SOME 4-SUBSTITUTED 1-(3-PYRIDYLMETHYL)PIPERAZINES WITH ANTIHISTAMINE ACTIVITY

Full text of DOI:10.1135/cccc19942343

New Compounds
2343
SOME 4-SUBSTITUTED 1-(3-PYRIDYLMETHYL)PIPERAZINES
WITH ANTIHISTAMINE ACTIVITY
a
b
a
Vojtech KMONICEK , Martin VALCHAR and Zdenek POLIVKA
a Research Institute for Pharmacy and Biochemistry,
130 60 Prague 3, The Czech Republic
b State Institute for the Drug Control,
110 00 Prague 10, The Czech Republic
Received July 1, 1994
Accepted July 28, 1994
Several compounds derived from nicotinic acid were prepared within a more extensive
programme aiming at the synthesis of new substances with expected antihistamine and
antidepressant activity. Some of these compounds display certain structural resem-
blance with the antidepressant agent piberaline1 (EGYT 475, Trelibet®, I) and its anal-
ogues2. The products were used as intermediates for the synthesis of further compounds
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2344
Kmonicek, Valchar, Polivka:
and most of them were subjected to pharmacological testing. Substituted nicotinic acid
piperazides IIa – IId and IVa – IVe were obtained by reactions of nicotinoyl chloride
(prepared in situ) with the correspondingly substituted piperazines. Reduction of the
piperazides IIa – IId and IVa – IVd with diborane “in situ” in tetrahydrofuran afforded
corresponding 1-substituted 4-(3-pyridylmethyl)piperazines IIIa – IIId and Va – Vd.
Whereas the alkylation of 1-(2-pyrimidinyl)piperazine3 with 2-(chloromethyl)pyridine4
in ethanol in the presence of triethylamine resulted in compounds Ve, compound Vf was
obtained by the addition reaction of 1-(3-pyridylmethyl)piperazine5 to acrylamide. The
piperazides VIe and VIf were prepared by reactions of 2-(3-pyridyl)acetic acid6 with
1-(2-pyrimidinyl)piperazine or 3-(1-piperazinyl)propionamide7 in N,N-dimethylform-
amide in the presence 1,1′-carbonyldiimidazole. A similar procedure starting from ni-
cotinic acid afforded the piperazide IVf.
Compounds Vc and Vd showed significant affinity for the histamine H1-receptors
(inhibition of binding of 2 nmol/l [3H]mepyramine in membranes from the rat brain:
Vc, IC50 = 28 nmol/l; Vd, IC50 = 148 nmol/l). They also proved active in test of his-
tamine aerosol in guinea pigs (PD50 = 4.1 mg/kg p.o. for compound Vc and 2.4 for
compound Vd). Results of a more detailed pharmacological testing of these compounds
will be published elsewhere.
EXPERIMENTAL
The melting points were determined with the Mettler FP-5 melting point recorder or on the Kofler
block. The analytical samples were dried in vacuo of about 40 Pa at a room temperature or at a
suitably elevated temperature. UV spectra (in methanol, λmax in nm (log ε)) were recorded with the
Unicam SP 8000 spectrophotometer; IR spectra with Unicam SP 2000 or Perkin–Elmer 298 spectro-
photometers, NMR spectra on a Tesla BS 567A (1H at 100 MHz, 13C at 25.14 MHz), and Varian
XL-200 (1H at 200 MHz), chemical shifts are given in ppm (δ-scale), coupling constants (J) in Hz.
The mass spectra were measured on a Varian MAT-44S (GC-MS) spectrometer. The homogeneity of
the products and composition of the mixtures were checked by thin-layer chromatography (TLC) on
silica gel (Silufol UV254). Preparative chromatographic separations were carried out on columns of
silica gel (Fluka 60). The extracts were dried with Na2SO4 or K2CO3 and evaporated under reduced
pressure on a rotary evaporator.
General Procedure for Preparation of Amides IIa – IId and IVa – IVe
A suspension of nicotinic acid (9.8 g, 0.08 mol) in dichloromethane (70 ml) was treated with py-
ridine (6.3 g; 6.2 ml; 0.08 mol) and then under stirring and cooling to 0 – 5 °C dropwise with SOCl2
(9.5 g; 5.7 ml; 0.08 mol) over 20 min. The mixture was stirred at the temperature indicated for fur-
ther 20 min, slowly warmed to 40 °C and stirred for 20 min. The solution obtained was cooled to
0 °C and added dropwise over 20 min to a solution of 0.08 mol of the corresponding piperazine
(0.08 mol) and pyridine (6.3 g; 6.2 ml; 0.08 mol) in dichloromethane (50 ml) at 0 – 5 °C. It was then
refluxed for 2 h under stirring. After cooling, the solution was washed with 50% NaOH (50 ml),
water (2 × 20 ml), dried and evaporated.
