New, Orally Effective Chromone Derivatives for the Treatment of Asthma

5 New, Orally Effective Chromone Derivatives for the Treatment of Asthma

Downloaded by MILLIKIN UNIV on February 19, 2015 | http://pubs.acs.org Publication Date: February 22, 1980 | doi: 10.1021/bk-1980-0118.ch005

H. CAIRNS Fisons Ltd., Pharmaceutical Division, R. & D. Laboratories, Bakewell Road, Loughborough, Leicestershire, England

It is of interest to note that, since the introduction of disodium cromoglycate (Intal, cromolyn) (I) in 1967 as the first prophylactic agent for the treatment of bronchial asthma, no successor products of this type are yet clinically available. This observation is of extreme importance from the medicinal chemist's view point, as in our interpretation i t high-lights the lack of clinically predictive screening models which can be used, reliably, in structure-activity studies. Perhaps this is best exemplified by considering the following facts; (i) that in the past 10 years, at least 65 pharmaceutical companies have filed patent applications describing compounds with cromolyn-like activity, (ii) that at least 25 of these companies have published papers describing some aspect of their scientific studies on compounds of this type, and (iii) that at least 9 of these latter companies have taken selected compounds to some stage of clinical evaluation as evidenced by appropriate publications (1 - 9). Yet despite this mammoth effort, my initial comments stand. We ourselves rank alongside the companies l i s t e d above, as f o r the past 10 years we have s t r i v e n t o i d e n t i f y a follow-up product t o cromolyn. T h i s paper presents a summary o f our work during t h i s p e r i o d , h i g h l i g h t i n g the s i g n i f i c a n t t h e o r e t i c a l and p r a c t i c a l achievements and f a i l u r e s which have marked our progress. Always our o b j e c t i v e was t o i d e n t i f y a new "cromolyn l i k e " d r u g , i . e . a compound whose b i o l o g i c a l mode o f a c t i o n was s i m i l a r t o that o f the parent drug. E a r l y i n our programme we decided t o concentrate on the search f o r an o r a l l y e f f e c t i v e agent as an a t t r a c t i v e a l t e r n a t i v e t o cromolyn which has t o be administered by i n h a l a t i o n . Despite extensive i n v e s t i g a t i o n , the p r e c i s e mechanism o f a c t i o n o f cromolyn i n man i s s t i l l unknown, but i t i s g e n e r a l l y accepted that t h i s agent exerts much o f i t s a n t i - a s t h m a t i c a c t i v i t y by i n h i b i t i n g the r e l e a s e o f mediators from s e n s i t i s e d mast c e l l s (10). I t i s perhaps p e r t i n e n t t o r e f l e c t on how t h i s aspect o f the drug's mode o f a c t i o n was f i r s t discovered. Cromolyn

0-8412-0536-l/80/47-118-099$05.00/0 © 1980 American Chemical Society

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


100

DRUGS AFFECTING THE RESPIRATORY SYSTEM

I

II



5.

