PYRIDINE DERIVATIVES AS HISTAMINE ANTAGONISTS
Dec., 1948 [CONTRIBUTION FROM
THE
4001
DEPARTMENT OF ORGANIC CHEMISTRY, RESEARCH LABORATORIES, THEWILLIAMS. MERRELL COMPANY]
Histamine Antagonists. Basically Substituted Pyridine Derivatives BY CHARLESH. TILFORD, ROBERTS. SHELTON AND M. G. VANCAMPEN, JR. I n the search for new antihistaminic agents,’ a series of P-dimethylaminoethyl ethers (11) of asubstituted-pyridinemethanols (I) was prepared. The most convenient method for the preparation of the intermediate carbinols was a modification of
nesium bromide3 or picolinic acid4 and the carbonyl compound as well as phenylmagnesium bromide and a pyridylcarbonyl derivativea6 A 3pyridinemethano16 was prepared in 30% yield from the reaction of 3-pyridylmagnesium bromide and benzaldehyde. From benzophenone and 2pyridylmagnesium bromide a 58% yield of a,adiphenyl-2-pyridinemethanolwas obtained. When aluminum was used in carrying out the condensation reaction, the higher boiling 4-pyridinemethanol could also be isolated. For each gram atom of aluminum used in the reaction with acetophenone, 0.44 mole of cr-phenyl-cu-methyl-2KZ pyridinemethano12 and 0.12 mole of a-phenyl-crI methyl-4-pyridinemethanol were obtained. The latter was identical with the product from the ~ N I, r C ‘ - - ~ ~ z ~ 4 ~ ( ~ ~reaction a ) z of 4-benzoylpyridine and methylmagnesium iodide. A pinacol, 2,3-diphenyl-2,3-butane* I Rz diol, was isolated in a 14% yield from a neutral I1 fraction. Another by-product obtained in a very R1 = H, alkyl or substituted alkyl. RZ alkyl, cyclo- small yield was 4,4’-dipyridyl.’ This suggests alkyl, phenyl, thienyl or substituted phenyl. RIRzC= that the reaction might proceed through the forcyclic structure. mation of a pyridyl radical. that of Emmert and Asendorff2in which a ketone Halogen, alkoxy and alkyl substituted aromatic was condensed with pyridine in the presence of aldehydes and ketones were used in the preparaaluminum or magnesium, mercuric chloride and tion (Table 11) of the substituted 2-pyridinemethiodine. anols in the reaction with pyridine and aluminum. In contrast to Emmert’s work, it was found that Although 2-methoxybenzaldehyde and 2-methylvery small amounts of mercuric chloride would acetophenone readily gave the desired carbinols, suffice when a few drops of mercury was also various 2-methoxyacetophenones failed to yield used, and that the reaction proceeded smoothly any of the desired pyridinemethanols. 1-Ciethylusing aldehydes as well as ketones. In one experi- amino-4-pentanone was used in the reaction, and ment, when pyridine, magnesium, acetophenone and a small amount of mercury were used in the regular condensation, the reaction occurred in the absence of mercuric chloride, though with more difficulty and (a lower yield of desired product. bH 01-1 When magnesium was used as the condensing I11 IV agent, any variation of the ratios of the reactants from the amounts given by Emmert and Asendorf2 usually resulted in lower yields of 2-pyridineinethanols. However, this was not the case when aluminum was used; a small amount of mercuric chloride catalyzed the reaction and increased V proportions of pyridine and aluminum increased the desired carbinol (111) was isolated. Aliphatic the yields, possibly by decreasing pinacol forma- and alicyclic ketones usually gave better yields tion. Magnesium was a superior agent for con- than the aromatic ones. densing benzaldehyde with pyridine, whereas with A dipyridinemethanol (IV) was synthesized substituted benzaldehydes the yields with alu- from 2-pyridylmagnesium bromide and methyl minum were about the same as those with magne- acetate in a lOyo yield. Since it is necessary to sium. Overhoff and Proost, Rec. frav. chim., 67, 179 (1938); Proost Preparation d carbinols of type I also has been and(3)Wibaut, ibid., 69, 971 (1940). reported in good yield using either pyridylmag(4) Ashworth, Daffern and Hammick, J . Chem. SOL,811 (1939).