1-Phenyl-4-nicotinoylpiperazine (IIa). Processing of 1-phenylpiperazine (13.0 g) by the general
procedure gave 18.8 g (88%) of the crude base IIa which was transformed to the dihydrochloride,
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

New Compounds
2345
m.p. 179 – 182 °C (methanol–ether). IR spectrum: 697, 769 (5 adjacent Ar-H); 1 489, 1 539, 1 600,
1
3 025, 3 040 (Ar); 1 643 (ArCON−R); 2 000, 2 118, 2 320 (NH+). H NMR spectrum (CD3SOCD3):
9.10 bs, 1 H (H-2); 9.00 bd, 1 H (J = 5.0, H-6); 8.56 bd, 1 H (J = 8.0, H-3); 8.05 dd, 1 H (J = 8.0,
J′ = 5.0 H-5); 7.40 m, 5 H (Ar-H); 3.20 – 4.00 bm, 8 H (H-2′, H-3′, H-5′, H-6′). For C16H19Cl2N3O
(340.3) calculated: 56.48% C, 5.63% H, 20.84% Cl, 12.35% N; found: 56.84% C, 5.82% H, 20.73% Cl,
12.66% N.
1-(3-Chlorophenyl)-4-nicotinoylpiperazine (IIb). Similar processing of 1-(3-chlorophenyl)pipe-
razine8 (15.7 g) gave 20.5 g oily base IIb, which was transformed to the dihydrochloride. Crystal-
lization from ethanol afforded 11.5 g (47%) of IIb dihydrochloride melting at 168 – 170 °C. IR
spectrum : 690, 800 (3 adjacent Ar-H); 886, 908 (solitary Ar-H); 1 485, 1 500, 1 550, 1 594, 1 604,
3 030 (Ar); 1 649 (ArCONR2); 1 995, 2 105, 2 370, 2 495 (NH+); 3 400 (H2O). UV spectrum: 253
1
(4.26); 290 infl. (3.31). H NMR spectrum (CD3SOCD3): 9.88 bs, 1 H (H-1); 9.05 bd, 1 H (J = 5.0,
H-6); 8.59 bm, 1 H (H-4); 8.20 m, 1 H (H-5); 7.00 – 7.40 m, 4 H (Ar-H); 3.70 bm, 4 H (H-2′, H-6′);
3.42 bm, 4 H (H-3′, H-5′). Mass spectrum, m/z (%): 301 (M+, C16H16ClN3O, 7), 166 (86), 148 (35),
106 (24), 78 (37), 56 (100). For C16H18Cl3N3O (374.7) calculated: 51.28% C, 4.84% H, 28.39% Cl, 11.22%
N; found: 51.32% C, 4.98% H, 28.73% Cl, 10.93% N.
1-(3-Trifluoromethylphenyl)-4-nicotinoylpiperazine (IIc). Similar processing of 1-(3-trifluoro-
methyl)piperazine9 (17.3 g) gave 20.5 g oily base which afforded 21.8 g (65%) of IIc dihydrochloride
hemihydrate, m.p. 184 – 186 °C. IR spectrum: 693, 814 (3 adjacent Ar-H); 900, 909 (1 solitary Ar-H);
1 122, 1 171, 1 323 (ArCF3); 1 582, 1 547, 1 604, 3 015, 3 028, 3 050 (Ar); 1 650 (ArCONR2);
1
1 980, 2 100, 2 370, 2 475 (NH+); 3 470, 3 520 (H2O). H NMR spectrum (base, CD3SOCD3): 8.70 m,
2 H (H-2, H-6); 7.80 m, 1 H (H-4); 7.00 – 7.50 m, 5 H (H-5, Ar-H); 3.80 bm, 4 H (Ar-H); 3.42 bm,
4 H (H-2′, H-6′); 3.30 bm, 4 H (H-3′, H-5′). Mass spectrum, m/z (%): 335 (M+, C17H16F3N3O, 14),
316 (3), 229 (7), 200 (100), 188 (7), 172 (24), 148 (36), 145 (15), 106 (34). For C17H18Cl2F3N3O +
0.5 H2O (417.3) calculated: 48.95% C, 4.59% H, 17.00% Cl, 13.66% F, 10.07% N; found: 49.11% C,
4.50% H, 17.36% Cl, 13.51% F, 10.11% N.
1-(4-Methoxyphenyl)-4-nicotinoylpiperazine (IId). Similar processing of 1-(4-methoxyphenyl)pipe-
razine10 (15.4 g) resulted in 19.9 g (84%) of crystalline IId, m.p. 85 – 87 °C. Analytical sample
melted at 96 – 98 °C (benzene–ether). IR spectrum: 710, 800, 885, 827 (3 and 1 adjacent and solitary
Ar-H); 1 013, 1 037, 1 248 (ArOMe); 1 511, 1 589, 3 030, 3 050, 3 075, (Ar); 1 622 (ArCONR2);
1
3 420 (H2O). UV spectrum: 241 (4.23); 289 (3.30). H NMR spectrum (CDCl3): 8.70 m, 2 H (H-2,
H-6); 7.32 bd, 1 H (H-4); 7.40 bdd, 1 H (H-5); 6.90 s, 4 H (Ar-H); 3.90 bs and 3.65 bs, 2 × 2 H
(H-2′ and H-6′); 3.78 s, 3 H (CH3O); 3.10 bs, 4 H (H-3′, H-5′). 13C NMR spectrum (CDCl3): 167.69 s
(C=O); 154.55 s (C-4 of aryl); 150.89 d (C-6); 147.97 d (C-2); 145.06 s (C-1 of aryl); 135.05 d
(C-4); 131.46 s (C-3); 123.47 d (C-5); 118.99 d (C-2 and C-6 of aryl); 114.51 d (C-3 and C-5 of
aryl); 55.50 q (OCH3); 51.17 t (C-3′, C-5′); 48.21 bt and 42.96 bt (C-2′, C-6′). For C17H19N3O2 + 0.5
H2O (306.4) calculated: 66.64% C, 6.58% H, 13.71% N; found: 66.83% C, 6.35% H, 13.63% N.