CAIRNS

Chromone Derivatives for Asthma

101

was synthesised during a programme o f work o r i g i n a l l y designed t o e x p l o i t the b r o n c h o d i l a t i n g p r o p e r t i e s of a n a t u r a l l y o c c u r r i n g 2-methylchromone known as k h e l l i n ( I I ) . Part o f the s t r u c t u r a l v a r i a t i o n a p p l i e d to the k h e l l i n molecule was to r e p l a c e the 2-methyl s u b s t i t u e n t by a carboxy group. By so doing, i t was soon apparent from our screening programme that we had l o s t a l l o f k h e l l i n ' s b r o n c h o d i l a t i n g a c t i v i t y , but continued i n v e s t i g a t i o n o f the b i o l o g i c a l p r o p e r t i e s of the 2-carboxy s e r i e s r e v e a l e d that they possessed a novel prophyl a c t i c anti-asthmatic a c t i v i t y . Thus when given before antigen challenge to an asthmatic s u b j e c t , these compounds i n h i b i t e d the expected onset o f bronchospasm. I would s t r e s s that t h i s a c t i v i t y was f i r s t i d e n t i f i e d i n a human asthmatic v o l u n t e e r . It was only subsequent to t h i s demonstration of the new p r o p h y l a c t i c a c t i v i t y o f the chromone-2-carboxylie acids i n man, that we began to r e v i s e our b i o l o g i c a l t e s t i n g programme — indeed cromolyn had been synthesised and i d e n t i f i e d as h i g h l y a c t i v e i n man before an animal model, which we could use to study the s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s o f these compounds, was i d e n t i f i e d . The animal model which Goose and B l a i r (11) o f our l a b o r a t o r i e s used to demonstrate a p o s s i b l e explanation o f the mode o f a c t i o n o f cromolyn was the r a t passive cutaneous anaphylaxis t e s t (PCA t e s t ) . At f i r s t s i g h t , t h i s PCA t e s t seemed to be a p o t e n t i a l l y u s e f u l model o f a l l e r g i c asthma as i t seemed to have s e v e r a l fundamental c o r r e l a t i o n s with the human d i s e a s e . Thus both systems i n v o l v e d mast c e l l s ; i n both systems these c e l l s were s e n s i t i s e d with antibodies o f the IgE c l a s s ; challenge o f such s e n s i t i s e d c e l l s with antigen r e s u l t e d i n the c o n t r o l l e d r e l e a s e of the pharmacological mediators o f anaphylaxis from these c e l l s . T h i s then was the background to the beginning o f our medi c i n a l chemistry approach to the i d e n t i f i c a t i o n o f an o r a l l y e f f e c t i v e a n t i - a s t h m a t i c agent, which began around 1969-1970. At that time we considered our stock data on a n t i - a s t h m a t i c compounds from experimental asthma s t u d i e s i n humans. Thus, we knew that mono- and bischromones were h i g h l y a c t i v e by i n h a l a t i o n , but that none o f the compounds which we had prepared up to that time were o r a l l y e f f e c t i v e . T h i s lack o f o r a l a c t i v i t y was, we decided, due to the high p o l a r i t y and low l i p o p h i l i c character o f the chromone d e r i v a t i v e s that we had prepared up to t h a t time. For example, cromolyn had a pKa o f about 1.5 and an octanol/water (pH 7.4 aqueous b u f f e r ) log D value o f about -3.5. Such a compound would be expected to have a very poor absorption p r o f i l e . T h i s was r e f l e c t e d i n i t s short plasma h a l f - l i f e f o l l o w i n g intravenous a d m i n i s t r a t i o n and the f a c t t h a t i t s plasma l e v e l s f o l l o w i n g o r a l a d m i n i s t r a t i o n in a number o f species were extremely low (12). Consequently when we decided to look f o r o r a l l y e f f e c t i v e analogues o f cromolyn, we chose e v e n t u a l l y to concentrate on molecular m o d i f i c a t i o n o f the monochromones as they were r a t h e r



