J. Med. Chem. 1989,32,683-688
683
3- (Aminoalkyl)- 1,2,3,4-tetrahydro-5H-[ 11benzopyrano[ 3,4-c Ipyridin-5-ones as Potential Anticholinergic Bronchodilators David T. Connor, Paul C. Unangst,* Charles F. Schwender, Roderick J. Sorenson, Mary E. Carethers, Chester Puchalski, Richard E. Brown, and Martin P. Finkel? Departments of Chemistry and Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105. Received September 1, 1988 A series of 3-(aminoalkyl)benzopyrano[3,4-c]pyridin-5-ones was prepared and tested as potential orally active anticholinergic bronchodilators. Inhibition of methacholine-induced collapse in guinea pigs and inhibition of pilocarpine-induced bronchoconstriction in dogs served as in vivo models. Simultaneous measurement of salivary inhibition in the dog model allowed determination of a pulmonary selectivity ratio. The benzopyrano[3,4-c]pyridjn-5-one parent ring system was prepared by Pechman condensation of phenols with a piperidine 8-keto ester. Alkylation with aminoalkyl halides, or with 1-chloro-2-propanone followed by reductive amination, yielded the 3-substituted target compounds. Bronchodilator potency was related to the extent of steric crowding surrounding the side-chain terminal amine function. Addition of a methyl substituent on the carbon a to the terminal amine often increased potency or pulmonary selectivity. After secondary pharmacological evaluation, compound 7a, designated CI-923, was selected for clinical trial as a bronchodilator.
Current drugs widely used for the treatment of asthma and allergic diseases include cromolyn sodium, theophylline, 8-adrenergic stimulants, and corticosteroids. All possess specific deficiencies, such as side effects or limited efficacy. Since cholinergic mechanisms are an important factor in producing air flow obstruction, anticholinergic agents represent a possible complementary addition to the above regimens.' Atropine and other related natural product anticholinergics have a long history in the treatment of asthma.2 However, the classical anticholinergic side effects (dry mouth, skin flushing, tachycardia, blurred vision, and gastrointestinal disturbances) associated with atropine led to its demise as an antiasthmatic drug, especially since the discovery of newer a- and 8-adrenergic agents. Interest in the use of anticholinergic agents has recently been revitalized with the development of newer drugs.3 Ipratroprium bromide: an inhalation agent with low systemic absorption (and thereby limited side effects), has recently received marketing approval in the United States as an anticholinergic bronchodilator. The use of anticholinergic agents in combination with 8-adrenergic stimulants or theophylline is also of current intereste5v6 A key element in the successful development of a drug of this type is selectivity, that is, the ability to produce bronchodilation at doses that produce minimal antisecretory, CNS, and cardiovascular side effects when compared to atropine. As part of a previous program,' a series of 3-substituted benzopyrano[3,4-c]pyridin-5-ones 1 were prepared and tested for their ability to protect guinea pigs from collapse induced by histamine challenge. Several compounds (4a, 4b, Table I) were found to provide protection against challenge by methacholine chloride (a cholinergic spasmogen) as well as histamine. Compounds 4a and 4b
1
served as the starting point for the further development of series 1 as potential orally active, selective, anticholinergic bronchodilators. The synthesis and biological activity of these compounds form the basis for the present paper. ?Department of Pharmacology. 0022-2623/ 89/ 1832-0683$01.50/0
Scheme I' Rz
OH
R1
2
3
4
imethod C
r
5
6
'Reagents: (method A) methyl 4-oxo-3-piperidinecarboxylate hydrochloride/H,SO,; (method B) C1(CH2),NR4R6/Et3N;(method C) l-chloro-2-propanone/KzC03; (method D)R4NHz/catalytic H,; (method E) R4R6NH/catalytic H,; (method F) R6CO2H/NaBH4.