1-Benzyl-4-nicotinoylpiperazine (IVa). The general procedure applied to 1-benzylpiperazine (14.1 g)
gave 18.2 g (81%) of crystalline base IVa, m.p. 74 – 76 °C (cyclohexane). 1H NMR spectrum
(CDCl3): 8.70 m, 2 H (H-2, H-6); 7.76 m, 1 H (H-4); 7.40 m, 1 H (H-5); 7.32 s, 5 H (Ar-H); 3.80 bm,
2 H and 3.45 bm, 2 H (H-2′, H-6′); 3.55 s, 2 H (CH2Ph); 2.50 bs, 4 H (H-3′, H-5′). 13C NMR spec-
trum (CDCl3): 167.69 s (C=O); 150.81 d (C-1); 148.05 d (C-6); 137.51 s (C-1 of benzyl); 135.05 d
(C-4); 131.76 s (C-3); 129.15 d (C-3 and C-5 of benzyl); 128.40 d (C-2 and C-6 of benzyl); 127.36 d
(C-4 of benzyl); 123.47 d (C-5); 62.82 t (CH2Ph); 52.96 t (C-3′, C-5′); 47.73 t and 42.2 t (C-2′,
C-6′). For C17H19N3O (281.4) calculated: 72.57% C, 6.81% H, 14.94% N; found: 72.34% C, 6.87% H,
14.74% N.
1-(4-Fluorobenzyl)-4-nicotinoylpiperazine (IVb). Similar processing of 1-(4-fluorobenzyl)pipe-
razine11 (15.5 g) afforded 12.3 g (82%) of oily IVb which was converted to the dihydrochloride, m.p.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2346
Kmonicek, Valchar, Polivka:
244 – 246 °C (ethanol–water). IR spectrum: 685, 770, 821, 831, 899 (Ar-H); 1 510, 1 601, 3 000,
3 040, 3 075 (Ar); 1 629 (ArCONR2); 1 995, 2 110, 2 385, 2 608, 2 680, 2 710 (NH+); 3 320, 3 440
1
(H2O). H NMR spectrum (CD3SOCD3): 8.90 m, 2 H (H-2, H-6); 8.36 bd, 1 H (J = 9.0, H-4); 7.90 dd,
1 H (J = 9.0, J′ = 5.0, H-5); 7.78 dd, 2 H (J(HH) = 9.0, J(HF) = 5.0 Hz, H-2 and H-6 of 4-FC6H5);
7.27 t, 2 H (J(HH) = J(HF) = 9.0, H-3 and H-5 of 4-FC6H5); 4.40 s, 2 H (CH2Ar); 3.70 bm, 4 H
(H-2′, H-6′); 3.30 bm, 4 H (H-3′, H-5′). Mass spectrum, m/z (%): 299 (M+, C17H18FN3O), 193, 164,
152, 150, 109 (100%), 106, 78. For C17H20Cl2FN3O (372.3) calculated: 54.84% C, 5.42% H, 19.05%
Cl, 5.10% F, 11.28% N; found: 54.82% C, 5.53% H, 19.19% Cl, 5.21% F, 11.09% N.
1-Benzhydryl-4-nicotinoylpiperazine (IVc). Similar processing of 1-benzhydrylpiperazine12 (14.1 g)
gave 14.3 g (80%) of crystalline IVc melting at 131 – 133 °C; analytical sample, m.p. 134 – 136 °C
(ethyl acetate–light petroleum). IR spectrum: 710, 752 (5 adjacent Ar-H); 823 (3 adjacent H in py-
ridine); 896 (1 solitary H in pyridine); 1 482, 1 490, 1 566, 1 583, 1 600, 3 020, 3 060, 3 080 (Ar);
1
1 627 (Ar−CO−N); UV spectrum: 254 (3.96), 224 infl. (4.22). H NMR spectrum (CDCl3): 8.87 m,
2 H (H-2, H-6); 7.74 dt, 1 H (H-4); 7.00 – 7.50 m, 11 H (H-5 and ArH); 4.28 s, 1 H (CHPh2); 3.77 bs,
2 H and 3.46 bs, 2 H (H-3′, H-5′); 2.44 bs, 4 H (H-2′, H-6′). For C23H23N3O (357.4) calculated:
77.28% C, 6.48% H, 11.76% N; found: 77.06% C, 6.61% H, 11.61% N. Succinate hemihydrate, m.p.
176 – 178 °C (ethanol–ether). For C27H29N3O5 + 0.5 H2O (484.5) calculated: 66.92% C, 6.24% H,
8.67% N; found: 66.97% C, 6.33% H, 8.43% N.
1-(4,4′-Difluorobenzhydryl)-4-nicotinoylpiperazine (IVd). Similar preparation starting from
1-(4,4′-difluorobenzhydryl)piperazine13 (23.1 g) gave 30.8 g (95%) of oily base IVe which was used
for the further step in crude state.
1-Nicotinoyl-4-(2-pyrimidinyl)piperazine (IVe). Similar processing of 1-(2-pyrimidinyl)piperazine3
(13.3 g) afforded 14.9 g (69%) of crystalline IVe melting at 125 – 135 °C. Analytical sample, m.p.