102


more l i p o p h i l i c than t h e i r bischromone counterparts. At the outset we decided t o accept the inherent problem o f the high a c i d i t y o f the chromone-2-carboxylie acids and t o attempt t o overcome t h i s by the i n t r o d u c t i o n o f l i p o p h i l i c s u b s t i t u e n t s i n t o the chromone nucleus, i n the hope t h a t the net r e s u l t would be the p r o d u c t i o n o f an a c t i v e compound with an acceptable absorption p r o f i l e . As our primary t e s t model we i n i t i a l l y decided t h a t we had to stay with the r a t PCA screen. However, s i n c e we were now i n t e r e s t e d i n o r a l l y e f f e c t i v e compounds we s t u d i e d the a c t i v i t y o f the chromones f o l l o w i n g t h e i r a d m i n i s t r a t i o n e i t h e r d i r e c t l y i n t o the stomach o r i n t o the i n t e s t i n e o f the animals, the l a t t e r f o l l o w i n g a n a e s t h e t i s a t i o n and laparotomy. Experience showed that the r e s u l t s obtained on intra-duodenal dosing were much more r e p r o d u c i b l e than those obtained by s t r a i g h t o r a l dosing and so f o r a number o f years we have used t h i s route o f drug a d m i n i s t r a t i o n t o determine the l i k e l y o r a l a c t i v i t y o f our compounds. Our e a r l y c l i n i c a l s t u d i e s i n the monochromone area had shown t h a t , o f the alkoxy s u b s t i t u t e d s e r i e s , those d e r i v a t i v e s which had the alkoxy group i n the 5- p o s i t i o n were the most a c t i v e . An i n v e s t i g a t i o n o f the b i o l o g i c a l a c t i v i t y o f a l a r g e v a r i e t y o f 5-alkoxy s u b s t i t u t e d chromones i n the r a t PCA t e s t , by the intra-duodenal route, r e v e a l e d that the most a c t i v e were those which c a r r i e d an u n s u b s t i t u t e d s t r a i g h t or branched a l k y l chain, c o n t a i n i n g four carbon atoms or more, on the oxygen atom (see Table I ) . Our next step was t o attempt t o overcome the weak l i p o p h i l i c c h a r a c t e r of the most a c t i v e compound from t h i s s e r i e s , FPL 50419, by the i n t r o d u c t i o n o f a l k y l and a l k e n y l s u b s t i t u e n t s around the benzene r i n g o f the chromone nucleus. These new compounds, l i k e those contained i n Table I, were prepared by the route shown i n Scheme I. An examination o f the data presented i n Table II shows the success o f t h i s approach. Each o f the compounds d e s c r i b e d was more a c t i v e than FPL 50419 by the intra-duodenal route, with optimal a c t i v i t y being found i n the 8 - a l l y l d e r i v a t i v e FPL 55618 which was 30 times more potent. Indeed FPL 55618 was 100 times more potent by the intravenous route, than cromolyn i t s e l f . Not wishing t o r e l y on a c t i v i t y data generated i n only one b i o l o g i c a l screen, we t e s t e d FPL 55618 i n a range o f in vitro and in vivo models o f immediate h y p e r s e n s i t i v i t y which had been developed by our b i o l o g i s t s . These models i n v o l v e d a l l e r g i c r e a c t i o n s i n the s k i n and i n the lungs o f r a t s , dogs, monkeys and guinea-pigs, as w e l l as i n a number o f in vitro systems and FPL 55618 was a c t i v e i n s e v e r a l o f these models o f a l l e r g i c disease (13). Our only worry at the time was that cromolyn d i d not have p a r t i c u l a r l y outstanding a c t i v i t y i n many o f these new screens, so t h e i r true value as models o f a l l e r g i c asthma were u n t r i e d . However, we decided to take FPL 55618, forward t o c l i n i c a l e v a l u a t i o n . In the event, the compound had


5.

CAIRNS


103

TABLE I

RO

0

OCX s

C0 Na


2

PCA E D * i n mg/kg 5 Q

R

Compound No.

intraduodenal

50268

>10

^*^3^^2^^2~

50271

CH CH0HCH 2

50

50291

PhOCH CH -

105

50419

Me CHCH CH -

50482

Et NCOCH -

50485

CH CHCH CH -

50489

PhCH -

50490

C1CH CH -

55671

CH (CH ) -

3

2

2

2

2

2

2

=

2

2

10 >10

2

2

3

6 »10

2

2

(i.d.)

2

2

4

>10 10

*Compounds were given i n t r a d u o d e n a l l y 7-10 min p r i o r t o antigen c h a l l e n g e . T h i s was shown t o be the optimal dosing schedule.




SCHEME I

RT, η

-

see Tables

I and

II



(a)

2

2

2

3

2

CH CH -

2

2

2

2

CH =CHCH -

3

2

CH CH CH -

3

CH CH -

CH =CHCH -

R

2

«

i.v.

PCA E D

2

:0 Na

5 Q

...

^»

0.02

0.03

0.02

0.07

(0.02 - 0.03)

(0.02 - 0.04)

(0.01 - 0.025)

(0.05 - 0.1)

(0.2 - 0.25)

i.d.

0.8

0.8

(0.5 - 1)

(0.5 - 1)

0.86 (0.8 - 1.2)

1.65 (1 - 3)

0.2

i n mg/kg (a)

0.008 (0.005 - 0.01)

II

il

The f i g u r e s i n brackets are the dose range w i t h i n which the estimated ED, was found t o l i e .

2

CH CH -

55727

3

CH =CHCH -

55679 2

H

55662

2

H

55636

l

H

R

55618

Compound No.