Chemistry The overall synthetic sequence for the preparation of compounds of type 1 is shown in Scheme I. The parent benzopyrano[3,4-c]pyridin-5-ones3 were prepared by a Pechmana condensation of methyl 4-oxo-3-piperidine(1) Gross,N. J.; Skorodin, M. S. Am. Rev. Respir. Dis. 1984,129, 856. (2) Rebuck, A. S.; Chapman, K. R.; Braude, A. C. Chest 1982 (Suppl.) 55s. (3) Baigelman, W. Chest 1984, 85, 297. (4) Pakes, G . E.; Brogden, R. N.; Heel, R. C.; Speight, T. M.; Avery, G. S. Drugs 1980,20, 237. ( 5 ) Shenfield, G. M. Drugs 1982,24, 414. (6) Chu, S. S. Drugs Today 1984,20, 575. (7) Brown, R. E.; Puchalski, C.; Shavel, J. Jr. US Pat. 3,991,196, November 9, 1976. (8) Sethna, S.; Phadke, R. Org. React. 1953, 7, 1. 0 1989 American Chemical Society
684 Journal of Medicinal Chemistry, 1989, Vol. 32, No. 3
Connor et al.
Table I. Bronchodilator Activity of 3-[2-(Alkylamino)ethyl]-and [ 11benzopyrano[3,4-c]pyridin-5-ones 3-[2-(Azabicyclo)ethyl]-1,2,3,4-tetrahydro-5HX
compd 4a 4b 4ce 4d 4e 4f 4g 4h 4i 4j 4k 41 4m 4n 40 4P 4q
4r 4s
R1 Me0
RZ Me0 Me0 Me0 H H H H H H H Me0 H H H H H Me0 Et0 Me H Me0 H Me0
Me0 Me0 Me0 Me0 Me0 Me0 Me0 Me0 Me0 Me0 H Me Et (Me)&H Me0 Me0 Et0 Me Me0 Me0 Me0 Me0
X' A B A
A B C D E F G H I I I I I I I I J J K K
guinea pig collapse time, minb 4.9 f 1.2 4.0 f 1.3 1.6 f 0.1 9.5 f 0.4 8.0 f 1.4 1.9 f 0.1 8.0 f 1.3 7.0 f 1.4 9.1 f 1.0 6.1 f 1.8 2.8 f 0.4 5.2 f 1.6 5.0 f 0.1 6.8 f 1.4 6.2 f 1.8 6.0 f 1.8 5.0 f 1.0 6.3 f 1.5 5.1 f 0.7 7.3 f 1.7 6.6 f 1.6 10.0 f 0.0 7.6 f 1.5
cholinergic dog
A: bronchospasm
B: salivation
pulmonary selectivity
IDwd
@/A)
ID,' -
-
-
205 223
141 398
394 428 246 1141
158 855 735 714
-
-
0.69 1.8
-
-
-
849 235 74 209 35 113 261 372 1026 119
68 452 41 128 104 530 210 223 154
-
0.40 2.0 3.0 0.63 -
0.08 1.9 0.55 0.61 3.0 4.7 0.79 0.60 0.15
4t 4u 4v 63 102 1.6 137 140 1.0 4w atropine 7.0 3.2 0.46 'For X: A = piperidino, B = hexamethyleneimino, C = dimethylamino, D = diethylamino, E = di-n-propylamino, F = pyrrolidino, G = morpholino, H = 2,2,6,64etramethylpiperidino, I = 3-azabicyclo[3.2,2]non-3-yl, J = 3-azabicyclo[3.3.l]non-3-yl, K = 2-azabicyclo[2.2.2]oct2-yl. *Collapse time (min) observed in the guinea pig methacholine challenge test f S.E.M. following a test drug dose of 25 mg/kg, PO. Dose of test compound (pg/kg) inhibiting dog cholinergic bronchoconstriction by 50% of control value. dDose of test compound (pg/kg) inhibiting dog salivation by 50% of control value. eThe side chain carbon bridge contains three methylene groups. Scheme 11'
Scheme 111'
,
ii
Me0
HO *2HCI
Et
4a.8d.Bi
9
10
11 Et
4r66e,6j
'Reagents: Et2SO,/K&03.