136 – 138 °C (benzene–hexane). IR spectrum: 709, 801 (3 adjacent and 1 solitary Ar-H); 1 508, 1 550,
1
1 583, 3 038, 3 060, 3 100 (Ar); 1 627 (ArCONR2). UV spectrum: 242 (4.47); 295 (3.63). H NMR
spectrum (CDCl3): 8.74 m, 2 H (H-2, H-6); 8.36 d, 2 H (J = 5.0, H-3 and H-5 of pyrimidine);
7.83 td, 1 H (J = 7.0, H-4); 7.40 m, 1 H (H-5); 6.58 t, 1 H (J = 5.0, H-4 of pyrimidine); 3.40 – 4.00 bm,
8 H (H-2′, H-3′, H-5′, H-6′). 13C NMR spectrum (CDCl3): 167.92 s (CO); 161.42 s (C-1 of pyri-
midine); 157.76 d (C-3 and C-5 of pyrimidine); 150.89 d (C-6); 147.97 d (C-2); 135.05 d (C-4);
131.39 s (C-3); 123.47 d (C-5); 110.62 d (C-4 of pyrimidine); 43.70 t (C-3′, C-5′); 47.73 bt, 42.96 bt
(C-2′, C-6′). For C14H15N5O (269.3) calculated: 62.44% C, 5.61% H, 26.00% N; found 62.35% C,
5.73% H, 25.89% N. Fumarate, m.p. 146 – 148 °C (ethanol). For C18H19N5O5 (385.4) calculated:
56.10% C, 4.97% H, 18.18% N; found 56.29% C, 5.11% H, 18.33% N.
General Procedure for Preparation of Amines IIIa – IIId and Va – Vd
A solution of the corresponding amide (22.5 mmol) in tetrahydrofuran (60 ml) was treated with
NaBH4 (2.5 g; 66 mmol), the mixture was cooled to 5 °C and then treated under stirring and cooling
in nitrogen atmosphere over 20 min with boron trifluoride etherate (9.0 g; 8.0 ml; 63 mmol). The
mixture was stirred for 2 h at room temperature and then refluxed for 4 h. After cooling, the stirred
mixture was slowly decomposed by addition of 50 ml dilute hydrochloric acid (1 : 1), refluxed for 2 h
and evaporated in vacuo. The residue was dissolved in 20 ml ethanol, the mixture was made alkaline
with a solution of KOH (25 g) in ethanol (35 ml) and refluxed for another 1 h. The solid was filtered
off, washed with 2 × 20 ml ethanol and combined ethanolic solutions were evaporated in vacuo. The
residue was distributed between toluene (20 ml) and water (20 ml). The toluene solution was evapo-
rated in vacuo to dryness.
1-Phenyl-4-(3-pyridylmethyl)piperazine (IIIa). Reduction of 6.0 g amide IIa using the general pro-
cedure led to 3.3 g (52%) of the crude base IIIa, m.p. 70 – 75 °C (the literature14 gave the value of
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

New Compounds
2347
74 – 76 °C). Treatment of the methanolic solution of the base with a solution of HCl in ether af-
forded the dihydrochloride, m.p. 213 – 215 °C (methanol–ether). IR spectrum: 694, 769 (5 adjacent
Ar-H); 1 491, 1 555, 1 595, 3 027 (Ar); 2 017, 2 100, 2 310 (NH+). For C16H21Cl2N3 (326.3) calcu-
lated: 58.90% C, 6.49% H, 21.74% Cl, 12.88% N; found: 58.68% C, 6.64% H, 22.02% Cl, 12.87% N.
1-(3-Chlorophenyl)-4-(3-pyridylmethyl)piperazine (IIIb). Reduction of the amide IIb (6.8 g) gave
6.9 g crude base IIIb which was transformed to the trihydrochloride monohydrate (5.2 g, 56%), m.p.
126 – 135 °C; analytical sample, m.p. 135 – 137 °C (ethanol–ether). IR spectrum: 693, 713, 779, 869
(3 and 1 adjacent and solitary Ar-H); 1 535, 1 591, 1 604, 3 010, 3 045, 3 060 (Ar); 1 930, 2 040,
1
2 070, 2 110, 2 390 (NH+); 3 220 (H2O). H NMR spectrum (CD3SOCD3): 9.34 bs, 1 H (H-2); 9.02 bd,
1 H (J = 5.0, H-6); 7.03 bm, 1 H (H-4); 7.29 t, 1 H (J = 5.0, H-5); 7.00 m, 4 H (H-2, H-4, H-5, H-6
of 3-ClC6H4); 4.78 bs, 2 H (CH2); 3.62 bm, 4 H (H-3′, H-5′); 3.40 bm, 4 H (H-2′, H-6′). Mass spec-
trum, m/z (%): 287 (M+, C16H18ClN3), 195, 147, 139, 120 (100), 92. For C16H21Cl4N3 + H2O (415.2)
calculated: 46.28% C, 5.58% H, 34.16% Cl, 10.12% N; found: 46.08% C, 5.62% H, 34.44% Cl,
9.86% N.
