e l e a s e of 10~ molar while a g a i n s t SRS-A r e l e a s e i t i s somewhat greater than 3 x l 0 ~ molar ( a c t u a l l y DSCG never q u i t e accomplished a f u l l 50% r e d u c t i o n of SRS-A r e l e a s e but r a t h e r p l a t e a u s i n i t s dose response at approximately 42% i n h i b i t i o n ) . In the primate lung system there appears to be no c o r r e l a t i o n between i n v i v o r a t PCA a c t i v i t y and t h i s i n v i t r o a c t i v i t y . One of the most a c t i v e compounds i n t h i s s e r i e s was the 3-amino4-hydroxy analog 7^3 which we have l a b e l e d as SK&F 78729-A. I t i s n e a r l y equipotent at i n h i b i t i n g both histamine and SRS-A r e l e a s e , with an ID o of approximately 3x10"" molar, n e a r l y 2 orders of magnitude b e t t e r than DSCG. Coupled w i t h i t s f a v o r a b l e i n t r a venous to o r a l potency r a t i o t h i s compound then i s our most i n t e r e s t i n g candidate and w i l l be the s u b j e c t of an e x t e n s i v e pharmacology review at the F e d e r a t i o n Meeting i n A p r i l , In c l o s i n g I would l i k e to thank my numerous c o l l e a g u e s who compiled the formidable number of compounds and b i o l o g i c a l t e s t data that was presented here today.


5

f

4

5

8

5

3

3

5

5


6

8.


TABLE I X .

Compound No.

R

157

Pyranenamines

SNADER E T A L .

I n h i b i t i o n of Antigen-Induced Histamine R e l e a s e i n P a s s i v e l y S e n s i t i z e d Fragmented Rat Lung

R,.

3

Rs

DSCG

NHC0CH(CH )

H

48

3

NH

73

OH

2

OH

NHCOCHa

77

81

NHC0CH CH 2

82

OH

3

NHC0CH(CH ) 3

(

H

OH

H

2

OH

2

H

H

H

H

H

10~l

1.6 χ 6.6x 10 6.6x 10 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

7

_5 x

l

- 6

0

χ 10

:

x io

5

χ 106 xlO xlO" x

l

0

8

-5 - 6

xlO xlO xlO"' χ 10 x

l

c

% Inhib. Histamine 56 (10) 47 (4) 32 (3)

1.3 x 10 2.7 χ 10 5.3x10

15

a)

In Vitro Cone. (M)

U

χ 10 xlO xlO"

8

-6

x 10 χ 10"

) i s the number of different lung preparations


45 ( 5 ) 44 (7) 34 (A) 92 (1) 60 (1) 47 61 42 26

(4) (5) (4) (4)

86 76 88 53 43

(5) (5) (5) (1) (1)

65 66 70 41

(4) (A) (4) (2)

78 (1) 81 (1)

a

158

DRUGS AFFECTING THE RESPIRATORY SYSTEM

TABLE X. Inhibition of IgE - Antihuman IgE Release of Histamine and SRS-A from Passively Sensitized Fragmented Rhesus Monkey Lung Tissue Û H O CUi j Λ"


Compound No. DSCG

H,

Cume. (M) 1.3 χ -3 2.7 χ 5.3 χ10 1.6 χ JO"' 3.3x10 6.6 χ 10 1 XJO , 5 X 1 X 1 X 5 X< 1 X 5 X ] X -5 1 X10 i X 1 X10 1 Xίο""· 1 X J X -6 1 X10 a

15

H

OH

tl

73

NH

OH

H

77

NHCOCHa

OH

H

«5

UH

H

NH

8b

OH

H

NHCOCHa

87 95

NH NHCOCH(OH)CHOH

H H

NHCOCa Il NHCOCHH )( C ) HaOH

a

a

a

a

l0

10

1 Inliib. 1 lnhib. Il j slami ne SUS- Λ 54 (4) 27 (4) 3 7(4) 36 (4) 24 (4) ] 1(4) 5y (7) 51 (7) 33 (10) 50 (10) 8.6 (5) J8 (5) bb (9) 56 (/) 49 (5) 40 (4) 22 (9) 1 (7) 4 (7) -24 (5) 25 (4) 33 (4) -31 (4) 5 (4) -32 (4) -Jl (4) 18 (2) 24 (3) 5 (2) -0.7 (3) 22 (2) 57 (2) 17 (2) 6 (2) 17 (1) 8 (1) 7 (2) 7 (2) -0.5 (2) -20 (2) - 7 (2) -30 (2) a

a) ( ) le the number of different lung preparations "Literature Cited" 1. Cox, J. S. G., Nature (London), (1967), 216, 1328; Cairns, H., et a l . , J. Med.Chem.,(1972), 15, 583. 2. For a recent review of antiallergic compounds see Oronsky, A. L. and Wasky, J. W. F., in Annu. Rep. Med.Chem.,(1977), 12, 70-79. 3. Willis, C. R., Snader, K. M., Miao, C. Κ., Mendelson, W. L. and Chakrin, L. W., 10th Middle Atlantic Regional Meeting, Philadelphia, PA, February 1976, Abstract No. J. 8. 4. Kiang, Α. Κ., Tan, S. F. and Wong, W. S., J.Chem.Soc.(C), (1971), 2721. 5. Goose, J. and Blair, A. M. J. N., Immunol., (1969), 16, 749. 6. Chakrin, L. W., et a l . , Agents and Actions, (1974), 4/5, 297. RECEIVED

August 6, 1979.


d

Pyranenamines: A New Series of Potent Antiallergic Compounds

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