R

l 1

0

TABLE I I


106



only weak a c t i v i t y against antigen challenge i n asthmatic p a t i e n t s (13). However, one very important p o i n t which arose from these c l i n i c a l s t u d i e s was the o b s e r v a t i o n t h a t , when given o r a l l y t o man, FPL 55618 blocked the p r o t e c t i v e a c t i o n o f i n h a l e d cromolyn. In our i n t e r p r e t a t i o n , we had evidence which suggested t o us that these s p e c i f i c a l l y designed o r a l chromones were being absorbed and, v i a systemic c i r c u l a t i o n , reaching the receptors i n the human lung r e s p o n s i b l e f o r the p r o t e c t i v e a c t i o n o f t h e i r i n h a l e d c l i n i c a l l y e f f e c t i v e analogues. For some reason, these newly designed compounds d i d not possess the a b i l i t y t o modify the r e c e p t o r i n man, i n a way which would t r a n s l a t e t o i n h i b i t i o n o f asthma. In a d d i t i o n , these o r a l d e r i v a t i v e s appeared t o have a stronger b i n d i n g a f f i n i t y f o r the r e c e p t o r than d i d cromolyn. It was time f o r our f i r s t major r e - t h i n k . B a s i c a l l y we had shown that our general medicinal chemistry approach t o o r a l a c t i v i t y had been s u c c e s s f u l . These more l i p o p h i l i c chromones were indeed being absorbed from the g a s t r o - i n t e s t i n a l t r a c t and reaching t h e i r r e q u i r e d s i t e o f a c t i o n , but we concluded that one could not use the r a t PCA t e s t , or indeed any o f our newly developed t e s t s , i n a q u a n t i t a t i v e l y p r e d i c t i v e sense, f o r the i d e n t i f i c a t i o n o f compounds which would be a c t i v e a n t i - a s t h m a t i c agents, o f the cromolyn type, i n humans. I suspect that others have more r e c e n t l y come t o the same c o n c l u s i o n about the PCA t e s t , f o l l o w i n g the c l i n i c a l e v a l u a t i o n o f t h e i r own s e l e c t e d compounds. The above c o n c l u s i o n s were r e i n f o r c e d by our next s o r t i e i n the area o f the 5-alkoxy chromone-2-carboxylie a c i d s . We decided t o ignore the r a t PCA data which i d e n t i f i e d the 5isoamyloxy d e r i v a t i v e , FPL 50419, as a lead compound. We r e v e r t e d i n s t e a d t o our e a r l y c l i n i c a l s t u d i e s which had shown that though i n a c t i v e o r a l l y , the 5-(2-hydroxypropoxy) d e r i v a t i v e , FPL 50271 ( I I I ) , was h i g h l y a c t i v e , when given by i n h a l a t i o n , i n b r o n c h i a l antigen challenge experiments i n asthmatic p a t i e n t s . The 8-propyl s u b s t i t u t e d analogue, FPL 52694 (IV), was prepared f o r c l i n i c a l e v a l u a t i o n . By t h i s time we recognised that FPL 52694 was not an i d e a l o r a l product as i t was s t i l l a h i g h l y a c i d i c compound and i t s l o g D value was s t i l l l e s s than zero (-0.65), but i t was s i g n i f i c a n t l y more f a t s o l u b l e than i t s predecessor FPL 50271 ( l o g D = -1.8). FPL 52694 was e v e n t u a l l y shown t o be extremely e f f e c t i v e against antigen challenge i n asthmatic p a t i e n t s by the o r a l route, but had t o be given at very high doses i n the order o f 1 - 2 gm per dose (13). We did not c o n s i d e r t h a t such a compound could be a u s e f u l t h e r a p e u t i c product, but from the medicinal chemist's viewpoint, we had e s t a b l i s h e d beyond doubt that chemical m o d i f i c a t i o n o f the h i g h l y a c i d i c , h i g h l y p o l a r chromone-2-carboxylie acids could l e a d t o o r a l l y e f f e c t i v e agents o f t h i s s e r i e s which could be u s e f u l t h e r a p e u t i c a l l y i n the p r o p h y l a c t i c c o n t r o l o f b r o n c h i a l asthma.



5.