1-(3-Pyridylmethyl)-4-(3-trifluoromethylphenyl)piperazine (IIIc): Reduction of 6.7 g of the amide
IIc gave 6.8 g of the crude base IIIc which was dissolved in ethanol (20 ml) and transformed by
treatment with HCl in ether to the dihydrochloride monohydrate (4.1 g, 40%), m.p. 158 – 165 °C;
1
analytical sample, m.p. 166 – 168 °C (ethanol–ether). H NMR spectrum (CD3SOCD3): 9.30 bs, 1 H
(H-2); 9.05 bd, 1 H (J = 5.0, H-6); 8.94 bd, 1 H (J = 8.5, H-4); 8.16 dd, 1 H (J = 8.5; J′ = 5.0, H-5);
7.00 – 7.60 m, 4 H (3-CF3C6H4); 4.77 s, 2 H (CH2); 3.62 bm, 4 H (H-3′, H-5′); 3.40 bm, 4 H (H-2′,
H-6′). Mass spectrum, m/z (%): 321 (M+, C17H18F3N3), 229, 173, 172, 147, 120. For C17H20Cl2F3N3
+ H2O (412.3) calculated: 49.52% C, 5.38% H, 17.20% Cl, 13.83% F, 10.19% N; found: 49.36% C,
5.32% H, 17.18% Cl, 13.61% F, 10.21% N.
1-(4-Methoxyphenyl)-4-(3-pyridylmethyl)piperazine (IIId). Reduction of 6.7 g of the amide IId af-
forded 6.2 g (98%) of the crude oily base IIId, which was dissolved in ethanol and converted by
treatment with a solution of 2.6 g maleic acid in ether to the hydrogen maleate monohydrate (6.7 g,
71%), m.p. 108 – 110 °C; analytical sample, m.p. 111 – 113 °C (ethanol–ether). Mass spectrum, m/z
(%): 283 (M+, C17H21N3O, 75), 191 (23), 162 (15), 150 (18), 147 (24), 136 (40), 135 (38), 120 (100),
92 (58), 56 (73). For C21H25N3O5 + H2O (417.5) calculated: 60.42% C, 6.51% H, 10.07% N; found:
60.53% C, 6.31% H, 9.87% N.
1-Benzyl-4-(3-pyridylmethyl)piperazine (Va). Reduction of 6.3 g of the amide IVa gave 6.0 g
(98%) of the crude oily base Va which was dissolved in methanol and converted by treatment with a
solution of maleic acid (5.1 g) in methanol to dihydrogen maleate monohydrate (8.4 g, 72%), m.p.
1
195 – 197 °C; Analytical sample, m.p. 197 – 199 °C (methanol). H NMR spectrum (CD3SOCD3):
9.24 d, 1 H (J = 1.5, H-2); 8.98 dd, 1 H (J = 1.5, J′ = 5.5, H-6); 8.75 dd, 1 H (J = 1.5, J′ = 8.2,
H-4); 8.04 dd, 1 H (J = 5.5, J′ = 8.2, H-5); 7.35 m, 5 H (Ar-H of benzyl); 6.91 s, 4 H (CH= of
maleic acid); 6.14 bs, 4 H (COOH); 4.71 s, 2 H (CH2-pyridine); 4.54 s, 2 H (CH2 of benzyl); 3.58 m,
4 H (H-3′, H-5′); 3.29 m, 4 H (H-2′, H-6′). For C25H29N3O8 + H2O (517.5) calculated: 58.01% C, 6.04% H,
8.12% N; found: 58.33% C, 6.07% H, 8.25% N.
1-(4-Fluorobenzyl)-4-(3-pyridylmethyl)piperazine (Vb). Reduction of 6.7 g of the amide IVb re-
1
sulted in 5.6 g (87%) of the crude base Vb. H NMR spectrum (CDCl3): 8.52 m, 2 H (H-2); 7.69 bd,
1 H (H-4), 7.30 m, 3 H (H-5; H-2 and H-6 of 4-FC6H4); 7.01 t, 2 H ((J(HH) = J(HF) = 9.0, H-3 and
H-5 of 4-FC6H5); 3.57 s, 4 H (2 × CH2); 2.58 s, 8 H (H-2′, H-3′, H-5′, H-6′). Mass spectrum, m/z
(%): 285 (M+, C17H20FN3, 5), 193 (10), 176 (20), 109 (100), 92 (46), 72 (45). Dihydrogen maleate,
m.p. 189 – 191 °C (aqueous ethanol). For C25H28FN3O8 + H2O (535.5) calculated: 56.07% C, 5.65% H,
3.54% F, 7.85% N; found: 55.94% C, 5.51% H, 3.27% F, 7.54% N.
1-Benzhydryl-4-(3-pyridylmethyl)piperazine (Vc). Reduction of 8.1 g of the amide IVc afforded
6.5 g (84%) of the crude crystalline base Vc (m.p. 90 – 95 °C) which was transformed to the hydro-
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2348
Kmonicek, Valchar, Polivka:
chloride, m.p. 228 – 230 °C (ethanol). IR spectrum: 690, 710, 863 (5 and 3 adjacent and solitary
Ar-H); 1 497, 1 552, 3 025, 3 045, 3 095 (Ar); 3 360, 3 420, 3 490 (OH, NH); 2 400, 2 500, 2 622
1
(NH+). H NMR spectrum (CD3SOCD3): 9.20 bs, 1 H (H-2); 8.96 bd, 1 H (J = 5.0, H-6); 8.80 bd, 1 H
(J = 8.5, H-4); 8.05 m, 1 H (H-5); 7.95 m, 7.40 m, 10 H (2 × C6H5); 5.90 bs, 1 H (CH); 4.70 s, 2 H
(CH2); 3.64 bm, 4 H (H-3′, H-5′); 3.35 bm, 4 H (H-2′, H-6′). Mass spectrum, m/z (%): 343 (M+,
C23H25N3, 4), 266 (2), 251 (9), 176 (98), 167 (66), 92 (100). For C23H28Cl3N3 + H2O (470.9) calcu-
lated: 58.67% C, 6.42% H, 22.59% Cl, 8.92% N; found : 58.45% C, 6.18% H, 22.59% Cl, 8.93% N.