-
(1) For review articles, see Feinberg, J . A m . Med. Assoc., 182,702 (1946); Viaud, Produifs pharm., 4, 53 (1947). ( 2 ) Emmert and Ascndorf, Bcr., TPB, 1188 (1939); Emmert and Pirot, ibid., 74, 714 (1941); German Patent 693.416 (1940).
(5) Tschitschibabin and Benewolenskaja, BY., BlB, 547 (1928). (6) LaForge, THIS JOURNAL, 60, 2487 (1928); no properties given. (7)Smith, ibid., 68, 279 (1931).
-100%
CHARLES
H.
TILFUKD, R O B E R T
s. SHELTON AND nf. G. VAN CAMPEN, JK.
Vul. 70
TABLE I A.
SWSTITUTED PYRIDINE DERIVATIVES I
--
No. 1 2 3 4 5 6 7
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
Free base--Distillation M. P., range Yield,= C. RZ "C. Mm. % Formula (cor.) H 147-1 51 0.3 74 GsHzoONz*HCI 109-105' H 148-152 7 CeHzrONz~HCI 144-146 .2 7.7 H 159-163 .1 CaHzsONz.HC1 122-123 H 152-154 .2 46 Ci~HzzOzNz~HCl 133-135 182-185 H 75 Ci7HzoOaNz.HCl 147-149 .1 H 174-176 ClaH1aONzCI.HCl 116-118 .15 43 145-153 75 CeHzlONz~HC1 169-170 CHs .4 7r, 146-155 CnHzi0N1.2HBr 118-120 CHs .3 145-155 53 CHs .2 C1sHtt0Nn.HCl 178-179 31 160-162 C1eHnr0NrHCl 172-174 CHI .1 $4 152-156 CHI CisH~t0NvHCl 134-136 .1 162-164 38 CaHaON:*HCl 152-154 CHI .08 42 160-165 CHa .15 CziHaONx.HC1 184-186 56 CnHzrONz*HCl 229-230 185-195 CHa .3 185-195 50 CziHxtONx*HCl 161-162 CHa .2 167-173 .2 60 CiaHxrOxNn-HCl 130-132 CH8 173-175 67 C1aH2t09Nz.HCl 152-153 CHa .2 175-180 CH3 .2 CnHzeOiNe-HCl 174-175 52 58 158-162 CH3 .1 C17HnONzCl*HCl 137-138 A0 154-156 .a CI~HZIONZC~*HC~ 162-164 CHs 39 180-185 CHn C17HaONnBr.HCl 126-128 .2 34 150-153 CzHs CisHztONz.HC1 201-202 .09 CH(CHa)x .1 34 CioH~sONz-HCl 161-163 158-162 d CHzCHzN(CH3: 70 CzoHsONa.2HBr 244-245 Phenyl 180-1 88 26 CzzHztON~*HCl 186-187 .3 Benzyl 175-180 . 2 5 40 C~HZEONY~HC 267-268 I 32 CH3 138-142 .2 Ci?HaONr*HCl 136-138 23 128-132 CeHaONvHCl 164'165 CHa .2 3R CHs 95-102 .28 CltHzzONvHCl 95-97 138-143 28 CHs .3 C17HaONz*HCl 95-96 CH(CHa)n 19 CifHz80Nz.HCl 95-103 187-188 .3 CHzCHzCHzN(CzHd2 155-160 0.23 41 C18HaiONs.3HCI 191-192 d 10 ClsHz10Ns.3HBr~ 154-156 CHI 41 155-158 CI~HZ~ONXS.HCI119-120 CHa 0.5
R 1
Phenyl a-Methylbenzyl 9-Cumyl 0-Anisyl 3,4-Methylenedioxyphenyl 2-Chlorophenyl Phenyl Benzyl p-Tolyl o-Tolyl m-Tolyl 3,4-XylyI Carvacryl a-Naphthyl &Naphthyl m-Anisyl p-Anisyl 3.4-Dimethoxyphenyl 3-Chlorophenyl 4-Chlorophenyl 3-Bromophenyl Phenyl Phenyl Phenyl Phenyl Benzyl 1-Cyclohexenyl Cyclohexyl Cyclopropyl n-Hexyl CH(CHdz CHs 2-Pyridyl 2-Thienyl
--c-
B.