(method G ) 48% aqueous HBr; (method H)
carboxylate and an appropriately activated phenol 2 (method A). The Pechman reaction on phenol itself is not synthetically useful; for the preparation of 3 where R1 = & = H, an alternate procedure was employed? Alkylation of 3 with aminoalkyl halides provided the 3-substituted amines 4 (method B), while alkylation with l-chloro-2propanone yielded intermediate methyl ketones 5 (method C). Reductive amination of 5 with primary amines produced analogues 7 containing a methyl group a to the terminal secondary amine (method D), while similar re(9) Connor, D. T.; Unangst, P. C.; Schwender, C. F.; Sorenson, R. J.; Carethers, M. E.; Puchalski, C.; Brown, R. E. J . Heterocycl. Chem. 1984,21, 1557.
12
Meow PNH
'reagents:
( I )
Et3N ; (ii)
,
(111)
HCI
Me0
3*
ductive amination with cyclic or other secondary amines produced the related a-methyl tertiary amines 6 (method E). N-Alkylation of 7 with a carboxylic acid and sodium borohydridelO allowed the preparation of examples of 6 with mixed alkyl (R4,R5) substituents (method F). (10) Gribble, G . W.; Jasinski, J. M.; Pellicone, J. T.; Panetta, J. A. Synthesis 1978, 766.
Journal of Medicinal Chemistry, 1989, Vol. 32, No. 3 685
Potential Anticholinergic Bronchodilators
Table 11. Bronchodilator Activity of 3-[2-(Alkylamino)propyl]-1,2,3,4-tetrahydro-5~-[l]benzopyrano[3,4-c]pyridin-5-ones.Cyclic Amines A
I Me
guinea pig collapse time, mina
cholinergic dog A: bronchospasm B: salivation IDW* IDWc
pulmonary selectivity (B/A)
R1 R2 n 4 10.0 + 0.0 88 190 2.2 H H 4 8.7 f 1.3 100 226 2.3 Me H 4 8.2 f 1.3 315 699 2.2 Me Me 4 10.0 f 0.0 17 23 1.4 Me0 Me0 4 9.4 f 0.6 99 163 1.6 Et0 Et0 5 10.0 f 0.0 38 219 5.8 H H 5 9.7 f 0.3 40 108 2.7 Me H 613 5 7.7 f 1.5 300 1158 3.9 Me Me 6h 5 10.0 f 0.0 129 168 1.3 Me0 Me0 6i 5 10.0 f 0.0 126 194 1.5 Et0 Et0 6j Me0 Me0 6 1.7 f 0.1 6k Me0 Me0 d 10.0 f 0 61 Me0 Me0 e 2.8 f 0.4 13 aCollapse time (min) observed in the guniea pig methacholine challenge test f S.E.M. following a test drug dose of 25 mg/kg, PO. *Dose of test compound (rg/kg) inhibiting dog cholinergic bronchoconstriction by 50% of control value. cDose of test compound (pg/kg) inhibiting dog salivation by 50% of control value. dThe side-chain terminal amine substituent is morpholino. 'The side chain is that as shown in Scheme 111. compd 6a 6b 6c 6d 6e 6f
In instances where 8,g-diethoxy substituents were desired in l, the corresponding 8,9-dimethoxy analogues were demethylated with HBr (method G, Scheme 11), and the intermediate 8,g-dihydroxycompound 8 was alkylated with diethyl sulfate (method H). The established1' rearrangement of piperidine derivative 9 (Scheme 111) via aziridinium ion intermediate 10 to the related pyrrolidine 11was employed in the preparation of analogue 13, in which the a-methyl substituent can be envisioned as being incorporated into the terminal amine substituent. Physical data for new compounds are listed in Table IV. Results and Discussion Compounds were initially screened for their ability to protect guinea pigs from collapse after challenge with aerosolized methacholine chloride. This screen was employed to identify compounds with oral activity suitable for further evaluation. Secondary testing was in a pilocarpine-treated dog model, which provided quantitative data on both the bronchodilator and antisecretory properties (as measured by inhibition of salivation) of the test compound in the same animal. The ratio of ID5ovalues for inhibition of salivation compared to inhibition of bronchospasm was defined as the pulmonary selectivity of the molecule. Atropine, being a more potent inhibitor of salivation than bronchospasm in this model, has a pulmonary selectivity ratio of