1-(4,4′-Difluorobenzhydryl)-4-(3-pyridylmethyl)piperazine (Vd). Reduction of 8.6 g of the amide
IVd gave 7.8 g (91%) of the crude crystalline base Vc, m.p. 114 – 116 °C (ether–light petroleum).
1H NMR spectrum (CDCl3): 8.54 d, 1 H (J = 2.0, H-2); 8.50 dd, 1 H (J = 2.0, J′ = 5.0, H-6); 7.65 bd,
1 H (J = 8.0, H-4); 7.30 m, 5 H (H-5, 2 × H-2 and H-6 of 4-FC6H4); 6.95 t, 4 H (J(HH) =
J(HF) = 9.0, 2 × H-3 and H-5 of 4-FC6H4); 4.22 s, 1 H (CH); 3.52 s, 2 H (CH2); 2.43 bs, 8 H (H-2′,
H-3′, H-5′, H-6′). 13C NMR spectrum (CDCl3): 161.87 s (J(F,C) = 244, 2 × C-4 from 4-FC6H4);
150.59 d (C-2); 148.64 d, (C-6); 138.19 s (2 × C-1 from 4-FC6H4); 136.69 d (C-4); 133.56 s (C-3);
129.30 d (J(FC) = 7.5, 2 × C-2 and C-6 from 4-FC6H4); 123.25 d (C-5); 115.37 d (J(FC) = 20.7, 2 × C-3
and C-5 from 4-FC6H4); 74.40 d (Ar2CH); 60.13 t (CH2); 53.26 t (C-2′ and C-6′); 51.69 t (C-3′ and
C-5′). Trihydrochloride hemihydrate, m.p. 114 – 116 °C (ethanol–ether). IR spectrum: 690, 783 (3 adjacent
Ar-H); 825 (2 adjacent Ar-H); 860 (solitary Ar-H); 1 231 (Ar-F); 1 510, 1 550, 1 603, 3 000, 3 045,
3 100 (Ar); 1 637 (H2O); 3 420, 3 485 (OH, H2O); 2 090, 2 400, 2 495, 2 620 (NH+). 1H NMR
spectrum (CD3SOCD3): 9.00 bd, 1 H (H-2); 8.88 d, 1 H (H-6); 8.00 m, 6 H (2 × H-2 and H-6
from 4-FC6H4, H-4 and H-5); 7.30 t, 4 H (2 × H-3 and H-5 from 4-FC6H4); 5.98 bs, 1 H (CH); 4.75 s,
2 H (CH2); 3.64 bm, 4 H (H-3′ and H-5′); 3.35 bm, 4H (H-2′ and H-6′). Mass spectrum, m/z (%):
379 (M+, C23H23F2N3), 287, 244, 203, 176 (100), 133, 92. For C23H26Cl3F2N3 + 0.5 H2O (497.8)
calculated: 55.49% C, 5.46% H, 21.37% Cl, 7.63% F, 8.44% N; found: 55.33% C, 5.25% H, 20.93% Cl,
7.69% F, 8.51% N.
1-(3-Pyridylmethyl)-4-(2-pyrimidinyl)piperazine (Ve)
A solution of 1-(2-pyrimidinyl)piperazine3 (3 g, 44.5 mmol) and 4.6 g (6.3 ml, 45 mmol) of triethyl-
amine in ethanol (60 ml) was treated over 30 min under stirring with a suspension of 3-(chloro-
methyl)pyridine hydrochloride4 (3 g, 44.5 mmol) in ethanol (40 ml). The mixture was stirred and
refluxed for 6 h, evaporated in vacuo to dryness, the residue was dissolved in chloroform (100 ml)
and made alkaline with a solution of NH3 in chloroform. The separated NH4Cl was filtered off and
evaporation of the filtrate gave 8.8 g (76%) crude product melting at 100 – 104 °C; analytical
sample, m.p. 102 – 104 °C (cyclohexane). IR spectrum: 718, 770, 792, 811 (3 adjacent Ar-H); 850
(solitary Ar-H); 1 480, 1 511, 1 540, 1 588, 3 028 (heterocyclic ring); 2 760, 2 775 (N-CH2).
1H NMR spectrum (CDCl3): 8.60 bs, 1 H (H-2); 8.55 bd, 1 H (H-6); 8.30 d, 2 H (J = 5.0, H-3 and
H-5 of pyrimidine); 7.28 bd, 1 H (H-5); 6.50 t, 1 H (J = 5.0, H-4 of pyrimidine); 3.84 bt, 4 H (H-3′
and H-5′); 3.58 s, 2 H (CH2); 2.51 bt, 4 H (H-2′ and H-6′. 13C NMR spectrum (CDCl3): 161.72 s
(C-1 of pyrimidine); 157.68 d (C-3 and C-5 of pyrimidine); 150.51 d (C-6); 148.79 d (C-2); 136.69 d
(C-4); 133.48 s (C-3); 123.32 d (C-5); 109.88 d (C-4 of pyrimidine); 60.28 t (CH2); 52.96 t (C-2′ and
C-6′); 43.62 t (C-3′ and C-5′). For C14H17N5 (255.3) calculated: 65.85% C, 6.71% H, 27.43% N;
found: 65.85% C, 6.84% H, 27.25% N.