CAIRNS


107

Chemically, we were moving i n the r i g h t d i r e c t i o n by attempting to i n c r e a s e the l i p o p h i l i c i t y o f our compounds. We knew that the compounds we were seeking would have to have r e l a t i v e l y high l o g D v a l u e s , probably i n excess o f +1.0. In terms o f the PCA t e s t s , we had by now e s t a b l i s h e d that w e l l absorbed o r a l products would have a r a t i o o f intra-duodenal t o intravenous PCA E D 5 0 values o f l e s s than 10 - p r e f e r a b l y the r a t i o would approach u n i t y f o r very w e l l absorbed compounds. Our experience had shown that compounds with a r a t i o o f >10 were i n general very p o o r l y absorbed i n the r a t and the dog f o l l o w i n g o r a l a d m i n i s t r a t i o n and, as a r u l e , were f a i r l y r a p i d l y excreted f o l l o w i n g intravenous dosing i n both s p e c i e s . But how could we s e l e c t s u i t a b l e compounds f o r f u r t h e r development from an a c t i v i t y viewpoint? None o f our e x i s t i n g animal screens was capable o f p r e d i c t i n g a c t i v i t y i n man! At about t h i s time, which was i n mid-1974, we decided t h a t the screening approach we would f o l l o w , would be one which i n v o l v e d the p r o f i l i n g o f our compounds f o r cromolyn-like a c t i v i t y , w h i l s t checking f u l l y t h e i r o r a l absorption p r o f i l e s . The type o f screen which would best i d e n t i f y t h i s a c t i v i t y , would be, we decided, one i n which we could demonstrate t h a t our compounds could occupy the same r e c e p t o r s as cromolyn. I t was o f l i t t l e consequence, we argued, what p a r t i c u l a r a c t i o n o f the drug we t r i e d t o mimic i n these screens, as we f e l t that none o f them would be completely c l i n i c a l l y p r e d i c t i v e . The best we could hope t o achieve was t o i d e n t i f y compounds which, i n some animal models, could be shown t o i n t e r a c t with and occupy the r e c e p t o r s cromolyn was known t o a c t i v a t e . Such molecules could perhaps occupy and a c t i v a t e the cromolyn receptors i n human lung. I f these compounds a l s o possessed physico-chemical c h a r a c t e r i s t i c s , e.g. s u i t a b l e p a r t i t i o n c o e f f i c i e n t s , which imparted acceptable absorption p r o f i l e s t o the e n t i t i e s , then we would s e l e c t one o r more f o r p r o g r e s s i o n to a c l i n i c a l e v a l u a t i o n . The f a c e t o f cromolyn's a c t i v i t y p r o f i l e on which we concentrated was the compound's r e p o r t e d t a c h y p h y l a c t i c a c t i o n i n both the r a t PCA screen and i n producing a B e z o l d - J a r i s c h r e f l e x induced f a l l i n blood pressure i n the anaesthetised dog (10. 141. In essence, a high dose o f the compound administered to a r a t 30 - 60 minutes before a second dose, given i n the normal manner at t h e time o f antigen c h a l l e n g e , i n h i b i t s o r a b o l i s h e s the p r o t e c t i v e e f f e c t o f the l a t t e r dose on the r a t PCA r e a c t i o n . In the anaesthetised dog, we have found that a f i f t e e n minute i n f u s i o n o f a low dose o f cromolyn blocks the normal depressor a c t i v i t y o f a subsequent bolus i n j e c t i o n o f the compound. The b l o c k i n g a c t i o n o f the i n f u s e d dose diminishes with time as shown i n F i g u r e 1. The l o s s o f a c t i v i t y with time i n these experiments probably r e f l e c t s the r a t e o f e l i m i n a t i o n of the cromolyn from the sensory r e c e p t o r s i n the l e f t v e n t r i c l e of the heart which have been shown t o be i n v o l v e d i n the



108

OH I

III

:

FPL 50271 : R = H

IV

:

FPL 52694 : R = -CH CH CH 2

3


2

3 Time i n hours Figure 1. Effect of infused doses of disodium cromoglycate on the depressor action of a bolus injection of disodium cromoglycate: (O—O) 20 ug/kg/min(+—m)lQOiKg/kg/min



5.

