N-Pyridinyl(methyl)-indole-1- or 3-propanamides and propenamides acting as topical and systemic inflammation inhibitors

Figures & data

Figure 1 Structure of some indole-based anti-inflammatory compounds.

Scheme 1 Reagents: (a) EtOH, 0.6M HCl, reflux, 92%; (b) NaH, DMF, MeI, rt, 68%; (c) (1) Cs₂CO₃, MeCN, (2) R¹Cl reflux, 72-96%; (d) K₂CO₃, DMSO, R¹Cl, rt, 88%; (e) Ph₃PCH₂COOMe, dioxane, reflux, 85%; (f) (EtO)₂POCH₂CO₂Et, NaH, THF, rt, 58-67%; (g) H₂, Raney Ni, THF, rt, quantitative; (h) 2M NaOH, EtOH, reflux, 32-97%; (i) acrylonitrile, triton B (40% in MeOH), dioxane, rt, 84-88%; (j) 10% KOH, reflux, 49-91%; (k) 2-chloro-1-methylpyridinium iodide, RNH₂, Et₃N, CH₂Cl₂, reflux, 30-82%; (l) (1) BrCCl₃, PPh₃, THF, (2) 2-amino-4,6-dimethylpyridine, reflux, 33-58%.

Table I.  Chemical data and TPA-induced mouse ear swelling inhibition of 3-(indol-3-yl)propanamides 29-47

Compound	R	R^1	R^5	Method Yield (%)	Anti-oedema effect after mouse oral administration
					at 0.1 mM/kg	ID50(μM/kg)
29		H	H	1:76	77 ± 3	41 ± 13
30		CH3	H	k:58	94 ± 0.1^a	32 ± 12
31		Bn	H	k:69	84 ± 3
32		4Cl-Bn	H	k:64	72 ± 1
33^b			H	k:32	63 ± 1
34		H	H	k:58	67 ± 5	29 ± 17
35		CH3	H	k:73	64 ± 5^c
36		Bn	H	k:52	61 ± 3
37		4Cl-Bn	H	k:58	64 ± 2.5
38		H	H	k:60	77 ± 5^c
39		CH3	H	k:78	69 ± 1.5	45 ± 37
40		Bn	H	k:78	70 ± 1
41		4Cl-Bn	H	k:78	92 ± 1	24 ± 13
42		CH3	Cl	k:61	84 ± 2
43		4Cl-Bn	Cl	k:46	64 ± 2
44		CH3	Cl	k:44	79 ± 1
45		4Cl-Bn	Cl	k:27	83 ± 2
46		CH3	Cl	k:82	66 ± 0.5
47		4Cl-Bn	Cl	k:75	84 ± 1
		Dexamethasone			82 ± 1.5	12 ± 1
		Ibuprofen			35 ± 7.5	180 ± 5

^a toxic^b tested as a dimaleate^c tested at 0.2 mM/kg.

Table II.  Chemical data and TPA-induced mouse ear swelling inhibition of 3-(indol-3-yl)propenamides 48-51 and 3-(indol-1-yl)propanamides 52-57.

Compound	R	R^1	R^5	Method Yield (%)	Anti-oedema effect after mouse oral administration at 0.1 mM/Kg
48		4F-Bn	H	1: 33	80 ± 2
49		4Cl-Bn	Cl	k: 25	80 ± 1
50		4Cl-Bn	Cl	k: 20	86 ± 1
51		4Cl-Bn	Cl	k: 38.5	ND^a
52		–	H	k: 53	77 ± 0.5
53		–	H	k: 43	74 ± 2
54		–	H	k: 43	88 ± 0.2
55		–	Cl	k: 54	80 ± 4
56		–	Cl	k: 56	62 ± 1.5
57		–	Cl	k: 40	64 ± 1.5
		Dexamethasone			82 ± 1.5
		Ibuprofen			35 ± 7.5

^a ND: not determinated (unstable compound).

Table III. TPA-induced mouse ear swelling inhibition after topical application.

Compound	Anti-oedema effect after mouse topical application of
	2 × 100 μg/ear	2 × 50 μg/ear
29	38 ± 3	ND
30	72 ± 2	50 ± 1
31	90 ± 1	70 ± 1
34	66 ± 3	53 ± 2
39	83 ± 1	72 ± 1
41	71 ± 1	53 ± 1
42	96 ± 1	75 ± 1
44	89 ± 1	74 ± 1
47	94 ± 3	74 ± 1
48	66 ± 2	52 ± 2
54	85.5 ± 1.5	ND
Dexamethasone	96 ± 2
Ibuprofen	59 ± 2.5