Dihydrogen maleate, m.p. 148 – 150 °C (ethanol). For C22H25N5O8 (487.5) calculated: 54.21% C,
5.17% H, 14.37% N; found: 53.99% C, 5.26% H, 14.27% N.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

New Compounds
2349
3-(4-(3-Pyridylmethyl)-1-piperazinyl)propionamide (Vf)
A solution of 1-(3-pyridylmethyl)piperazine5 (12.3 g, 70 mmol) in ethanol (20 ml) was treated under
stirring with a solution of acrylamide (5.0 g, 70 mmol) in ethanol (20 ml), the mixture was refluxed
for 12 h, cooled to room temperature and treated with a solution of maleic acid (24.4 g, 0.21 mol) in
ethanol (150 ml). The separated crystalline trihydrogen maleate was filtered, washed with ethanol (50 ml)
and dried; yield 34.2 g (82%), m.p. 144 – 146 °C; analytical sample, m.p. 150 – 152 °C (aqueous
ethanol–ether). 1H NMR spectrum (CD3SOCD3): 8.60 bm, 2 H (H-2 and H-6), 7.82 bd, H (H-4),
7.45 bm, 1 H (H-5), 6.23 s, 6 H (=CH− of maleate), 3.72 s , 2 H (pyridyl-CH2). Mass spectrum, m/z
(%): 249 (M+ + 1, C13H20N4O), 177, 135, 92, 56, 44. For C25H32N4O13 (596.6) calculated: 50.33% C,
5.41% H, 9.39% N; found: 50.36% C, 5.55% H, 9.19% N.
1-(3-Pyridylacetyl)-4-(2-pyrimidinyl)piperazine (VIe)
A solution of 2-(3-pyridyl)acetic acid6 (5.5 g, 40 mmol) in 70 ml dimethylformamide was treated
over 20 min with 1,1′-carbonyldiimidazole (7.0 g, 45 mmol), added in parts, which was followed by
1-(2-pyrimidinyl)piperazine3 (6.6 g, 40 mmol) in N,N-dimethylformamide (40 ml) and reaction mix-
ture was stirred for 16 h at room temperature. The solution was evaporated in vacuo to dryness, the
residue was mixed with ethanol (10 ml) and the crystalline solid was filtered; 7.1 g (63%) amide VIe,
1
m.p. 127 – 133 °C; analytical sample, m.p. 133 – 135 °C (ethanol). H NMR spectrum (CDCl3): 8.52 bm,
2 H (H-2 and H-6); 8.32 d, 2 H (J = 5.0, H-3 and H-5 of pyrimidine); 7.65 bd, 1 H (J = 7.0, H-4);
7.28 dd (J = 5.0, J′ = 7.0, H-5); 6.56 t, 1 H (J = 5.0, H-4 of pyrimidine); 3.50 – 3.90 bm, 10 H (H-2′,
H-3′, H-5′, H-6′ and CH2CO). 13C NMR spectrum (CDCl3): 168.74 s (CO), 161.49 s (C-1 of pyri-
midine), 157.83 d (C-3 and C-5 of pyrimidine), 150.06 d (C-6), 148.42 d (C-2), 136.62 d (C-4),
130.72 s (C-3), 123.55 d (C-5), 110.62 d (C-4 of pyrimidine), 45.79 t (CH2), 43.62 t (C-2′ and C-6′),
41.75 and 37.72 t (C-3′ and C-5′). IR spectrum: 709, 767, 793, 814 (3 adjacent ArH); 850 (solitary
ArH); 1 480, 1 499, 1 542, 1 581, 3 000, 3 020, 3 045 (Ar); 1 641 (RCONR2). UV spectrum: 203
(5.16), 241.5 (5.43), 303 (4.33). For C15H17N5O (283.3) calculated: 63.58% C, 6.05% H, 24.72% N;
found: 63.30% C, 6.03% H, 24.52% N.
Hydrogen maleate, m.p. 132 – 134 °C (ethanol). For C19H21N5O5 (399.4) calculated: 57.13% C,
5.30% H, 17.54% N; found 57.01% C, 5.35% H, 17.68% N.
3-(4-(3-Pyridylacetyl)-1-piperazinyl)propionamide (VIf)
A similar reaction of 3-(1-piperazinyl)propionamide7 (4.5 g, 29 mmol) with 2-(3-pyridyl)acetic acid6
(4.0 g, 29 mmol) gave 5.2 g (66%) of the base VIf, m.p. 156 – 163 °C; analytical sample, m.p. 166 – 168 °C
(ethanol–hexane). 1H NMR spectrum (CDCl3): 8.44 m, 2 H (H-2 and H-6); 7.64 dt, 1 H (J = 7.0, J′ =
2.0, H-4); 7.38 bs, 1 H and 6.80 bs, 1 H (CONH2); 7.35 dd, 1 H (J = 7.0, 5.0, H-5); 3.77 s, 2 H
(CH2CO); 3.50 bt, 4 H (H-2′ and H-6′); 2.54 t, 2 H (J = 7.0, NCH2CH2); 2.36 bt, 4 H (H-3′ and
H-5′); 2.22 t, 2 H (J = 7.0, NCH2CH2). 13C NMR spectrum (CDCl3): 173.22 s (CO), 168.29 s
(CH2CO-piperazine), 150.36 d (C-6), 147.52 d (C-2), 136.92 d (C-4), 131.84 s (C-3), 123.25 d (C-5),
53.78 t (CH2CH2CONH2), 52.66 t and 52.14 t (C-3′ and C-5′), 45.19 t (C-2′ and C-6′), 36.23 t
(CH2CO-piperazine), 32.79 t (CH2CONH2). For C14H20N4O2 (276.3) calculated: 60.85% C, 7.30% H,
20.28% N; found: 60.59% C, 7.34% H, 20.26% N.