'
i \z
% Halogen
(ionizable) Calcd. Obs. 12.05 12.10 11.00 11.00 10.64 10.85 10.85 10.90 10.53 10.48 10.85 10.90 11.58 11.50 35.8 35.0 11.02 11.05 11.02 11.12 11.02 11.00 10.64 10.50 9.78 9.73 9.98 10.00 9.98 10.00 10.53 10.45 10.53 10.45 9.68 9.68 10.40 10.45 10.40 10.35 9.2 9.3 11.00 10.95 10.64 10.70 32.8 33.2 9.65 9.62 16.35 16.25 11.40 11.55 11.32 11.25 13.18 13.18 11.28 11.30 11.82 11.86 25.6 25.5 45.4 45.2 11.32 11.30
Hiat~ ~.-. amine activit b
r/k. 0.05 1.0 0.5 5.0 2.0 1.0 0.05 5.0 0.05 5.0 0.5 1.0 5.0 5.0 5.0 0.05 0.1 20.0 0.1 0.1 0.1 0.5 5.0 1.0 1.0 20.0 0.1 3.0 10.0 5.0 10.0 20.0 1.0 10.0
P
(,/&~(+oc&~-N(cHa)~
CYCLIC %PYRIDINE DERIVATIVES
L/
35 Cyclohexylidene 36 dE-Bornylidene 37 dE-Fenchylidene 38 1-Indanylidene
139-142 134-138 135-138 162-164
I .0
0.2 .2 .3
14 48
ClrHz4ONz*2HCI 163-164 ClaHsONz.PHC1 146-148 ClaHsaONz.HC1 197-198 CisHlnONa*HCl 137-139
61 28
22.08 18.95 10.50 11.12
21.95 19.10 10.45 11.15
20.0 5.0 1.0 5.0
79-81 103-105 282.5-284.5 152-154 162-164 153-155
23.70 23.55' 12.05 12.12 20.65 20.20 37.05 37.15 11.02 11.05 11.02 11.12
1.0 0.5 20.0 5.0 1.0 0.1
143-144 73-75 109-111
45.80
20.0
Rz C. 2-, 3-
39 40 41 42 43 44
Ri 3-Pyridyl 4-Pyridyl 4-Pyridyl (2-PyridyWtnethyl 2- (4-Picolyl) 2-(6-Picolyl)
Ra Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl
AND
Ra H H CHD H CHs CHI
D.
45 46 47
RI Phenyl Phenyl Phenyl
:Rz
C:Ha CHI CHI
I I
4-PYRIDINE DERIVATIVES Ri-C-OCzHjN(CHa)z
Rs 160-165 145-148 158-160 150-160 152-156 145-150
0.2 .2 .3 .5 .1 .3
55 3%
51 7 66 30
VARIATION OF SIDE CHAIN
kN&C-oy I
Rz
Y CaHa--N(CHa)r4CHaI CrHiN(CHa)x.HO-CzHaCl CxHa--N(C:Hdr
CiaHzaONs*HBr CieHzo0N~HCl CaHzzONz*2HCl CaHzzONz.2HBr CiaHz40Nz.HCl CiaHzrONz.HC1
150-156
0.2
47 75 73
CioHnrONzI: Ci8HnOaNaCI CIsHoON:.HBr
9.80
21.18
45.10 9.65 21.18
0.5
0.5
Dec., 1948
4003
PYRIDINE DERIVATIVES AS HISTAMINE ANTAGONISTS TABLEI (Continued’,
No. Ri 48 Phenyl 49 Phenyl
R:! CHs CHI
Phenyl
CHI
51
Phenyl
CHa
.52
dl-Penchyl-g
M. p.,
7
(cor.) 147-149 177-179
Halogen (Tonizable) Calcd. Ob. 11.02 11.10 10.22 10.30
OC.
Histamine activ-
;XI$.
148-151 160-166
.05
61
08
RR
Formula CiaHztONz-HCI CzoHsONz~HCI
Ifi8-171
1
RI
CisHzrOnNz.HC1
184-186
10.17
10.20
1.0
CHZ-CHX
156-162
.1
53
Ci#HadON:-HCl
145-147
10.68 10.60
1.0
CHz- HI CPH~-N(CP%)P
150-156
.2
fiA
CiiHarONz*HCI
192-194
CHaCH(CHa)-N(CHa)t CZHIN(CH~)~CHZ h
50
Free baseDistillation range Yield,= OC. Mm. % ’
Y
Hydrohalide
-
7-
-CPHIN(CHP)ZO(CHZ)P CaHa--N