CAIRNS


109

depressor response to bolus i n j e c t i o n s o f cromolyn (15). Rescreening o f a number o f our more l i p o p h i l i c chromone2 - c a r b o x y l i c a c i d s along t h i s new approach i d e n t i f i e d an already e x i s t i n g s e r i e s of compounds which possessed an o v e r a l l p r o f i l e c l o s e to that which we were seeking. These compounds were p r i n c i p a l l y 5-hydroxy-6,8-dialkyl chromone-2-carboxylic a c i d s and the a c t i v i t y p r o f i l e o f one o f these, FPL 52757, i s shown i n Table I I I . One can c o n t r a s t t h i s data with that f o r FPL 52694, which had the f o l l o w i n g p r o f i l e : ( i ) l o g D = -0.65, (ii) PCA E D 5 0 r a t i o = 10, ( i i i ) plasma l e v e l s i n the dog, from an o r a l dose o f 20 mg/kg, never exceeded 2.5 ug/ml over the 5 hour sampling p e r i o d , ( i v ) plasma t j i n dogs = 0.3 h. FPL 52757 was c l e a r l y a much more l i p o p h i l i c compound and encouragingly had a much s u p e r i o r o v e r a l l o r a l p r o f i l e i n the r a t and the dog. In a d d i t i o n i t was c l e a r l y capable o f occupyi n g the cromolyn receptors i n these two s p e c i e s . Consequently, FPL 52757 was submitted f o r c l i n i c a l e v a l u a t i o n and i n s e v e r a l s t u d i e s i n v o l v i n g antigen p r o v o c a t i o n the compound was shown to be o r a l l y e f f e c t i v e , at a dose o f 50 to 100 mg t . i . d . , as an a n t i - a s t h m a t i c agent. U n f o r t u n a t e l y , longer term s t u d i e s i n dogs r e v e a l e d that continued o r a l dosing with the compound produced an i n c i d e n c e o f l i v e r t o x i c i t y which was r e l a t e d to the metabolism o f the drug and the compound was withdrawn from f u r t h e r c l i n i c a l study (13). F o r t u n a t e l y , we had not s e t t l e d s o l e l y f o r the chance o f FPL 52757 making the grade as an o r a l l y e f f e c t i v e agent. Whilst t h i s compound was under d e t a i l e d i n v e s t i g a t i o n , we had begun another programme o f work on the chemical m o d i f i c a t i o n o f a f u r t h e r monochromone which had been i d e n t i f i e d as c l i n i c a l l y a c t i v e by i n h a l a t i o n back i n the e a r l y I 9 6 0 s . This d e r i v a t i v e was the t r i c y c l i c compound FPL 52845; i t was chosen f o r the present study as an a l t e r n a t i v e to the 5-alkoxy s e r i e s because o f i t s i n t r i n s i c a l l y higher f a t s o l u b i l i t y (log D o f FPL 52845 being -0.2 compared to -1.8 f o r the 5-alkoxychromone FPL 50271). T h i s p a r t i c u l a r study proved extremely f r u i t f u l and many o f the compounds produced were a c t i v e i n our screens. As can be seen i n Table IV, the i n t r o d u c t i o n o f a p r o p y l s u b s t i t u e n t i n t o the 10 p o s i t i o n o f FPL 52845, to give FPL 57579, produced a noticeable improvement i n the o r a l p r o p e r t i e s of t h i s t r i c y c l i c compound. Thus the l i p o p h i l i c i t y o f the compound was i n c r e a s e d over 10 f o l d and t h i s was r e f l e c t e d i n an improved PCA r a t i o , higher plasma l e v e l s a f t e r o r a l dosing i n the dog and a longer plasma h a l f - l i f e f o l l o w i n g intravenous admini s t r a t i o n i n the dog. However, the plasma t£ o f FPL 57579 was considered to be r a t h e r short f o r a p o t e n t i a l o r a l product. A f u r t h e r c o n s i d e r a t i o n o f our previous s t u d i e s i n d i c a t e d that the i n t r o d u c t i o n o f a hydroxyl s u b s t i t u e n t i n t o the 5 - p o s i t i o n o f the chromones would lead to an i n c r e a s e i n l i p o p h i l i c i t y and t h i s proved to be the case a l s o i n t h i s 1



110

TABLE I I I

HO

E t

ο

YiT^ η ^ ^

0

C0 H 9

1


Et FPL 52757 Log D

+ 0.65 Octanol/water

PCA E D

5 Q

: i.v. i.d. ratio i.d./i.v.

Plasma l e v e l s i n dogs - dose (20 mg/kg p.o.)

5.0 mg/kg 5.0 mg/kg 1.0

Time post dosing 1 h 3 h 5 h

Plasma t j i n dogs

3 yg/ml 13 yg/ml 13.5 yg/ml

2.4 h

Cross tachyphylaxis : r a t

dog

70 mg/kg i . v . at 45 min blocked the e f f e c t o f disodium cromoglycate 2 mg/kg Infusion o f 200 yg/kg/min blocked the depressor a c t i o n o f disodium cromoglycate f o r up to 3 hours

Chemical and b i o l o g i c a l data a v a i l a b l e on FPL 52757



H

H

H0-

52845

57579

57787

2

2

3

2

2

CH CH CH -

CH CH CH -

3

l

H

R

oct

+ 1.8

+ 1.0

-0.2

log D

6.4 (5 - 10)

1.6 (1 - 4)

0.4 (

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