3-(4-Nicotinoyl-1-piperazinyl)propionamide (IVf)
Reaction of 3-(1-piperazinyl)propionamide7 (4.7 g, 30 mmol) with nicotinic acid (3.7 g, 30 mmol)
and 1,1′-carbonyldiimidazole (5.6 g, 35 mmol), carried out similarly like in the two foregoing cases,
afforded 5.2 g (67%) of the base IVf, m.p. 171 – 175 °C; analytical sample, m.p. 173 – 175 °C
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2350
Kmonicek, Valchar, Polivka:
1
(ethanol–hexane). H NMR spectrum (CDCl3): 8.70 bm, 2 H (H-2 and H-6); 7.80 bd, 1 H (J = 7.0,
H-4); 7.30 dd, 1 H (J = 7.0, J′ = 5.0, H-5); 7.20 bs and 5.75 bs, 2 × 1 H (NH2); 3.62 bt, 4 H (H-2′
and H-6′); 2.70 t, 2 H (J = 7.0, CH2CH2CONH2); 2.50 bt, 4 H (H-3′ and H-5′); 2.40 t, 2 H (J = 7.0,
CH2CH2CONH2). 13C NMR spectrum (CDCl3): 174.79 s (CONH2), 167.62 s (CO), 150.89 d (C-6),
147.90 d (C-2), 134.98 d (C-4), 131.31 s (C-3), 123.47 d (C-5), 53.63 t (CH2CH2CONH2), 52.59 t
(C-3′ and C-5′), 47.23 t and 42.26 t (C-2′ a C-6′), 32.27 t (CH2CH2CONH2). IR spectrum: 711, 821
(3 adjacent ArH); 898 (solitary ArH); 1 480, 1 490, 1 568, 1 590, 3 005 (Ar); 1 616 (ArCON); 1 684
(RCONH2); 2 820 (NCH2); 3 165, 3 330 (NH2). UV spectrum: 253 (4.58), 259 (4.58). For
C13H18N4O2 (262.3) calculated: 59.52% C, 6.92% H, 21.36% N; found: 59.38% C, 6.94% H, 21.39% N.
Hydrogen maleate, m.p. 157 – 159 °C (ethanol). For C17H22N4O6 (378.4) calculated: 53.96% C,
5.86% H, 14.81% N; found: 53.85% C, 5.87% H, 14.74% N.
The authors thank the following colleagues at the Research Institute for Pharmacy and Biochemistry
in Prague for co-operation: Mr M. Cech, Mrs R. Svatosova and Mrs A. Svatonova (elemental analysis),
Dr E. Svatek and Mrs A. Hradkova (IR spectra), Dr J. Holubek (NMR spectra), Dr M. Ryska and Mrs
O. Matousova (mass spectra), Dr H. Blehova and Mrs L. Horakova (animal pharmacology).
REFERENCES
1. Anonym: Drugs Future 9, 30 (1984); 14, 88 (1989); 18, 88 (1993).
2. Kmonicek V., Svatek E., Holubek J., Ryska M., Valchar M., Protiva M.: Collect. Czech. Chem.
Commun. 55, 1817 (1990).
3. Howard K. L., Steward H. W., Conroy E. A., Denton J. J.: J. Org. Chem. 18, 148 (1953).
4. Vejdelek Z., Protiva M.: Chem. Listy 45, 451 (1951).
5. Rondahl L.: Acta Pharm. Suec. 17, 292 (1980).
6. Malan R. L., Dean M. P.: J. Am. Chem. Soc. 69, 1797 (1947).
7. Protiva M., Jilek J., Cervena I., Pomykacek J., Bartl V., Dlabac A., Valchar M., Metysova J.,
Holubek J., Svatek E.: Collect. Czech. Chem. Commun. 51, 2598 (1986).
8. Pollard C. B., Wicker T. H. jr.: J. Am. Chem. Soc. 76, 1853 (1954).
9. Kopicova Z., Nemec J., Protiva M.: Collect. Czech. Chem. Commun. 41, 459 (1976).
10. Valenta V., Vlkova M., Holubek J., Svatek E., Metysova J., Protiva M.: Collect. Czech. Chem.
Commun. 55, 797 (1990).
11. Bartl V., Dlabac A., Protiva M.: Collect. Czech. Chem. Commun. 45, 3182 (1980).
12. Zikolova S., Konslantinova R.: Farmatsia (Sofia) 25, 1 (1978); Chem. Abstr. 84, 59388 (1976).
13. Donnert D., Schweer K.H.: J. Labelled Compd. Radiopharm. 9, 405 (1973); Chem. Abstr. 80,
37072 (1974).
14. Giannini M. (Malesci S.a S., Istituto Farmacobiologico): Belg. 820 242; Chem. Abstr. 84, 59553
(1976).
Translated by M. Protiva.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)